Medical Radiology

Radiation Oncology

Series Editors

Luther W. Brady
Hans-Peter Heilmann
Michael Molls
Carsten Nieder

For further volumes:

http://www.springer.com/series/4353
Seymour H. Levitt • James A. Purdy
Carlos A. Perez • Philip Poortmans
Editors

Technical Basis of
Radiation Therapy
Practical Clinical Applications

Fifth Edition

123
Seymour H. Levitt, MD, DSc. Carlos A. Perez, MD
Department of Oncol-Pathol Department of Radiation Oncology
Karolinska Institutet Washington University Medical Center
Stockholm 4511 Forest Park Boulevard
Sweden St. Louis, MO 63108
e-mail: levit002@umn.edu USA
e-mail: perez@radonc.wustl.edu
James A. Purdy, Ph.D.
Department of Radiation Oncology Philip Poortmans, Ph.D.
University of California Department of Radiation Oncology
Davis Medical Center Institute Verbeeten
4501 X Street Brugstraat 10
Sacramento, CA 95817 Tilburg, 5042 SB
USA The Netherlands
e-mail: james.purdy@ucdmc.ucdavis.edu e-mail: poortmans.ph@bvi.nl

ISSN 0942-5373
ISBN 978-3-642-11571-4 e-ISBN 978-3-642-11572-1
DOI 10.1007/978-3-642-11572-1
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Contents

Part I Basic Concepts in Radiation Oncology

Practical Time–Dose Evaluations, or How to Stop Worrying

and Learn to Love Linear Quadratics . . . . . . . . . . . . . . . . . . . . . . . . . 3
Jack F. Fowler

Radiobiology of Stereotactic Radiosurgery and Stereotactic Body

Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Chang W. Song, Heonjoo Park, Robert J. Griffin, and Seymour H. Levitt

Imaging in Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Cynthia Ménard, Ursula Nestle, and David Jaffray

Physics of Radiotherapy Planning and Delivery . . . . . . . . . . . . . . . . . . 85

James A. Purdy, Philip Poortmans, Carlos A. Perez, and Seymour H. Levitt

Simulation in the Determination and Definition of Treatment

Volume and Treatment Planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Sasa Mutic, Mary Coffey, James A. Purdy, Jeff M. Michalski,
and Carlos A. Perez

Clinical Applications of High-Energy Electrons . . . . . . . . . . . . . . . . . . 157

Bruce J. Gerbi, Youlia M. Kirova, and Roberto Orecchia

Proton Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Nancy Price Mendenhall and Zuofeng Li

Physical, Biological and Clinical Background for the Development

of Light Ion Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Anders Brahme

Three-Dimensional Treatment Planning and Conformal Therapy . . . . . 253

James A. Purdy, Philip Poortmans, and Carlos A. Perez

Linac-Based Image Guided Intensity Modulated Radiation Therapy . . . 275

Ruijiang Li, Paul Keall, and Lei Xing

v
vi Contents

Tomotherapy Image Guided Radiation Therapy. . . . . . . . . . . . . . . . . . 313

Walter H. Grant III, E. Brian Butler, and Dirk Verellen

Robotic Image Guided Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . 325

Rodney E. Wegner, Dwight E. Heron, Arlan H. Mintz, and M. Saiful Huq

Cranial Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

Joseph R. Simpson, Robert E. Drzymala, Keith M. Rich,
and Brigitta G. Baumert

Stereotactic Body Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363

L. Chinsoo Cho, Valérie Fonteyne, Wilfried DeNeve, Simon S. Lo,
and Robert D. Timmerman

Physics and Clinical Aspects of Brachytherapy. . . . . . . . . . . . . . . . . . . 401

Bruce Thomadsen, Jack Venselaar, and Zuofeng Li

Principles and Clinical Applications of Pulsed Dose

Rate Brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Bethany Anderson, Christine Haie-Meder, and Erik Van Limbergen

Clinical Applications of High-Dose-Rate Brachytherapy . . . . . . . . . . . . 461

Subir Nag and Granger R. Scruggs

Quality Management and Safety in Radiation Oncology . . . . . . . . . . . . 485

James A. Purdy, Eric E. Klein, Philip Poortmans, and Coen Hurkmans

Quality Assurance for Multi-Institutional Clinical Trials . . . . . . . . . . . 531

James A. Purdy and Philip M. Poortmans

Promises and Pitfalls of Health Technology Assessment . . . . . . . . . . . . 549

Yolande Lievens, Peter Dunscombe, and Andre Konski

Part II Clinical Applications

Central Nervous System Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565

William A. Hall and Walter J. Curran

Head and Neck Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601

Allen M. Chen and K. S. Clifford Chao

Breast Cancer: Intact and Post Mastectomy . . . . . . . . . . . . . . . . . . . . . 641

Elizabeth S. Bloom, Philip Poortmans, Marianne Aznar,
Thomas A. Buchholz, and Eric A. Strom

Accelerated Partial Breast Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . 685

Ben Wilkinson, Laurie Cuttino, Dorin Todor, and Frank Vicini
Contents vii

Esophageal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717

Brian G. Czito and Christopher G. Willett

Cancer of the Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755

Joe Y. Chang

Cancers of the Colon, Rectum, and Anus . . . . . . . . . . . . . . . . . . . . . . . 777

Jonathan B. Ashman, Matthew D. Callister, Michael G. Haddock,
and Leonard L. Gunderson

Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801

Peter Han, Marvin Rotman, Alan R. Schulsinger, Bradley R. Pieters,
Caro C. E. Koning, Floris J. Pos, Maarten C. C. M. Hulshof,
and Philip Poortmans

Radiation Therapy for Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . 829

Kathryn E. Dusenbery and Bruce J. Gerbi

Technical Aspects of Radiation Therapy in Endometrial

Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
Higinia R. Cárdenes, David L. Andolino, and Jennifer E. Zook

Vulva . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889
Carlos A. Perez and Imran Zoberi

Carcinoma of the Vagina. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917

Higinia R. Cardenes, Jennifer E. Zook, and David L. Andolino

Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949
Jeff M. Michalski and Thomas Wiegel

Testicular Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027

Gerard C. Morton and Maria Pearse

Extremity Soft Tissue Sarcoma in Adults . . . . . . . . . . . . . . . . . . . . . . 1041

Karl E. Haglund, Thomas F. DeLaney, David C. Harmon,
Andrew E. Rosenberg, and Francis J. Hornicek

Total Body Irradiation Conditioning Regimens in Stem

Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
Kathryn E. Dusenbery and Bruce J. Gerbi

Radiation Therapy for Hodgkin Lymphoma and

Other Hematopoietic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
Chung K. Lee and Philip Poortmans

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1141
Contributors

Bethany Anderson Department of Human Oncology, University of Wisconsin,

600 Highland Avenue, Madison, WI 53792, USA, e-mail: anderson@humonc.
wisc.edu
David L. Andolino Department of Radiation Oncology, Indiana University
School of Medicine, 535 Barnhill Drive, RT 041, Indianapolis, IN 46202, USA
Jonathan B. Ashman Department of Radiation Oncology, Mayo Clinic Col-
lege of Medicine and Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ 85054,
USA e-mail: ashman.jonathan@mayo.edu
Marianne Aznar Department of Radiation Oncology, Rigshospitalet/Copen-
hagen University Hospital, Copenhagen, Denmark
Brigitta G. Baumert Department of Radiation-Oncology (MAASTRO) and
GROW (School for Oncology and Developmental Biology), University
Medical Center Maastricht (MUMC), Maastricht, The Netherlands
Elizabeth S. Bloom Division of Radiation Oncology, The University of Texas
M. D. Anderson Cancer Center, Houston, TX 77030, USA
Anders Brahme Department of Medical Radiation Physics, Karolinska
Institutet, Box 260, 17176 Stockholm, Sweden, e-mail: anders.brahme@ki.se
E. Brian Butler Radiation Oncology, The Methodist Hospital, Houston, TX
77030, USA
Matthew D. Callister Department of Radiation Oncology, Mayo Clinic College
of Medicine and Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ 85054, USA
Higinia R. Cardenes Department of Radiation Oncology, Indiana University
School of Medicine, 535 Barnhill Drive, RT 041, Indianapolis, IN 46202, USA
e-mail: hcardene@iupui.edu
Joe Y. Chang Department of Radiation Oncology, MD Anderson Cancer
Center, Houston, TX, USA, e-mail: jychang@mdanderson.org

ix
x Contributors

Allen M. Chen UC Davis Cancer Center, 4501 X Street, Sacramento, CA, USA,
e-mail: allen.chen@ucdmc.ucdavis.edu
L. Chinsoo Cho Department of Radiation Oncology, University of Minnesota
Medical Center, 420 Delaware St, SE MMC-494, Minneapolis, MN 55455,
USA, e-mail: choxx106@umn.edu
K. S. Clifford Chao Weill Cornell Radiation Oncology, 622 West 168th Street,
New York, NY 10032, USA
Mary Coffey Discipline of Radiation Therapy, School of Medicine, Trinity
Centre for Health Sciences, St. James’ Hospital, Dublin 8, Ireland
Walter J. Curran Department of Radiation Oncology, Winship Cancer Insti-
tute, Emory University, Atlanta, GA, USA
Laurie Cuttino Department of Radiation Oncology, Massey Cancer Center,
Virginia Commonwealth University, Richmond, VA 23298, USA
Brian G. Czito Department of Radiation Oncology, Duke University Medical
Center, Morris Bldg, Box 3085, Durham, NC 27710, USA, e-mail:
Czito@radonc.duke.edu
Thomas F. DeLaney Francis H. Burr Proton Therapy Center, Massachusetts
General Hospital, Harvard Medical School, 30 Fruit Street, Boston, MA 02114,
USA
Wilfried DeNeve Department of Radiotherapy-Oncology, Ghent University
Hospital, De Pintelaan 185, 9000 Ghent, Belgium
Robert E. Drzymala Department of Radiation Oncology, Washington
University School of Medicine, 4921 Parkview Place, Campus Box 8224, St.
Louis, MO 63110, USA
Peter Dunscombe Department of Oncology, University of Calgary, Calgary,
AB T2N 1N4, Canada
Kathryn E. Dusenbery Therapeutic Radiology–Radiation Oncology University
of Minnesota Medical School, MMC 494, 420 Delaware St SE, Minneapolis,
MN, 55455, USA, e-mail: dusen001@umn.edu
Valérie Fonteyne Department of Radiotherapy-Oncology, Ghent University
Hospital, De Pintelaan 185, 9000 Ghent, Belgium
Jack F. Fowler Human Oncology and Medical Physics, Medical School of
University of Wisconsin, Madison, WI, USA; Gray Laboratory, Northwood,
London, UK; 150 Lambeth Road, London SE1 7DF, UK
Bruce J. Gerbi Department of Therapeutic Radiology, Radiation Oncology,
University of Minnesota, Mayo Mail Code 494, 420 Delaware St SE, Minne-
apolis, MN 55455, USA; Therapeutic Radiology–Radiation Oncology,
University of Minnesota Medical School, MMC 494, 420 Delaware St SE,
Minneapolis, MN 55455, USA; Department of Therapeutic Radiology-
Radiation Oncology, University of Minnesota Medical School, MMC 494, 420
Delaware St. S.E, Minneapolis, MN 55455, USA
Contributors xi

Walter H. Grant III Department of Radiology, BCM 360, Baylor College of

Medicine, Houston, TX 77030, USA, e-mail: wgrant@bcm.edu
Robert J. Griffin Department of Therapeutic Radiology-Radiation Oncology,
University of Minnesota, 420 Delaware St. SE, Mayo Mail Code 494,
Minneapolis, MN 55455, USA
Leonard L. Gunderson Department of Radiation Oncology, Mayo Clinic
College of Medicine and Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ 85054,
USA
Michael G. Haddock Department of Radiation Oncology, Mayo Clinic College
of Medicine and Mayo Clinic, 200 2nd St. SW Desk R, Rochester, MN 55905,
USA
Karl E. Haglund Radiation Oncology Branch, National Cancer Institute,
10 Center Drive, Building 10/CRC, Bethesda, MD 20892, USA, e-mail:
haglundke@mail.nih.gov
Christine Haie-Meder Institut Gustave Roussy, Brachytherapy Unit, 114 rue
Edouard Vaillant, 94800 Villejuif, France, e-mail: christine.haie@igr.fr;
Christine.HAIEMEDER@igr.fr
William A. Hall Department of Radiation Oncology, Winship Cancer Institute,
Emory University, Atlanta, GA, USA e-mail: whall4@emory.edu
Peter Han Department of Radiation Oncology, State University of New York,
Health Science Center at Brooklyn, 450 Clarkson Aven, Box 1211, Brooklyn,
NY 11203-2098, USA, e-mail: Peter.Han@downstate.edu
David C. Harmon Hematology Oncology, Department of Medicine, Massa-
chusetts General Hospital, Harvard Medical School, Yawkey 7944, 30 Fruit
Street, Boston, MA 02114, USA
Dwight E. Heron Department of Radiation Oncology, University of Pittsburgh
Cancer Institute, 5150 Centre Avenue, #545, Pittsburgh, PA 15232, USA;
Department of Otolaryngology, University of Pittsburgh Cancer Institute,
Pittsburgh, PA, USA
Francis J. Hornicek Orthopedic Oncology, Department of Orthopedic Surgery,
Massachusetts General Hospital, Harvard Medical School, Yawkey 3B, 30
Fruit Street, Boston, MA 02114, USA
Maarten C. C. M. Hulshof Department of Radiation Oncology, Academic
Medical Center/University of Amsterdam, P.O. Box 22660, Z0-214, 1100 DD
Amsterdam, The Netherlands
M. Saiful Huq Department of Radiation Oncology, University of Pittsburgh
Cancer Institute, 5150 Centre Avenue, #545, Pittsburgh, PA 15232, USA
Coen Hurkmans Department of Radiation Oncology, Catharina Hospital,
Eindhoven, The Netherlands
David Jaffray Princess Margaret Hospital, University of Toronto, 610
University Avenue, Toronto, ON, M5G 2M9, Canada
xii Contributors

Paul Keall Radiation Physics Laboratory, University of Sydney, Sydney

Medical School—Central Room 475, Blackburn Building D06, Camperdown
2006, NSW, 3590, Australia
Youlia M. Kirova Department of Radiation Oncology, Institut Curie, 26 Rue
d’Ulm, 75005 Paris, France
Eric E. Klein Department of Radiation Oncology, Washington University
School of Medicine, St. Louis, MI 63110, USA
Caro C. E. Koning Department of Radiation Oncology, Academic Medical
Center/University of Amsterdam, P.O. Box 22660, Z0-214, 1100 DD Amster-
dam, The Netherlands
Andre Konski Department of Radiation Oncology, Wayne State University
School of Medicine, Karmanos Cancer Center, Detroit, MI 48201, USA
Chung K. Lee Department of Therapeutic Radiology–Radiation Oncology,
University of Minnesota, Minneapolis, MN, USA
Seymour H. Levitt Department of Therapeutic Radiation Oncology, University
of Minnesota, Minneapolis, MN 55455, USA; Department of Therapeutic
Radiology-Radiation Oncology, University of Minnesota, 420 Delaware St. SE,
MI 494, Minneapolis, MN, 55455, USA
Zuofeng Li Department of Radiation Oncology, University of Florida Proton
Therapy Institute, University of Florida, Jacksonville, FL 32206, USA;
University of Florida Proton Institute, 2015 North Jefferson Street, Jackson-
ville, FL 32206, USA
Ruijiang Li Department of Radiation Oncology, Stanford University, 875
Blake Wilbur Drive Room G204, Stanford, CA 94305-5847, USA, e-mail:
rli2@stanford.edu
Yolande Lievens Radiation Oncology Department, Universitaire Ziekenhuizen
Leuven, 3000, Leuven, Belgium, e-mail: yolande.lievens@uzleuven.be
Simon S. Lo Department of Radiation Oncology, Case Western Reserve
University, University Hospitals Case Medical Center, 11100 Euclid Avenue,
Lerner Tower B 181, Cleveland, OH 44106, USA
Cynthia Ménard Princess Margaret Hospital, University of Toronto,
610 University Avenue, Toronto, ON, M5G 2M9, Canada e-mail: cynthia.
menard@rmp.uhn.on.ca
Nancy Price Mendenhall University of Florida Proton Institute, 2015 North
Jefferson Street, Jacksonville, FL 32206, USA e-mail: menden@shands.ufl.edu
Jeff M. Michalski Department of Radiation Oncology, Washington University
School of Medicine, Mallinckrodt Institute of Radiology, Siteman Cancer
Center, 4921, Parkview Place, St. Louis, MO 63141, USA; Department of
Radiation OncologyWashington University School of Medicine, 4921 Parkview
Place, St. Louis, MO 63110, USA
Arlan H. Mintz Department of Neurological Surgery, University of Pittsburgh
Cancer Institute, Pittsburgh, PA, USA
Contributors xiii

Gerard C. Morton Radiation Oncologist, Sunnybrook Odette Cancer Centre,

University of Toronto, 2075 Bayview Avenue, Toronto, ON, M4N 3M5,
Canada, e-mail: gerard.morton@sunnybrook.ca
Sasa Mutic Department of Radiation Oncology Washington University School
of Medicine, Mallinckrodt Institute of Radiology, Siteman Cancer Center,
4921, Parkview Place, St. Louis, MO 63141, USA e-mail: mutic@ra-
donc.wustl.edu; mutic_s@radonc.wustl.edu.
Subir Nag Northern California Kaiser Permanente, Santa Clara, CA 95070, USA;
Stanford School of Medicine, Stanford, CA, USA
Ursula Nestle University Hospital Freiburg, Robert-Koch-Strasse 3, 79106
Freiburg im Breisgau, Germany
Roberto Orecchia Department of Radiation Oncology, European Institute of
Oncology and University of Milan, Milan, Italy
Heonjoo Park Department of Therapeutic Radiology-Radiation Oncology,
University of Minnesota, 420 Delaware St. SE, Mayo Mail Code 494,
Minneapolis, MN 55455, USA; Inha University, Inchon, Korea
Maria Pearse Radiation Oncologist, Sunnybrook Odette Cancer Centre, Uni-
versity of Toronto, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada;
Department of Radiation Oncology, University of Auckland Medical School,
Auckland, New Zealand
Carlos A. Perez Department of Radiation Oncology, Washington University
School of Medicine, Mallinckrodt Institute of Radiology, Siteman Cancer
Center, 4511, Forest Park Boulevard, St. Louis, MO 63141, USA; Department
of Radiation Oncology, Washington University Medical Cente, 4511, Forest
Park Boulevard, Suite 200, St. Louis, MO 63108, USA; Department of Radi-
ation Oncology, Mallinckrodt Institute of Radiology, Washington University
School of Medicine, St. Louis, MO 63110, USA
Bradley R. Pieters Department of Radiation Oncology, Academic Medical
Center/University of Amsterdam, P.O. Box 22660, Z0-214, 1100 DD Amster-
dam, The Netherlands
Philip Poortmans Department of Radiation Oncology, University of California
Davis Medical Center, Sacramento, CA 95817, USA; Department of Radiation
Oncology, Institute Verbeeten, Tilburg, The Netherlands
Floris J. Pos Department of Radiation Oncology, The Netherlands Cancer
Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX
Amsterdam, The Netherlands
James A. Purdy Department of Radiation Oncology, University of California,
Davis 4501, X Street, Suite G126, Sacramento, CA 95817, USA; Department
of Radiation Oncology, University of California Davis Medical Center, Sac-
ramento, CA 95817, USA
Keith M. Rich Department of Neurological Surgery, Washington University
School of Medicine 660 South Euclid Avenue, Campus Box 8057, St. Louis,
MO 63110, USA
xiv Contributors

Andrew E. Rosenberg Surgical Pathology, Department of Pathology, Massa-

chusetts General Hospital, Harvard Medical School, Warren 2, 30 Fruit Street,
Boston, MA 02114, USA
Marvin Rotman Department of Radiation Oncology, State University of New
York, Health Science Center at Brooklyn, 450 Clarkson Aven, Box 1211,
Brooklyn, NY 11203-2098, USA; Department of Radiation Oncology, Long
Island College Hospital, Brooklyn, NY, USA
Alan R. Schulsinger Department of Radiation Oncology, State University of
New York, Health Science Center at Brooklyn, 450 Clarkson Aven, Box 1211,
Brooklyn, NY 11203-2098, USA; Department of Radiation Oncology, Long
Island College Hospital, Brooklyn, NY, USA
Granger R. Scruggs Department of Radiation Oncology, Charles A. Sammons
Cancer Center, Baylor University Medical Center–Dallas, Texas, USA
Joseph R. Simpson Department of Radiation Oncology, Washington
University School of Medicine, 4921 Parkview Place, Campus Box 8224, St.
Louis, MO 63110, USA e-mail: jsimpson@radonc.wustl.edu
Chang W. Song Department of Therapeutic Radiology-Radiation Oncology,
University of Minnesota, 420 Delaware St. SE, Mayo Mail Code 494, Min-
neapolis, MN 55455, USA e-mail: songx001@umn.edu
Eric A. Strom Division of Radiation Oncology, The University of Texas
M. D. Anderson Cancer Center, Houston, TX 77030, USA
Bruce Thomadsen Departments of Medical Physics, Engineering Physics,
Biomedical Engineering and Industrial and Systems Engineering, University of
Wisconsin, Madison, WI 53705, USA, e-mail: thomadsen@humonc.wisc.edu
Robert D. Timmerman Department of Radiation Oncology, University of
Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, TX
75390-9183, USA
Dorin Todor Department of Radiation Oncology, Massey Cancer Center,
Virginia Commonwealth University, Richmond, VA 23298, USA
Erik Van Limbergen Department of Radiation Oncology, University Hospital
Leuven, Leuven, Belgium, e-mail: erik.vanlimbergen@uzleuven.be
Jack Venselaar Department of Clinical Physics, Institute Verbeeten, 5000 LA,
Tilburg, The Netherlands
Dirk Verellen Department of Radiation Oncology and Biomedical Physics, UZ
Brussel, Vrije Universiteit Brussel, Brussel, Belgium
Frank Vicini Department of Radiation Oncology, Beaumont Cancer Institute,
Oakland University William Beaumont School of Medicine, Royal Oak, MI
48073, USA, e-mail: fvicini@beaumont.edu
Rodney E. Wegner Department of Radiation Oncology University of Pitts-
burgh Cancer Institute, 5150 Centre Avenue, #545, Pittsburgh, PA 15232, USA
Contributors xv

Thomas Wiegel Department of Radiation Oncology, University Hospital, Ulm,

Germany
Ben Wilkinson Department of Radiation Oncology, Beaumont Cancer Insti-
tute, Oakland University William Beaumont School of Medicine, Royal Oak,
MI 48073, USA
Christopher G. Willett Department of Radiation Oncology, Duke University,
Durham, NC, USA
Lei Xing Department of Radiation Oncology, Stanford University, 875 Blake
Wilbur Drive Room G233, Stanford, CA 94305-5847, USA
Imran Zoberi Department of Radiation Oncology, Washington University
School of Medicine, Campus Box 8224, 4921 Parkview Place, St. Louis, MO
63110, USA
Jennifer E. Zook Department of Radiation Oncology, Indiana University
School of Medicine, 535 Barnhill Drive, RT 041, Indianapolis, IN 46202, USA
 Part I

Basic Concepts in Radiation Oncology

 Practical Time–Dose Evaluations, or How
to Stop Worrying and Learn to Love Linear
Quadratics
Jack F. Fowler

This chapter is written mainly for those who say ‘‘I don’t understand this a/b business—I can’t be
bothered with Linear Quadratic and that sort of stuff.’’ Well, it might seem boring—depending on
your personality—but it is easy, and it makes so many things in radiation therapy wonderfully and
delightfully clear. Experienced readers can turn straight to Sect. 4, about a quarter of the way
through.

Contents 5 Some of the Best-Known Schedules for Head

and Neck Tumor Radiotherapy ............................. 20
5.1 Standard Fractionation............................................... 20
1 Introduction.............................................................. 8 5.2 Hyperfractionation ..................................................... 21
5.3 Radiation Therapy Oncology Group Four-Arm
2 The Simplest Modeling ........................................... 10
Fractionation Trial (RTOG 90-03) ........................... 21
2.1 The Seven Steps to LQ Heaven: Brief Summary.... 10
5.4 Head and Neck Schedules that were Initially
3 The Seven Steps to LQ Heaven:The Details ........ 12 ‘‘Too Hot’’ in Table 2 ............................................... 22
3.1 Development of the Simple LQ Formula................. 12 5.5 Shortening the Wang 2-Fraction-a-Day Schedule
3.2 Biologically Effective Dose ...................................... 14 Using BED to Adjust Individual Doses ................... 22
3.3 Relative Effectiveness ............................................... 15 5.6 General Considerations of Head and Neck
3.4 Overall Treatment Time............................................ 16 Radiotherapy .............................................................. 24
3.5 Acute Mucosal Tolerance ......................................... 17 5.7 Appropriateness of Linear Quadratic Modeling
3.6 To Convert from BED into NTD or EQD2 Gy......... 18 in the Age of SBRT, IMRT, and IGRT? ................. 25
3.7 One Example ............................................................. 18 5.8 Do’s and Don’ts for Optimum Overall Times,
3.8 Gamma Slopes, the Standard of Precision with H&N Schedules as Examples........................... 26
of Estimates of BED or NTD ................................... 19 5.9 The Difference between the Short Value for
Mucosa of Tk = 7 Days and Longer Values
4 How to Evaluate a NewSchedule—Brief of 14–32 Days for Carcinomas is What
Summary................................................................... 19 DrivesMulti-week Fractionated Radiotherapy.......... 26
6 The Problem of Optimum Overall Time.............. 28
6.1 The Essential Condition for Any
Optimum Schedule .................................................... 28
6.2 Finding Optimum Schedules ................................... 28
6.3 Rate of Accumulation of Radiation Damage
in Normal Mucosa..................................................... 29
6.4 Faster Rate of Accumulation of Radiation Damage
in Tumors than in Normal Mucosa .......................... 29
6.5 Finding Optimum Overall Times: For Any
Radiotherapy .............................................................. 30
J. F. Fowler (&) 6.6 The Summarized Optimization Process .................. 31
Human Oncology and Medical Physics, 6.7 Constructive Lengthening and its Ability
Medical School of University of Wisconsin, to Increase Tumor-Effective Dose:
Madison, WI, USA A Counterintuitive Move?......................................... 32
e-mail: jackfowlersbox@googlemail.com 7 The Results: Tumor Accumulated EQD Plotted
J. F. Fowler Against Number of Fractions or Overall Time ... 32
Gray Laboratory, Northwood, London, UK 7.1 Two Fractions a Day give more Tumor Log Cell
Kill than One Fraction a Day ................................... 33
Present Address:
J. F. Fowler
150 Lambeth Road, London, SE1 7DF, UK

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 3
DOI: 10.1007/174_2011_305,  Springer-Verlag Berlin Heidelberg 2012
4 J. F. Fowler
7.2 The Effect of Assuming Faster or Slower
Repopulating Rates....................................................
7.3 The Exceptional Cases of Very
Fast Repopulation ......................................................
7.4 Discussion: Is One Fraction a Day Still
to be Used? ................................................................
7.5 The First Main Conclusion .......................................
7.6 The Second Main Conclusion...................................
7.7 Discussion: Smaller and Smaller Fractions..............
7.8 Discussion: How Long is Really Too Long?...........
7.9 For Slightly Slower Growing Tumors,
the Radiation-only Gains for 2F/d are Notably
Greater than the Once-Daily Treatments..................
8 Discussions: How Short is Too Short?..................
8.1 Discussions: Is a Week Too Short?..........................
8.2 Discusssion: The Increase of Therapeutic Ratio
with More and Smaller Fractions .............................
8.3 Acute Mucosal Tolerance Calculations are
also Worth Doing .....................................................
8.4 Incomplete Recovery (IR) as an Enhancer
of Radiation Damage.................................................
8.5 Incomplete Recovery as a Loss of Effect
in Prolonged Fractions ..............................................
9 Conclusions ...............................................................
References..........................................................................
Abstract
33
This 9-section chapter begins with an elementary
33 explanation of the Linear Quadratic model of
Radiation Response, to make sure readers haven’t
34
35
missed out on understanding this robust and
36 reliable way of comparing different schedules in
36 Radiation Oncology. A detailed account of its
36 many applications has recently been published as
‘‘21 Years of BED (Biologically Effective Dose)’’
37 (Fowler Br J Radiol 83:554–568, 2010). The
essential feature of this modeling is that a given
38
38 dose has very different biological effects on
neighbouring but different tissues because of their
39 biological alpha/beta ratios and their ‘‘kick-off’’ or
‘‘onset’’ times of repopulation during continuing
39
irradiation. In Sections 4 and 5 comparisons of
40 actual clinical trials are presented that have shaped
the current and emerging schedules of treatments
44
of Head & Neck tumors, going on to SBRT
46 (Stereotactic Body Radiation Therapy), IMRT
46 (intensity Modulated Radiation Therapy) and IGRT
(Image Guided Radiation Therapy). Some insights
into how the biological strategies of fractionated
radiotherapy actually deliver therapeutic advanta-
ges are introduced. Section 6 explains how
Optimum Overall Times can now be predicted,
using basially least two constraints, one for Late
Complications and the other for Acute Tolerance
Doses. This is a fairly new break-through (2008).
Section 7 goes into detail on why Overall Times
might be too short or too long, with examples from
modern schedules still being clinically trialed.
Section 8 goes further into non-standard schedules,
with updated emphasis on the Recovery Times of
various tissues and tumors, intervals between frac-
tions and extended fraction times. The chapter ends
with an explanatory table of best and next-to-best
schedules for Head and Neck radiation oncology.
The continuing need to obtain data on individual
tumor T-1=2 and repopulation is emphasized.
Abbreviations
a, alpha Intrinsic radiosensitivity. Loge
of the number of cells sterilized
non-repairably per gray of dose
of ionizing radiation
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
b, beta Repair capacity. Loge of the num-
ber of cells sterilized in a repairable
way per gray squared
a/b, alpha/ The ratio of ‘‘intrinsic radiosensi-
beta ratio tivity’’ to ‘‘repair capability’’ of a
specified tissue. This ratio is large
([8 Gy) for rapidly proliferating
tissues and most tumors. It is small
(\6 Gy) for slowly proliferating
tissues, including late normal-tissue
complications. This difference is
vital for the success of radiother-
apy. When beta (b) is large, both
mis-repair and good-repair are
high. It is the mis-repair that causes
the cell survival curve to bend
downward
Accelerated Fractionated schedules with shorter
fractionation overall times than the conventional
7 (or 6) weeks
BED Biologically effective dose, pro-
portional to log cell kill and there-
fore more useful as a measure of
biological damage than physical
dose, the effects of which vary with
fraction size and dose rate. For-
mally, ‘‘the radiation dose equiva-
lent to an infinite number of
infinitely small fractions or a very
low dose-rate’’. Corresponds to the
intrinsic radiosensitivity (a) of the
target cells when all repairable
radiation damage (b) has been
given time to be repaired. In linear
quadratic modeling, BED = total
dose 9 relative effectiveness (RE),
where RE = (1 ? d/[a/b]), with
d = dose per fraction, a = intrinsic
radiosensitivity, and b = repair
capacity of target cells
bNED Biochemically no evidence of dis-
ease. No progressive increase of
prostate specific antigen (PSA)
level in patients treated for prostate
cancer
CI Confidence interval
(usually ±95%)
CLDR Continuous low dose rate
5
Con-Len Constructive lengthening: when
adding a day (or two) followed by a
not-too-small fraction (or two)
adds to the accumulated radiation
damage in the tumor, rather than
allowing it to fall by tumor repop-
ulation, or minimizes any loss
CTV Clinical tumor volume. The volume
into which malignant cells are
estimated to have spread at the time
of treatment, larger than the gross
tumor volume (GTV) by at least
several millimeters, depending on
site, stage, and location. See also
GTV and planning treatment
volume (PTV)
Dt Time interval between fractions,
recommended to be not less than 6 h
EBR External beam radiation
EGFR Epithelial growth factor receptor,
one of the main intracellular bio-
chemical pathways controlling rate
of cell proliferation
EQD Biologically equivalent total dose,
usually in 2 Gy dose fractions. The
total dose of a schedule using, for
example, 2 Gy per fraction that
gives the same log cell kill as the
schedule in question. If so, should
be designated by the added digit
‘‘2’’ EQD2 Gy
EUD Equivalent uniform dose. A
construct from the DVH of a
non-uniformly irradiated volume of
tissue or tumor that estimates the
surviving proportion of cells for
each volume element (voxel), sums
them, and calculates that dose
which, if given as a uniform dose to
the same volume, would give the
same total cell survival as the given
non-uniform dose. Local fraction
size is taken into account by
assuming an a/b ratio for the tissue
concerned
18
FLT F Fluorothymidine, a radioactive
label for freshly synthesized DNA
to indicate actively dividing cells.
6 J. F. Fowler
The radioactive label 18F emits
positrons
Gamma, Slope of a graph of probability,
c-50, c-37 usually tumor control probability
(TCP), versus total fractionated
dose (NTD or EQD), as percentage
absolute increase of probability per
1% increase in dose. The steepest
part of the curve is at 50% for
logistic-type curves and at 37% for
Poisson-type curves. Tumor TCP is
usually between a gamma-50
(or -37) of 1.0 and 2.5. The
difference between c-50 and c-37
is rarely clinically significant
G Dose rate factor. A number less
than 1 that describes the decrease of
biological effect if the duration of
irradiation is longer than a few
minutes
Gy, gray The international unit of radiation
dose: one joule per kilogram of
matter. Commonly used radiother-
apy doses are approximately 2 Gy
on each of 5 days a week
Gy10, Gy3, Biologically effective dose (BED),
Gy1.5 with the subscript representing the
value of that tissue’s a/b rati-
o = 10 Gy for early radiation
effects, 3 Gy for late radiation
effects, and 1.5 Gy for prostate
tumors. The subscript confirms that
this is a BED, proportional to log
cell kill, and not a real physical dose
GTV Gross tumor volume. The best
estimate of tumor volume visual-
ized by radiological, computed
tomography (CT) scan,
magnetic resonance, ultrasound
imaging, or positron emission
tomography
HDR High dose rate. When the dose
fraction is delivered in less than
five or ten minutes; that is, much
shorter than any half-time of repair
of radiation damage
Hyper- More (and smaller) dose fractions
fractionation than 1.8 or 2 Gy
Hypo- Fewer (and larger) dose fractions
fractionation than 1.8 or 2 Gy
IGRT Image Guided Radiotherapy. Using
superimposed images from CT-
scans or Magnetic Resonance
Imaging or PET-scans
IMRT Intensity Modulated Radiotherapy:
instead of a constant dose rate from
all angles, the dose rate is made to
vary with the angle from which it is
delivered, by computerized dose
planning; leading to deliberately
non-uniform dose-planning and
‘dose-painting’ in tumors or ‘dose-
avoidance’ of critical organs
IR, Incomplete Residual radiation damage that may
Recovery add to the effect of the next fraction
if a too short interval occurred
(Thames and Hendry 1987). Repair
usually refers to intracellular repair.
Recovery refers to other processes
too and is a more general term
Isoeffect Equal effect
LC Local control (of tumors)
LDR Low dose rate. Officially (ICRU),
less than 2 Gy/h; but this is decep-
tive because any dose rate greater
than 0.5 Gy/h will give an
increased biological effect com-
pared with the traditional 0.42 Gy/h
(1000 cGy per day). For example at
2 Gy/h, the biological effects will
be similar to daily fractions of 3.3
and 2.8 Gy on late complications
and on tumors respectively
Linear effect Directly proportional to dose
Ln, loge Natural logarithm, to base e. One
log10 is equal to 2.303 loge
Log10 Common logarithm, to base 10.
‘‘Ten logs of cell kill’’ are
23.03 loge of cell kill
LQ Linear quadratic formula: loge cells
killed = a 9 dose ? b 9 dose-
squared
LQ(L) A linear cell survival curve sug-
gested by some authors to replace
the higher dose downward curva-
ture of a standard LQ curve, which
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
some authors fear, probably
wrongly, but the issue is not yet
resolved
Logistic A symmetrical sigmoid or S-shaped
curve graph relating the statistically
probable incidence of ‘‘events’’,
including complications or tumors
controlled, at a specified time after
treatment, to total dose (NTD). This
curve is steepest at the probability
of 50%
LRC Loco-regional tumor control. LC
would be local control
MRI Magnetic Resonance Imaging.
Scans of body tissues which can
show the chemical state of mole-
cules, instead of only their density
as CT scanning does
NTCP Normal tissue complication
probability
NTD Normalized total dose of any sche-
dule. The total dose of a schedule
using 2 Gy per fraction that gives
the same log cell kill as the
schedule in question. The NTD will
be very different for late effects
(with a/b = 3 Gy and no overall
treatment time factor) than for
tumor effect (with a/b = 10 Gy
and an appropriate time factor)
NSCLC Non-small-cell lung cancer
Oligo- The use of a few large fractions, say
fractionation 5–20 Gy or higher, and only a few
of them, say ten or less (Ling et al.
2010)
PET Positron Emitting Tracer. A radio-
active nuclide that emits positrons,
that is, a pair of oppositely charged
electrons in exactly opposite direc-
tions, so that they can be detected
in PET Scanning within a few
millimeters of accuracy to indicate
parts of a tumor that might contain
dangerously live cells
Poisson A near-sigmoid graph of probabil-
curve ity of occurrence of ‘‘events’’, such
as tumor control at X years, versus
total dose or NTD. Based on
7
random chance of successes among
a population of tumors or patients,
the probability of curve P = exp
(–n), where an average of n cells
survive per tumor after the sche-
dule, but 0 cells must survive to
achieve 100% cure. If an average of
1 cell survives per tumor,
P = 37%. If 2 cells survive,
P = 14%. If 0.1 cells survive on
average, P = 90%. This curve is
steepest at the probability of 37%
PTV Planning treatment volume—larger
than CTV to allow for setup and
treatment-planning errors
PSA Prostate-specific antigen: can be
measured in a blood specimen as a
measure of activity of the prostate
gland. Often taken as a measure of
activity of prostate cancer
Prec Proportion of a dose fraction that is
recoverable, the beta-only term,
which is d/[a/b] or Gd/[a/b] as a
proportion of the whole
RE = (1 ? d/[a/b]) or (1 ? Gd/
a/b]). The ‘‘1’’ part of the RE is the
non-recovering, fixed part, inde-
pendent of time after irradiation
Quadratic Effect proportional to dose squared,
for example from two particle
tracks passing through a target
QED Quod Erat Demonstrandum – Latin
for ‘‘That’s what we wanted to
show!’’
RE Relative effectiveness. We multiply
total dose by RE to obtain BED.
RE = (1 ? d/[a/b]), where d is the
dose per fraction
Red Shell An annuloidal shell surrounding a
PTV, during treatment planning, to
delineate tissues at risk from late
reactions when prescription doses
exceed normal tissue tolerance of
nearby organs, at mm distances
before sufficient dose falloff has
occurred (Yang et al. 2010)
RTOG Radiation Therapy Oncology
Group, USA
8 J. F. Fowler
SF Surviving fraction after irradiation,
usually of cells
SIB Simultaneous Internal Boost.
The addition of a deliberate ‘‘hot
spot’’ into a planned non-uniform
tumor dose distribution to enhance
the local effect; a form of ‘dose
painting’ by IMRT
SBRT Stereotactic Body Radiatiotherapy.
Very accurately guided beams,
often of small diameter and
usually delivered by only a few
large dose fractions, to treat
cancer in certain organs outside
the brain
SRT Stereotactic Radiosurgery: it usu-
ally means in radiotherapy the use
of a single treatment fraction,
often in brain. Originated from the
precise localizations in brain
physiotherapy research. Has
sometimes been wrongly used for
SBRT
Tpot Potential doubling time of cells in a
population; before allowing for the
cell loss factor. Tpot is the recipro-
cal of cell birth rate. It can only be
measured in a tissue before any
treatment is given to disturb its
turnover time
Tp Cell doubling time in a tissue
during radiotherapy; probably
somewhat faster than Tpot. Deter-
mined from gross tumor (or other
tissue) results when overall time is
altered
Tk Kick-off or onset time: the apparent
starting time of rapid compensatory
repopulation in tumor or tissue
after the start of treatment, when
it is assumed that there are just
two rates of cell proliferation
during radiotherapy: zero from
start to Tk, then constant doubling
each Tp days until end of treatment
at T days. Accelerating
repopulation is discussed in
Sect. 5.6
TCP Tumor control probability
1 Introduction
The role of radiotherapy in combination with
systemic therapy is still being actively defined. This
chapter explains optimal radiotherapy schedules and
their surprisingly subtle relationships. There is no
excuse for not aiming for the best that radiotherapy-
alone can do, before deliberately under-dosing, if
required, to avoid specific complications for systemic
methods. These can be by chemotherapy (Bernier
2009), gene expression (Bentzen 2009), epidermal
growth factor (Harari et al. 2009), or any of apoptosis,
repopulation, angiogenesis, proteonomics, hypoxia,
or other biological targeting (Nimmadda et al. 2009).
Meta-analysis has shown that pure hyperfraction-
ation with dose escalation conferred an absolute
overall benefit of 7% for tumor control in advanced
head and neck cancer, and about the same for
concurrent chemotherapy added to conventional
radiotherapy-only (Le and Raben 2009). This chapter
concentrates on the radiotherapy-only schedules
described here. It eventually presents some schedules
(Sects. 8 and 9) which should be safe to deliver, with
minimal clinical testing in any new environment, such
as perhaps leaving out the last fraction or two only to
‘‘check or confirm’’ local dosimetry. It is emphasized
that for those recommended schedules, each practical
overall time suggested must not be shortened or a risk
of severe acute reactions could occur.
It is well known that the simplest description of
radiation dose, the total dose, is not adequate because
its effect varies with the size of dose per session
(the dose fraction) and with the dose rate. If we
double the dose per fraction from 2 to 4 Gy (keeping
total dose constant), the effect is 20% greater for
tumors but 100% greater for late complications.
Further, if a given physical dose is spread evenly over
24 h instead of 2 min, its effect is reduced by 20% for
most tumors, but to about half for late complications.
We need a way of expressing radiation ‘‘dose’’ in
some quantitative way that is more proportional to the
observed biological effect. This is the object of cal-
culating a biologically effective dose (BED), and an
equivalent dose in 2 Gy fractions (EQD or NTD), so
that a 20% increase or decrease of BED or NTD or
EQD2 Gy will lead to a reasonable approximation of a
20% increase or decrease of the expected biological
effect. The interesting point is that the same change in
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
physical dose is likely to alter the incidence of late
complications to double or half of its effect on tumors.
So how can we deal with that?
The basic truth in radiotherapy is that any change
in the schedule of dose delivery has a different effect
on tumors from its effect on late complications, unless
both dose per fraction and dose rate are kept constant.
These differences provide some of the remarkable
advantages of radiation therapy, and also some
puzzles until they are explained. BED can take these
differences into account, and preferably explain them.
In the 25 years since the linear quadratic (LQ)
formula has been used for the evaluation of radio-
therapy schedules, it has proved remarkably reliable. It
is now the main and generally accepted method of
rationalizing the improved time–dose-fractionation
schedules that have been developed to replace, in some
body sites, the standard ‘‘2 Gy given five times a week
for 6 or 7 weeks’’ schedules. It was first of all useful in
identifying the important difference in the effect of
dose-fraction size between rapidly proliferating tissues
(most tumors) and slowly proliferating tissues (most
late complications). This explained the blindly used,
but not always wrong, predominance of multi-small-
fraction schedules, such as 1.8 or 2 Gy five times a
week for 6 or 7 weeks. As explained below, the
theoretically ideal overall time would be close to the
time at which rapid repopulation in the tumor kicks off,
designated Tk days after starting treatment.
In the early years of the development of the LQ
formulation, there was no overall treatment-time factor
(Douglas and Fowler 1976; Barendsen 1982; Withers
et al. 1983). This was added later (Travis and Tucker
1987; van de Geijn 1989; Fowler 1989), based on
LQ-aided analyses of animal and clinical data
(Denekamp 1973; Turesson and Notter 1984a, b;
Thames and Hendry 1987). Since then, the strong
effect of repopulation of tumor cells during radiother-
apy has been well substantiated so that a repopulation
term has been added for tumors (Fowler 1978, 1989;
Withers et al. 1988; Fowler and Lindstrom 1992;
Hendry et al. 1996). More recently, a different set of
parameters has been described to predict acute mucosal
reactions in human patients (Fowler et al. 2003c).
Although the accuracy and even the nature of the
LQ factors has been queried a few times, for example
whether the parameters are unique or distributed (King
and Mayo 2000; Brenner and Hall 1999, 2000; King
and Fowler 2002; Dasu et al. 2003; Moiseenko 2004),
9
the LQ formulation has remained solidly useful and has
aided in the design of clinical trials that have changed
the practice of radiotherapy (Thames et al. 1983).
Examples include the design of hyperfractionated
(more and smaller fractions) and accelerated fraction-
ation (shorter) trials, the avoidance of gaps in radiation
treatment, the development of high dose-rate brachy-
therapy, and a better understanding of when to use or
avoid hypofractionation (fewer and larger fractions).
The recent growth of stereotactic body radiotherapy is a
subset of the latter category (Fowler et al. 2004a, b).
These developments have led to questions about the
validity of LQ at high doses per fraction which will be
answered in Sect. 5.7, and to the proposal to call very
large fractions ‘‘oligo-fractions’’ (by analogy with
oligo-metastases) to distinguish them from the kind of
hypofractionation that has ‘‘slightly higher doses per
fraction than 2 Gy and slightly fewer fractions than
usual’’ (Ling et al. 2010). It is one of a dozen new terms
in the Glossary since 2006. One of the most interesting
series of modeling investigations concerns oral and
laryngeal cancers in which the overall times were
deliberately shortened until the acute reactions became
too severe, in several well-known schedules in different
countries. Each schedule was then moderated in some
way until it became tolerable. The modeling then
showed that not only did the acute mucosal reactions
fall into a narrow band of BED, but the modeled tumor
responses were then all close to 11 log10 of predicted
tumor cell kill for a variety of different time–dose
schedules. This fact will be discussed in this chapter.
Although the numerical results of modeling
depend to some extent on the values assumed for the
parameters, ratios of parameters such as a/b ratios and
time–dose tradeoffs (grays per day) are often known
sufficiently well for reasonable variations to lead to no
clinically significant differences in predicted total
dose or BED or NTD. In the modeling described
below, we take care to limit the assumed values of
parameters to a small library of values selected from
experience, avoiding ‘‘elegant variation’’. Then,
results that are useful and self-consistent are obtained.
Unlike some other attempts at modeling, the
number of initially viable cells per mm3 is not
essential in LQ modeling for time–dose evaluations,
because it is largely cancelled out against radiosen-
sitivity a in the standard BED formulation. This
is also true of equivalent uniform dose (EUD;
Niemierko 1997). Both BED and EUD enjoy similar
10
stability for this reason. The most essential biological
factor in LQ formulation is the a/b ratio of the tissue
concerned, which appears in the BED with weighting
equal to dose per fraction. The other significant
factors are the ‘‘kick-off time’’ of rapid tumor
repopulation Tk and the doubling time of repopulating
tumor cells Tp, which together with the a value all
appear in the repopulation term which is usually, but
not always, a small proportion of BED.
A glossary of terms is attached at the end of this
chapter for the readers’ convenience.
It is unfortunate that the abbreviation BED is ambiguous.
Its proper meaning as defined here is Biologically
EFFECTIVE Dose, defined by the formula in Sect. 2.1 as
originally by Barendsen (1982). However, it has occa-
sionally been used as Biologically EQUIVALENT Dose
as this is something that is often required by readers as
well. In fact the ‘‘Equivalent Dose in familiar 2 Gy
fractions’’ is already designated by EQD or EQD2 or
EQD2Gy or even LQED. Care should be taken not to
confuse the two meanings of BED versus EQD; it is a
matter of good education, good memory, and better
manners, not to mention the avoidance of the sort of
mistakes that ‘‘liters vs gallons’’ of fuel can cause. An
EQD is smaller than a BED by a factor of 1.67 or 2.0 for
late complications (with a/b ratios of 3 or 2 Gy) and by a
factor of 1.2 for most tumors and all rapidly proliferating
tissues (with a/b ratios of 10 Gy). Any BED can be easily
converted into its EQD by dividing the BED by the
Relative Effectiveness (RE = 1 ? d/[a/b]), where d is a
standard dose per fraction of say 2 Gy, and a/b is the
relevant value for the tissue concerned. Hence, the 1.67 or
1.2 divisors for tissues with a/b = 3 or 10, respectively.
2 The Simplest Modeling
Earlier, mathematical models were regarded with
suspicion or with derision as playthings for children—
but not any more. Modeling has become an important
scientific tool in the design and evaluation of
topics from global warming to engineering design of
aircraft and pharmacological development of drugs,
replacing expensive experimentation in many cases
(Prof. Gordon Steel 1990, personal communication).
With the aid of computers, mathematical modeling
using optimization and new imaging are continuing to
revolutionize treatment planning in radiotherapy, as
other chapters in this book will show.
‘‘There are good reasons for believing that the
primary effects of radiation on biological tissues
are cell damage and cell depopulation in renewing
populations’’ (Thames and Hendry 1987). This is true
J. F. Fowler
whether the concern is damage to normal tissues or
the elimination of every malignant cell in tumors.
However, certain indirect biological end points, such
as radiation sickness or extent of late fibrosis, do not
appear to depend only on the number of cells steril-
ized, although it does not mean that they are not a
strong function of cells sterilized. The phantom of
immunological response keeps rearing its head, with
little practical effect. The additive effect of chemo-
therapy seems to apply most effectively when used
concomitantly, and till date amounts to around 10%
of the total cell kill compared with radiotherapy. The
strength of radiation as a treatment strategy is that it
can and does reach, wherever the physical plan puts it,
with increasing efficiency of positional accuracy.
The object of the present modeling is to find bio-
logical effects of the radiotherapy treatments with
which we are familiar, as against different scheduling
of time and dose. That is the ‘‘isoeffect modeling’’
that has much history, passing through the ‘‘cube root
law’’ of the 1930s, the ‘‘Strandqvist slope’’ of the
1940s, and the ‘‘Nominal Standard Dose’’ (NSD) or
‘‘Time–dose Factor’’ (TDF) of Dr Frank Ellis in the
1960s and 1970s—and then to evaluate methods of
doing better. We start by writing down some ideas for
explaining the non-linear action of ionizing radiation
in damaging biological cells.
Radiation sterilizes cells, meaning that they do not
die immediately, but at the time of the next cell divi-
sion, or a few divisions later. An important factor is the
repair occurring in cells between irradiation and the
next cell division. This repair in cells, i.e., recovery in
tissues, depends on the turnover rate of renewing
tissues—a day or so for rapidly proliferating tissues and
most tumors, but many months for organs that normally
proliferate slowly. This is the important difference in
the tissues that LQ modeling helped to bring out, with
the help of the famous or infamous ratio a over b.
2.1 The Seven Steps to LQ Heaven:
Brief Summary
First, we list here the ‘‘Seven (algebraic) Steps to LQ
Heaven’’, before explaining them in detail Sect. 4.
Alpha is the intrinsic radiosensitivity of the cells,
defined as how many logs (to the exponential
base ‘‘e’’) are killed (sterilized) per gray, in a
‘‘non-repairable’’ way. Beta is the repairable portion
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
of the radiation damage, requiring 6 h or more for
complete repair. It can be regarded as the result of two
charged-particle tracks passing through a sensitive
target in the cell nucleus in less than 6 h, so this term
has to be multiplied by d squared. E is the loge sum of
the non-repairable a term and the partly repairable b
term. So for n fractions of d Gy dose each:
E ¼ nðad þ bd 2 Þ ð1Þ
E ¼ ndða þ bdÞ ð2Þ
E=a ¼ ndð1 þ db=aÞ ð3Þ
Then dividing throughout by a to express a/b as a
ratio.
 
E d
¼ nd 1 þ ð4Þ
a a=b
With no repopulation considered; as for most types
of late complication.
This is the limited definition of BED. It applies to
late effects. BED = E/a = total dose 9 RE, where
RE = (1 ? d/[a/b]), and is very useful.
Next, we subtract the log cell kill due to repopu-
lation of any cells during radiotherapy, after the
‘‘kick-off’’ or onset time Tk, where T is the overall
time and Tp is the average cell-number doubling time
(in days) between Tk and T.
E ¼ ndða þ bdÞ  ðT  Tk Þ
 rate of repopulation per day ð5Þ
E ¼ ndða þ bdÞ  loge 2ðT  Tk Þ=Tp ð6Þ
ðloge 2 ¼ 0:693Þ
To transform the total log cell kill E into the total
BED requires the same division throughout by a as
carried out in step 3 (Eq. 3) above:
 
E d 0:693
BED ¼ ¼ nd 1 þ  ðT  Tk Þ ð7Þ
a a=b aTp
BED can be expressed as Gy3 (or Gy2) for late
complications, or as Gy10 (or Gyx) for tumor or early
normal-tissue reactions, the subscript referring to the
a/b of the relevant tissue used in its calculation. Gy3
and Gy10 values must not be mixed, as US and
Canadian or Hong Kong dollars cannot. However,
several segments of a schedule can have their Gy10
11
values added together, and their Gy3 values added
separately, for a comparison of the total BEDs
amounting to a ‘‘therapeutic ratio’’ of Gy10/Gy3—
representing tumor cell damage divided by late
normal-tissue damage. This notation (Gysubscript)
should always be used, or confusion quickly sets in. It
reminds us that this is a BED, not the real physical dose,
and also confirms which a/b ratio was used and thus for
which tissue each BED or EQD2 Gy or NTD is calcu-
lated. We should state each time ‘‘late’’ or ‘‘tumor’’ or
‘‘early’’ BED or NTD or EQD (Fowler 1989).
A further measure of radiation damage from these
formulae is:
Loge cell kill = E = BED 9 a, so that in the
‘‘common log to base 10 scale’’, log10 cell kill =
loge cell kill/2.303.
To convert from BED to EQD 2 Gy or NTD
(total equivalent dose in 2 Gy fractions):
For late complications, divide Gy3 by 1.667. For
tumor or early effects, divide Gy10 by 1.2.
The explanation comes from the identity
BED1 = BED2, where ‘‘1’’ is for ‘‘d Gy per frac-
tion’’ and ‘‘2’’ is for ‘‘2 Gy per fraction’’, so for
identical BEDs, we have:
Total dose1  RE1 ¼ total dose 2
 ðRE for 2 Gy and the same a=bÞ:
NTD  ð1 þ 2=a=bÞ ¼ BED: Then solve for NTD:
The confusion between Biologically EFFECTIVE
Dose and Biologically EQUIVALENT Dose has led
to the use of two subscripts to specify EQDs, instead
of the single subscript used previously to designate
the a/b ratio of a tissue given a stated dose in the
correct BEDs as in Eq. 7. The BEDs continue to
use only the same single subscript for a/b, and EQDs
are referred to in this chapter as EQD3/2 or EQD10//2,
with the double subscript. The first number of the
double subscript is the a/b ratio and the second is the
dose-per-fraction of the standard of comparison, often
but not necessarily 2 Gy. Sometimes in other writing,
this standard dose per fraction of 2 Gy will be given
in the text-line instead of as a subscript, viz EQD23 or
EQD210, in an attempt to get the 2 ‘‘carved in stone,
it’s so Standard’’. IMRT and oligo fractions contradict
this standard small dose of 2 Gy in a big way, but
when there is a single subscript, it is always only for
the a/b ratio being basic to each tissue.
12
3 The Seven Steps to LQ Heaven:
The Details
This section will seem familiar to experienced
modelers for whom Sects. 4 and 5 will be more
interesting, where comparisons of actual schedules
are tabulated and discussed. The mathematics of the
LQ formula are very simple and are taught in courses
before the end of the high school syllabus at age 15 or
16 years. Solving an algebraic quadratic equation and
manipulating the conversion of an exponential into
logarithmic form are the only steps requiring an effort
of memory and are only necessary for excess calcu-
lations than normally required. This sort of arithmetic
normally requires no more than the four simplest keys
(+, –, 9, /) on a hand calculator, or even just the back
of an envelope. The ‘‘Seven Steps to LQ Heaven’’ are
intended to ensure that the reader is never puzzled
by such simple calculations. Having followed and
understood the seven steps that follow, the reader
should be able to use them with confidence for any
comparisons of radiotherapy schedules to be made in
terms of BED (Fowler 1989, 1992a, b).
BED is proportional to log cell kill for cells of the
specified a/b ratio, and so is a strong function of
biological effect. BED is itself a ratio (E/a), the two
parameters of which are not individually important.
Mathematically, E/a is simply a linkage term showing
equivalence between two schedules—their ‘‘iso-
effect’’ in the time–dose scale—as well as providing a
useful number, the BED. Its numerical value is a
convenient number, representing a dose without the
repairable component, that is avoiding dose per
fraction or dose rate, until relative effectiveness (RE)
is built in. Modelers become accustomed to thinking
of Late Effects in the range of 90–133 Gy3 but Tumor
Effects in the range of 60–90 Gy10. When these are
divided by the RE for 2 Gy fraction size they both
become NTD or EQD in 2 Gy fractions, in the
50–80 Gy range of total doses.
3.1 Development of the Simple LQ
Formula
 
E d
¼ nd 1 þ ð4Þ
a a=b
J. F. Fowler
Cell depopulation is the main effect of radiation,
both for eliminating tumors and for damaging normal
tissues. In addition, some genes are activated, which
can be relevant in those cells that survive irradiation,
and some apoptosis (cell death independent of mito-
sis) may be caused. Although apoptosis does not
appear to be the major effect of radiation, when it
happens it adds to the effect. The promising strategy
of damaging tumors by depleting their blood supply,
with pharmacological or enzyme-pathway aid (Fuks
et al. 1994), can be regarded as considering the neo-
vasculature (that is, rapidly proliferating endothelial
cells (Hobson and Denekamp 1984) as legitimate
oncogenic targets, as well as the directly malignant
tumor clonogens (Hahnfeldt et al. 1999). Radiation
can reach them all.
If a dose of radiation D sterilizes a proportion of
cells in a given tumor or normal organ so that the
number of viable cells is reduced from the initial N0 to
Ns: the surviving proportion is Ns/N0, which is des-
ignated S.
This process is represented as S ¼ eD=Do ¼
expðD=Do Þ, in its simplest form, where Do is the
average dose that would sterilize one cell. This shows
that the surviving proportion of cells is reduced
exponentially with radiation dose. That is, each suc-
cessive equal increment of dose reduces the surviving
cells by the same proportion, and not by the same
number. The proportion of surviving cells would then
decrease from 1 to 0.5, to 0.25, to 0.125, etc.; if higher
doses per fraction were used, from 0.1 to 0.01 to 0.001.
Another way of writing this is: loge S = -D/Do,
which plots out as a graph of loge S vertically versus
dose horizontally to give a straight line of slope minus
D/Do. This would be called a ‘‘single-hit’’ curve. The
dose Do would reduce survival by one loge which is to
37% survival. You can see that Do = 1/a in the LQ
formula, that is 1/(the dose to reduce cell survival by
one loge).
Plotting graphically the proportion of surviving
mammalian cells against single dose of radiation
gives a curve, and not a straight line. This curve starts
from zero dose with a definite non-zero slope, grad-
ually bending downward into a ‘‘shoulder’’ at less
than 1 Gy of dose, and continuing to bend downward
until at least 10 or 20 Gy. At higher doses, the cell
survival curve appears to become nearly straight
again but of course steeper than at the origin (Gilbert
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
Fig. 1 The simple cell survival curve for linear quadratic cell
kill versus radiation dose, for a single dose of radiation
delivered within a few minutes. The alpha component increases
as shown linearly with dose. The beta component is added to
this in a curving pattern, increasing with the square of the dose.
This example is numerically correct for the a/b ratio of 3 Gy
et al. 1980). This is the well-known ‘‘cell survival
curve’’ where the logarithm of the surviving propor-
tion of cells is plotted downward, against radiation
dose on the horizontal axis (Fig. 1). It is the same
curve as the negative logarithm of the fraction of cells
‘‘killed’’—actually ‘‘sterilized’’ so that they die later,
after the next cell division or a few divisions.
This is the plot of loge proportion of cells surviving:
S ¼ ad  bd2 :
Therefore also : loge proportion of cells sterilized
ðkilledÞ ¼ þad þ bd2 :
This logarithm of the number of cells sterilized can
be divided into one part proportional to dose ad; and
another part proportional to dose-squared bd2 (that is
‘‘quadratically’’, where two sublesions combine, each
produced in number proportional to dose). The loga-
rithm (proportion) of lethal events caused by a dose d
is then:
E ¼ ad þ bd 2
The linear component is found to be not repairable
beyond a few milliseconds after the irradiation, but
this does not mean that it cannot be altered, by oxygen
13
Fig. 2 The survival curve for four equal radiation doses given
sequentially, with sufficient time—at least 6 h, or preferably
longer—between them to allow complete repair of the beta
component of radiation damage. Since the shape of each is then
a repetition of the previous dose, the track of the result after
each dose fraction is a straight line when plotted as log cell kill
against dose as shown
if present at the time of irradiation as one major
example. However, the dose-squared damage gradu-
ally fades over a few hours. It is repaired by several
processes within the biological cells, mostly within
the DNA, so that cell survival recovers toward the
straight initial a slope. Cells and tissues are said to
‘‘recover’’ and biochemical lesions in DNA are said to
be ‘‘repaired’’.
Let us call this cell-number damage E, the loga-
rithm of the number of cells sterilized by a dose d in
grays (Gy). Then, we write the first equation as:
E ¼ ad þ bd 2
where a and b are the coefficients of the linear com-
ponent and the dose-squared component, respectively.
This is the first step in explaining the LQ formulation,
commonly taught as the ‘‘Seven Steps to Heaven’’. If
this starting formula can be remembered there will be
no trouble at all with the next three steps. ‘‘LQ
Heaven’’ is reached when the LQ steps are understood
well enough and not forgetten soon.
The next step is the simple one of adding several
fractions of daily doses, each of d grays, to obtain
the total dose if n fractions (daily doses) are given.
Figure 2 illustrates the sequence of equal fractions,
giving a total curve that is made up of a sequence of
small shoulders, into an exactly linear locus, of slope
depending on the value of Eq. 1 at each dose d, using
the same numbering as in the previous two sections:
14
E ¼ nðad þ bd 2 Þ ð1Þ
The dose per fraction d can be taken outside the
parentheses, nd being the total dose:
E ¼ ndða þ bdÞ ð2Þ
We usually know the ratio of the two coefficients,
a/b, for given cells and tissues much better than we
know their individual values, so the next step is to
express E in terms of this ratio. It is usually done by
dividing both sides of Eq. 3 by a (Barendsen 1982). If
instead we divide by b, then the resulting BED would
be in terms of dose squared, which would be awkward.
E=a ¼ ndð1 þ db=aÞ ð3Þ
which is also identical to:
 
E d
¼ nd 1 þ ð4Þ
a a=b
Because a is defined as a number (log number of
cells sterilized) ‘‘per gray’’, the term E/a has the
dimensions of dose. The BED we are seeking to
calculate is given by Eq. 4. We are halfway up the
‘‘Steps to Heaven’’ and this equation enables us to do
many useful things in predicting biological damage
(Fowler 1989; also ‘‘Robotic Image Guided Radiation
Therapy’’ and ‘‘Cranial Stereotactic Radiosurgery’’ in
Steel 2002).
3.2 Biologically Effective Dose
The basic concept of BED was defined by Barendsen
(1982), who first called it extrapolated tolerance dose
(ETD), meaning that dose which if given as an infinite
number of infinitely small fractions (along the initial
slope of the cell survival curve), or at a very low dose
rate (so that all the quadratic damages have been
repaired), would cause the same log cell kill as the
schedule under consideration, considering the maxi-
mum dose that a normal tissue would tolerate. Since it
was obvious that this conceptual extrapolation to very
small dose per fraction could be applied to any level
of damage, and not just to the maximum tolerated
level or only to normal tissues, it was soon renamed
extrapolated response dose (ERD) and later to the
more general BED (Fowler 1989). It is illustrated
graphically in Fig. 3. Because BED is defined in
J. F. Fowler
Fig. 3 Graphical illustration of the concept of biologically
effective dose. The dashed line represents the log cell kill of 20
(or more) well-spaced equal fractions of radiation. BED is
the dose that would cause the same log cell kill E as the
schedule with n 9 d fractions, if it could be delivered in an
infinite number of infinitely small fractions, or at very low dose
rate. All the beta components would then have been repaired,
and the straight line representing the log cell kill versus total
dose would follow just the initial slope alpha as shown, its slope
determined by the value of alpha only. The ratio of BED to the
real physical dose is the RE, relative effectiveness = BED/total
physical dose
relation to the initial slope, i.e., the linear component
of damage, it is E/a. Because a has the dimensions of
1/dose, E/a has the dimensions of dose, as we require.
We refer here to an averaged value of a during the
weeks of radiotherapy. Different values of a could be
applied to different segments of a schedule, but there
is no evidence yet to justify this.
Since the definition of BED is the ratio E/a, the
individual values of E and a are irrelevant for esti-
mating the relative total doses. The ratio E/a is
mathematically a link function, signifying biological
equivalence between two schedules having equal
effect. The individual values of E or a have no nec-
essary biological significance in LQ formulation.
Values of a are particularly vulnerable to variation of
tumor size, stage of tumor, and accuracy of dose,
provided that the ratio between E and a (and Hb) does
not vary—between one theoretical prospective pop-
ulation in a clinical trial and another—there are no
effects on ratios of doses between schedules, which
are what we want to compare. This is the important
reason that BED, like EUD (Niemierko 1997), is
robust. They are relatively stable if parameters are
varied by modest amounts.
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
These biological ratios between log cell kill and
cellular radiosensitivity have in fact been determined
in certain biological experiments concerning skin and
intestinal clones in mice (Withers 1967, 1971), hence
these tissues can be placed on a more exact basis
concerning the number of cells per millimeter of
mucosal surface. However, the use of a number to
designate log cell kill in tumors depends on a specific
assumption of how many viable malignant cells were
present per mm3 of tumor volume, which is usually
unknown. The number has wildly varied between ten
thousand million (1010) and one-tenth per tumor
among various authors for various tumors (the latter
being curable with 90% probability). Because of the
real variability between tumors and patients, a value
for a [derived for example from a gamma-50 slope of
dose versus tumor control probability (TCP)] cannot
be regarded as a reliable guide to cell numbers, as
some writers have assumed and argued about. Heter-
ogeneity decreases the extracted value of a from pop-
ulations. What is interesting is that, as more detailed
and precise descriptions for stage of tumors are
developed, as they are by various international agree-
ments, the recorded gamma-50 slopes from clinical
data become steeper (or a values higher), illustrating
less heterogeneity (Hanks et al. 2000; Regnan et al.
2004). All the log10 cell kill values quoted in the tables
in this chapter assume a = 0.35 loge per Gy.
3.3 Relative Effectiveness
The BED thus comprises the total dose ‘‘nd’’ multi-
plied by a parenthesis term (1 ? d/a/b). This term is
called RE, and is one of the most useful concepts of
the LQ formulation. RE determines the strength of
any schedule when multiplied by the total physical
dose. BED is simply total dose multiplied by RE:
BED ¼ ndð1 þ d=a=bÞ ¼ nd  RE ð4aÞ
or
BED ¼ total dose  RE
When dose rate varies, the term containing b
includes, in additon to d, the dose rate and the
recovery rate of tissues as a ratio, as discussed in
detail in (Barendsen 1982; Thames and Hendry 1987;
Fowler 1989).
15
The concern of RE is dose-per-fraction size, in
relation to the a/b ratio for different tissues. RE is
larger for larger dose per fraction and for smaller
ratios of a/b. Dose per fraction is therefore one of
the three major factors in LQ formulation, the
co-equal second being the a/b ratio. The third is
overall time, which we deal with in the remaining
three ‘‘steps to LQ heaven’’ below. The major
biological importance of RE depends on the fact that
a/b is large for rapidly proliferating tissues, such as
most tumors, and small for slowly proliferating tis-
sues such as late complications. This is attributed to
the fact that slowly proliferating tissues, with long
cell cycle times, have more time to carry out repair
of radiation damage than short cell cycles (Curtis
1986; Fowler 2001). These differences enable
conventional radiotherapy to succeed, often using a
large number of small fractions such as 30 or
35F 9 2 Gy. We discuss the differences in a/b in the
following section.
RE is high when d is high and a/b is low, for
example as in hypofractionation (fewer and larger
fraction sizes than normal), which could therefore
cause excessive damage in slowly responding,
late-reacting tissues, i.e., in late complications. By
contrast, RE is naturally low for hyperfractionation
(more and smaller fractions) and for low dose-rates
(lower than 100 cGy/h; ICRU can be criticized for
defining low dose rates as ‘‘up to 200 cGy/h’’,
because their BEDs differ significantly from those for
50 or 100 cGy/h). It is the difference in doses per
fraction above or below 2 Gy that has biased radio-
therapy in the direction of many small fractions. The
total doses at 2 Gy per fraction should be above
60 Gy for the cure of all except a few radiosensitive
types of tumor; and preferably above 70 to 90 Gy
NTD2 Gy for many tumors of stage II or III sizes.
Equations 4 and 4a enable a great many aspects of
radiotherapy to be compared simply and quickly.
A question often asked is ‘‘what new total dose
should be used if dose per fraction is changed from d1
to d2?’’ This is easily answered by taking the inverse
ratio of the two values of RE. If the two total doses
are D1 and D2, of which D1 is known and D2 is the
value sought, both the BEDs have to be equal, by
definition:
BED = total dose 9 RE = D1 9 RE1 = D2 9
RE2; hence cross-multiplying gives a reversal as
follows:
16
D2 RE1 ð1 þ d1 =a=bÞ
So that ¼ ¼ ð4bÞ
D1 RE2 ð1 þ d2 =a=bÞ
meaning that the Original Dose D1 should be multi-
plied by the ratio of RE1/RE2 to obtain the New
Total Dose D2. Or better still, remember that if d
goes up, the new total dose must be lower in inverse
proportion to their RE’s.
A simple example is to compute the schedule that
gives the same prostate tumor cell kill as D1 = 78 Gy
in 2 Gy fractions, if we change the dose per fraction
from 2 to 3 Gy assuming a tumor a/b ratio of 1.5 Gy.
The result is D2 = 78 9 (1 ? 1.33)/(1 ? 2.0) =
60.66 Gy, which could be delivered in 20 fractions of
3.033 Gy. This also shows that schedules using 20F
of just 3.0 Gy deliver the equivalent of only 77.2 Gy,
that is, an ‘‘underdose of 1% compared to 78 Gy in
2 Gy fractions’’. Not clinically significantly different,
but more accurate and worth taking care about.
3.4 Overall Treatment Time
The major effects of radiation are diminished by any
proliferation occurring in the cell populations during
the weeks of radiotherapy, obviously by replacement
of some of the cells that were sterilized by irradiation.
In slowly proliferating tissues, naturally those in
whom the reactions appear late, this replacement by
repopulation is negligible (as in nerve tissue) (Stewart
1986). In rapidly proliferating tissues, however,
including most tumors, it can counteract up to one-
third of the cell-killing effect of the radiotherapy
although there is a delay of some days (called Tk)
before repopulation begins in tumors. Tk is more rapid
in normal mucosa, starting at 7 days in oral mucosa,
and this difference in the Tk values is very important
as we shall see below.
The longer delay in tumor repopulation is because
the tumor needs time to shrink due to the treatment, so
as to bring more of the surviving cells into range of
the generally poor blood supplies in the tumor. In
solid tumors above a few millimeters in diameter, the
daily production of cells is much faster than the vol-
ume growth rate would suggest. In most carcinomas,
there is a cell loss factor of 70–95% due to nutritional
failure and, to a lesser extent, due to apoptosis. This
large loss rate causes the volume doubling times of
tumors to be as slow as months, although the number
J. F. Fowler
of cells born would cause the population to double in
only a few days if no such cell loss occurred.
Therefore, the clinically observed doubling time of a
tumor is no guide to the cell repopulation rate inside
the tumor. This is one of the curious facts in cancer
that has only been apparent from kinetic population
studies in the 1970s, using originally radioisotope
labels and recently immunological fluorescent labels
with flow cytometry (Begg and Steel 2002).
Most human carcinomas have volume doubling
times varying from 1 month to 3 months, but their cell
population birth rates yield cell-number doubling
times of 2–10 days, with 3–5 days commonly found.
The cell doubling times are called Tpot (potential
doubling times, meaning cell birth rate ‘‘in the absence
of nutritional or apoptotic cell loss’’). Prostate tumors
are exceptionally slowly proliferating with median cell
doubling times of 42 days (range 15 days to[70 days).
Thus, if a number S of cells survives a certain
phase of treatment, this number will increase at the
rate of Seþ1=Tp per day and Seþt=Tp in t days. This
means that the number of cells increases by a constant
proportion per day. This rate is conventionally
described as the time in days required to double the
number of cells, Tp, hence the population increases by
loge2/Tp per day. Therefore, the loge number of cells
killed by our treatment decreases by loge2/Tp per day
due to repopulation, meaning its change is –0.693/Tp
per day and –0.693 t/Tp in t days. This has to be
subtracted from Eq. 4a above.
It is important that we do not forget the delay in
the start of repopulation mentioned above, after a
‘‘kick-off’’ or ‘‘onset’’ time designated Tk days.
Allowing for this, the time available for repopulation
is t = T – Tk days, where T is the overall treatment
time in days. It is important to note that the treatment
begins at day 0, and not day 1. The loge amount of
repopulation is then 0.693(T – Tk)/ Tp, and it has to be
subtracted from the loge cell kill E that we calculated
above in Eq. 4a. Thus, the total amount of log cell
kill, allowing for repopulation, is:
E ¼ ndða þ bdÞ  ðT  Tk Þ
 rate of repopulation per day ð5Þ
E ¼ ndða þ bdÞ  loge 2ðT  Tk Þ=Tp ð6Þ
where T = overall treatment time (in days, the first
day being 0 not 1), Tp = cell population doubling
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
time during treatment, Tk = starting time of repopu-
lation, and Tp = average cell-number birth rate
during the irradiation. Note that Tp may be different
from Tpot, which can only be measured before any
treatment is given; Tp is possibly somewhat faster.
This simple modeling, assuming zero repopulation up
to Tk days and a constant doubling time Tp after Tk, is
certainly an approximation to a smooth curve of
accelerating Tp, but several more complex models to
add different times at which faster Tp is assumed have
not succeeded in giving better correlations with the
clinical outcome (van Dyk et al. 1989; Denham and
Kron 2001). Fenwick has recently proposed a
Delayed Feedback (from the level of cell depletion
reached) which deals with this concept. Recent clin-
ical data agrees with the model of Strigari et al.
(2009) and this chapter, but Fenwick’s prediction
was too high.
To transform E into the total BED requires the
same division throughout by a that we carried out in
step three (Eq. 3), and this is the final equation, the
seventh step:
 
E d 0:693
BED ¼ ¼ nd 1 þ  ðT  Tk Þ ð7Þ
a a=b aTp
Putting it into words:
E A particular application of Eq. 7 above has been a
BED ¼
a
¼ Total dose  Relative effectiveness
ðloge 2Þ  ðDays available for repopÞ
 point of view. A comprehensive review of published
alpha  Cell doubling time
ð7aÞ
It will be noted that the LQ formula now involves
three more parameters, so we might think that LQ has
‘‘lost its innocence’’ when repopulation is included.
A value must be chosen for radiosensitivity a and
the start of rapid repopulation in tumors Tk, and for
the doubling time Tp of viable cells thereafter. There
are, however, some clinical data that enable ratios of
these parameters to be estimated. (There is a practical
snag wherein it is easy to forget the a in the last term!
But, if you remember that this repopulation term is
usually about 0.5–0.8 Gy10 per day for rapidly pro-
liferating tissues including most tumors, you can
easily make a rough check on the subtraction from the
simpler BED of step four (Eq. 4)). For Eqs. 8 and 9 to
calculate Actue Tolerance, see Sect. 5.9.
17
In radiotherapy practice, late-responding normal
tissues generally have a normal turnover time of many
months, and these are reflected first of all in their
kick-off time of acceleration, Tk, after starting radio-
therapy (Stewart and van der Kogel 2002), and also
obviously in the value of Tp after compensatory
repopulation has started (Hendry et al. 1996; Fowler
and Chappell 2000), which may be a little shorter than
Tpot measured, as it can only be, before any treatment.
It is this repopulation aspect of radiobiological mod-
eling that has brought most radiotherapy departments
to pro-actively avoid gaps in the treatment, and in
many to choose shorter schedules (Hendry et al.
1996). To a radiobiology modeler, it is surprising that
this took so long to realize (Fowler 1978; Withers
et al. 1988; Fowler and Lindstrom 1982; Hendry et al.
1996). The huge difference between gross tumor
volume doubling time and the cell birth doubling
time, Tpot, is due to the high cell loss factor (70–90%)
in carcinomas. The kick-off time for tumor repopu-
lation, Tk, could be between 14 days and 32 days in
human head and neck tumors (Brenner 1993; Roberts
and Hendry 1999).
3.5 Acute Mucosal Tolerance
long-term development of a collection of data about
head and neck radiotherapy schedules that are judged
to be clinically just tolerable from the acute reaction
head and neck schedules with consequential recom-
mendations for a ‘‘tolerance zone of early BED’’ was
published by the present author and colleagues
(Fowler et al. 2003c). The best matching with these
not particularly small H & N treatment fields, for
‘‘nearly intolerable’’ acute mucosal reactions in many
types of fractionation regime, was found to be at
BED = 59–63 Gy10 if the following specific param-
eters in Eq. 7 were used: a/b = 10 Gy; a = 0.35 Gy
per loge; Tk (starting time of repopulation) = 7 days
for oral mucosa (Dörr et al. 2002); and Tp = 2.5 days
(average mucosal cell doubling time during irradiation).
There is provisional information that the tolerated range
of BED may be somewhat higher in rectal mucosa, for
example 64–69 Gy10 together with a mucosal area
limitation down to a few centimeters squared for doses of
78–80 Gy NTD (Huang et al. 2002; Vargas et al. 2005).
18
Table 1 Conversion of BED Type of tissue
into NTD or EQD3/2
Late complications
Early and tumor effects
Exceptions would be:
Late CNS with a/b = 2 Gy
Prostate tumors a/b = 1.5 Gy
A practical conclusion from our acute mucosal review
(Fowler et al. 2003c) was that if a new schedule
causes too strong acute reactions, these can be avoi-
ded easily by extending the overall time by a few
days. Acute BED for mucosa is normally reduced at a
rate of about 0.8 Gy10 per day (with 2 Gy fractions),
after the time Tk = 7 days from starting daily radio-
therapy (Dörr et al. 2002).
3.6 To Convert from BED into NTD
or EQD2 Gy
We have talked in terms of BED in Gy3 and Gy10
mainly, and familiarity with these terms and num-
bers is recommended. However, those not using
them regularly are often more comfortable with
their conversion into the biological equivalent of
total dose in 2 Gy fractions. This conversion of
BEDs into EQD2 Gy or NTD (normalized total dose/
normalized to 2 Gy fractions; Maciejewski et al.
1986; Joiner et al. 2002) is a further mathematical
step, which experienced modelers may not wish to
do, but is very simple, as described below. Impor-
tantly, it gives different EQD and NTD values
for late complications from the EQD and NTD for
tumors in the same schedule, so that subscripts for
BEDs in Gy3 or Gy10, etc. must be kept rigorously
through every step of every calculation. Further, the
translation from ‘‘tumor BED’’ or ‘‘late complica-
tions BED’’ into ‘‘tumor NTD’’ or ‘‘late complica-
tions NTD’’ must be made when the results are
summarized. Such designations of Gy3 or Gy10,
and ‘‘Late’’ or ‘‘Tumor’’ or ‘‘Acute’’ are necessary
each time, or readers (and you the writer!) may get
confused.
We can see, from the obvious equality of BED of
any schedule 1, called BED1, required to be equal in
radiobiological effect to BED2, shows that the total
dose D1 9 ‘‘the RE for its dose per fraction’’ must
J. F. Fowler
Same a/b when converting Divide the BED by the
BED to EQD (Gy) RE for 2 Gy fractions::
3 (1 ? 2/3) = 1.667
10 (1 ? 2/10) = 1.2
2 (1 ? 2/2) = 2.0
1.5 (1 ? 2/1.5) = 2.333
be equal to NTD2 Gy 9 RE for 2 Gy fractions, with
the appropriate a/b ratio so that we obtain the
formula:
NTD2 Gy  RE2 ¼ BED1; therefore;
dividing both sides by RE2; we get :
NTD2 Gy ¼ BED1=RE2 usingthe appropriate
a=b ratio
¼ BED1=ðRE for 2 Gy fractionsÞ: QED
Therefore, an NTD2 Gy or EQD2 Gy can be derived
from any BED by simply dividing that BED by the
RE for 2 Gy fraction size and the same a/b ratio as
used to calculate the BED (Table 1).
3.7 One Example
First let us look at the simple example of a 60 Gy dose
given with different fraction sizes, starting with 2 Gy 9
30F in 6 weeks. The ‘‘late complications BED’’ is
usually calculated first, assuming a/b = 3 Gy, and
from Eq. 4 it is:
BED ¼ ndð1 þ d=ða=bÞÞ
60ð1 þ 2=3Þ ¼ 60  1:667 ¼ 100 Gy3
Recall from the end of Sect. 2.1 that when two
subscripts are used, the first gives the a/b ratio of the
tissue concerned and the second gives the dose per
fraction of the schedule.
The ‘‘tumor response BED’’ is calculated assuming
a/b = 10 Gy and is therefore:
60ð1 þ 2=10Þ ¼ 60  1:2 ¼ 72 Gy10
Both the late BED of 100 Gy3 and the tumor BED
of 72 Gy10 correspond to an NTD, with subscripts
NTD10/2 or NTD3/2 respectively, for 2 Gy fractions of
60 Gy. We divide the Gy3/2 by 1.67 and the Gy10/2
by 1.2 respectively, obtaining the EQD of 60 Gy
for both.
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
For a stronger schedule of 70 Gy = 2 Gy 9 35 F
the corresponding ‘‘late’’ (complications) BED and
the early (tumor) BED would be 70 9 1.667 = 117
Gy3/2 and 70 9 1.2 = 84 Gy10/2, respectively. Both
the late BED of 117 Gy3/2 and the tumor BED of
84 Gy10/2 correspond to the NTD at 2 Gy fractions
which is an EQDa/b/2 of 70 Gy. The four values of
BED form useful reference points when considering
other schedules. In particular, the late complications
BED of 117 Gy3 should not be exceeded except in
special circumstances, such as limited volumes and
research for IMRT-related ‘‘new’’ schedules. The
NTD can be obtained by dividing the BED by 1.667
for ‘‘late complications’’ or by 1.2 for the ‘‘early or
tumor effects’’, respectively, as described in Table 1
in Sect. 3.6.
3.8 Gamma Slopes, the Standard
of Precision of Estimates of BED
or NTD
How much margin of tolerance can we allow before
being concerned about an overdose to normal tissues,
above the arbitrary but currently practical limit of
117 Gy3/2 (= 70 Gy EQD3/2)? And how much should
we be concerned about tumor BEDs below the 70 Gy
NTD or EQD3/2Gy, which is below a BED of 84 Gy10/
2? These questions require whole papers to answer
them properly, involving slopes of dose–response
curves. Such slopes are often called gamma-50 or
gamma-37, a term derived from photographic film
density, meaning a change in absolute percentage
response for a 1% change in the total dose or NTD
(and BED if fraction size is not changed). However, a
common sense answer is that about a 7% change in
BED or total dose at 2 Gy fraction size would probably
be large enough to be clinically noticeable, and a 3%
change would probably not, until many hundreds of
patients had been treated in the same way. The degree
of anxiety about an over- or under-dose would also
depend on the actual circumstance of what risk is most
important for the individual patient.
Gamma-50 or gamma-37 is used to define the
steepest part of a dose–response curve, which is at
50% probability for logistic modeling, but at 37% for
Poisson probability modeling. The difference is rarely
important in comparison with the precision of clinical
results. For many types of tumors gamma-50 or -37
19
slopes found are about 1.5–2 times the percentage
change in the total dose (and BED if dose per fraction is
unchanged). This is in the middle range of the sigmoid
response curve between about 20 and 70% for local
control (LC). Thus tumor response often corresponds
to a gamma slope of 1.5 or 2. For doses above or below
that middle range, the slopes will be smaller. For cer-
tain types of tumors that have been well classified in
detail so that narrow risk categories are available, the
change of response with BED may be greater than
twice the percentage (Hanks et al. 2000; Regnan et al.
2004). In general a 10% change in tumor or NTD10/2 or
EQD10/2 might mean a change in LC of approximately
20%. Wadsley and Bentzen (2004) showed that there
was a highly statistical relationship (P = 0.00017)
between loco-regional control (LRC) and later overall
survival in head and neck cancer, 5-year overall sur-
vival averaging two-thirds of the 2-year LRC.
For normal tissues, the dose–response curves are
often steeper than for tumors, because normal tissues
are less heterogeneous in physiological properties
than tumors are. Gamma-50 slopes of three or four in
the steepest range of late complications are found,
although slopes are shallower at the lower incidences
of a few percent that are common for serious com-
plications; the ‘‘toe’’ of the curve (and at the top, if we
see any result close to 90 or 100%).
4 How to Evaluate a New
Schedule—Brief Summary
We now summarize the four main weapons in our
armamentarium for assessing any proposed schedule,
before irradiating any patient. For example, we may
wish to add an introductory phase-I dose-escalation
study of effects in normal tissues before deciding on a
particular dose level in a long clinical trial. A calcu-
lation of BEDs or NTDs would enable any arm to be
evaluated theoretically in relation to known sched-
ules. Such theoretical comparisons do not replace
phase-I clinical trials, but they can be put into critical
perspective and save time-wasting steps with dose
intervals that may be too wide or too narrow.
1. Calculate late complications BED, a/b = 3 Gy,
with no time factor (Eq. 4), keeping below 117 Gy3.
2. Estimate tumor BED including repopulation,
as Gy10 (Eq. 7). For head and neck or lung tumors
assume:
20 J. F. Fowler

Table 2 Modeling landmark head and neck schedules

Schedule (reference) Dose/fraction 9 Total Overall Tumor log10 Late effect Acute mucosal
number of fractions dose time cell kill BED (Gy3) BED (Gy10)
(Gy) (days)
1. Standard 7 weeks 2 Gy 9 35F 70 46 10.26 116.7 53.1
2. EORTC HFX 7 weeks 1.15 9 70F 81.5 46 11.13 113 58.9
(Horiot et al. 1992)
3. RTOG HFX 7 weeks 1.2 Gy 9 68F 81.6 45 11.48 114 61.3
(Fu et al. 2000)
4. Concomitant boost 1.8 Gy 9 72 39 11.03 113 59.1
6 weeks (Knee et al. 1985) 30F ? 1.5 Gy 9
12F
5. Wang split course 6 weeks 1.6 Gy 9 42F 67.2 39 10.04 103 52.6
(Wang 1988)
6. 4–5 weeks (Leborgne 1.6 Gy 9 40F 64–70.4 28–33 11.15–11.21 103–108 61.3–61.1
et al. 2000) to 44 F
7. GORTEC 1 3 weeks 2 Gy 9 32F 64 21 11.47 107 64.9 ??
(Bourhis et al. 2000)
8. CAIR 1 5 weeks 2 Gy 9 35F 70 34 11.46 117 ? ? 62.6 ?
(Maciejewski et al. 1996)
9. HARDE 1 5 weeks 1.4 9 1.2 Gy 9 76 33 12.01 112 66.2 ???
20F ? 1.6 9 10F ? 20F ? 2 Gy 9 4F
(McGinn et al. 1993)
Parameters for tumor log10 cell kill: a/b = 10 Gy; a = 0.35 ln/Gy; Tk = 21 days; Tp = 3 days; of which a is inversely
proportional both to log cell kill and to BED (= E/a) in this formulation; so its actual value is not a sensitive factor. For
acute mucosal BED: a/b = 10 Gy; a = 0.35 ln/Gy; Tk = 7 days; Tp = 2.5 days
? Probably too high to be clinically tolerable

Tk = 21d, Tp = 3d, a = 0.35 loge/Gy, and a/b =
10 Gy, until further data allow the parameters
to be re-estimated; or as log10 cell kill = E = a 9
BED/2.303; and compare with known schedules.
3. Calculate acute mucosal BED Gy10; assume Tk =
7d, Tp = 2.5d, a/b = 10 Gy, a = 0.35 (Eq. 7);
keeping below 59–63 Gy10, for oral and pharyn-
geal mucosa (Fowler et al. 2003c). Possibly higher
than 63 Gy10 for late rectal mucosa, but with strict
volume limits.
4. Check Incomplete Recovery between fractions if 2
fractions a day are used, including overnight gaps, or
in hypofractionation if 5F per week are used.
5 Some of the Best-Known Schedules
for Head and Neck Tumor
Radiotherapy
Baumann et al. (2002) have written an excellent
general review of ‘‘Altered Fractionation’’, which
includes both hyperfractionation (smaller doses per
fraction and higher total doses) and accelerated frac-
tionation (shorter overall times and lower total doses).
Bourhis et al. (2004) reviewed the results of 15
randomized trials between 1970 and 1998. They
concluded that an absolute benefit on LRC of 7%, from
46 to 53%, at 5 years was obtained, depending on the
type of schedule. Many of those trials and some more
recent ones are included in the present analysis.
Table 2 lists some of the strongest published
radiotherapy schedules that have been used to treat
patients with oral and pharyngeal cancer. The first
five were successful schedules, with one possible
exception, but the last three in the table gave too
many complications, so that they were later revised to
become clinically acceptable. We can learn from
these three pairs of later-modified schedules.
5.1 Standard Fractionation
The first line in Table 2 shows a standard treatment of
2 Gy 9 35F = 70 Gy in 7 weeks (SF). This schedule
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
also gives the standard top level of ‘‘late BED’’ at
116.7 Gy3. The acute mucosal BED of 53.1 Gy10 for this
schedule is comfortably below our ‘‘tolerance zone’’ of
59–63 Gy10 for oral and pharyngeal irradiations (Fowler
et al. 2003c) and hence acute mucosal reactions appear
tolerable for the tissue volumes usual in head and neck
radiotherapy, including some coning down, in accord
with known clinical experience for 7-week schedules.
5.2 Hyperfractionation
The second row of Table 2 shows the EORTC
hyperfractionation clinical trial of 1.15 Gy twice a
day for 70 F = 81.5 Gy in 7 weeks, which was the
first randomized clinical trial to show an advantage
for a non-standard fractionation schedule, with 325
patients in two arms (Horiot et al. 1992). The control
arm was 70 Gy in 7 weeks (Row 1). The increase of
5y LC at 3 years was from 40 to 59% with good
significance at P = 0.02. The difference in log cell
kill with our parameters was 0.8 log10,that is 8%.
Thus if the gamma-50 slope was approximately 2.0
for these tumors, a difference in LC of about 16%
might have been expected. The observed difference of
19% was not statistically significantly different from
this expected gain. The late complications were not
significantly different in the two arms. Although they
were slightly higher in the hyperfractionated arm,
which was not expected, the low incidence of late
effects and the number of patients (325) did not
allow the difference to be significant. The interval
Dt between two fractions per day is emphasized as
being critical in any schedule. The acute mucosal
reactions in Gy10 were strong at 58.9 Gy10, just
below the lower end of our arbitrary ‘‘tolerance zone’’
(Fowler et al. 2003c), but tolerable. There is less
repairable damage to worry about if a/b is 10 Gy than
if it is 3 Gy, in the RE bracket. It is also predictably
less for the smaller doses per fraction.
5.3 Radiation Therapy Oncology Group
Four-Arm Fractionation Trial
(RTOG 90-03)
The Radiation Therapy Oncology Group (RTOG) was
then encouraged to set up its four-arm randomized
clinical trial 90-03, which ran from 1990 to 2000 and
21
accumulated close to 280 patients in each arm
(Fu et al. 2000). Table 2 shows that it consisted of:
Row 1: the standard 2 Gy 35F in 7 weeks, five
treatments a week (designated SF).
Row 3: a hyperfractionation arm [of 68F 1.2 Gy twice
a day (b.i.d.) = 81.6 Gy in 7 weeks (HFX)].
Row 4: the Concomitant Boost at 72 Gy in 6 weeks,
with 1.8 Gy given daily for 6 weeks plus 1.5 Gy
at two fractions a day in the final 12 treatment
days, designated AF-C.
Row 5: the CC Wang split-course accelerated sche-
dule of 1.6 Gy (2 fractions a day) 42F = 67.2 Gy
in 6 weeks, designated AF-S. This had a 2-week
planned gap in it.
All these schedules are summarized in the first
five lines of Table 2, including their ‘‘late BED’’ in
Gy3, tumor cell kill in log10, and ‘‘acute mucosal
BED’’ in Gy10. Two of these schedules in RTOG
90-03 yielded 54% 2y LC, and two yielded 46%, the
difference being significant (Fu et al. 2000). Both the
54% arms gave more than an estimated 11 log10 cell
kill, using our stated parameters. Both the 46% arms
gave barely over 10 log10 of cell kill, as shown in
Table 2. These results give a guide to the calibration
of our currently used radiobiological model parame-
ters for tumor BED. A difference of one log10 repre-
sents a difference of about 10% in log cell kill, from
10 log10 to 11 log10 and, therefore, up to about 20%
in predicted change of percentage LC for tumors
whose gamma-50 is about two. Non-uniformity
between tumor sizes and stages could flatten this
dose–response gamma-50 from 2 to about 1, as
appears to have happened in this trial. About 30% of
the patients were T4 or N2A, whereas those in the
EORTC trial previously mentioned were T2–T3 and
N0, hence the difference in gamma-50 is probably due
to stage difference.
How do the parameters for complications in normal
tissues hold up for consistency? Only one of the ‘‘late’’
BEDs in the table and none of these first five ‘‘acute
mucosal’’ BEDs were above the limits described
above (117 Gy3 for ‘‘late’’ and 59–63 Gy10 for ‘‘acute
mucosal’’). However, the acute Gy10 for concomitant
boost is in the modeled ‘‘maximum mucosal tolerance
zone’’ at its lower edge, which does not contradict its
acute reactions reported as the highest of the four
arms from the RTOG trial. Concomitant boost is an
ingenious method of shortening a previous 8-week
schedule so that the overall time was reduced to
22
6 weeks (Knee et al. 1985). The coned-down boost
dose was inserted as a second dose of 1.5 Gy on the
last 12 treatment days of the basic 6 weeks of 1.8 Gy
fractions (with Dt = 6 h), so that two fractions a day
were required in only the last 2.5 weeks.
The finally listed arm of RTOG 90-03 was the
C.C. Wang schedule using 1.6 Gy fractions twice a
day, with a planned break of 2 weeks after 32 Gy in
2 weeks (row 5, Wang 1988). This offered the lowest
acute mucosal BED, the lowest ‘‘late effect’’ BED of
103 Gy3 and, not surprisingly, the lowest predicted
tumor log cell kill, equal to that of the standard 70 Gy in
the 7-week schedule. The originator, Dr. C.C. Wang,
often added one or two fractions if reactions in indi-
vidual patients justified doing so, but this was not done
in RTOG 90-03. However, Drs. J. and F. Leborgne in
Montevideo explored this elective variability in 471
head and neck radiotherapy patients. They compared
the acute reactions caused by one or two more fractions
of 1.6 Gy, together with one or two days shorter or
longer gap in the planned split after 32 Gy, so as to
cancel out some of the increase in reaction level due
to the increased dose. In this way, they reduced the
2-week split so that the overall time is shortened to just
over 4 weeks, still with acceptable mucosal reactions
as described in the following section (Leborgne et al.
2000). The 7-year LC was increased from 46 to 59% by
a median reduction of 13 days overall time. Row 6 in
Table 2 summarizes the best of their schedules.
It is interesting that most of the first six schedules
listed in Table 2 predict log10 cell kill values of 11 or
slightly above, except for the two schedules tested in
RTOG 90-03, which came in with significantly lower
LC by about 8%, and which were predicted by this
modeling as being close to 10 log10 instead of
11 logs. The remaining three rows in Table 2 show
tumor cell kill values well above 11 logs10, but they
also show acute mucosal BEDs above the middle of
our recommended maximum acute mucosal tolerance
zone. All three schedules were judged too strong for
continued use, and were modified to reduce their BED.
5.4 Head and Neck Schedules that were
Initially ‘‘Too Hot’’ in Table 2
In Table 3, three of the same schedules as above
are listed: GORTEC (Bourhis et al. 2000), CAIR
(Continuous Accelerated Irradiation; Maciejewski
J. F. Fowler
et al. 1996), and HARDE (High-Dose Accelerated
Dose-Per-Fraction Escalation; McGinn et al. 1993),
rows 1 to 6, together with the moderated versions.
These regimes first set at an apparently too high total
dose or BED, were found to give too many compli-
cations (rows 1, 3, and 5), and were subsequently
reduced in dose per fraction and in extended overall
time by 4 days in the case of CAIR, to obtain clini-
cally acceptable acute reaction levels (rows 2, 4, and
6 in Table 3). The final column shows that this was
achieved. The modeling results found for log cell kill
of the ultimately acceptable schedules are then
remarkably similar, all in the range 10.9–11.1 log10
cell kill, and also similar to the highest acceptable log
cell kill values given in Table 2. So also are the
results for acute mucosal BEDs (58–61 Gy10). Indeed
it was these types of data that enabled our ‘‘tolerance
zone’’ to be investigated and defined originally
(Fowler et al. 2003c).
5.5 Shortening the Wang 2-Fraction-a-
Day Schedule Using BED to Adjust
Individual Doses
One other set of data added to and confirmed our
choice of a ‘‘maximum tolerance zone’’ (Fowler et al.
2003c) for radiotherapy-only acute mucosal tolerance
in oral and pharyngeal irradiation. These data are
summarized in Table 3, row 8, by a single-institute
set of protocols (Leborgne et al. 2000) using the
1.6 Gy b.i.d. regime with, initially, a planned 2-week
gap based on C.C. Wang’s schedule (Wang 1988) as
in RTOG 90-03 (row 7). This protocol was gradually
shortened from 6 weeks to 4 weeks, testing one less
or one more fraction against one more or one less day
of the gap, depending on the theoretical acute BED
Gy10 and the reaction in the patients. In the end, an
‘‘optimum estimated tumor log cell kill’’ can be
estimated, as a maximum value before acute mucosal
BEDs rises above 63 Gy10 and the late BED rises too
close to 117 Gy3.
This appears, from both Tables 2 , 3, to be a log10
cell kill value of 11.1–11.2 log10, which is also
25–26 loge. This was for the nominal value of tumor
BED of 72–74.5 Gy10 (= tumor EQD of 60–62.1 Gy),
and the acute mucosal range of 59–63 Gy10 (Fowler
et al. 2003c) in many types of schedules, assuming
a = 0.35 ln/Gy. It appears difficult to find any
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 23

Table 3 Head and neck schedules moderated (1?2) to avoid too-severe, acute normal tissue reactions
Schedule (reference) Dose/fraction 9 number of Total Overall Tumor log Late effect Acute
fractions dose time 10 cell kill BED mucosal
(Gy) (days) (Gy3) BED (Gy10)
1. GORTEC 1: 2F/day 2 Gy 9 32F 64 21 11.47 107 64.9 ??
(Bourhis et al. 2000)
2. GORTEC 2: 2F/day 1.75 9 36F 63 23 11.05 100 61.4
(Bourhis 2002, personal
communication)
3. CAIR 1: 7F/week 2 Gy 9 35F 70 34 11.46 117 ? ? 62.6 ?
(Maciejewski et al. 1996)
4. CAIR 2: 7F/week 1.8 Gy 9 39F 70.2 38 10.9 112 58.3
(Skladowski et al. 2000)
5. HARDE 1: 2F/day 1.2 Gy 9 20F ? 1.4 9 76 33 12.01 112 66.2 ??
20F ? 1.6 9 10F ? 2 Gy
9 4F
6. HARDE 2: 2F/day 1.2 Gy 9 36F+ 73.2 37 11.0 106 59.1
(Harari, personal 1.5 Gy 9 20F
communication)
7. Wang Split 2F/day 1.6 Gy 9 42F 67.2 39 10.04 103 52.6
(Wang 1988)
8. 2F/day (Leborgne et al. 1.6 Gy 9 40F 64 25 10.88 98.1 60.0
2000) 1.6 Gy 9 40F 64 28 10.59 98.1 57.6
9. 2F/day (Leborgne et al. 1.6 Gy 9 41F 65.6 29 10.76 100.6 59.5
2000) 1.6 Gy 9 42F 67.2 29 11.05 103 60.5
10. 2F/day (Leborgne et al. 1.6 Gy 9 43F 68.8 29 11.33 105.5 62.4
2000)
11. 2F/day (Leborgne et al. 1.6 Gy 9 43F 68.8 30 11.23 105.5 61.6
2000)
12. 2F/day (Leborgne et al. 1.6 Gy 9 44F 70.4 30 11.51 107.9 63.4 ??
2000)
13. 2F/day (Leborgne et al. 1.6 Gy 9 44F 70.4 33 11.21 107.9 61.1
2000)
Parameters for tumor log10 cell kill: a/b = 10 Gy; a = 0.35 ln/Gy; Tk = 21 days; Tp = 3 days: of which a is inversely pro-
portional both to log cell kill and to BED (= E/a) in this formulation; so its actual value is not a sensitive factor. For acute mucosal
BED: a/b = 10 Gy; a = 0.35 ln/Gy; Tk = 7 days; Tp = 2.5 days
? Probably too high to be clinically tolerable

fractionation schedule that provides more tumor cell
kill than 10.9–11.3 log10 without causing too many
late or early complications in head and neck irradia-
tions, more than 117 late Gy3, and more than 63 acute
mucosal Gy10. Until more years of IMRT or stereo-
tactic body radiotherapy or concurrent chemotherapy
have been tested, this appears to be the current opti-
mum tumor cell kill obtainable for head and neck
radiotherapy at the time of writing, as identified by
LQ modeling. The BED value of 72–74.5 Gy10 is,
however, a less parameter-dependent figure than log
cell kill (because log cell kill requires the assumption
of a value for a, which is less certain than the ratio
a/b). This BED of 72–74.5 Gy10 corresponds to a
tumor 60–62 Gy NTD or EQD in 2 Gy fractions, for
head and neck tumors. We shall discuss the Actue
Mucosal limit of 50–52 Gy EQD10/2 in Sect. 5.9.
The four-arm trial RTOG 90-03 was later updated
(Trotti et al. 2005) with no significant changes in the
conclusions described above. Patients treated with HFX
and Concom-Boost had significantly better 5-year local-
regional control (p = 0.037 and 0.042) than those
24
treated with the Wang SFX as described. Those two
altered schedules, but not the Wang SFX) showed a
higher incidence of acute effects; our Acute Mucosal
modeling had predicted that they would be at the top of
the Grey Scale and SFX much lower.
5.6 General Considerations of Head
and Neck Radiotherapy
There are three other head and neck schedules worth
discussing briefly.
The first ingenious head and neck radiotherapy
schedule is that designed at Umeå, Sweden, by
Zackrisson et al. (1994). This regime delivered a
1.1 Gy fraction in the morning and a 2 Gy fraction in
the afternoon. The idea was that if a slow component
of recovery of radiation damage was present, the
smaller dose fraction would have less damage to
repair in the 5-h or 6-h interval, while the larger
fraction would have a longer interval overnight to
repair the greater repairable damage (defined as
greater by the d/a/b term in the RE). This 5-week
schedule’s specifications are:
Total dose = 68 Gy in 5 weeks (at the longer end of
likely Tk values)
Late BED = 106.7 Gy3; late EQD2 Gy = 64 Gy
NTD (well below the nominal late tolerance of
70 Gy NTD)
Tumor BED = 73.4 Gy10; log10 cell kill = 11.20
(among the highest values of any H&N schedule;
Table 3)
Acute mucosal BED = 61.4 Gy10 (in the middle of
the acute mucosal tolerance ‘‘grey zone’’ for
H&N, as for concomitant boost)
These specifications are seen as good, when com-
pared with the moderated schedules from Table 3,
rows 2, 4, and 6. Long-term tumor results remain to
be reported, but this schedule has been in use satis-
factorily for more than a decade now.
The second interesting schedule is the Trans-
Tasmanian Radiation Oncology Group (TROG) ran-
domized phase-III trial 91.01 (Poulsen et al. 1999,
2001). Advanced tumors of stages III and IV were
treated. Two fractions a day of 1.8 Gy were given
5 days a week for 33 fractions in 23 days. The total
dose was 59.4 Gy, giving an estimated 10.45 log10
of tumor cell kill on our scale, which is slightly above
the 70 Gy control tumor estimate of 10.26 log10.
J. F. Fowler
This is a difference of 2% in BED, predicting a 4–5%
increase in LRC in the accelerated arm at the dose
used. With a total of only 170 patients entered in each
of two arms, however, a difference of 15% in LRC
would be necessary for significance at the P = 0.05
level and 90% power (12% difference in LRC for
80% power). It is therefore no surprise that the long-
term tumor results are not significantly different from
those of the control arm; they could not be with those
patient numbers if our modeling was anywhere near
correct, which it appears to be. There was a small but
non-significant percentage in favor of the accelerated
arm, as predicted by our modeling. The 5-year LRC
was increased by 5% (from 47% to 52%), and the
disease-free and disease-specific survivals both
increased by 6% (Poulsen et al. 2001).
Fewer late complications were seen, as expected,
from the lower late BED (95 Gy3), except for the late
mucosal effects, attributed to the ‘‘consequential late
effects’’ of strong acute reactions, previously thought
to occur after failure of acute reactions to heal up.
Acute reactions started sooner, became more intense,
then healed more quickly, as expected, and healing
was complete in both arms. Because in the accelerated
arm the acute reactions did heal up but still showed
the same incidence of late mucosal effects as in the
other arm, the description of ‘‘consequential’’ should
be altered slightly to ‘‘after sufficiently severe early
reactions, whether healed up or not’’.
Denham and Kron (2001) carried out some good
mathematical modeling of tumor control, testing
several descriptions of gradually accelerating prolif-
eration rates after a range of Tk values. They modestly
claimed not to find an ideal model, but they were
convincing in showing that some biomathematical
model incorporating an acceleration of repopulation
during the radiotherapy would give better matching
than the present two-rate model of ‘‘zero up to Tk and
thereafter a constant Tp’’. This approach is developed
further (Fenwick et al. 2008; Strigari et al. 2009).
The modeling of tumor response and acute mucosal
response must be done separately. The acute reactions
were reported as 1,157 naso-gastric feeding days for
the accelerated arm versus 1,154 days for the control
arm, and the Australian dollar costs were closely the
same for both arms with the accelerated arm costing
1.4% less, although delivering 2F/day.The similarity
in tumor response in the two arms is due to the rel-
atively small number of patients, and does not
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
contradict our assumptions of Tk = 21 days and
Tp = 3 days. The late complications BED was a
‘‘safe’’ 95.0 Gy3 (provided Dt = 6 h); hence,
although small numbers might prevent a significant
difference between the two arms, it would be expec-
ted that extended follow-up might show an advantage
for the accelerated arm with its lower total dose and
BED. The shorter overall time is a potential advan-
tage for patients, and for resources since the dollar
cost is no greater. This is a treatment at least as good
as the standard 70 Gy, but in only just over 3 weeks,
which can be an advantage against the 7-week dura-
tion of a once-daily treatment. The present modeling
shows that this hyperfractionation approach is prom-
ising and could be developed further at lower doses
per fraction (e.g. 1.5 or 1.6 Gy).
The third noteworthy schedule is the highly prac-
tical Danish development of six fractions a week, to
shorten the overall time from 7 weeks to 6 weeks.
The total doses in the two randomized arms were
33F 9 2 Gy = 66 Gy in either 6 weeks or 7 weeks.
Two fractions a day are given on only one of the five
working days each week (Dt = 6 h) or on a Saturday.
The late BED is a warm but safe 110 Gy3, equally for
the 6-week or the 7-week arm (both giving 66 Gy),
and no significant difference was seen in the incidence
of late reactions at 5 years. The acute mucosal BED
increased from a very safe 49.9 Gy10 to 53.9 Gy10.
The frequency of confluent mucositis was increased
from 33% in the 7-week arm to 53% in the 6-week
arm, but were all healed within 3 months of the start
of treatment (Overgaard et al. 2003). The calculated
tumor cell kill, allowing for tumor cell repopulation at
a doubling time of Tp = 3 days after Tk = 21 days,
increased from a modest 9.5 log10 to a respectable
10.2 log10 on our scale. Disease-specific survival at 5
years was reported to increase by 7% absolute, and
LRC by 12% absolute (Overgaard et al. 2003). Both
these clinical gains conform well to the modeled
increase of BED by 7.5%, since LRC always shows a
higher percentage gain than overall survival (Wadsley
and Bentzen 2004). To be over-precise, the modeled
BED gain of 7.5% had predicted an approximate15%
gain in LC by this 1-week shortening; an acceptable
agreement with the observed 12%. It is interesting
that our modeling from retrospective head and
neck radiotherapy in 1992 predicted 14% per week,
averaged for a dozen data sets before clinical trials
came available (Fowler and Lindstrom 1992)—a
25
good mark for modeling, especially for retrospective
data! The DAHANCA curve for clinical results of
overall survival had a gamma-50 of unity, and the
slope for LRC had a gamma-50 of 1.7 instead of 2.
It only remains to emphasize that whatever we
can do with one fraction a day, we can do somewhat
better in relation to late BED with two fractions a
day, as long as tumor a/b is as high as about 10 Gy, late
effects a/b ratios of the normal tissues are as low as
2–4 Gy, and intervals of at least 6 h are used. Model-
ing calculations can show how much better any pro-
posed protocol might be. Treatments of 7 days a week
should be avoided because of a risk of unrecovered
normal-tissue damage at 24 h being compounded
if there is no gap longer than 24 h (Fowler 2002;
Maciejewski et al. 1996; Skladowski et al. 2000).
It is interesting that the Australian accelerated hyper-
fractionation schedule described as ‘promising and
could be developed further’ earlier in this chapter has
indeed been developed (1.8 Gy bid 9 47F = 84.6 Gy in
35 days median (delivering an EQD10/2 of 75 Gy at
2 Gy fractions on my usual tumor scale, assuming
repopulation beginning at 21 days) for an entirely dif-
ferent body site—NSCLC (non-small cell lung cancer,
(Wurstbauer et al. 2010)). Oesophogeal and pneumonitis
Grade 2 complications were reasonable at 2/30 (7%).
The 2-year survival was 63% but the 5y survival was
only a standard 23%. Probably because even the 75 Gy
EQD used was not as high as other current recommen-
dations to go up to 100 Gy EQD10/2 for NSCLC (Fowler
et al. 2004a).
5.7 Appropriateness of Linear Quadratic
Modeling in the Age of SBRT, IMRT,
and IGRT?
Since we have just mentioned the even greater chal-
lenge of NSCLC, it is appropriate to deal with a
criticism that arose about Linear Quadratic modeling
that emerged from considerations of modeling 3F 9
20 Gy and above (Park et al. 2008) as SBRT (ste-
reotactic body radiotherapy) to treat NSCLC. The
criticism was that the present modeling suggested that
more that 20 logs10 had to be killed to give a good
success rate (*80% survival at 3–5 years), whereas
Timmerman and colleagues felt that 10 or 12 logs10
would be a more reasonable target, and that LQ was
wrong because of its continued downward bend as
the dose per fraction increased. This criticism has
given rise to needless doubt and much unnecessary
26
RAISING the α/β RATIO effectively straightens the line
LQ IS ALIVE AND WELL
0 aB10Gy
α = 0.3 loge /Gy
Loge Cell Kill
-10
Tangent at 7 Gy
0.72 loge / Gy
-20 for α/β = 10Gy
-30
0 10 20
Dose Gy
Fig. 4 Increasing the a/b ratio straightens the cell survival
curves. The black solid points are for LQ survival curves
having a/b ratios of 10, 15, and 20 Gy, as for more rapidly
dividing tissues (Maciejewski et al. 1989). The red line is a
straight survival curve drawn from the LQ curve of a/
b = 10 Gy at the same slope as the LQ line at 7 Gy on the
X-axis, as proposed by Park et al. (2008). It can be seen that it
intersects the other three LQ curves at various doses along the
axis
inventivess to ‘‘do something different’’, in their
case to stick on a straight segment of cell survival
curve matched at the LQ slope of about 7 Gy.
(Park and Timmerman). There is no definitive evi-
dence in favor of this, and the real answsers are
that such high doses as 3 9 *20 Gy WILL be
needed (a) if there are still hypoxic cells present in
the tumor, or (b) we are missing some of the cells
possibly by migration outside the GTV (gross tumor
volume).
Even if there does turn out to be some substance
in the need for a straighter cell survival curve (and
this case is not settled yet, August 2011), it is very
easy to simulate this effect by altering the a/b ratio
for NSCLC cells from 10 to 15 or 20 Gy. Figure 4
illustrates this, showing that there is no need to
depart from LQ at all. There is good radiobiologcal
evidence that rapidly proliferating tumors tend to
have higher a/b ratios than 10 Gy (Maciejewski
et al. 1989). So, to please Bob Timmerrman
(whose modified cell survival curve has the
virtue of engineering-like simplicity, which I
admire without needing to adopt it), I have some-
times assumed a/b = 20 instead of 10 Gy for
NSCLC (Fig. 4); but the issue remains unsettled
(mid-2011). Combined Chemotherapy is mentioned
in Sects. 5.8, 5.9 and 7.1.
J. F. Fowler
5.8 Do’s and Don’ts for Optimum Overall
Times, with H&N Schedules
as Examples
aB20Gy
aB15Gy
After twenty years of experience in basic BED Eq. 7
(Sect. 3.4 ) and seven years of the Grey Zone of Acute
α/β= 20 Gy Mucosal Tolerance (Sects. 3.4, 4, and 5.4), the author has
α/β= 15 Gy
recently developed a rather full analysis of Optimum
Overall Times and how multifraction radiotherapy
α/β= 10 Gy actually works—how short is too short and how long is
too long, why 2 fractions a day are better than one a day,
30
and by how much—for immediate use in H&N Radio-
therapy (Fowler 2008a), but not limited to those sites.
This analysis forms the next part of the chapter.
Some of this radiobiology is subtle and surprising.
Both the main BED Eq. 7 (Sect. 3.4) and the Acute
Mucosal Tolerance version of it (Sect. 3.5) have together
been used to estimate the additional BED or EQD con-
tributed by concomitant chemoradiotherapy (Kasibhatla
et al. 2008; Fowler 2008c; Lee and Eisbruch 2009;
Hartley et al. 2010). The Grey Zone was proposed ‘‘from
59 Gy10 to 63 Gy10 (= EQD10/2 of 49–52.5 Gy), for
areas of normal oropharyngeal mucosa exceeding a few
square cm (*10 cm2)’’. A similar Tolerance Dose Grey
Zone has also been suggested for rectal mucosa in
prostate treatments (Leborgne and Fowler 2008), pro-
vided that the usual rectal wall or volume constraints are
also respected (Huang et al. 2002; Vargas et al. 2005;
Peeters 2006). Any volume of tissue containing muco-
sal, lip, or endothelium is probably responding with
acute reactions from radiation in a similar way. Thus, we
are able to specify an Acute Mucosal Constraint EQD10/2
of 51 ± 1 Gy (=61 Gy10 BED) as the mid-range of
the Acute Grey Scale, assuming a/b = 10 Gy, alpha =
035 loge per Gy, but Tk = 7 days and Tp = 2.5 days
(Fowler et al. 2003c). These constants enable the
following analyses to be consistent.
5.9 The Difference between the Short
Value for Mucosa of Tk 5 7 Days
and Longer Values of 14–32 Days
for Carcinomas is What Drives
Multi-week Fractionated
Radiotherapy
The important difference between carcinomas (tumors
originating from epithelial tissues) and normal
mucosa is in the kick-off time of repopulation; their
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
1400
Cell number/mm epithelium
1200
1000
800
600
400
200
0 0
0 7 14 21 28
Day of treatment
Fig. 5 Radiation induced changes in mucosal cell numbers.
Cell numbers in patients before RT onset were about 1,000/mm
of epithelium. Data points represent mean values (+1 SEM) of
individual patients. The slowing of the fall of cell counts after
7 days is interpreted as due to repopulation from surviving
cells. [Reproduced from Fig. 2, p. 914, in Dörr et al. (2002)
with permission from Elsevier Inc.]
doubling rates after Tk are not very different. Tumors
however seem to take more time to rearrange them-
selves after the start of radiotherapy and get repopu-
lation going. Normal human oral mucosa begins to
repopulate only 7 days after starting daily irradiation,
and this gives it a great advantage in accumulating
less damage than is caused in tumors as the multiple
fractions proceed. It is not until two to four weeks
later that the similar rate of repopulation becomes
evident in tumors. We shall assume Tk = 7 days or
21 days, respectively, here, for normal mucosa or for
head and neck or lung tumors (Roberts and Hendry
1999; Brenner 1993; Arvidson et al. 2009). Repopu-
lation can be imaged by PET scanning using a DNA
label such as FLT (18F Fluorothymidine). Starmans
et al. (2010) are developing a prognostic tumor pro-
liferation genetic signature from a tumor biopsy to
predict optimal therapy for a specific patient.
Dörr et al. (2002) published the seminal informa-
tion from cell counts in biopsies from patients
receiving standard radiotherapy and it is worth look-
ing at their results. Figure 5 shows that the number of
cells per mm in a strip of mucosa falls to about a
quarter in seven days of irradiation and then falls
more slowly. Figure 6 shows the time course of the
labeled cells, those actually dividing, and the picture
is even sharper. The number of labeled cells falls
rapidly, reaching about one tenth by 7 days, at which
time the fall changes to a sharp rise. That is the
clearest evidence of Tk for repopulation one could
27
80
Labelled cells / min epithelium
60
40
20
35 42 49 0 7 14 21 28 35 42 49
Day of treatment
Fig. 6 Radiation induced changes in proliferative activity of
mucosal cells. Labelled cells indicate cells actively dividing at
the indicated times during RT. [Reproduced from Fig. 3,
p. 915, in Dörr et al. (2002) with permission from Elsevier Inc.]
wish for. It enabled Fowler et al. (2003c) to finalize
their attempts to define the parameters for the toler-
ance of acutely reacting oropharyngeal mucosa and to
propose the Grey Zone for Acute Mucosal Reactions
graded from slight at 49 Gy EQD10/2 to severe at 52.5
EQD10/2. (Equivalent to 59 Gy10 to 63 Gy10 BED).
It is now well known that for non-standard frac-
tionation it is the acute reactions that limit the dif-
ferent total doses that will be tolerated by different
schedules (Kaanders et al. 1999). Therefore, the tol-
erance of the mucosal tissues will be one of the
important dose constraints to be taken into account.
The approximate center of the Fowler et al. (2003c)
proposed Grey Scale was an EQD10/2 of 51 Gy in
2 Gy fractions, corresponding to a BED of 61.20
Gy10. We shall use this as our Acute Mucosal Con-
straint, calculating it with the modification of Eq. 7 to
the form of Eq. 8:
Acute Mucosal BED ¼ ndð1 þ d=10Þ
ðT  7Þ
 0:693 ð8Þ
2:5a
The Late Complications Constraint of BED = 117
Gy3 (EQD = 70 Gy 3/2) has been well known since
1982 (Barendsen 1982), and has been used in non-
standard schedules as described above. It has no time
factor and is simply
Late Complications BED ¼ ndð1 þ d=3Þ
¼ 116:7 Gy3 ð9Þ
28 J. F. Fowler

12
TumLogCellK
Tumor
optimization is used. In Fig. 7 there is no hint of any
Harari2 Cair2 ConcomBoost RTOG EQD peaks or troughs that could suggest any optimum
Arcon

H
overall time, except possibly to avoid the shortest one

or G H
11 60 Gy

I
R
Estimated Tumor Log Cell Kill

io
TO

t E FX
of all, CHARTWEL, which was never actually

O
R
D

TC
ah
10

St
used (Bentzen et al. 2002; Saunders et al. 2010);
Za rgn
Tr ch
G
Le 2

an

d
M

or
og es

Sa 0 x
ck e
bo

ca

35
an

te

ris

6
ng 1.3
C

x
or developed further (to somewhat longer and two
ha

so

ui G
50 Gy

2G

I
ne y
rtw

n
9
te

y
tti
el

fractions of 1.6 Gy daily instead of three) as in

8 Table 3 above.
40 Gy

I
7

6
6.1 The Essential Condition for Any
15 20 25 30 35 40 45 50
Optimum Schedule
Overall Time (days) JFF 11.10.08

Fig. 7 The points represent estimates from the present mod- The essential condition for obtaining any optimum
eling of log10 cell kill (left Y-axis) from the H&N schedules schedule is that all the necessary constraints must be
used by the named centers and authors, described in Tables 2 fully reached simultaneously. This is obvious, but
and 3 and associated text. Schedules shown to be below 10.5
log cell kill would record Loco-regional control 8–12% lower
seldom stated.
than those close to 11.0 log cell kill. The right Y-axis gives the It means that both the Late Complications constraint
calculated radiation damage accumulated in tumors at the end of 70 Gy EQD using the Gy3 BED of 116.7 familiar to
of each schedule in Gy at equivalent 2 Gy per fraction, modelers, and the Acute Mucositis constraint of 51 Gy
allowing for tumor repopulation. [Reproduced from Fowler
(2010) with permission from the British Institute of Radiology]
EQD (or the BED of 61 Gy10, becoming familiar to
modelers), must occur at the same place and time. The
failure of any constraint to be fully met results in a
This is the same as Eq. 4 in Sect. 3.3, taking the corresponding decrement in Tumor BED, at a rate of
a/b ratio 3 for Late Effects under the ‘‘d’’ inside the 0.8 Gy10 per day, which is 0.67 Gy EQD per day in
bracket. terms of ‘‘realistic physical dose’’.
IMRT (intensity modulated RT) and SBRT
(Stereotactic Body RT) methods are actively explor-
6 The Problem of Optimum Overall ing higher constraint doses based on the steepness
Time of falloff of local dose from PTV to nearby normal
tissues; and much is still to be learnt from these
The puzzling problem of Overall Time is illustrated in ongoing developments.
Fig. 7. A dozen published schedules used in centers in
many countries are shown as their estimated Tumor 6.2 Finding Optimum Schedules
Log Cell Kill and EQD values calculated according
to the BED equation 7, assuming a/b = 10 Gy, The process of searching for any Optimum Schedule
alpha = 0.35 Gy-1, Tk = 21 days, and Tp = 3 days. for any type of tumor requires computer testing of
The points plotted lie close to the dotted line repre- modeled schedules covering a wide range of overall
senting 11 logs of cell kill; that is, only one in 1011 times and fraction sizes. The ones that we investigate
cells surviving at the end of treatment. Some are must be chosen to have their Late and Acute Con-
slightly above the line at 11.1 or 11.2 logs, and others straints Doses fully met. This is easy for the Late
are disappointingly low, including both our well- Complications BED corresponding to 70 Gy EQD,
known standard schedule of 35F 9 2 Gy in seven because that constraint is expected not to vary with
weeks, and DAHANCA unless its total dose is overall time, hence it can be rapidly calculated in
increased from the original 66 Gy (Overgaard et al. advance. In this way we set up the dose per fraction
2003). It appears that whatever schedule is used which delivers 116.7 Gy10 (=70 Gy EQD, that is,
internationally, no more than 11.2 logs of cell kill in ordinary real 2 Gy doses) for every number of
from radiotherapy alone seems to be obtained any- fractions (from one fraction of 17.1 Gy to say 100
where—until the presently proposed method of fractions of 0.9 Gy), using only Eq. 4 in Sect. 3.1, the
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 29

a b EQD
Cumulative EQD to Tumor
EQD & EQD to Mucosa
100 Tk=7d Cumulative EQD to Mucosa 100 Tk=7d Tk=21d
(Gy) (Gy)

Total Dose @ 2 Gy per Fraction

.
Total Dose @ 2 Gy per Fraction

ti on tion n
la ula tio
80 pu op 80 ula
o
&r
ep pop
rep ps re
ga h
no th wit
60 ut Wi 60
,b
ps
ga
40 nd 40
ke
ee
W
20 20

0 0

0 20 40 60 80 0 20 40 60 80
Overall Time (days) Overall Time (days)

Fig. 8 a The increase of Early accumulated radiation damage Tk = 7 days. The ‘‘tolerance’’ mucosal dose at 51 Gy EQD is
(a/b =10 Gy) from 5 fractions of 2 Gy every week (left reached at 46 days. b Early damage in tumors superimposed on
Y-axis), in terms of 2 Gy fraction size equivalent doses, the same plot, showing that repopulation does not begin in
showing the onset of repopulation in normal human mucosa at tumors until the assumed onset time of Tk = 21 days

Barendsen (1982) RE algorithm (Relative Effective- leading to a total accumulation rate of 1.43 -0.67 =
ness = nd (1 ? d/3), where d is dose-per-fraction for 0.76 EQD10/2 per day. This continues until the total
n identical fractions in any schedule, with no influ- dose reaches some constraint dose at which irradia-
ence of overall time. From 40 to 50 fractions we tion must stop. (Here, at 51 Gy EQD10/2). Thus the
calculate for both one and two fractions per treatment average rate of accumulation of damage in normal
day, and for more than 50 fractions at 2 fractions of mucosa is about 40% of its intuitively expected rate of
increasingly small size per day. A step from two to 2 Gy per day, for all except the first week of treatment
three fractions-a-day is not recommended because of (Fig. 8a). This reduced rate of accumulation of dam-
the diminishing returns, as shown below, and because age in normal mucosa is a major advantage for the
of a greater danger of incomplete repair in late- Therapeutic Ratio.
responding normal tissues.

6.4 Faster Rate of Accumulation

of Radiation Damage in Tumors
6.3 Rate of Accumulation of Radiation than in Normal Mucosa
Damage in Normal Mucosa
Contrast the rate of accumulation of damage in
First, let us consider an ordinary treatment delivering tumors with that in normal mucosa. Figure 8b shows
2 Gy per treatment day, 5 days a week (Fig. 8a). For both accumulation graphs plotted together. The tumor
the first five days the 2 Gy fractions deliver 5 9 the graph continues at 1.43 Gy EQD (reduced only by the
daily BED = 2(1 ? 2/10) = 2.4 Gy10 = 2 Gy EQD weekend gaps) until the tumor Tk time, which is
per day. Then comes a weekend with two days of no assumed in this model to be 21 days, with a range of
treatment, hence the average rate of accumulation of uncertainty of 14–32 days. This rate of rise of damage
damage falls to 5/7ths of the previous daily rate, to is nearly twice as fast as the rate of rise of 0.67 Gy
2 Gy EQD 9 5/7 = 1.43 Gy EQD10/2 per day aver- EQD per day in normal mucosa, and gives us the
age. On the first Monday, however (Day 7), repopu- large therapeutic advantage of daily fractionation,
lation begins in Mucosa because Tk = 7 d (Dörr et al. until the tumor Tk time (of 3 weeks here), when
2002), hence the rate of accumulation of damage falls repopulation begins in the tumor, at nearly the same
further (by 0.8 Gy10 per day = 0.67 Gy EQD10/2) rate as in normal mucosa. Damage in tumor therefore
30
70 Gy EQD = BED of 117 Gy3 LATE CONSTRAINT
70
60
LATE EQD from Gy3
Gy
50
70
=
35
40
yx
2G
30
20
10
2 wks 4 wks 6 wks
0
0 10 20 30 40 50 60
OVERALL TIME (days)
Fig. 9 The increase of late complications damage (a/b = 3 Gy),
left-hand Y-axis, with time during RT at 2 Gy five times a week.
The ‘‘tolerance’’ constraint dose is 70 Gy in 2 Gy fractions
(BED = 116.7 Gy3) reached also at 46 days
becomes greater than in mucosa at the rate of about
0.67 Gy EQD a day for this initial period of 3 weeks,
reaching on the 21st day (at the Tumor Tk) to a gross
difference of 10 EQD (=5 fractions of 2 Gy). After Tk
in the tumor, there is little difference in the rates of
accumulation of damage in tumor and in mucosa;
damage continues to increase in both until some
safety constraint causes irradiation to be stopped at
the end of treatment. There is by then an accumulated
difference (of at least 10 Gy10) more damage in tumor
than in normal mucosa (Fig. 8b).
At each weekend after the tumor Tk there is the
repopulation-caused fall of accumulated damage in
both tumor and mucosa of about 0.67 Gy EQD per
day, nearly equal in both. This is a loss of about
two-thirds of one daily dose of 2 Gy in the two days
each weekend (and it might become slightly greater in
mucosa towards the end of treatment because of
possible acceleration, but by a total accumulated EQD
only 5% greater, according to the clinical observa-
tions of Strigari et al. 2009).
This is what happens until the end of treatment,
which is set by the constraint doses of 70 Gy EQD for
Late Complications at 46 days and 50–53 Gy EQD in
mucosa, both at a similar time of about 46 days, as
shown by comparing Fig. 8b for the day of reaching
51 Gy for Acute and Fig. 9 for reaching 70 Gy Late
reactions.
J. F. Fowler
6.5 Finding Optimum Overall Times:
For Any Radiotherapy
In theory, it is possible to set up a differential equation
that will indicate when Tumor Log Cell Kill should be
maximal, but the weekend gaps and the discontinuous
nature of the mucosal tolerance days make it easier to
calculate for a set of fraction numbers from One at
Day Zero (note) to 115 fractions at Day 80 and look at
the shape of the resulting curve of Tumor Effect
versus Overall Time.
Setting the Late Constraint Dose-per-fractions is
70 80 easy, because they do not vary with the overall
time of treatments, as explained earlier, hence for
any chosen number of fractions a BED of 116.7
Gy3 must be given (from Eq. 9 in Sect. 5.9). We
can then write the list of fraction sizes for each
number of fractions very quickly. For example, for
one fraction it is 17.3 Gy, for 2F = 11.8 Gy, for
3F = 9.4 Gy, all delivering 116.7 Gy3 = 70 Gy
EQD. Figure 9 illustrates the rate of accumulation
of Late-Reactions BED with time at 2 Gy fractions
a day, reaching the Late Constraint dose of 70 Gy
EQD3/2 at 46 days, the Friday of the 7th week
(Referring back to Fig. 8b shows that at this time,
the normal mucosa (lower curve) reaches just
51 Gy EQD10/2—its own constraint—while the
tumor damage has gone up to 63 Gy EQD10/2,
which exceeds the effect on normal mucosa by
more than 10 Gy EQD.
Setting the Acute Mucosal Constraint for each
fraction size however is much more complicated,
because it might not occur on the exact number of
days natural for that number of fractions. Indeed it
will usually not do so, and the Overall Time to be
used with a given number of fractions is often a few
days longer than the obvious choice at 5 or 10 frac-
tions a week. We shall call it the Practical Overall
Time, meaning the smallest number of days in which
that number (and preset size) of fractions could be
given without exceeding the Acute Constraint dose of
51 Gy EQD (=BED of 61 Gy10) (Fowler et al. 2003c).
It will be calculated by using the Acute Mucosal
Formula (Sect. 3.5 and Eq. 8 in Sect. 5.9—assuming
a/b = 10 Gy and the Tk = 7d instead of 21 or 28d
that applies to tumors (Brenner 1993, Roberts and
Hendry 1999)), and Tp = 2.5d instead of 3d, but still
with a/b = 10 and a = 0.35 Gy -1.
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 31

6.6 The Summarized Optimization H&N Fig 2

Process
Late Tolerance Constraint EQD = 70Gy
log10

EQD10 /2 Gy fractions equivalent

70Gy
This procedure can be best described as a series of TumourEQD
Cell
2F/day AcuteMucos Kill
discrete mini-calculations carried out for each number 1F/day
11

I
60Gy
of fractions from 1 to 100 in sequence, each step Tk=7d 10

I
leading to a different list of values important
50Gy 9

I
for each fraction size. These steps reveal not only Acute Tolerance
‘‘the optimum’’ overall times, but other schedules that Constraint 8

are almost as good, without any systemic therapy. It is
convenient to examine them as either one or two
fractions a day, but not more fractions a day for
reasons that will soon become clear.
The following steps are conceptually the same,
whether done by computer or hand.
Reminder: Refer to the end of Sect. 2.1, the para-
graph on the Subscript notation: EQD10/2 or EQD3/2
and the conversion from BED in Gy10 or Gy3 to EQD
(Sect. 3.6). It is not necessary to use two subscripts for
the a/b ratio of a tissue, because the same a/b ratio
applies to that tissue for any schedule; however, it is
necessary to be more specific for an EQD of a given
schedule, which is the normalized dose in ‘‘real total
dose at 2 Gy fractions’’ (EQD), in its effect on
either Early or Late reacting normal tissues, but
different effects on each type of tissue, specified by
the a/b ratio. The same radiation dose can have those
different biological effects on the different tissues—
that is what this modeling is all about.
The following steps are then carried out:
1. Tabulate each fraction number from 1 to 100
against its permitted fraction size in Gy using
Eq. 9 in Sect. 5.9.
2. For every fraction number find the minimum
number of treatment days into which each number
of fractions will simply fit, excluding weekend
days if that is the usual department policy. Note
that the first day of treatment is Day 0, and not
Day 1.
3. Do this for 5 fractions a week up to 40 fractions.
For more than 30 fractions do this also for 2
fractions a day = 10 fractions a week, giving +0.3
or +0.5 days for any odd number of days. A few
days’ overlap from 30 to 50 fractions is helpful.
4. Now calculate the Acute Mucosal EQD10/2 for
each fraction number for that minimum overall
time, using a/b = 10 Gy, alpha = 0.35 Gy-1,
Tk = 7 d, and Tp = 2.5 d only.
This is Eq. 8 in Sect. 5.9.
I
1F/day 2F/day NTD = 51 Gy
40Gy
OVERALL
TIME: 20d 30d 40d 45d 50d 60d70d 80d Approx
0 20 40 60 80 100 120 140
Number of Fractions
Fig. 10 Curve joining the calculations described in Sect. 6.6
showing tumor accumulated damage in 2 Gy fractions (crosses)
and mucosal damage (open circles) in the same units (open
circles), plotted against number of fractions (both with a/
b = 10 Gy). Separate curves are plotted for 1F/d or 2F/day,
and each shows a definite hump representing an optimum
number of fractions. [Reproduced from Fowler (2008a) with
permission from Elsevier Ltd]
5. If the value is between 50.3 and 51.0 Gy EQD10/2
ONLY, accept and record it for use with that
number of days, the Practical Overall Time. It will
be the closest you can get to ‘‘just below the
constraint dose of 51 Gy EQD10/2’’.
6. If however the value is 51.01 Gy EQD or higher,
you must recalculate with a longer overall time
until you obtain the constraint EQD10/2 of 51.0 Gy
or lower. (It usually requires no more than 2 or 3
extra days, and is called Constructive Lengthening.
Although slightly longer, the resulting Tumor BED
is higher.) This Overall Time is now recorded as
the ‘‘Practical Overall Time’’; and is the shortest
overall time in which this number of fractions can
be given while keeping within the constraint of
51.0 Gy EQD10/2.
7. Finally, calculate the Tumor BED and EQD and
the estimated Log Cell Kill using the recorded
Practical Overall Time obtained in Note 5 or 6.
8. Record them all to plot versus either Fraction
Number or versus Practical Overall Time, as
shown in Figs. 10 and 11.
Step 6 is the tricky one. It is rather like the end-
game of chess when the opponent has nothing left but
a king and one other piece, and keeps slipping away
from a checkmate by yet one more move.
32 J. F. Fowler

Fig. 11 Exactly the same

points, plotted now against the TumourEQD
practical overall time, so that 70Gy AcuteMucos
Late Constraint EQD 70 Gy log 10
any optimum overall times Cell

EQD @ 2 Gy fractions equivalent

40F/39d
can be read off. Triangles for 1F/day 63F/46d 2F/day Kill

I
tumors, open circles for 15F/22d

I
60Gy 11
mucosal accumulated 100F x 0.9Gy
20 25

I
damage, in 2 Gy equivalent 10F/15d 35F/46d in 67d

I
30F
fractions EQD10/2. 10
8F/14d 40F/53d

I
[Reproduced from Fowler 50Gy

I
(2008a) with permission from 5F 9
Elsevier Ltd.] Acute Mucosal

I
I
Constraint
8
40Gy Tumor Tk = 21d EQD = 51 Gy
1F Tumor Tp = 3d 1F/day
α/β = 10Gy 2F/day
α = 0.35 Gy/ln
0 10 20 30 40 50 60 70 80 Days
Overall Time: minimum days to deliver the number &
size of fractions & keeping just below both constraints

Finding the Practical Overall Time with its
constraint of Acute Mucositis BED of just under
51 Gy EQD (= 61 Gy10) is the patience-requiring step
in this because it involves a calculation using the
Acute Mucosa Equation which is Eq. 8 in Sect. 5.9.
The overall time for each fraction has to be
calculated separately.
6.7 Constructive Lengthening and its
Ability to Increase Tumor-Effective
Dose: A Counterintuitive Move?
If however the EQD was above the constraint dose of
51 Gy EQD—and many of them were—it had to be
recalculated using one or a few days longer, to bring
the dose down to just below 51 Gy. This is a simu-
lation of what one can do in clinical praxis if a new
schedule turns out to be too ‘‘hot’’ for acute reac-
tions—one could lengthen the treatment to ‘‘give the
patient a day or two’s rest’’. (This is apparently
counterintuitive, and not to be recommended unless
being checked with the present modeling, because we
can lose Tumor BED by repopulation in tumors at the
now familiar average rate of 0.8 Gy10 per day of BED
(= 0.67 Gy EQD10/2/day). However, if the next day’s
fraction (or 2 fractions) exceeds a total of 0.67 9
7/5 = 0.94 Gy EQD/day by a good margin, these
extra fractions will add usefully more to the total
damage in the tumor in spite of the extra day or so, and
the total increase has to be modeled over the total
fractions to see whether the one day’s repopulation
lost now will be more than compensated for by the
increase in the total dose (Fowler 2008a). The differ-
ence between 0.67 and 0.94 Gy EQD loss per day is
because treatments are on 5 days but repopulation
continues for 7 days per week. It is no longer coun-
terintuitive, but logical! This COULD however, go on
for too long, unless checked by modeling, just like this.
This is known as ‘‘constructive lengthening’’
(Con-Len) because the Acute Tolerance dose can
then be kept very close under 51 Gy with a mini-
mal loss of Tumour BED (0.67 Gy EQD for each
day of Con-Len), and even with a likely increase in
tumor damage, as shown in some of the following
graphs. The choice of the exact Overall Time to
yield just under the Acute Mucosal Constraint Dose
is crucial (Kaanders et al. 1999). We have known it
in principle for 10 years, but had not worked out
exactly how it could be manipulated until recently
(Fowler 2008a).
7 The Results: Tumor Accumulated
EQD Plotted Against Number
of Fractions or Overall Time
Then for each fraction we calculate the Tumour
BED or EQD using the exact Practical Overall Time
(with no irradiation on a Saturday or Sunday unless
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
we are investigating such deviations). Finally, we plot
the calculated Tumour EQD for each schedule’s
number of fractions either against Fraction Number
(Fig. 10), or against the Practical Overall Time
(Fig. 11). Crosses represent Tumor EQDs and circles
represent the Acute Mucosal EQDs, each EQD being
proportional to the accumulated damage as 2 Gy
fractions equivalent (left) and as log10 cell kill (right).
Figure 10 is a smooth curve showing a clear Opti-
mum Tumor-Effect Hump for both one and two
Fractions-per-day schedules, entirely separately. The
open circles show how the Acute Mucosal points can
be kept close to the constraint dose of 51 EQD by
judicious Constructive Lengthening. In Fig. 11 the
Tumor EQD curves suffer small deviations due to the
day-to-day division into integral numbers of days,
with obvious dips in the curves due to two days off
radiation at weekends.
It can be seen in Figs. 10 and 11 that the Acute
Mucosal EQD can be maintained from its Tk of
7 days up to as long as 30 days at one fraction a
day, and even up to about 50 days if two smaller
fractions a day are given. The most important point
is that all the 2F/day schedules give higher Tumor
EQDs than the 1F/day schedules, by 3 to 4 Gy of
EQD, which is 1‘ to two fractions of 2 Gy,
for the assumed tumor repopulation doubling
time of 3 days illustrated in Figs. 10 and 11
(but not necessarily for faster repopulation, as
shown below). This is worth a debatable clinically
significant difference of 6 to 8% Local Control at
2 or 3 years.
This trend can easily be understood because the
smaller fraction sizes used at 2F/d deliver higher
effective tumor BEDs (in Gy10) at a given maximum
Late Complications constraint of 70 Gy EQD (= BED
of 117 Gy3). The differing BEDs in the same dose and
volume in the same beam in two different tissues
illustrate what radiobiological modeling is all about.
The last column in Table 4 (in § 80 below) shows how
the Therapeutic Ratio always improves as dose-per-
fraction becomes smaller for tumors with a/b greater
than 3–5 Gy. Figure 12 shows exactly the same tumor
points as in Figs. 10 and 11 but the graph is cleaned
up, containing tumor data only (and was not shown in
Fowler 2008a). It is an important graph for discussing
optimum H&N schedules, and probably other tumor
sites too.
33
7.1 Two Fractions a Day give more
Tumor Log Cell Kill than One
Fraction a Day
It was shown that the superiority of two fractions a
day over one fraction a day varies with the rate of
repopulation Tp (Fowler 2008a), and with how early
repopulation begins and how long it continues (to the
end of irradiation is assumed here). The advantage for
two fractions a day rises to 6 to 7 Gy if Tp is 5 days
instead of 3 days. In a practical population of tumors
with a range of repopulation rates, a median or
average of 3 days Tp means that a few tumors may be
doubling at Tp = 2 days but also more at 4 or 5 days,
because of the natural skew distribution towards
longer Tp. It is only with very short repopulating
doubling times of less than 3 days, together with
rather early starting of repopulation such as 21 days
or earlier, that repopulation has enough force to spoil
the general superiority of two fractions a day over one
fraction a day, making shorter schedules than 4 or
5 weeks essential for really rapid tumors.
7.2 The Effect of Assuming Faster
or Slower Repopulating Rates
Figure 13 shows the effect of assuming slower
repopulation at Tp = 5 days (the triangular points),
with the previous curves for Tp = 3 days shown by
dots. It is clear that the advantage of using two frac-
tions a day is then even larger, increasing from
3–4 Gy to 8–9 Gy, equivalent to nearly five fractions
of EQD at 2 Gy/Fr. This is somewhat more than the
average increase of local and regional control
(LRC) due the addition of chemotherapy to H&N
radiotherapy in many data sets, which was—when
analyzed correctly—three to four fractions of 2 Gy
(Kasibhalta et al. 2007; Fowler 2008c; Lee and
Eisbruch 2009; Hartley et al. 2010).
7.3 The Exceptional Cases
of Very Fast Repopulation
Figure 14 is for faster repopulation, Tp = 2 days, and
shows the very rapid fall of tumor EQD immediately
after the Tk time, which was altered to 32 days in this
34 J. F. Fowler

Table 4 Therapeutic Efficiency of various schedules defined as tumor EQD10/2 divided by late complications EQD3/2
Schedule fractions Tumor Tumor EQD at 2 Late - BED Complications EQD % Efficiency = Tumor
total Gy BED  Gy10 Gy/F Gy3 at 2 Gy/F EQD10/2//Late EQD3/2
3F 9 228 190 598 359 52.9%
23 Gy = 69 Gy
3F 9 180 250 460 276 54.4
20 Gy = 60 Gy
3F 9 125 104 304 182 57.0
16 Gy = 48 Gy
3F 9 113 94 270 163 57.4
15 Gy = 45 Gy
5F 9 132 110 300 180 61.1%
12 Gy = 60 Gy
7F 9 132 110 283 170 64.7
9.61 = 67.2 Gy
10 9 132 110 264 159 69.4
7.53 = 75.3 Gy
15F 9 132 110 243 146 75.4
5.63 = 84.45
20F 9 132 110 228 137 80.0%
4.539 = 90.78
30F 9 132 110 209 125 87.9
3.307 = 99.21
40F 9 132 110 196 118 93.6
2.616 = 104.6
35F 9 84 70 117 70 100%
2 Gy = 70 Gy
60F 9 1.3 = 78 Gy 88 63 112 67 110
68F 9 91 67 114 69 111
1.2 = 81.6 Gy

diagram (Roberts and Hendry 1999); it was equally
rapid when Tk = 21 days was assumed as before (not
shown), without even the few days’ delay before the
higher values reached when Tp is slightly longer at
3 days in the previous Figures, shown here in black
dots. A difference in these two diagrams is that the Tk
kick-off of tumor repopulation is assumed to be later
at 32d (triangles) instead of 21d (black dots), so that
radiotherapy can do much better at 66 instead of
61 Gy EQD10/2 to tumors treated at 5F/wk. This very
fast repoulation of Tp = 2 days is the only situation
in which the One-fraction-a-day schedules give about
as good results as the 2F/d schedules, but note their
much narrower time peak. The 2F/day schedules
show a much broader time crest from about 40 to
50 days and so must be more reliably treated over that
period, and easier to adjust when developing in Phase
I trials. We do not know what proportion of any
tumor’s range of repopulation rates might be as fast as
2 days; it is something to aim for measuring.
7.4 Discussion: Is One Fraction a Day
Still to be Used?
If 1F/day is still to be used for such relatively rapidly
proliferating tumors, incuding H&N and Lung
Tumors, its optimum schedule should be similar to
the Manchester-type schedules, preferably with 16
fractions of 3.45 Gy delivered in 21 days. This
schedule is notable for including the third weekend
within its overall time, thus gaining the three extra
days that allow the Constructive Lengthening to keep
acute reactions within their constraint dose. It speaks
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 35

63 x 1.294 Gy
57 x 1.397 70 x 1.193 Late Normal Tissue Constraint 70 Gy EQD
70
65 Gy Tumour 5F/wk Exactly reached at every schedule Log10
Log10 65
Tk=32d Tk=21d as Tumour cell

Tumour EQD @ 2Gy frs

--11 Tp=2d Tp=3d before 10F/wk kill
60 1F/day X Tk=21d as __ 11
Tumour EQD 2Gy

X 2F/day 60 Tp=3d before

__
55 --10 55 10
Unstable peak @ 32d, Tumour
15 x 3.56Gy 35 X 2Gy 50 __
Coincidence of a Friday & 10 F/wk 9
50 20 x 2.94 -- 9
45 the onset of repop Tk=32d, Tk=32d
25 x 2.53
-- washed out by tumour Tp = 2d
DAHANCA
45 Constraints EQD-2Gy 40 to tumour variation.
66 & 68 Gy
Late Normal Tiss = 70 Gy
IN 6 WEEKS 35
40 Acute Mucosa 49 - <51 Gy
-10 0 10 20 30 40 50 60 70
Overall Time days
0 10 20 30 40 50 60 70
Practical Minimum Overall Time (days) Fig. 14 Another set of calculations but with faster repopulation
of Tp = 2 days (which will give lower Tumor EQDs), but with
Fig. 12 The same points as in Fig. 11, plotted against practical the Tumor Tk assumed later at Tk = 32d instead of 21d (which
overall time as before, but for tumors only, and cleaned up, with will give higher Tumor EQDs). The black dots are the same
the schedules labeled [Reproduced from Fowler (2010) with points as in Fig. 12. The important point is the immediate rapid
permission from the British Institute of Radiology] fall of the Tumor 5F/wk curve as soon as the (new) Tk (32d) is
reached. It was equally rapid from Tk = 21d when that was
tested (not shown). If Tp is as short as 2 days, it causes a very
Tumour repop Tp = 5 days short peak around the Tk value which leaves little choice for an
80 - - - - - - Tp = 3d as before Late Tolerance ‘‘Optimum Overall Time’’. The question is, how many tumors
OOOO Acute Mucosal EQD Constraint 70 Gy have Tp as short as 2d, if their median Tp is 3 days? [Reproduced
Tumour EQD in 2Gy fractions

75 as before
70
65 5F/wk
60 Gy
55
50
45
40
35
30
0 10 20
Overall Time days
Fig. 13 A similar set of calculations but assuming a slower
repopulation rate of Tp = 5 days. The previous calculations
assuming Tp = 3 days are shown by black dots. The increases
in tumor damage are obvious. [Reproduced from Fowler
(2008a) with permission from Elsevier Ltd]
well of the clinical acumen of the Radiation Oncol-
ogists in Manchester, U.K., who made that choice of
Overall Time in the 1940s, because a ‘‘neat’’ 15
fractions in 18 days does not give quite such a high
accumulated tumor EQD within the same constraints.
The gain in tumor BED for 16F/21d is about 4% of
total dose or 3 Gy EQD; small but better to gain it
than lose it. Only for the most rapid tumors the
optimum time slot is, for one-fraction-a-day sched-
ules, very narrow and close to the Tk time.
One fraction a day commits us to using schedules
no longer than 5 weeks (32 days), as shown by the
EQD
Log10 from Fowler (2008a) with permission from Elsevier Ltd.]
cell
10F/wk
kill
__ 11
5F/wk 10F/wk __ 10
1F/d curves in Figs. 11 and 12. The contrast with 2F/
day is obvious, where a wide range of schedules from
Acute Mucosal __ 9
Constraint 51Gy
1.8 to 1.2 Gy twice a day with optimum overall times
5F/wk
EQD from about 40 to 50 days gives almost as much tumor
10F/wk EQD and log cell kill as their collective point optimum
which is actually at 1.3 Gy twice day, but note - in
30 40 50 60 70 80 90
42 days, not the ‘‘neat’’ 39 days of a traditional 30F
schedule. (We note that the ‘‘neat 39 days’’ was found
clinically by Sanguinetti et al. (2004) to be too short
for 60F 9 1.3 Gy = 78 Gy, as predicted by the cal-
culated Acute Mucosal Dose in the present modeling.)
Thus Dr Sanguinetti did a ‘‘Manchester trick’’ and
went to the following Monday for his Overall Time.
That wide range of nearly equal EQDs with 2F/d made
them acceptable to use, in contrast to the more sharply
falling one-fraction–a-day schedules after 5 weeks.
7.5 The First Main Conclusion
The first main conclusion of this chapter is that
2F/day causes more tumor cell kill than 1F/day for all
tumor repopulation rates slower than the fastest Tp of
2 days. The advantage of 2F/day becomes highly
clinically significant for tumors repopulating more
slowly than Tp = 3 days, and for tumors starting
36
Improvement of tumour control with smaller fraction sizes
1.0
Estim Probability Rec Free Survival
Constant EQD 3/2
Late Constraint
0.8
0.6
0.4
0.2
Retraced from Arvidson et al R&O 2009; 91: 379-385
0.0
0 10 20 30 40
Number of Fractions (2F/day)
Fig. 15 Similar calculations were done (Arvidson et al. 2009)
for 2 fractions a day of progressively decreasing size, but with
only the single constraint dose of 57.6 Gy Late EQD3/2. The
crosses show tumor damage in terms of estimated two-year
Progression-Free Survival. There was no limitation on Acute
Mucosal BED or EQD. The successive waves show the
continually increasing effect on Tumor EQD10/2. [Reproduced
from Fowler (2010) with permission from the British Institute
of Radiology]
repopulation later than Tk = 21 days. It is therefore
logical that more efforts should be spent to find these
proliferation characteristics in individual tumors, so
that we would know which tumors to possibly use
short schedules for; and for which tumors to use
somewhat longer schedules.
7.6 The Second Main Conclusion
The second main conclusion of this chapter is to
investigate individual Tumor Repopulation Rates and
to use an appropriate length of schedule, some pos-
sibly longer. A gain of at least 0.7 to 2 Gy per extra
treatment-day, more with 2F/day, could be obtained
by ‘‘constructive lengthening’’ especially for slower
growing tumors. Modeling should be used to check
each such schedule, and information about the indi-
vidual tumor rate of proliferation is needed.
7.7 Discussion: Smaller and Smaller
Fractions
Figure 15 shows the consequences of continuing the
use of two fractions a day to smaller and smaller
fractions, but with only the Late dose constraint.
J. F. Fowler
The dips at every weekend are obvious, with the first
increase (corresponding to a change in dose per
fraction from 1F/d to 2F/d) being the largest. But the
fact is that tumor EQD continues rising continually,
far beyond an assumed kick-off time of tumor repop
Tk, although each step becomes progressively smaller
(Arvidson et al. 2009). There seems no obvious limit,
but the limit comes in when Acute Complications are
taken into account. We progressively lose out for
overall times beyond 35 days for 5F/week, beyond
45-50 days for 10F/week, beyond 60–65 days for
50 60 15F/week, and so on.
The Practical Overall Times at 2F/day rise to 55, 62,
and 70 days for 1.1, 1.0, and 0.9 Gy fractions respec-
tively, to get the 10 fractions a week in, and those times
become sufficiently longer than the Tk time of 21 days
to allow more cell loss than the extra doses will then
compensate. For example, an extra 10 days loses about
7 Gy EQD of radiation damage in the tumor, equiva-
lent to losing about one log10 of cell kill in 10 days, and
the equivalent of a factor of ten in number of tumor cells
by repopulation. Thus an extra 10 days of Con-Len
(‘‘constructive lengthening’’) is not constructive any
more, as doses per day add up to less than the BED that
is lost by repopulation in tumors.
The practical limit is 45–50 days (7 weeks) unless
we think of using more than 2 fractions a day, to obtain
smaller fraction sizes. This is always inconvenient and
possibly dangerous from Incomplete Recovery in Late
Complications. An ultimate biological limit arises
when the added daily dose (in any number of fractions)
falls below an overall average equal to the tumor
repopulation rate of about 0.8 Gy10 (=0.67 Gy EQD)
per average day, below which dose per day the tumor
must win.
7.8 Discussion: How Long is Really
Too Long?
Since the tumor EQD must start falling as soon as the
irradiation stops, the planned end of the schedule is
obviously the time of maximum tumor damage,
recorded as the maximum tumor EQD reached.
Although Constructive Lengthening could theoreti-
cally continue much longer, the Late Constraint
(calculated using a/b = 3 or 2 Gy) cannot increase at
all, and reaching it, whenever that is, becomes the
definite end-time of a schedule. For continuous low
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 37

dose rate (CLDR) for example, it might become very 210 F x

0.426 Gy
105F x 0.863 Gy /54 d
long indeed, limited then by the tumor repopulation (3F/day) / 62 d
65 63F x 1.294 Gy /45d
rates which have to be counteracted by the LDR. Fr3.per.day
(2F/day)
15F /wk
Fr1.per.day
It becomes easier to see why the very LDR treatments 60
Fr2.per.day

from such permanent implants as Iodine-125 could

Tumor EQD 10/2

give good results even with prostate tumors whose 55
10 F /
famously low a/b ratios, recently confirmed by sev- 50
5F / week week

eral meta-analyses (Dasu 2007; Proust-Lima et al.

2010; Miralbell et al. 2010), respond well also to large
doses per fraction. To respond well to such opposite
strategies has been a puzzle. For I-125 to work at all
in prostate tumors they must repopulate at less than
0.2 Gy/day, which is three or four times slower than
in head and neck tumors.
There is however a longer theoretical limit for the
Acute Constraint just mentioned, although in practice it
would require so many very small fractions that it is
never likely to be a real constraint. This is when the
average daily EQD over the whole week falls too low to
counteract tumor repopulation, that is at the BED of 0.8
Gy10 per day (=0.67 EQD per day, which becomes
larger 9 7/5 when 5 treatment days a week are
used, = 0.94 Gy per treatment day). For 2F/d this
means 2F 9 0.489 Gy/d, and for 3F/d it would mean
3F 9 0.332 Gy/d, just to keep repopulation from
regrowing the tumor. These doses are much lower than
any that are seriously envisioned, and would take 19,
20.6, or 21 weeks, respectively, to reach the late
Normal-Tissue Constraint of 116.7 Gy3 BED (=70 Gy
EQD10/2), hence the strategy of cruising along gently
just keeping repopulation down is not a practical one.
Apart from the risk of a tumor becoming more
aggressive during such a long treatment, and the spread
of metastases, it does not lead definitely to increasing
the cell kill of every malignant cell in a tumor. It was
suggested as a strategy to treat Ca breast with weekly
chemotherapy in the 1980s (Thomlinson 1987, who
was a wonderful writer), so as to reduce the toxicity of
the anticancer drugs; but it is no longer suggested.
In order to check that three fractions a day do
not give much improvement over 2F/d, the present
modeling was continued with 3F/d in Fig. 16, using
both the same Late and Acute constraints as earlier in
this chapter. The 3F/d tumor results are shown by
circles with crosses in them. They achieve greater
tumor cell kill beyond 50 days, as shown by the rising
curve, while the falling curve is for the 2F/day
schedules from the previous figures which met its
same constraint dose at 42 days and then fell after the
Late constraint 70 Gy EQD3/2
45 (As above)
Early constraint 51 Gy EQD10/2
40
0 10 20 30 40 50 60 70
Practical Minimum Overall Time (days)
Fig. 16 Similar calculations for 3F/day (open circles with
crosses in them) from 30 to 62 days. Both our constraints of
70 Gy EQD3/2 Late and 51 Gy EQD10/2 Acute are in operation
for all the points in this diagram; the Tumor EQD10/2 goes on
rising because of the decreasing size of doses-per-fraction at
3F/day. The falling curve is for the 10F/week schedules which
had larger doses per fraction (1.3 Gy at 2F/d) and therefore ran
out at the Late Constraint of 70 Gy3/2 at 42 days so treatment
had to stop there, followed immediately by the fall in tumor
EQD. The 3F/day schedule would run out at the same Late
Constraint at 63 days, hence we only see its maximum tumor
effect here
end of treatment. But even up to the number of 210
fractions of 0.426 Gy x 3F/day in 63 treatment days
(= 14 weeks at 5 treatment days a week, continuously
boosted by Con-Len), but only up to one more day
than in the upper curve in Fig. 16, they only achieve
an accumulated tumor EQD10/2 of 66 Gy, which is
ony 1 Gy EQD above the peak of the 2F/d scheduled
to end at 42 days (6 weeks, using 60F 9 1.3 Gy as
shown, but notably not at 39 days). Thus 3F/week at
lower doses per fraction is not worth the extra weeks
and fractions of treatment, although the boosting of
the Acute Constraint by Con-Len (if it could be
achieved by IMRT and SIB simultaneous internal
boost,) for example is fascinating.
7.9 For Slightly Slower Growing Tumors,
the Radiation-only Gains for 2F/d are
Notably Greater than the Once-Daily
Treatments
This is illustrated in Fig. 12 and Sect. 7.1.
If slower repopulation occurs than our average
assumed Tp = 3d, which is quite likely in about half
38
of even these rapidly proliferating tumors, at 4 or
5 days doubling time, Fig. 12 shows that the gain for
2F/day above 1F/day rises to 9 or 10 Gy EQD10/2,
equivalent to five fractions of 2 Gy instead of only
two such fractions.
There are a number of clinical publications dem-
onstrating the superiority of 10 fractions a week over
5 fractions a week for H&N cancer treatments (Horiot
et al. 1992, Stuschke and Thames 1997, Fu et al. 2000,
Bourhis et al. 2006, with the ingenious 6F/week
schedule of Overgaard et al. (2003) showing as second
best if its total dose is increased from 66 to 68 Gy.
In Sect. 9, some practical good schedules are lis-
ted, with emphasis on their carefully calculated
Overall Times which are often a few days longer than
expected before the presnt modeling was done.
Every effort has to be made by the treatment teams
to keep the treatments within the Prescribed Overall
Time, with procedures precalculated in every
department for corrections if the time is inadvertently
over-run (Hendry et al. 1996).
8 Discussions: How Short is Too
Short?
First, a single radiation dose is the worst kind of
radiobiological tradeoff between Tumor Damage and
Late Complications Damage (with a/b = 2 or 3 Gy).
See Table 4. It also allows no time for reoxygenation
of any hypoxic radioresistant cells (except during the
minutes of that single dose delivery), nor of move-
ment of cells out of a resistant phase of the cell cycle.
Even two fractions would allow for some of those
changes, and more fractions would allow more such
chances of avoiding initial radiation resistance. Thus
large single doses cannot be recommended on any
radiobiological rationale for treatments of tumors.
A single dose is the least efficient use of radiation, as
illustrated in Table 4. Thus if it is safe it delivers only
half the dose needed to cure any tumor. If the single
dose was high enough to have a good chance of
curing a tumor, it would cause a serious overdose to
normal tissues.
In that case, where between 2 and 277 fractions are
we likely to find the best tumor cell kill and the best
ratio of that to normal tissue damage? It is at the last
fraction before reaching the Late Constraint Dose at
which irradiation must stop (because of normal tissue
J. F. Fowler
damage). This does not depend on any biological
choice of Overall Time, but only on the total dose and
volume irradiated. In fact the Prescription Dose is the
highest dose we believe we are able to deliver to the
tumor, which is determined entirely by the potential
damage to the normal tissues irradiated.
8.1 Discussions: Is a Week Too Short?
If we use only a few large fractions there are
three dangers (1) loss of Therapeutic Ratio with
larger fractions (2) enhanced Late Complications
by Incomplete Recovery between fractions, and
(3) enhanced Acute Complications if a few very large
fractions are given too quickly. All these problems get
worse with increasing fraction size. In practice,
schedules as short as one week have been shown to be
vulnerable to the Incomplete Recovery problem, in
breast treatments with 10 9 3.85 Gy in five days,
where unexpected late complications were reported
(Bentzen and Yarnold 2010) as discussed in Sect. 8.4.
A different problem was also found with Acute
reactions in carcinoma of prostate cyberknife treat-
ments using 5F 9 7.25 Gy in five days (King et al.
2009; Fowler and King 2009), which was solved by
giving a few more days of Overall Time—the five
fractions on alternate days, 9 days instead of 4. This
‘‘constructive lengthening’’ can be done for acute
reactions only (at close to 0.8 Gy10 (BED = 0.67 Gy
EQD) spared per day) if the overdoses are not more
than a few Gy, as in adjusting a new schedule that is
nearly correct.
Is there any advantage in using a schedule shorter
than Tk, the start ot tumor repopulation, or more
precisely the time at which repopulation has risen to
significance? Yes for tumors of low a/b ratio
(\&5 Gy) only, but No for tumors of higher a/b
ratio, with which more and smaller fractions are
best.
However, modeling shows that this is only true for
the most rapidly repopulating cells of the spectrum of
tumor repopulating rates, those with cell doubling
times Tp about 2 days, even shorter than our expected
Hd & Nk or lung tumor average of 3 days. See
Figs. 10 and 11 to clarify this. For all other types of
tumor, including those with Tp of close to 3 days, the
optimum Overall Time is some days after the tumor
Tk. For example, using the modeling data in the
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
present figures, for Tk = 21 days, the Optimum
Overall Time increases from 21 days to a flattish
optimum hump at 30–32 days using one fraction a
day with our preferred tumor repopulation doubling
time of 3 days, and then to 40–50 days for two frac-
tions a day, and as Tp increases from 3 to 5 days.
The Optimum Overall Times are appreciably later
than the tumor Tk times, for all except the very fastest-
repopulating tumors. This consideration tends to
encourage long schedules rather than shorter ones, and
modeling does not contradict that tendency except for
the most rapidly poliferating tumors, with Tp less than
3 days, which should be as short as Tk for the tumors.
8.2 Discusssion: The Increase
of Therapeutic Ratio with More
and Smaller Fractions
Table 4 shows that the oligo-fractionated schedules
(large-dose-per-fraction and few-fraction) used in
Stereotactic Body Radiotherapy (Timmerman et al.
2010) have remarkably low Therapetic Ratios (Tumor
EQD divided by Late Normal-tissue Complications
EQD), only about half those of conventional sched-
ules (shown at the bottom of Table 4).
The advantages of more and smaller fractions
apply to most tumors but not to those with very low
a/b ratios, especially prostate, where these advantages
are reversed.
Some of these ‘‘oligo-fractionation’’ schedules
(Ling et al. 2010) might be re-thought. Figures 10 and
11 show that no schedules attain a good tumor
response until more than 20 days of ‘‘daily’’ frac-
tionation with fractions as numerous as 15 and
smaller than 3.6 Gy were given. This roughly defines
the boundary between oligo-fractionation and ordin-
ary Hypo-fractionation (Ling et al. 2010). In the
oligo-fraction region, there will be some tissues, just
outside the PTV boundary, that could receive
destructive doses until the doses outside the PTV fall
to 70 or 60 Gy, or lower doses, which are designated
by the Red Shell (Yang et al. 2010) to be at lower risk
for destruction, but might be permissible within a
‘‘parallel type’’ organ. These SBRT schedules would
be considered too short (at less than about 3 weeks)
for normal fractionation and in non-parallel tissues.
They do not employ the opportunity of improved
theratpeutic efficiency from more and smaller
39
fractions. However, for any tumors with low a/b
ratios, these larger doses per fraction and fewer
fractions are the correct way to go.
It can be seen from Fig. 12 that the 15 frac-
tion schedule of 3.56 Gy cannot be given in its natural
18 days (3 weeks of Monday to Friday treat-
ment days), but requires 21 days. The slightly smaller
doses-per-fraction in the 16F schedule (3.45 Gy) can
however be given in 21 days, with a gain of 2.8 Gy
total EQD on the fourth Monday compared to
the ‘‘tolerable’’, but less tumor-effective, lower total
dose in the shorter overall time of the third Friday.
Similarly, the 20 fraction schedule cannot be given
in the tidy 25 days (4 weeks of Mondays to Fridays),
but requires 28 or 29 days. In fact the best result for any
one-fraction-a day schedule occurs at 32 days, the fifth
Friday, with 25 fractions of just 2.53 Gy, and it is then
as late as 11 days after the assumed tumor Tk. All the
days of loss by repopulation have been made up by the
extra 10 Gy of total dose (53 to 63 Gy EQD10/2)
delivered in the extra ten slightly smaller fractions (25
instead of 15 F), even with two weekends intervening.
The three schedules give very similar tumor results as
shown in Fig. 12, and also more similar late and acute
reactions. With one-fraction-a-day treatments how-
ever, they do not become effective until 20 days of
nearly 4 Gy fractions, and they lose effectiveness if
longer than 32d, as shown in Figs. 11 and 12.
Single Doses higher than 17 or 18 Gy, or three
fractions higher than 9 or 10 Gy each, or five fractions
of 7 to 7.6 Gy in 4 days (Table 5) will cause serious
Late Reactions in later months. That is the Red Shell
question, applying especially for SBRT (Yang et al.
2010) ,which always remains a potential problem and
a non-neglible biological risk to be checked by the
modeling we are talking about.
8.3 Acute Mucosal Tolerance
Calculations are also Worth Doing
Such large oligo-fractionation doses per fraction
can also be checked by our Acute Mucosal Eq. 8
(Sect. 5.9), to see whether they will cause serious
Acute Reactions too. Applying these Acute Mucosal
checks to some of the rows in Table 5 shows that for
the 3F row, all the schedules are acceptable if deliv-
ered within a week at the doses given in Table 5, that
is up to 3F 9 10.14 Gy. However, the use of much
40 J. F. Fowler

Table 5 Doses above which If constraint is Late EQD3/2 50 Gy 60 Gy 70 Gy 80 Gy

late reactions are a
quantifiable risk BED Gy3/2 83.3 Gy 100 Gy 116.7 Gy 133.3 Gy
1 Fraction 14.38 Gy 15.89 Gy 17.27 Gy 18.56 Gy
3 Fractions 7.75 8.61 9.41 10.14
5 Fractions 5.73 6.39 7.00 7.57
10 Fractions 3.72 4.18 4.60 5.00
15 Fractions 2.85 3.22 3.56 3.88
20 Fractions 2.34 2.65 2.94 3.22
Tissues receiving higher than these doses are in danger of losing cells by Late Effect Cell killing
unless volumes are restricted. Any of these Constraint Doses, or a lower dose, could be used for
the lower boundary of a Red Shell in planning

higher doses per fraction such as 3F 9 23 Gy is four
times too high and 3F 9 15 Gy is about twice too
high, in terms of the Acute Mucosal BED or EQDs in
the ‘‘Grey Zone’’ (Fowler et al. 2003c), hence skin
trouble can be anticipated unless the entry ports are
altered between each of the 3 irradiations. With 5F 9
7.25 Gy, an overall time of 10 days would be
acceptable for Acute Reactions, but 4 days is not
acceptable (Monday to Friday, counting Monday as
Day 0) (Fowler and King 2009).
For 10 fractions of 4.6 Gy, as another example,
11 days (its natural Monday–Friday spacing at
5F/week), is not acceptable, but 15 days would be. If
however the 10 fractions were of 4.4 Gy, they could
all be delivered in 11 days, the ‘‘neat’’ time.
The examples show that these Acute checks are
worth making for local doses in any hypofractionation
schedules. If there is any doubt that such hypofrac-
tionated schedules would yield BEDs more than
halfway up in the Grey Zone, then fewer fractions per
week could be used until tested out in treatments.
Whether such excessive acute reactions cause serious
side effects will depend on which tissues are irradi-
ated and on how much volume—but above all on the
total dose dose and on days of overall time. This is
worth a routine check.
All the examples immediately above are taken
from actual ‘‘gently hypofractionated’’ schedules.
If we look instead at some oligo-fractionation, the
acute reactions could be even more hazardous. Nev-
ertheless, Timmerman et al. (2010) have shown that
peripheral lung, if away from central regions with big
blood or airway vessels, does seem to stand those 3
big fractions of 20–23 Gy.
The current explanation is that the high-dose
volume of peripheral lung does not stand those doses,
and is destroyed, being tolerated only because it is a
sufficiently small volume—and also not leading to
serious blood loss.
This leaves us with the possibility that the Large
Blood and Airway vessels DO have the Constraint
Doses we have used here of no more than 70–80 Gy
EQD Late (=117 - 133 Gy3 BED for very small
volumes or areas of structural wall) and 51 Gy EQD
Acute (=61 Gy10 BED) after all, and should only be
irradiated at higher doses to very small volumes,
away from critical structures, as has been stated
before (Timmerman et al. 2010).
Table 5 lists the fraction sizes that get into trouble,
for four levels of late normal-tissue risk, represented
by the four columns headed 50, 60, 70, and 80 Gy
EQD, respectively, assuming a/b = 3 Gy for normal
lung-tissue damage. Table 5 provides the list of
warning doses above which Late Reactions become
likely to be serious, depending on the type of tissue and
the volume receiving doses higher than those listed.
This table is constructed using the well-known LQ
‘‘Late Complications’’ algorithm RE = 1 ? d/[3 or 2],
initially as a guide for Red Shell planning (Yang et al.
2010, Sect. 5.9 and Eq. 9), but the possible separate
risks from Acute Reactions arose as further consider-
ations. The Acute Mucosal a/b ratio is instead assumed
to be 10 Gy with repopulation starting as soon as
7 days, as described in Sect. 5.9 and Eq. 8.
8.4 Incomplete Recovery (IR)
as an Enhancer of Radiation Damage
In addition, there is Incomplete Recovery to consider.
The word Recovery is used instead of ‘‘Repair’’
because other tissue processes might be involved as
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
well as intracellular repair. Bentzen et al. (1999)
reported clinical evidence for long half-times of
recovery, 4.9 h for laryngeal edema, 3.8 h for for skin
telangiectasia, and 4.4 h for subcutaneous fibrosis. If
we take these long half-times at face value it is rea-
sonable to assume an average T‘ = 4 h. Now the
important LQ conclusion is that the proportion of
recoverable damage is only the beta term in the
quadratic part of BED, because BED = Total Dose 9
RE (Relative Effectiveness) and RE = (1 ? d/[a/b]),
where d = dose-per-fraction. This means that for a
dose per fraction of 2 Gy, the Relative Effectiveness
is 1.667 (RE = 1 ? 2/3), of which however only the
0.667 proportion is recoverable. That is, 0.667/1.667,
which is 40% of the proportion of total radiation
damage recoverable after each 2 Gy fraction. If it is
not fully recovered, significant overdoses could occur.
Further, RE is larger if a/b is smaller, making Late
Complications the most serious hazards of IR.
Since the beta term is multiplied by dose squared,
the Recoverable Proportion (Prec) rapidly increases
with dose per fraction, becoming more than 50%
for doses per fraction above 3 Gy. For example,
the Recoverable Proportions for late complications
(a/b = 3 Gy) rise to 77% for doses per fraction of
10 Gy and to 88% for 23 Gy. If T‘’s are really as long
as 4 h, it is a lot of radiation damage in Gy to get
recovered before the next dose fraction; in fact most of
the total dose delivered. Unfortunately, tumors with
their usually high a/b ratios about 10 are less likely to
gain damage from IR than late complications with
a/b = 2 or 3 Gy. But of course any tumors with very
low a/b ratios will gain from large doses per fraction
and high dose rates, especially prostate tumors with
their very long doubling times (median 42 days, so
a/b = 1.5 Gy), and breast tumors whose a/b ratios are
about 4 Gy and are quite close to those for late com-
plications, being simlar in recovery behavior.
The alarm bell has recently been rung for 2 frac-
tions of 3.85 Gy per day in 5 days a week (Bentzen
and Yarnold 2010), and simple calculations assuming
the T‘ value of 4 h mentioned above identify
Incomplete Recovery as a major problem indeed.
Considering these implications, for 3.85 Gy twice a
day given as 10 fractions in 5 days, the IR (incom-
plete recovery) due to the 6 h between the two frac-
tions, is 36% of the Recovery Proportion (Prec) of
56%, which is 20.2% of the first dose of 3.85 Gy, but
10.1% of each separate fraction each day, that is
41
10.1% of the total dose; a serious overdose immedi-
ately in comparison with calibration accuracy.
Further, the residual damage on the next day, at
18 h after the second dose, contributes to 4.5% of the
56% of the recoverable part of the second dose next
morning, leaving 2.5% of the second dose of the
previous day’s 3.85 Gy. (Plus 0.9% of the first dose of
the day still influencing the outcome, raising each
morning’s total IR to 3.4%). This is accumulated
(like compound interest) by 1.034 to the power 4 over
the 4 nights in the 5-day week = 1.143, thus by 14%,
although the 2-day interval at the weekend diminishes
the accumulation to zero, so that each week has no
more than the same 14% accumulation. Both aspects
of IR therefore appear likely to deliver 1.10 9
1.143 = 1.258%, thus about 26% overdose to the
whole treatment is predicted for late complications,
if T ‘ = 4 h. The equivalent late complications
EQD/3/2 of 52.7 Gy is then inflated to 66 Gy, in good
agreement with Bentzen and Yarnold’s estimation of
65–68 Gy which predicts a very high incidence
(75–82%) of moderate and severe late changes unless
strongly reduced volumes are treated.
This would certainly have been unacceptable, but in
very much worse percentages of Grades 2+ reaction
than the percentages reported clinically. There were
three reports summarized by Bentzen and Yarnold:
Chen et al. (2010), 4.2y 12/94 (13%)—‘‘Is volume the
NSABP problem?’’
Hepel et al. (2009) 1.3y 11/60 (18%)—
‘‘Unacceptabe’’
Jagsi et al. (2010) 2.5y 7/34 (21%)—‘‘Stopped’’
Two of the three were frankly unacceptable, and
unlikely to improve with longer follow-up, although
the numbers were small. The NSABP result is judged
marginally acceptable (Bentzen and Yarnold 2010)
with a strong warning about large volumes. But to the
author, to assume a mono-exponential T‘ is wrong,
and half of the additional overdose from Incomplete
Recovery could be avoided by spreading the overall
time beyond 4 days (Monday to Friday)–it is the
‘‘Accelerated’’ that more than doubles the overdose
from IR.
Even assuming that the T‘ = 4 h accounts for
no more than half of recovery, the remainder being
much faster, might not be enough to explain this
42 J. F. Fowler

Table 6 Recovery for 2F/day of 3.85, 2, 1.6, and 1.2 Gy per fraction assuming initially a mono-exponential T‘ of 4 h: Doses for
Late Complications (a/b = 3 Gy). CNS could be worse extra dose, in ratio 2.0/1.67
Dose/fraction 2F/d 3.85 Gy 2F/d 2 Gy 2F/d 1.6 Gy 2F/d 1.2 Gy 2F/d
Dt = 6 h T‘ = 4 h; Late
a/b = 3 Gy
Late RE-3 = (1+d/3) 2.283 1.667 1.533 1.40
LQ Recovery 1.283/2.283 0.667/1.667 0.533/1.533 0.4/1.4
Proportion 0.561 0.40 0.348 0.286
% IR @ 6 h 0.36 9 0.561 0.36 9 0.40 =14.4% 0.36 9 0.36 9 0.286=10.3%
=20.2% 0.348=12.5%
20.2% div by 14.4% div by 12.5% div by 10.3% div by
6 h IR/day 2 = 1.101 2 = 1.072 2 = 1.063 2 = 1.051

Overnight BED 4.5% 9 0.561 4.5% 9 0.40 4.5% 9 0.348 4.5% 9 0.286
18 h % IR Prop’n = 2.52% Propn = 1.8 Propn = 1.57% Propn = 1.287%
24 h % IR + 36% = 0.91 9 0.36(4 h) = 0.64 9 0.36 = 0.56 9 0.36 = 0.463
Tot Ov’nt % 18 = 24 h ? 18 ? 24 h = 2.44% 18 ? 24 h = 2.1% 18 ? 24 = 1.75%
2.52 ? 0.91= 3.43%
4d accum = So (1.034)4 =1.144 So (1.0244)4 = 1.101 So (1.0213)4= 1.088 So (1.0175)4 = 1.070
Accum/4d = Both = 1.101 9 1.144 = 1.072 9 1.101 =1.063 9 1.088 = 1.051 9 1.072
6 h RI+ Accum 4d 1.259 1.180 1.157 1.127
RI combined
Conclusions
If T‘ = 4 h only Extra 26% dose Extra 18% dose Extra 15.7% dose Extra 12.7% dose
(a/b = 3 Gy)
If the T‘ = 4 h component is 50% instead of 100% of the recovery, then half those extra %’s in the line above will apply:
13% 9% 7.9% 6.4%

large discrepancy of 75–82% down to *20%.
However, it does confirm the presence of the two
components as described by Fowler et al. (2004b),
and half of the excess of 26% in very good agree-
ment with the results of 13% reported by Chen et al.
Ling et al. (2010), in a recent major review, agreed
with two T‘’s of recovery for late complications.
Because tumors are more likely to have an even
wider range of genomic variation than normal tis-
sues, there is no reason why they should not be
different. However, their mostly higher a/b ratios
will cause lower rates of loss of effect in prolonged
dose delivery. Tumors however that have low a/b
ratios, such as Prostate and Breast (with a/b = 1.5
and 4 Gy respectively) are expected to behave like
late-responding normal tissues, as displayed for
various fraction sizes in Figs. 1 and 2 of Fowler
et al. (2004b).
While two fractions a day, especially in IMRT
or hypofractination regimes, are the most obvious
sources of IR risk, they can be made worse by treating
on 5 or 6 days a week (or definitely by using 7 days),
and diminished by using every-other-day treat-
ments—or simply once a day—and best of all by
choosing overall times longer than the obvious
apparent minimum overall times in spite of conve-
nience or cost concerns. Simple modelling could be
done, as here, but the big uncertainty is what to
assume for the T‘ values. More clinical effort needs
to be put into finding out urgently what these really
are for various late effects. Perhaps some non-lethal,
limited-volume, large-animal experiments could
speed up the acquisition of knowledge.
Even an apparently modest 2F/day schedule of 2F
9 2 Gy daily (5F/wk) delivers an IR of 40% (the
Recoverable Proportion at 2 Gy) 9 36% at a 6 h
interval = an overdose of 14.4% for the pair of doses
every treatment day, that is 7.2% for every fraction,
plus the 4-night 2.52% next-morning x its Recoverable
Proportion of 0.4 multiplied by (4.5 T‘’s ? 6T ‘’s)
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics
‘‘compound interest’’ of 1.0244 to the power
4 = 1.101, thus in total 1.072 9 1.101 = 1.18. This is
an overdose of 18% (every week continuing), appli-
cable to the whole total dose. An overdose of 18%
would be intolerable, which is perhaps why all the
2 Gy 9 2F/day regimes that have been tried in the
past have been abandoned. It is a coincidence, due to
the 5-day week, that the two types of IR (‘‘6 h gap’’
and ‘‘overnight accumulated’’) are rather similar in
amount.
A 2F/day regime of 1.6 Gy 9 2F/day would, with
the same assumption of T‘ = 4 h, give a Late IR of
34% 9 36% at 6 h = 12.5%/2 = 9 1.0625 ‘‘daily
6 h’’ overdose from the pair of doses, multiplied by
the overnight accumulation of 1.021 to the power 4,
that is 1.088 ‘‘compound interest’’ IR over the 4
nights each week, totalling together 1.063 9
1.088 = 1.157, which is a 15.7% overdose for the
whole treatment. If true, this would be hard to miss.
None of the clinical users of 1.6 Gy 9 2F/day
reported any such suspicion (Wang 1988; Fu et al.
2000; Leborgne et al. 2000; Trotti et al. 2005).
Finally, the lowest-dose-per-fraction 2F/day sche-
dule in use today is 1.2 Gy 9 2F/day. This delivers
28.5% Prec 9 36% at 6 h = 10.3% for the first, but
5.15% averaged for both doses of 1.2 Gy, repeated
‘‘daily at 6 h’’, plus 1.052 multiplied by 1.0175% to the
power 4 = 1.072 from the week’s overnight accumu-
lations, hence the total = 1.052 9 1.072 each
week = 1.12.8, that is, 12.8% total overdose from both
aspects of IR. This might or might not be large enough
to be obvious, until large numbers could be reviewed.
Apart from the previous example, the above quan-
titative examples of IR, using the T‘ of 4 h, amount to
a reductio ad absurdum for a mono-exponential
assumption of T‘ = 4 h only, and suggest that we
would then be over-estimating the overdosing from IR.
They help in the conviction that there is not just one
component of recovery with the 4 h mono-exponential
half-time. The examples of good schedules used in
Tables 2 and 3 do not contradict that impression being
mostly somewhat lower in the Late Complications
BED column than the expected 116.7 Gy3., as if
clinicians have learnt the hard way to allow for some,
but not huge, amounts of IR from 2F/day head & neck
schedules. I have to disagree with my respected col-
league Soeren Bentzen for his analyses of T‘ = 4 h
quoted at the beginning of this Section. I believe he has
analyzed correctly that there is a component of about
43
4 h involved in the IR—but it is only the longest of
several different recovery rates, probably accounting
for 40 to 60% of all the recoveries, from many animal
experiments. Alternatively, a single T‘ of 3 h would
also provide about half of the IR calculated for
T‘ = 4 h above, but the multiple rates of decay is the
more likely biological scenario, from a range of pos-
sible recovery processes.
Even if only half the recovery had a T‘ as long as
4 h (which I am convinced is the case because of the
T‘ = 4 h evidence described above and multiple
recovery rates (Dale et al. 1999; Fowler 2002).
A 6-h interval between two fractions as large as
3.85 Gy a day would give a 10.5% extra dose to late
complications due to that interval; and with overnight
incomplete recovery accumulated to a further 14%
increase of serious late complications. Since half of
all those extra percentages means multiplying the
original total dose by 1.05 9 1.072 = 1.13, which is a
13% overdose, and not the 26% calculated assuming
the T‘ of 4 h only. This is a good match to the
observation of Chen et al. as pointed out above.
A strong volume effect is also reported.
For 10F 9 3.85 Gy, the total dose of 38.5 Gy
delivers 88 Gy3 equivalent to an apparently safe late
BED of 52.8 Gy EQD/3/2, similar to the dose given
often by true EBRT, although volume constraints are
recommended. But if we assume that RI adds about
13% overdose instead of the 26% obtained assuming
a pure T‘ = 4 h, then the EQD would be just under
59 Gy EQD instead of *66 Gy; this overdose is
close to known tolerances of *60 Gy. It would not
be problematical for most patients, but is likely to
be for some, especially those with larger volumes
irradiated. Half of this overdose due to overnight
accumulation (5.5% of total) could be avoided
by going to every-other-day treatments; it is the
‘‘Acceleration to as short as one week’’ in the NSABP
project that provides just over half of the extra IR.
Future modeling can predict successful new
schedules if some additional Recovery and Repopu-
lation data are obtained from clinical results.
Further, for CAIR 1 (Maciejewski et al. 1996),
who treated 7 days a week and thus ran into a large
‘‘compound interest’’ probably exceeding 30% excess
late IR dose on their Late Effects. They interpreted
this as as ‘‘consequential acute damage’’, although it
was more probably Incomplete Late Recovery
instead, as suggested by my ‘‘117+’’ in Table 3.
44 J. F. Fowler

Table 7 Recommended modeling to check safety and effictiveness of schedules

TO EVALUATE ANY SCHEDULE
Calculate late complication BED = nd(1 ? d/[a/b]) with = 3 Gy (Barendsen 1982) No overall time factor, keeping \ 117 to
133 Gy3 = EQD3/2 70 to 80 at 2 Gy fr’s
Calculate Tumor BED (Eq. 7) with repopulation starting at Tk = 21 to 28 days, as Gy10, or as EQD10/2., as Log Cell
Kill = BED/2.303 *11 to 11.3 logs, and with Tp = 3d for H&N & lung Ca.Tk = 21 days. Then compare with known good
schedules. (Fowler 1989)
Calculate acute mucosal BED (Eq. 8) with repopulation starting at Tk = 7 days & Tp = 2.5d, a/b = alpha = 0.35/Gy. Keep
BED below 63 Gy10 = 52.5 EQD10/2. (Fowler et al. 2003c)
Calculate incomplete recovery (IR) for the Beta term, including overnight repair if 2F/day, Assuming two half times of repair,
50% of each, 24 min & 4 h. (Sects. 8.4 and 5) (Fowler et al. 2004b; Bentzen and Yarnold 2010)

Maciejewski et al. (1996) then modified their sche-
dule downwards and 4 days longer, a little more than
they needed to, but it certainly became safely
acceptable. The 4-day extension gave them more
saving of BED than their reduction of dose-per-
fraction.
All such extra effects of Incomplete Recovery of
radiation damage will be greater with larger doses per
fraction and with smaller a/b ratios. It is not only for
Acute Reactions that too-strong reactions can be
spared with a few extra days of Overall Time; mod-
eling can now distinguish between the two problems.
We now have the mathematical tools to examine the
risks of various schedules. We need more information
about individual timor repopulation rates, and a great
deal better information about Recovery Rates in all
tissues and tumors.
8.5 Incomplete Recovery as a Loss
of Effect in Prolonged Fractions
We are concerned with the time elapsed between
switching the beam onto a patient and the end of his
or her treatment for that fraction or session, including
setup time for alterations. Division into micropulses
or beamlets and spaces is irrelevant regarding the
average gross dose rates—up to now (2011).
Fowler et al. (2004b) considered this question
assuming that two components of recovery were
operative in mammalian tissues, 50% of T‘ 24 min
(0.4 h) and 50% of 4 h; and assuming the LQ model
with its RE and BED modeling as described in the
previous Sections to define the Recoverable Propor-
tion (Prec) of any dose fraction. Their diagrams are
still entirely relevant to this topic.
A thorough review of the repair and recovery
processes and their dependence on fraction size and
probable dependence on the LQ model was published
recently by Ling et al. (2010). No new reliable clin-
ical or animal data have been presented in the inter-
vening six years, but more cell culture data has been
published, without being particularly relevant to live
animal or human data; hence our choice of the word
‘‘recovery’’ instead of just ‘‘cell repair’’. Ling et al.
(2010) agreed with our choice of the two components
for Late Normal Tissue Damage, but found no
evidence for two components in tumor data, perhaps
because of the absence of clinical and animal data.
Thus their conclusions about the loss of effectiveness
in a one-hour dose-fraction (instead of 2 or 3 min
duration), agreed with those of Fowler et al. (2004b),
of 17–23% loss of BED during a fraction of 10 Gy) in
normal tissues. They preferred not to comment on
larger doses per fraction; I do not see why not, since
Fowler, Welsh, and Howard did. It is all up for
disproving!
They (Ling et al. 2010) also agreed that the loss of
BED in most tumors (with a/b *10 Gy) would be
less, at a speculated half of ours (12–15%). However,
Ling et al. saw no evidence for any repair other than
single-exponential in tumors and chose a modest loss
rate with a long T‘ of 3 or 4 h (their Figure 1), which
might be minimzing the loss in tumors. Although the
predicted losses were similar to those of Fowler et al.
(2004b) at the bend in their two-component curve at
one hour, the fall was faster with the latters’ two-
component model before one hour and slower after an
hour. We are still greatly in need of some reliable
clinical data both for tumors and late complications.
Any such losses of effectiveness will be greater
with larger dose-per-fraction and with lower a/b ratio.
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 45

Table 8 Examples of good schedules for H&N radiation-only treatments. Note that all the 2F/d treatments are better than the 1F/d
treatments, the last nine of which are relatively poor
Schedule Ov.T Tumor Log10
EQD Cell Kill
(A) Two fractions a day, Ten fractions a week, Recommended
41 9 39 d 62.67 11.43
1.8 = 73.8 Gy
48 9 42 d 62.69 11.44
1.6 = 76.8 Gy
52 9 43 d 62.65 11.43
1.5 = 78.0 Gy
62 9 45 d 62.69 11.44
1.3 = 80.6 Gy
70 9 48 d 63.00 11.49
1.2 = 84.0 Gy
Note that all of these are above 11.4 Tumor Loge Cell Kill
(B) One fraction a day, Five treatment days a week, not as good as 2F/day (as above in Part A)
Note the importance of using the calculated Practical Overall Times and not any shorter schedule. Even if it looks possible in the
reduced number of days, it is not safe.
OE marks the only 1F/d schedules exceeding 11.0 Log10 Cell Kill
Schedule Ov.T Tumor Log10 Comment
EQD Cell Kill
15 9 18 d 58.22 10.62 Dose/Fr limited by acute reaction (also by Late constraint of 70 Gy for
3.450 = 51.75 Gy a/b = 3)
15 9 21 d 60.34 OE But at 3 days longer, acute reation is tolerable at the higher dose/Fr
3.559 = 53.39 Gy 11.01
16 9 21 d 61.00 OE This is the Best combination of dose and overall time for 1 Fr/day. It is a
3.412 = 54.59 Gy 11.13 higher Tumor EQD than 15F because one extra fraction of slightly smaller
size delivers this peak, even at 4 days longer overall time.
18 9 25 d 60.13 10.97 But now, with 2 more fractions, this total dose needs more days to keep
3.158 = 56.84 acute response tolerable – and this is too long, so Tumor EQD is lower.
19 9 28 d 59.09 10.78 No Tumor EQD improvement. All these schedules deliver the same risk of
3.047 = 57.89 ‘‘Late’’ complication at the ‘‘Late’’EQD of 70 Gy.
20 9 28 d 59.99 10.88 Tumor EQD now improving again
2.944 = 58.88
21 9 28 d 60.21 10.98 Back up to the 18 fraction level
2.849 = 59.83
22 9 28 d 60.74 OE Even better—just above 11 Logs10. Another peak: not quite as good as 16F
2.761 = 60.74 11.08 in 21 d.
23 9 28 d 60.15 10.97 Fairly good
2.679 = 61.62
24 9 28 d 60.11 10.96 Fairly good
2.603 = 62.47
25 9 32 d 60.03 10.95 Fairly good
2.531 = 63.28
26 9 35 d 58.84 10.73 Falling back again—now too long. Schedules with 27–35 fractions are
2.464 = 64.06 successively lower in Tumor Log Cell Kill, falling from 10.71 to 10.26, as
shown in Figs. 11 and 12.
Assuming that c50 = 1.7 for H&N, a 3% change of EQD means a change of 5% in Local Control. At the center of this range, the
3% of EQD is about 2 Gy EQD or a difference in Log10 Cell Kill of approx 0.3
46
9 Conclusions
The present LQ and BED modeling has continued to
be used widely (Fowler 2010) including its variants
like the High LET variant (Dale and Jones 1999) and
the Acute Mucosal Tolerance Grey Zone (Fowler
2003c). Table 7 summarizes the four types of rela-
tively simple calculations now considered necessary
to evaluate any new or proposed schedule. This
chapter ends with discussions demonsrtating the need
to obtain better information about individual tumor
repopulation and any repair data preferably from
clinical trials and animal experiments.
For 1F/day schedules, IR adds no significant
radiation effect with doses per fraction less than about
2 Gy, unless schedules like the CAIR 1 schedule of
Maciejewski et al. (1996) with no gaps at weekends is
used. For 2F/day schedules however, some calcula-
tions may become necessary, but decreasingly for
smaller doses per fraction, as can be found out with
experience. Any schedules can be calculated for
Incomplete Repair (IR) with the best T‘ data avail-
able, with equal attention to the 6-hour interval every
day and to the residual overnight IR after the 18 h gap
before giving the first dose next day, accumulating
this over one week only, if one or two full days
off radiation occur. Sections 8.4 and 5 gave worst-
case IR calculations assuming a single component of
T‘ = 4 h resulting in an estimate for two fractions-
a-day of 3.85 Gy, of 10% extra dose from IR equally
every day, plus an overnight contribution of about
14% making a possible total of 26%, but more likely
about half that as reported by Chen et al. (2010). This
is evidence for the two half-times of Recovery
described by Fowler et al. (2004b). As both authors
have emphasized, better Recovery data is required
which is a very present challenge. For smaller doses
per fraction of 2 Gy and below, as used in H&N
radiotherapy, the extra dose from IR is likely to be no
more than 6 to 10%,—unless some schedule giving
only one or zero days of gap at weekends becomes
used. In future, attention should be paid to Incomplete
Recovery, particularly if doses per fraction larger than
2 Gy are used in IMRT.
Preferably with more animal experiments, and
above all with carefully collected clinical data
whenever possible.
J. F. Fowler
There remains only to indicate some near-optimum
schedules for practical head and neck radiotherapy.
These schedules are jntended to give accurately
tolerable schedules without chemotherapy, and at
present without Incomplete Repair correction,
because of the uncertainties described above about the
proportions of various T‘ times, especially those of
the longest.
Table 8 lists the best schedules calculated for
head and neck radiotherapy using the constraints
described in this chapter. Part A is for 2F/day which is
definitely recommended because all those sched-
ules give 0.4 log10 more Tumor cell Kill than any of
the 1F/day schedules, more so for slightly slower
growing tumors. Some of the small changes, up or
down, caused by giving an extra fraction in an extra
day or two, can be traced in Table 8 and in Fowler
2008a.
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 Radiobiology of Stereotactic Radiosurgery
and Stereotactic Body Radiation Therapy
Chang W. Song, Heonjoo Park, Robert J. Griffin,
and Seymour H. Levitt
Contents
1 Introduction..............................................................
2 Vascular Factors in SRS and SBRT .....................
2.1 Vascular Changes in Tumor by Radiation ...............
2.2 Implication of Vascular Damage for SRS
and SBRT ..................................................................
3 Role of 4 Rs in SRS and SBRT .............................
3.1 Reoxygenation ...........................................................
3.2 Repair of sub-lethal Radiation Damage ...................
3.3 Redistribution.............................................................
3.4 Repopulation ..............................................................
4 Linear-Quadratic Model in SRS or SBRT...........
References..........................................................................
C. W. Song (&)
H. Park
R. J. Griffin
S. H. Levitt
Department of Therapeutic Radiology-Radiation Oncology,
University of Minnesota, 420 Delaware St. SE,
Mayo Mail Code 494, Minneapolis, MN 55455, USA
e-mail: songx001@umn.edu
H. Park
Inha university, Inchon, Korea
S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_264, Ó Springer-Verlag Berlin Heidelberg 2012
Abstract
In recent years, increasing number of cancer
52 patients are treated with stereotactic radiosurgery
53 (SRS) or stereotactic body radiation therapy
53 (SBRT), which deliver hypofractionated irradia-
tion with high-dose per fraction . It is highly likely
54
that the radiobiological principles such as 4 Rs
56 (Reoxygenation, Repair, Redistribution, Repopu-
56 lation) for the conventional fractionated radiother-
57
57 apy with small-dose per fractions do not apply for
58 SRS and SBRT. Reoxygenation: When tumors are
exposed to high-dose per fraction, e.g. [10 Gy,
58
significant vascular damage will occur. Conse-
59 quently, intratumor environment becomes hypoxic
and acidic, which not only will prevent reoxygen-
ation of hypoxic cells but also will cause indirect
cell death. Repair: delivery of SRS or SBRT lasts
considerable lengths of time, which may allow
repair of sub-lethal radiation damage during the
irradiation exposure. Redistribution: high-dose
irradiation prevents cell cycle progression and
cells undergo interphase death in the cell cycle
phases where they are irradiated. Repopulation:
Since SRS or SBRT treatment is completed within
1-2 weeks, repopulation of tumor cells during the
course of treatment may be negligible. The linear-
quadratic (LQ) model , which is used to calculate
isoeffect doses for different hyperfractionated
irradiation schemes, may be applied for hypofrac-
tionated SRS or SBRT, provided that indirect cell
death due to vascular damage is negligible.
51
52
1 Introduction
In the early era of radiotherapy which began soon
after X-rays were discovered in 1895, tumors were
irradiated with high-doses of X-rays in a single frac-
tion. However, by the 1930s, it was realized that
irradiation with multiple fractions of small doses is
more effective than irradiation with a large single
dose for causing cancer control and sparing normal
tissue late damage (Coutard 1932). Relevant to such
clinical observations, irradiation of the scrotum of
rams with fractionated daily irradiation was found to
be more effective than a single large dose irradiation
to sterilize the rams without causing severe skin
damage (Hall 2006). These early clinical and radio-
biological observations led to the development of
current practice of fractionated radiotherapy, where
tumors are irradiated 30–70 tines with small fractio-
nated doses, e.g. 1.2–2.0 Gy, over several weeks.
Further clinical and radiobiology research revealed
that tumor response and normal tissue damage caused
by fractionated radiotherapy are governed by 4
radiobiological principles at cellular and tissue levels,
which are commonly referred to as 4 Rs, that is,
Reoxygenation, Repair of sublethal damage, Redis-
tribution of cells in the cell cycle and Repopulation of
cells (Withers 1975; Hall 2006). The introduction of
the linear-quadratic model (LQ model) in 1980s based
on radiobiological observations with tumor cells or
experimental tumors and normal tissues made it
possible to calculate cell killing by different total
dose, size of fraction and fraction number in radio-
therapy (Fowler 1989). With the support of these
radiobiological principles, fractionated radiotherapy
with small dose per fraction has been the major reg-
imen of radiotherapy for treating divergent cancers in
the past.
However, interest in hypofractionated radiotherapy
with high-dose per fraction has resurged in recent
years mainly influenced by the rather encouraging
clinical outcomes of stereotactic radiosurgery (SRS)
of brain tumors, which delivers high-doses of radia-
tion, e.g. 15–25 Gy, to brain lesions in 1–2 fractions.
This unique technique was developed in 1950–1960
initially to deliver a large dose of radiation to non-
malignant vascular lesions in brains using a 60Co unit
(gamma knife) (Leksell 1951), but it is now used to
treat brain tumors, mainly inoperable intracranial
C. W. Song et al.
metastases (Leksell 1983). The concept and technique
of SRS have then been adapted to irradiate extra-
cranial tumors, which is generally referred to as ste-
reotactic body radiation therapy (SBRT). The recent
remarkable improvements in tumor imaging techni-
que and radiation delivery system now make it pos-
sible to accurately and precisely deliver high-dose
radiation to target tumors (Potters et al. 2004; Levitt
et al. 2008). Numerous clinical trials conducted
throughout the world clearly demonstrated that SBRT
with doses up to 60–70 Gy in 1–5 fractions is often
effective to eradicate various malignant tumors in
lung, breast, liver, prostate and spine with generally
acceptable levels of normal tissue damage (Timmerman
et al. 2007; Timmerman 2008; Yamada et al. 2008;
Kavanagh 2008; Dolinsky and Glatstein 2008; Milano
et al. 2008; Whelan et al. 2008; Ritter 2008; Nedzi
2008; Timmerman et al. 2010).
In the mean time, a legitimate question arose as to
whether or not the radiobiological principles such as 4
Rs play any role in the response of tumors to SRT and
SBRT (Hall and Brenner 1993; Dolinsky and
Glatstein 2008, Milano et al. 2008; Story et al. 2008).
Another important question is whether the LQ model
which is widely used to calculate the effect of total
dose and dose per fraction in conventional fraction-
ated radiotherapy can be applied for SRS and SBRT
(Brenner et al. 1995; Fowler et al. 2004a, b; Brenner
2008; Kirkpatrick et al. 2008; Ritter 2008; Park et al.
2008).
Blood vessels are important components of tumors,
which directly control the intratumor microenviron-
ment and thus the survival and proliferation of tumor
cells. Therefore, changes or damage in tumor blood
vessels by radiation will markedly impact the out-
come of radiotherapy by altering intratumor envi-
ronment such as oxygenation status or acidity. It is
therefore important to elucidate the effects of high-
dose irradiation on tumor vasculatures for effective
use of SRS or SBRT. Most of the previous studies on
the radiation-induced vascular changes in human
tumors have been aimed at gaining insights into the
vascular changes caused by fractionated irradiation
with low-dose per fraction. In this chapter, we will
first address the vascular damages in tumors caused
by high-dose fraction irradiation, and its potential
implication for the treatment outcome of SRS or
SBRT, and will discuss the role of 4 Rs in the
response of tumors to SRS or SBRT. Finally we will
Radiobiology of Stereotactic Radiosurgery
discuss whether LQ model is applicable for modeling
SRS and SBRT.
2 Vascular Factors in SRS and SBRT
2.1 Vascular Changes in Tumor
by Radiation
The tumor blood vessels are formed by angiogenesis
through sprouting or intus-susceptive microvascular
growth, vasculogenesis by progenitor and other stem-
like cells from the blood and bone marrow and
co-option of neighboring vessels in normal tissues
(Folkman 1985; Hammersen et al. 1985, Konerding
et al. 1998; Dewhirst et al. 1996; Yancopoulos et al.
1998; Jain 2003). The structure and physiological
aspects of vascular bed in tumors are markedly dif-
ferent from those in normal tissues (Jain 1989; Vaupel
et al. 1989; Konerding et al. 1998; Endrich and
Vaupel 1998; Song 1998; Dewhirst et al. 1996) and
thus the hastily formed immature capillary-like tumor
blood vessels are composed of single-layer endothe-
lial cells often separated by gaps between the endo-
thelial cells occupied by tumor cells without
underlying basement membrane. As such, tumor
vessels are highly leaky as compared with normal
tissue blood vessels (Song and Levitt 1971a, b).
Furthermore, tumor vessels are frequently devoid of
innervations and thus they are unable to autoregulate
in response to external stresses such as ionizing
radiation. Unlike the well-organized web-like net-
work of capillaries in normal tissues, tumor blood
vessels are irregular in diameter, often sharply bent,
tortuous, sinusoidal and branched with multiple dead
ends. Consequently, the blood perfusion through such
disorganized and rough tumor vascular networks is
sluggish, and intermittently stationary. Furthermore,
fractions of tumor perfusion are shifted often to
arteriole-venous shunts. Because of the lack of ade-
quate draining through the lymphatic system in vas-
cular networks in combination with elevated leakness
of blood vessels, the interstitial pressure of tumors is
significantly elevated leading to collapse of small
capillary-like tumor blood vessels intermittently or
permanently. However, the structural and functional
features of the vascular bed in slowly-growing human
tumors are less pathologic than those in fast-growing
animal tumors or human tumors growing in window
53
chambers. Nevertheless, the abnormal features of
tumor vasculatures probably account for the hypoxic,
nutritionally deprived and acidic intratumor micro-
environment, and also the differential response of
tumor and normal tissue to ionizing radiation (Lee
et al. 1997; Song 1998; Vaupel 1996; Endrich and
Vaupel 1998; Park et al. 2000; Dewhirst et al. 1996).
The important role of tumor blood perfusion in the
response of tumors to radiotherapy was reported as
early as in 1936 by Mottram (1936), who observed
that the regions in tumors with good blood supply
were more vulnerable to radiation than those lacking
adequate blood supply. The subsequent demonstra-
tions that oxygen supply through blood perfusion
greatly impacts the radiosensitivity of tumor cells
prompted many investigators to elucidate the effects
of radiation on tumor vasculatures. Although a variety
of tumors were studied and different methods were
used for assessing the radiation-induced vascular
changes, the conclusions of the studies were similar:
when human tumors are treated with conventional
fractionated radiotherapy with 1.5–2.0 Gy per frac-
tion, the blood perfusion tends to increase during the
early period of treatment, but returns to the pre-irra-
diation levels or declines to the levels lower than that
before the treatment toward the end of treatment
(Mäntylä et al. 1982; Pirhonen et al. 1995; Marry
et al. 1996). In a recent study by Ng et al. (2007),
vascular changes in human non-small-cell lung cancer
were determined after irradiation with 9, 18 and
27 Gy in 4.5 Gy per fraction. The functional vascu-
larity significantly increased in the tumor rim while it
increased only slightly in the tumor center. It was
possible that the blood vessels in the tumor rim were
of normal tissue origin and thus dilated upon irradi-
ation, similar to the blood vessels in other normal
tissues.
Much of present knowledge on the effects of high-
dose fraction radiation on tumor blood vessels are
obtained using animal tumor models or human tumor
xenografts. It has been shown that an irradiation with
high-doses, i.e. 10 Gy or higher, in a single fraction
causes severe vascular damage in human tumor xe-
nografts (Bruberg et al. 2006; Kioi et al. 2010) or
animal tumors (Song and Levitt 1971a, b; Song et al.
1972, 1974; Wong et al. 1973; Clement et al. 1976,
1978; Chen et al. 2009; Fenton et al. 2001). Figure 1
shows the changes in tumor volume, intravascular
volume (vascularity) and the rate of extravasation of
54
Fig. 1 Effects of 30 Gy irradiation in single dose on the tumor
weight (as an indication of tumor size) (a), intravascular
volume (b) and extravasation rate of plasma protein (c) in
Walker 256 carcinoma grown subcutaneously in the leg of
Sprague–Dawley rats. The solid lines in a, b and c indicate the
means of 6–10 tumors used at the different time points
indicated. The dotted lines in b and c are the mean values of
15 control tumors weighing 0.3–2.0 g; the shaded areas show
the range of standard error of the mean
plasma protein (vascular permeability) in the Walker
256 carcinoma of rats after irradiation with 30 Gy in a
single dose. The tumor weight or size continuously
increased for 7–8 days after irradiation and then
markedly decreased until 15 days after irradiation.
The vascular volume significantly decreased within
one day after irradiation and further decreased for
about 12 days and then began to recover. The
extravasation rate of plasma or vascular permeability
significantly increased soon after irradiation, declined
thereafter until 12 days post-irradiation and then
began to recover. The continuous increase in tumor
size for several days after irradiation with 30 Gy may
be ascribed to delayed disintegration of dead cells and
induction of edema as a result of increased vascular
permeability. Although the tumor size began to
increase from about 15 days post-irradiation, it is
possible that proliferation of tumor cells began before
C. W. Song et al.
the recovery of tumor size became visible (Hermens
and Barendsen 1969). In this connection, it was of
interest that the tumor vasculature began to recover
2–3 days prior to the recovery of tumor size sug-
gesting that proliferation of tumor cells and recovery
of vasculatures are closely related. It has been
reported that the recovery of tumor vascularity after
irradiation is due to vasculogenesis using stem-like
cells in the blood circulation (Kioi et al. 2010). As
shown in Fig. 1 and also reported elsewhere (Wong
et al. 1973; Song et al. 1974), the functional vascu-
larity in tumors decreases within several hours after
irradiation with doses higher than 10–15 Gy. Such a
rapid decline in functional vascularity after high-dose
irradiation may be due to death of endothelial cells
and also, at least in part, due to collapse of the fragile
tumor vessels as a result of an increase in the inter-
stitial fluid pressure caused by extravasation of
plasma protein (Fig. 1) (Wong et al. 1973; Song et al.
1972, 1974). The endothelial cells in tumors have
been reported to undergo ceramide-mediated apop-
tosis soon after irradiation of the tumors with doses
higher than 8–10 Gy leading to indirect tumor cell
death (Garcia-Barrps et al. 2003; Fuks and Kolesnick
2003). The late decrease in functional vascularity in
irradiated tumors may be attributed not only to the
direct effect of radiation on the tumor vasculatures but
also to the disorganization in vascular networks
resulting from the shrinkage of tumor volume (Song
et al. 1974). It has been demonstrated that the blood
vasculatures in the inner regions of tumors are pref-
erentially destroyed as compared with those in the
tumor periphery (Ng et al. 2007; Fenton et al. 2001),
and that the blood vessels in smaller tumors are more
radiosensitive than those in larger tumors (Song and
Levitt 1971b). Parts of vascular networks in the tumor
periphery are normal tissue blood vessels that are
incorporated into the tumor mass, and thus they might
be relatively resistant to radiation as compared to the
newly formed tumor blood vessels.
2.2 Implication of Vascular Damage
for SRS and SBRT
The survival and proliferation of tumor cells are
directly dependent on the blood supply. Therefore, it
would be reasonable to anticipate that vascular dam-
age by irradiation will cause indirect death in tumor
Radiobiology of Stereotactic Radiosurgery
cells. Denekamp (1984) pointed out that one endo-
thelial cell subtends a segment of a tumor cord con-
taining as many as 2000 tumor cells. Since the blood
vessels are serial tissues, injury even at a single focal
point of vessels may obstruct or completely halt the
down-stream blood flow, thereby causing an ava-
lanche of tumor cell death along the defunct vessels.
The recent clinical studies conducted at a numer-
ous institutes have demonstrated that SRS of cranial
tumors with about 20 Gy in 1–2 fractions or SBRT of
extracranial tumors with 20–60 Gy in 1–5 fractions
are highly effective in achieving local tumor control.
For example, SRS with 20–24 Gy in a single expo-
sure produced local control in more than 80% of brain
metastases (Shiau et al. 1997; Vogelbaum et al. 2006;
Kim et al. 2010). Similarly, 90% local control could
be achieved when metastatic spinal lesions were
treated with 18–24 Gy in a single dose (Yamada et al.
2008). In a phase II study for stage 1 non-small-cell
lung cancer, the local control rate was 95% after
treating the tumors with 3 fractions of 20 Gy (total
60 Gy)(Timmerman et al. 2010). Importantly, these
rather high-tumor responses occurred despite the fact
that significant fractions of clonogenic cells in human
tumors are hypoxic. In an effort to reveal the bio-
logical mechanisms underlying the response of
tumors to SBRT, Brown et al. (2010) evaluated the
expected level of cell killing by different regimens of
SBRT. The mathematical calculation showed that
irradiation with 25 Gy in a single exposure will
reduce the cell survival by 3.3 logs and 20 Gy 9 3
irradiation will reduce cell survival by 7.7 logs
assuming that the a/b ratio of the tumor cells is 10,
and 20% of the tumor cells are hypoxic. It was con-
cluded that even the 60 Gy/3-fraction regimes is
barely sufficient to control a small tumor. Fowler et al.
(2004b) concluded that, for the control of 1–10 gm
tumors with SBRT, three fractions of at least 23 Gy
(3 9 23 Gy) is needed to reduce viable hypoxic
tumor burden to 10-10–10-11 if it is assumed that
20% of tumor cells are hypoxic, oxygen enhancement
ratio is 3, no reoxygenation occurs and no repopula-
tion of tumor cells occurs during the course of treat-
ment. One may then wonder how the impressive
clinical results could be obtained as indicated above
by SRS or SBRT overcoming the hypoxic protection
with such insufficient radiation doses. It seems
imperative to conclude that extreme hypofractionated
radiotherapy is capable of overcoming hypoxic
55
Fig. 2 Contribution of direct death and indirect death due to
vascular damage to total clonogenic death of cells in tumors
irradiated with various doses of radiation in a single fraction. In
the tumors, 10% of tumor cells are assumed to be hypoxic cells.
The dotted lines indicate the response of oxic (- - - - -) and
hypoxic (– – – –) tumor cells in the tumors. The response at
doses 0–5 Gy is dominated by oxic cells (a), while that at
5–12 Gy is dominated by hypoxic cells (b). As radiation dose is
increased above 12 Gy, indirect cell death due to vascular
damage prevails (c)
radioprotection through mechanisms other than
directly killing tumor cells via DNA damage such as
immune response and damage to vasculature (Brown
and Boong 2008; Brown et al. 2010). In support of
this conclusion, Kirkpatrick et al. (2008) and Kocher
et al. (2000) reported that the total cell death in the
tumors receiving SRS or SBRT is the product of cell
death directly caused by radiation and the cell death
indirectly caused by radiation-induced vascular/stro-
mal damage. Relevant to this contention, Clement
et al. (1978) reported that irradiation of rodent tumors
with 10–20 Gy in a single dose caused vascular
damage, which then killed a substantial proportion of
hypoxic tumor cells. Figure 2 illustrates a possible
contribution of direct death of tumor cells and indirect
tumor cell death caused by vascular damage to the
total clonogenic cell death after irradiation of tumors
with various doses. In this calculation, 10% of the
tumor cells were assumed to be hypoxic. The initial
steep decline in the cell survival by irradiation with
doses lower than 5 Gy corresponds to the direct
killing of oxic cells by radiation while the subsequent
56
shallow phase of the survival curve between 5 and
12 Gy irradiation relates to the death of hypoxic cells
by direct effect. When tumors are exposed to doses
higher than 10–12 Gy, indirect cell death due to
vascular damage becomes predominant, which is
demonstrated by the second sharp decline in cell
survival. The relative importance of direct death
versus indirect death to the total death of tumor cells
after SRS or SBRT will depend on the size of fraction.
A recent development in cancer biology is the
realization that small fractions of tumor cells in human
tumors are self-renewing cancer stem cells which are
radioresistant and thus give rise to relapse after the bulk
of non-stem cancer cells are killed by radiotherapy
(Dean 2006; Baumann et al. 2008). Interestingly,
tumor perivascular niche has been identified as the
home of cancer stem cells and that the tumor endo-
thelial cells supply factors that maintain the cancer
stem cells in a self-renewing and undifferentiated state
(Calabrese et al 2006; Charles and Holland 2010). It is
therefore conceivable that eradication of cancer stem
cells as a result of death of endothelial cells and
destruction of vasculatures might be an additional
explanation why extreme hypofractionated radiother-
apy with relatively small total doses, e.g. 20 Gy, are
capable of inducing tumor control.
It should be noted that SBRT or SRS are not always
given with extremely high-dose fractions. For instance,
human prostate tumors were treated with 36.15 Gy in 5
fractions of 7.23 Gy (Pawlicki et al. 2007). Treating
brain metastases with 36 Gy in 6 fractions or 20 Gy in a
single exposure exhibited similar survival time while
the fractionated irradiation was less toxic to patients
(Kim et al. 2010). When tumors are treated with such
fractions, indirect cell death due to vascular damage
may be negligible particularly in tumor periphery
regions in which most of blood vessels are of normal
tissue origin. In fact, irradiation of non-small-cell lung
cancer with 4.5 Gy per fraction up to total dose of
27 Gy was reported to increase blood perfusion in
tumor rim (Ng et al. 2007).
3 Role of 4 Rs in SRS and SBRT
It is well-known that the effectiveness of fractionated
radiotherapy with multiple small doses is directly
influenced by the following four radiobiological prin-
ciples which are referred to as 4 Rs: Reoxygenation of
C. W. Song et al.
hypoxic tumor cells, Repair of sub-lethal radiation
damage, Redistribution of cells in cell cycle phases and
Repopulation of cells (Withers 1975; Hall 2006). In
this section, the possible role of 4 Rs in the response of
tumors to SRS or SBRT is discussed.
3.1 Reoxygenation
Varying fractions of clonogenic cells in tumors are
radio-resitant hypoxic cells. However, when tumors are
treated with conventional fractionated radiation with
small dose per fraction, proportions of hypoxic cells
are reoxygenated during the interval of fractions
(Van Putten 1968; Howes 1969; Kallman 1972;
Clement et al. 1978; Hall 2006). It is believed that such
reoxygenation of hypoxic cells and resultant restora-
tion of radiosensitivity is the major benefit gained by
treating tumors with multi-fractionated radiotherapy.
The reoxygenation of hypoxic cells is believed to occur
as a result of death of oxic tumor cells and resultant
decline in oxygen demand enabling oxygen to diffuse
from blood vessels to previously hypoxic regions
(Clement et al. 1976, 1978). Therefore, vascular dam-
age by radiation will prohibit reoxygenation of hypoxic
tumor cells. This implies that reoxygenation of hypoxic
cells may not occur after tumors are treated with high-
dose fraction SRS and SBRT because of vascular
damage. Instead, it is likely that, as discussed in the
previous section, varying proportions of hypoxic cells
as well as oxic cells may undergo secondary death
following treatment with high-dose fraction SRS or
SBR. It should be emphasized that the extent of vas-
cular damages by irradiation are usually heterogeneous
throughout the tumor volume. It is therefore likely that
some regions in tumors may remain oxic and some
hypoxic cells may even undergo reoxygenation
although the overall oxygen supply to tumor will be
markedly diminished when tumors are treated with
high-dose fraction SRS or SBRT. Contrarily, certain
extent of reoxygenation may be expected to occur in the
tumors treated with mildly fractionated SRS or SBRT,
e.g. 3–8 Gy per fraction, because vascular damage will
be insignificant in such tumors.
There have been interesting discussions in recent
years as to whether SRS or SBRT should be applied in
a single fraction or multi-fractions (Hall and Brenner
1993; Ling et al. 2006; Fowler 2007; Dolinsky and
Glatstein 2008; Story et al. 2008). Hall and Brenner
Radiobiology of Stereotactic Radiosurgery
(1993) concluded that SRS of brain tumors should be
given in 5 or 6 fractions instead of a single fraction to
take advantage of reoxygenation of hypoxic cells and
also to reduce the late complication of normal tissues.
Fowler (2007) also strongly argued that SBRT should
be fractionated with several doses, even two or three, in
order to allow hypoxic cells to undergo reoxygenation
so that the tumors become sensitive to subsequent
irradiation. It must be emphasized that the fraction size
should be small enough to avoid significant vascular
damage when SRS or SBRT are fractionated in order to
induce reoxygenation of hypoxic cells.
In summary, when tumors are treated with a single
fraction or extremely high-dose fraction SRS or
SBRT, the intratumor environment will become
hypoxic leading to secondary cell death due to vas-
cular damage. However, reoxygenation of hypoxic
cells may occur in the tumors treated with hypofrac-
tionated irradiation with relatively low-dose per
fraction, i.e. \10 Gy.
3.2 Repair of sub-lethal Radiation
Damage
The extent of repair of sub-lethal damage in irradiated
cells greatly influences the fate of the cells (Elkind
and Sutton 1960; Belli et al. 1966). It has been shown
that the repair rate of radiation damage is related to
various factors such as dose per fraction, dose rate and
the nature of the tissue or cells (Ang et al. 1987; Hall
and Brenner 1991; Fowler et al. 2004a, b). In treating
tumors with conventional fractionated irradiation, the
delivery of 1.2–2.0 Gy is completed in a short period.
Therefore, repair of sub-lethal damage during the
radiation exposure is negligible. On the other hand,
the delivery of large doses of radiation in treating
tumors with SRS or SBRT usually lasts considerably
long times, and thus substantial repair of sub-lethal
radiation damage may occur during the radiation
exposure (Fowler et al. 2004a; Ling et al. 2010). It has
been known that the repair kinetics of sub-lethal
radiation damage in irradiated cells is biphasic. It was
reported that the median half-time of the faster
components is about 0.3 h while that of subsequent
slow components is about 4 h (Fowler et al. 2004a).
Therefore, at least 10% of biological effectiveness is
lost due to the repair of damage when irradiation
exposure lasts longer than half an hour such is the
57
case in treating tumors with SRS or SBRT. The loss
of biological effectiveness due to repair of sub-lethal
radiation damage is expected to be greater for late
complications in certain normal tissue than tumors
because the a/b ratio for normal tissues is usually
lower than that for tumors. Additionally, the vascular
injury and ensuing chaotic intratumor environment
such as hypoxic, acidic and nutritionally-deprived
environment caused by high-dose fraction SRS and
SBRT, may significantly hinder the repair of radiation
damage. Needless to mention, no repair would occur
after treatment with an ablative radiation dose.
In summary, when tumors are treated with SRS or
SBRT, considerable repair of sub-lethal radiation
damage may take place during the prolonged radiation
exposure. The estimated loss of radiation effect due to
repair of radiation damage is greater than 10% when
the irradiation of tumors lasts longer than 30 min.
3.3 Redistribution
Ionizing radiation delays cell cycle progression by
causing dose-dependent arrest of cells in the cell cycle
phases. The extent and kinetics of cell cycle arrests by
irradiation vary depending on phase of the cell cycle,
cell type and microenvironment. The G1 arrest is
absent or negligible in many cell types after irradiation
with doses lower than several Gy, and the S-phase
delay usually occurs after irradiation with relatively
low radiation doses, i.e. 1–5 Gy. The G2 arrest occurs
after irradiation with doses as low as 1 Gy in practi-
cally all types of mammalian cells. Therefore, G2
arrest is far more pronounced than G1 arrest or S-phase
delay. The transient arrests of cells in different phases
of the cell cycle are caused by activation of cell cycle
checkpoints, which are to prevent the progression of
cells into next cell cycle phase before the radiation-
induced damage is repaired. For example, G1/S
checkpoint inhibits the progression of G1 cells with
damaged DNA into S-phase. This process allows cells
to repair DNA damage and prevents the duplication of
damaged DNA if the cells with the damaged DNA
progress into S-phase. Likewise, during G2 arrest that
is caused by G2/M checkpoints, damages in DNA are
repaired before cells enter mitosis. If cells enter mitosis
with incompletely repaired DNA, they may be unable
to complete the complicated mitosis and die, which is
termed mitotic death or post-G2 apoptosis. When cells
58 C. W. Song et al.

are irradiated with moderate doses of radiation, the cell

cycle arrest eventually disappears and the distribution
of cells though the cell cycle phases is restored to pre-
irradiation state, which is referred to as redistribution
of cell cycle. However, after an exposure to rather
high-doses of radiation, cells tend to be arrested
indefinitely in the cell cycle phases in which they are
irradiated, and undergo apoptosis or necrosis, that is,
cells die in the G1 phase, S-phase or G2 phase wher-
ever they were at the time of irradiation. As shown in
Fig. 3, a pronounced G2 arrest occurred in HL-60 cells
after irradiation with 4 Gy. Thereafter, small fractions
of cells progressed into G1 phase while the majority of
the cells died of apoptosis. On the other hand, after
irradiation with 20 Gy, there was no change in cell
cycle distribution and cells died from the cell cycle
phases in which they were irradiated. These observa-
tions imply that interphase death of tumor cells will
prevail when tumors are treated with high-dose
fraction SRS or SBRT.
In summary, irradiation with moderate doses cau-
ses transient cell cycle arrest predominantly in G2
phase and induces mitotic cell death. However, after
irradiation with extremely high-doses of irradiation,
i.e. [15–20 Gy, in a single fraction, cells are indefi-
nitely arrested in the phases of cell cycle where they
were irradiated and undergo interphase death.

Fig. 3 Cell cycle progression of HL-60 cells after irradiation.

3.4 Repopulation
During the course of fractionated radiotherapy for an
extended period, tumor cells or normal cells that
survive the radiation exposure begin to proliferate.
Therefore, the number of tumor cells that must be
sterilized increases when tumors are treated with
conventional fractionated irradiation. Such compen-
satory repopulation of tumor cells is evoked usually
3–4 weeks after initiation of radiotherapy. Since SRS
or SBRT treatment lasts for a short period, at most
2 weeks, repopulation of tumor cells will not be
substantial during the course of SRS or SBRT.
4 Linear-Quadratic Model in SRS
or SBRT
The LQ model, is widely used for calculating radio-
therapeutic isoeffect doses for different fractionated
radiotherapy schemes (Fowler 1989). The LQ model
Cells were irradiated with 4 or 20 Gy and the cell cycle
progression (DNA histograms) was measured with flow
cytometry. Most of the cells were in late S and G2 phases
4 h after 4 Gy irradiation, and then died of apoptosis as
indicated by the large increase in the sub-G1 fraction. When
irradiated with 20 Gy, no cell cycle progression occurred and
the cells died of interphase death in the cell cycle phases, where
the cells were at the time of irradiation (Park et al. 2000)
encompasses two components, a and b, which rep-
resents non-repairable and repairable damage,
respectively. This model assumes that the biological
outcome of irradiation is directly proportional to total
dose and fraction size and that the ratio of a and b
(a/b) indicates the sensitivity of tissues to different
fraction size. The radiation-induced cell death and
sub-lethal damage repair are incorporated in the LQ
model. Brenner et al. (1995) proposed to include cell
cycle redistribution and reoxygenation into the LQ
model, which is termed LQR model, in order to
improve the usefulness of LQ model. Although the
Radiobiology of Stereotactic Radiosurgery
LQ model has been proven to be very useful for
comparing the effectiveness of different fractionated
radiotherapy protocols, there have been considerable
discussions in recent years as to whether or not LQ
model is applicable for SRS or SBRT (Brenner 2008;
Kirkpatrick et al. 2008; Fowler et al. 2004b; Park
et al. 2008). The primary concern has been that the
radiation dose–response survival curve calculated by
LQ model bends downward at high-radiation doses
whereas the experimental radiation dose–response
curves are linear. It was therefore argued that LQ
model overestimates cell death or underestimate cell
survival at high-radiation doses, and thus the model
cannot be used for SRS or SBRT. It should be noted,
however, that there is no much experimental data that
supports the assertion that dose–response curves
remains linear at 10-10–10-11 survival range, clini-
cally relevant levels, because it is technically difficult
to determine the clonogenic survival at such low
levels. Furthermore, in vitro studies are carried out
using growth media which select cells that proliferate
fast in culture, unlike the cells in tumors in animals or
human patients which are influenced by hormonal and
microenvironmental factors. It is conceivable that the
a/b ratio of cells in such environment may be
unnaturally high rendering the survival curve remain
linear at high-radiation doses. Brenner (2008) repor-
ted that LQ model is still acceptable for doses per
fraction of 15–18 Gy although the model becomes
progressively less accurate at doses above 10 Gy. An
important fact that must be addressed here is that
irradiation with doses higher than 10–12 Gy in a
single exposure is likely to cause significant vascular
damage followed by indirect cell death. Therefore, the
LQ model may become increasing inaccurate for
hypofractionated irradiation with fraction size larger
than 10–12 Gy. However, it should also be noted that
SRS or SBRT is often given with fractions smaller
than 10 Gy. When tumors are treated with mildly-
fractionated irradiation, i.e. \10 Gy per fraction, the
conventional LQ model will be a useful model to
calculate the radio-therapeutic isoeffect doses for SRS
and SBRT.
Guerrero and Li (2004) proposed to modify the LQ
model to more accurately describe radiation response
for high fraction/acute doses by adding a new
parameter to the LQ model and reported that the
modified LQ model (MLQ model) produced a better
fit to the iso-effect data than the LQ model. Park et al.
59
(2008) constructed an alternative model termed USC
(universal survival curve) by hybridizing the LQ
model and the classical multi-target model, and con-
cluded that USC provides an empirically and clini-
cally well-justified rationale for SBRT while
preserving the strengths of the LQ model for the
conventional fractionated radiotherapy. More
recently, Wang et al. (2010) proposed a generalized
LQ (gLQ) model that encompasses the entire range of
possible dose delivery patterns. The authors con-
cluded that gLQ model could derive the traditional
LQ model for low-dose and low-dose rate irradiation
and the target model for high-dose irradiation.
A recent study suggested that the value of b para-
meter in the LQ model might impact the calculation
of clinical relative biological effectiveness (RBE)
of high-LET radiation such as proton especially
when the radiation exposure is hypofractionated
(Carabe-Fernandez et al. 2010). Unfortunately, it is
apparent that all these modified LQ models will not be
applicable for high-dose fraction radiotherapy
because the indirect cell death caused by vascular
damage is not incorporated into the models.
In summary, the indirect tumor cell death due to
vascular damage render the LQ model inapplicable
when tumors are treated with extremely high-dose
fraction radiotherapy. However, the LQ model should
be applicable for hypofractionated radiotherapy with
fraction size smaller than approximately 10 Gy.
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 Imaging in Radiation Therapy
Performance in Integration
Cynthia Ménard, Ursula Nestle, and David Jaffray
Contents
1 Imaging Performance..............................................
2 Imaging Modalities ..................................................
2.1 Computed Tomography.............................................
2.2 Magnetic Resonance Imaging ...................................
2.3 Positron Emission Tomography ................................
3 Next generation of Online Integration..................
References..........................................................................
C. Ménard (&)
D. Jaffray
Princess Margaret Hospital, University of Toronto,
610 University Avenue, Toronto, ON M5G 2M9, Canada
e-mail: cynthia.menard@rmp.uhn.on.ca
U. Nestle
University Hospital Freiburg, Robert-Koch-Strasse 3,
79106 Freiburg im Breisgau, Germany
S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_303, Ó Springer-Verlag Berlin Heidelberg 2012
1 Imaging Performance
63 Favorable clinical outcomes after radiotherapy are
65
dependent on the technical performance of delivery.
65 As a result, systems have evolved with a dedicated
68 emphasis on the quality with which they can deliver
74 the radiation dose to a specified target. In parallel,
77 imaging systems have advanced at an accelerated
78
pace of innovation bringing outstanding performance
in cancer characterization and diagnosis. Hallmarks of
quality in diagnostic imaging have focused on dis-
tinguishing tissue contrasts for categorization of dis-
ease, high throughput, and low radiation exposure.
However, as these images are now increasingly inte-
grated in the radiotherapy workflow, it is important to
now define what constitutes high-quality imaging for
the purpose of radiotherapy guidance.
The application of imaging in the radiotherapy
setting begins in treatment planning; with an emphasis
on the identification of anatomic and target boundaries,
and the characterization of disease targets in order to
select appropriate dose objectives and uncertainty
margins. This may include such characteristics as
cancer density, motion, and metabolism, including
surrogates of radio sensitivity (e.g. hypoxia). A focus
on quality is well justified, as errors introduced are
often systematically propagated through treatment.
Arguably one of the weakest points in the radiotherapy
process, target volume delineation is still characterized
by substantial inter-observer variability.
Imaging performance and integration methods may
have tremendous impact, as may the expertise and
education of the staff. Therefore, the need for advanced
imaging knowledge in the context of radiation oncol-
ogy, and for interdisciplinary communication between
63
64 C. Ménard et al.

Fig. 1 Imaging has become a Temporal Scales of

primary input into the design
and execution of state-of-the- Adaptive Radiation
art radiotherapy. In the Therapy
adaptive radiation therapy Therapeutic Intent
Intent (Prescribed Dose and
paradigm, treatment is
evaluated and modified at Constraints)
multiple time points and at
different time scales to Image-based
achieve the therapeutic intent. Off-line On-line Real-time Information To
Computerization, robotic Auto- MV/kV CT, on- kV Fluoro, MR-RT, Inform Adaptation
segmentation, line planning, ultrasound, robotic
control of the treatment (Geometry, Biology)
deformation, dose needles/couches,
delivery (medical linear inverse planning, accumulation, motion tracking,
accelerators, brachytherapy dose rapid QA, gating, control, Adaptive Intervention
robots) and imaging are the accumulation, monitoring, prediction (External Beam,
response deformation, Brachytherapy)
enabling technologies for this assessment, seed detection
change in practice PET/MR/CT

Information

imaging specialists and radiation oncologists cannot be

overemphasized. Beyond GTV, high performance in Response
& Adaptation
imaging can also impact the design and concepts for
CTV. At the extreme, high imaging performance many
enable the omission of CTV altogether. This is of
special importance in the age of highly conformal
radiotherapy and radiosurgery applications. Geometric Tissue
Imaging is later applied directly during delivery in Integrity Contrast
Imaging
an attempt to respond to variations in geometry from
the planned patient model; a process broadly termed Performance
image-guided radiotherapy (IGRT). Finally, individ- Guidance Delineation
ual response during a course of radiotherapy can be & Targeting Spatial & Dosing
Resolution
captured with repeated imaging and potentially used
to adapt the radiotherapy plan in a patient-specific
manner (Fig. 1). For each level of application, key
features at the core of image quality include geo-
metric integrity, quantitative tissue contrast, and
spatial resolution (Fig. 2). Fig. 2 Diagram depicting the importance of optimizing imag-
ing performance based on the fundamental objectives of
Trade-offs between geometric integrity and spatial radiotherapy (outer circle). Trade-offs between geometric
resolution (for accuracy in targeting and serial/multi- integrity, tissue contrast, and spatial resolution must be
modality registration), and tissue contrast (for boundary considered when designing time-efficient image acquisition
delineation, dose selection, and response assessment) protocols (Reproduced with permission from Dawson and
Ménard (2010)
must be carefully considered during the design of
imaging systems and selection of imaging protocols.
The importance of quantitative metrics in this regard to technical, and monetary constraints in the radiotherapy
support computational tools for automated segmenta- setting, less than optimal imaging quality is frequently
tion, tracking, and response analysis must also be employed (especially in the online environment) despite
emphasized. Given the finite clinical time, space, the priority of accurate precise localization.
Imaging in Radiation Therapy
This chapter underscores the current implemen-
tation of oncology-specific methods that increase the
quality of imaging in a manner aligned to the goals
of radiation therapy, and highlight promising inte-
gration strategies that are the subject of ongoing
research. Here, we review the current concept in
high-performance and integration solutions specific
to each of the three major imaging modalities in
radiotherapy; computed tomography (CT), magnetic
resonance imaging (MRI), and positron emission
tomography (PET). Promising advances in ultra-
sound and optical imaging systems are expected to
present fewer barriers in future online use.
2 Imaging Modalities
2.1 Computed Tomography
2.1.1 History and Development
Radiation therapy’s transition from a ‘technique-
based’ to an ‘image-based’ treatment modality was
enabled through the development of CT. The early
advances in CT for radiation therapy were motivated
in-part by the desire to characterize the radiation
transport characteristics of the patient’s anatomy for
purpose of accurate dose computation (Hounsfield
1976). Figure 3a illustrates an early pantograph used
in the determination of the patient contour.
As recently as the mid 1990s, these tools were used to
estimate the depth of the tumor within the patient for
purposes of dose computation. Of course, CT imaging
offered much more including, contours in multiple
planes (i.e. 3D), characterization of the electron
densities for use in heterogeneity corrections, and, of
course, localization and characterization of diseased
and normal tissues.
Briefly, CT works on the principle of partial X-ray
attenuation by tissues within the human body. The
differences in attenuation of anatomical tissues in the
energy range of 60–140 keV are sufficiently large
relative to the overall attenuation of X-rays by the
entire body that it is possible to collect ‘X-ray shad-
owgrams’ from multiple directions and reconstruct
from these an estimate of the distribution of attenu-
ation coefficients within the body. Remarkably,
through the use of efficient detectors and well-
designed electronics, it is possible to estimate
65
attenuation coefficients to within *1% (10 HU) using
a total imaging dose of *10 cGy. Furthermore, the
high geometric integrity of the resulting images is
intrinsic to the mechanical design and movements of
the CT scanner, and therefore very robust and inde-
pendent of the scanned object. These many factors
come together in a reliable and effective system in
today’s modern CT scanners.
While these advances have benefited radiation
therapy, they have largely been driven by the desire to
detect subtle differences in contrast for imaging of the
brain, and have been made faster (now imaging at 3
volumes/s) to enable 4D imaging of the heart, and
increase in resolution performance to allow accurate
characterization of vascular anatomy. Contrast agents
are also employed in CT to increase the visibility of
normal (e.g. vessels) and disease structures
(e.g. compromised vasculature in cancerous tissues).
It is important to note that the imaging dose associ-
ated with CT is not insignificant and has become a
topic of significant focus in recent years. While the
dose delivered is small in comparison to that deliv-
ered in radiation therapy, it needs to be monitored
appropriately and every effort should be taken to
minimize the dose while achieving the relevant clin-
ical objective.
2.1.2 Radiation Therapy-Specific
Developments
There are a number of important radiation-therapy
specific issues that need to be raised given the degree
of integration of these systems into radiation therapy.
The replacement of conventional radiographic simu-
lators with CT scanners led to the phrase ‘CT-
simulation’. A CT-Simulator now refers to a suite in
the radiation therapy environment that houses the CT
scanner and is equipped with a number of additional
ancillary devices that are used in preparation for
treatment. This includes a set of dedicated positioning
lasers that mimic the geometry of the treatment room.
These assure that the patient is positioned straight
before scanning begins. In some cases, these lasers
can be programmed to move and create skin marks
that identify the ‘treatment isocenter’ on the patient
based upon the CT-derived location of the target
volume. This, of course, requires a dedicated work-
station to be present in the CT-simulation suite for the
physician to draw target volumes and extract the
66 C. Ménard et al.

a b

c FB d 2000
CT Sim 2

1500 90 kVp
120 kVp
140 kVp
CT Number [HU]

1000

500

0
0.0 0.5 1.0 1.5 2.0

4D -500

-1000

Fig. 3 Computed tomography in radiation therapy practice.
a The external contour of the patient is a critical input to the
accurate computation of dose at depth and ‘pantographs’
provided this information prior to the broad introduction of
dedicated CT-simulation suites in radiation therapy. b A CT-
simulation suite includes a dedicated CT scanner, lasers for
positioning, as well as a workstation to allow image interpre-
tation at the time of imaging. c The development of 4D CT
permitted increased accuracy in localization of targets affected
by respiratory motion as well as the elimination of artifacts
associated with the combined motion of the table and the lung
anatomy. A free-breathing scan (FB) can produce gross errors
in delineation relative to a single phase of a 4D CT scan. d One
of the strongest motivators for CT in radiation therapy was
providing accurate estimates of electron density within the
body for purposes of dose calculation. This remains an
important part of the role that CT plays in the accuracy of
RT treatment. Calibration curves similar to the one shown are
part of routine RT planning in modern facilities. Note copyright
clearance required for (c)—Med.Phys. TG76-Keall et al.
Imaging in Radiation Therapy
isocenter coordinates and transfer these to the mobile
laser system (Ragan et al. 1993).
In addition to the laser system and workstation, the
CT simulation suite also includes other features, such
as, a flat table top that imitates the treatment room
couch, as well as, the preference for a large-bore CT
scanner to accommodate the preferred patient posi-
tioning (e.g. frog-leg positioning for extremity sar-
coma) and devices (e.g. tilt board for breast RT) used
in radiation therapy. The demand for large bore
scanners has driven all the major vendors to offer CT
scanners with larger bores (i.e. 80 cm or even larger).
Any ancillary devices used to treat the patient are also
first applied in the context of the CT-simulation suite.
The use of devices that control the patient’s breathing
(breathhold) (Keall et al. 2006) or active breathing
control (Wong et al. 1999) must also be first tested
within the CT-simulation suite, as they will impact the
location of the patient’s internal anatomy with respect
to the CT scanning geometry. This is particularly
critical if the treatment is to employ gating techniques
to mitigate the impact of respiration-induced target
movement. In this case, an additional device (e.g.
optical monitoring system/RPM or bellows/strain-
gauge) must be used to monitor the patient’s breathing
cycle during CT scanning to assure that the scan cor-
responds to a specific phase of the breathing cycle
during which treatment will be delivered. More
recently, this technology has generalized into
‘4D-CT’, in which, continuous monitoring of the
breathing phase and slow scanning of the patient
permits the creation of a set of typically ten 3D CT
images corresponding to ten phases of the patient’s
breathing cycle (Ford et al. 2003; Pan Lee et al. 2004).
In many ways, the introduction of 4D CT returned the
fluoroscopic functionality of the conventional R&F
simulator to the clinic with the substantial advantage
of allowing 3D specification of the target volume. It is
now considered a clinical standard to employ 4D CT
simulation in all patients with targets influenced by
respiratory motion since it affects not only target
localization but also addresses the significant issue of
breathing-induced artifacts in CT images that signifi-
cantly distort the patient anatomy and gross tumor
volume (Keall et al. 2006). Figure 3c is taken from the
AAPM Task Group #76 on Respiratory Motion.
67
As mentioned earlier, the development of CT
simulation was driven by both an interest in localizing
the treatment target, as well as, increasing the accu-
racy of the dose calculation by deriving estimates of
electron density from the CT images themselves.
Given the differences in energy between the X-rays
used to form the CT image (*30–120 keV) and those
used to treat the patient in radiation therapy
(*200–25,000 keV), it is not straightforward to
relate the observed CT numbers or Hounsfield Units
(HU) to the attenuation coefficients associated with
the attenuation of the treatment beam within the
patient. The reason for this arises from the different
interaction processes, photoelectric versus Compton,
that dominate at kilovoltage versus megavoltage
energies, respectively. For this reason, standardized
phantoms of known electron density are scanned for
each CT imaging energy to create a ‘CT to Electron
Density’ look-up table. These tables are subsequently
used to convert the CT number at each voxel into an
electron density that can be used to ‘correct’ the path
length of X-ray transport and ‘scale’ the range of
charged particles. It has been shown that a two-slope
linear fit is a good approximation to the measured data
and that it is possible to simplify the problem by using
a single calibration curve for a range of different CT
scanning energies. Early approaches embedded a
range of CT calibration inserts within the couch of the
CT unit to monitor CT number accuracy. This is no
longer routine practice, the AAPM task group guid-
ance on QA of radiation therapy equipment suggest
monthly monitoring of CT number accuracy for
materials other than water, which remains part of the
daily QA (Mutic et al. 2003). A plot of CT number as
a function of known electron density is shown in
Fig. 3d for a common CT scanner used in RT. This
plot shows the typical ‘two linear slopes’ seen in such
calibration curves as well as the dependence on
scanning technique (Constantinou et al. 1992).
There are ongoing improvements in CT that will
impact radiation therapy. The recent development of
large area, cone-beam CT scanners with diagnostic
image quality will enable true 4D CT imaging and
also permit large FOV perfusion CT scans as a routine
part of radiation therapy simulation (Coolens et al.
2009). The benefits of true 4D scanning will most
68
likely be manifested as increased robustness in the
clinical workflow—occasionally 4D CT acquisitions
are not successful due to variations in breathing pat-
tern or patient non-compliance. Coolens et al. repor-
ted on the use of a 320 slice CT scanner capable of
16 cm of coverage and a minimum scan period of
0.23 s. In addition, there are also potential advance-
ments in radiation therapy through the development
of dual-energy CT scanners that can offer segmenta-
tion and quantification of materials (Le and Molloi
2011). While it is unclear whether it will assist in the
delineation of disease, it may be useful in automating
the segmentation of normal structures which has
become a time-consuming component of radiation
therapy with the growing development of intensity
modulated RT.
2.1.3 Perfusion or Dynamic Contrast
Enhancement CT
Developments in rapid CT scanning led to the
development of perfusion (or DCE) CT methods in
the early 1990s to probe the vasculature and com-
partmental integrity of tumours. DCE-CT involves
continuous CT scanning of a specified region of
interest during a period of bolus contrast agent
injection. The resulting series of images are analyzed
at each voxel location or region-of-interest through
time-series compartmental analysis techniques or
more simple curve-based analysis methods (Miles
1991; Tofts and Kermode 1991). The potential and
challenges of DCE methods in the context of radiation
therapy have recently been reviewed by Cao et al.
(2011). There is enthusiasm for these techniques with
a number of small studies suggesting that DCE CT
methods could have a role as a predictor of early
tumor response to chemotherapy and radiation ther-
apy (Hermans et al. 2003; Wang et al. 2009). While
exciting and potentially relevant to adaptive radiation
therapy concepts, DCE-CT has not been qualified as a
surrogate endpoint for radiation therapy at this point.
2.2 Magnetic Resonance Imaging
2.2.1 Historical Perspective
The physicochemical phenomenon of nuclear mag-
netic resonance, discovered in 1946 by Bloch and
Purcell, was first translated into the field of medicine
C. Ménard et al.
as a method to characterize human tissues ex vivo.
The observation that malignant tissues have longer
relaxation times than benign tissue, reported by
Damadian in 1971, spurred optimism for the diag-
nostic and non-invasive application of this technology
to oncology. Shortly thereafter, techniques for spatial
encoding of the NMR signal were discovered by
Lauterbur (1973), (Garroway et al. 1974), and (N)MR
imaging was born.
After the first image of in vivo human anatomy in
1977, evolution of the technology accelerated over the
ensuing decade, and clinical translation into the field of
diagnostic radiology flourished. Because MR imaging,
much like radiation oncology, is at the crossroads
between medicine and chemistry, physics and computer
science groups with strong interdisciplinary relation-
ships and cross-fertilization became scientifically
fruitful. Dedicated clinical MR equipment became
available in the early 1980s, and has since predominated
within departments of diagnostic radiology.
The integration of MR images in the treatment
planning process for radiosurgery (Fabrikant et al.
1985), followed by radiotherapy (Fraass et al. 1987)
and brachytherapy (Houdek et al. 1989), were initially
reported in the late 1980s. In 1996 the first MRI
simulator was reported in Japan, whereby patients
were imaged in the treatment position using a per-
manent open magnet system with high-precision
lasers used exclusively for radiotherapy (Mizowaki
et al. 1996). Due to geometric considerations, the
open MRI scanner architecture was later adapted and
dedicated to MRI simulation by radiotherapy depart-
ments in Bristol, Heidelberg (Krempien et al. 2002),
and Philadelphia (Chen 2004). More recently, radia-
tion oncology departments have acquired or partnered
for dedicated access to standard cylindrical high-field
MRI scanners towards the integration of quality
imaging in the radiotherapy workflow.
MRI addresses fundamental unmet needs in high-
precision radiotherapy; including superior soft tissue
contrast and unparalleled resolution of surrounding
anatomy and structure. This key strength is best con-
veyed in images (Figs. 4, 5, 6 and 7), and corroborated
by the literature demonstrating improved observer
performance (Shuman et al. 1985, Ten Haken et al.
1992, Dubois et al. 1998, Milosevic et al. 1998, Khoo
et al. 2000, Emami et al. 2003, Smith et al. 2007,
Rosewall et al. 2009, Ahmed et al. 2010) and closer
correspondence to ground truth histology (Milot et al.
Imaging in Radiation Therapy
Fig. 4 Judicious design of dedicated and/or flexible MRI coils
enables high-performance imaging of the neck with thermo-
plastic mask immobilization, improving registration workflow,
and accuracy. Despite attempts at reproducing the neck position
2010) compared with reference CT. At the end of the
spectrum, some tumors can only be visualized on MRI
(e.g. prostate tumors) (Hricak et al. 2007) (Fig. 6b)
and seldom seen on CT. MRI features have also been
used to distinguish a gradient between gross and
microscopic disease. For example, disruption of white
matter tracks identified on diffusion tensor images
(DTI) are proposed to represent ‘high risk CTV’
regions (Jena et al. 2005). Overall, current standard
care sites for application of MRI in RT planning
include the brain, base of skull, cervix, liver, and some
prostate cancers.
It is worthwhile emphasizing that such conspicuity
in tissue contrast is complementary to sharp bone and
air contrast acquired with CT, which also readily
69
within standard diagnostic H and N coils (right panels)
deformation is introduced (note chin to spine alignment),
increasing computational demands without appreciable gain in
soft tissue resolution of the anatomy
provides accurate topographic surface geometry and
electron density for dose planning as described.
Although strategies for omitting (and replacing) CT in
MRI-based planning solutions have been pursued,
tangible gains in integrating MRI to the radiotherapy
workflow are most likely to be achieved with a ded-
icated focus on the value-added strengths of MRI,
namely in soft tissue contrast.
2.2.2 External Beam Radiotherapy
In the current workflow model, MRI is registered to a
reference CT image. Imaging protocols must there-
fore balance performance in tissue contrast with high
spatial resolution in order to support accuracy in
automated rigid registration. At a minimum, voxel
70
Fig. 5 Case of a patient with cervical cancer treated with PDR
brachytherapy, demonstrating value of multi-planar (a—axial,
b—coronal, c—sagittal) and high spatial resolution MRI for
delineating tumor targets (arrow). Day 3 (d) shows value of
frequent image-guidance given displacement of intrauterine
resolution should strive to match that of the reference
CT. In more traditional 2D multislice diagnostic
acquisition modes, high-resolution (\2–3 mm) in the
slice-selection plane (typically SI) is often hindered
with poor SNR and associated with longer acquisition
times prone to motion blurring.
The importance of high-resolution in the SI
dimension extends beyond improved performance in
automated registration, with recognized value in sag-
ittal and/or coronal visualization at the time of clinical
image review and target delineation (Rasch et al. 2010)
(Fig. 5). In diagnostic practices, this problem has been
addressed by acquiring 2–3 separate thick-slice images
in orthogonal planes. In radiotherapy, such an
approach fails largely because of the inability of most
commercial treatment planning systems to manage
non-axial images, and partly due to degraded perfor-
mance in image registration to CT when using thick
C. Ménard et al.
stem applicator relative to the tumor target despite standard-
care vaginal packing and patient immobilization. (Personal
communication Dr. Michael Milosevic, Princess Margaret
Hospital)
slices. A more appropriate strategy is the use of fast
isotropic 3D acquisitions now supported through
modern pulse sequence designs (e.g. 3D TSE with
variable flip angle—SPACE, CUBE, VISTA). It
remains that acquisition times (and therefore volumes)
must be kept to a minimum as these sequences are
highly vulnerable to degradation in quality from tissue
motion during the acquisition.
Reproducing the treatment position during MRI is
unnecessary with high-resolution isotropic acquisi-
tions in non-deformable and stable organs (e.g. brain).
As the prostate gland moves relative to the sur-
rounding pelvic architecture between treatments (and
therefore imaging sessions), prostate-to-prostate reg-
istration is considered standard and most accurately
achieved in the presence of implanted fiducial mark-
ers. This approach eases constaints in perfectly
matching the pelvic position and states of bladder and
Imaging in Radiation Therapy
bowel filling during MRI (Parker et al. 2003;
Huisman et al. 2005; van Lin et al. 2006). In both
these examples, the use of better performing multi-
channel imaging coils apposed as closely as possible
to the imaging volume, despite somewhat compro-
mising treatment set-up, yields a favorable balance in
achieving the goals of radiotherapy.
However, in the case of target structures highly
deformed by small variations in set-up (and given the
absence of robust clinical tools for deformable reg-
istration), positioning and immobilication during MRI
is paramount to useful integration in the radiotherapy
workflow. Newer systems that integrate posterior
imaging coils within a flat table surface are best suited
to the RT environment. MRI solutions in radiotherapy
to the neck have also explored creative use of avail-
able flexible imaging coils combined with thermo-
plastic mask immobilization in lieu of standard head
and neck diagnostic imaging coils (Webster et al.
2009; Ahmed et al. 2010; Hanvey et al. 2009). With
careful selection and design of imaging coils and
protocols, image quality and SNR in the neck can
approach that of diagnostic set-ups (Fig. 5), balancing
the trade-offs of registration accuracy and image
quality. Future imaging coils designed specifically for
imaging in the radiotherapy position (± immobiliza-
tion) may further improve performance in targets sites
such as the neck, spine, breast, and extremity.
Beyond delineation of GTV and CTV, patient-
specific assessment of target motion using MRI may
assist in designing appropriate PTV uncertainty mar-
gins and motion management approaches (Plathow
et al. 2004; Liu et al. 2004; Ghilezan et al. 2005;
Kirilova et al. 2008; Eccles et al. 2011). Supervised
automated tracking tools (Prakash et al. 2008) or
tagging sequences can be used to extract quantitative
motion data in a clinically feasible workflow.
2.2.3 Brachytherapy
In brachytherapy planning, integration is somewhat
simplified whereby imaging can focus on a relatively
small-volume target tissue structure and its relation-
ship to inserted devices. Image data on surface
topography and electron density are generally not
mandated. If the location of applicators or implanted
seeds can be accurately defined on the MR image, the
need for CT or X-ray imaging may be reduced,
enabling treatment planning to be primarily based on
MRI (Beriwal et al. 2009).
71
MR compatible devices are now commercially
available, and a number of novel strategies have been
reported in order to accurately depict brachytherapy
hardware on MRI relative to tissue targets. In the case
of plastic interstitial catheters, high-resolution 3D
proton-density (PD)-weighted (or T2-weighted using
lower TE) spin echo images (e.g. PD-SPACE) can
readily resolve catheter voids with minimal suscep-
tibility artefact (Ménard et al. 2004) (Fig. 6e). In the
case of gynaecological applicators, plastic devices
may be favored due to their lower susceptibility
profiles. Custom water-based markers have been
introduced to generate positive contrast at the level of
the first dwell position in order to aid catheter
reconstruction (Zwahlen et al. 2009; Perez-Calatayud
et al. 2009; Haack et al. 2009) (Fig. 6). An alternative
and more promising approach described by Berger
et al. combines a true geometric model of the Vienna
applicator fit to the MR image in a single recon-
struction step. (Berger et al. 2009) Marker cavities
within the applicator naturally fill with fluid in situ,
creating positive contrast points for registration.
Caution must be exercised when using titanium or
other metal alloy devices (Haack et al. 2009; Wills
et al. 2010; Hellebust et al. 2010), or gradient echo and
echo-planar pulse sequences near air cavities, as local
susceptibility artifacts may distort geometry in a
manner highly dependent on the specific system and
imaging protocol employed. Applicator commission-
ing practices are strongly recommended in this regard
(Hellebust et al. 2010). Brachytherapy also presents an
ideal opportunity for improved performance in image
quality compared with that achieved in diagnostics to
date by physically integrating imaging coils within
brachytherapy applicators. This concept has been
explored successfully in the field of interventional
radiology, where internal coils have served as receiver
imaging coils for augmented SNR in soft tissue
imaging and/or device tracking (Wacker et al. 2005).
Finally, online MRI-guidance during applicator
insertion in order to improve implant quality has been
reported by a number of groups. Investigators at
Harvard were the first to translate the conventional
transperineal ultrasound technique into an open MRI
scanner architecture (D’Amico et al. 2000). Even at
low field strength, the peripheral zone of the prostate
gland (where the vast majority of cancers are known
to reside) could now be distinguished from the central
gland and specifically targeted. A similar strategy has
72 C. Ménard et al.

Fig. 6 Case example of a

patient with recurrent prostate
cancer in the right lateral
peripheral zone best
visualized as restricted
diffusion on ADC map (b).
MRI-guided prostate biopsy
(c—green target and
underlying biopsy needle
void) permits histological
sampling and precise mapping
onto T2-weighted anatomic
images (d—pink malignant,
green benign). Reducing
uncertainty in GTV boundary
determination (e) enables
tumor-targeted HDR
brachytherapy dose escalation
(f) with minimal increase in
OAR exposure

been applied to prostate HDR brachytherapy with
specific targeting of tumors (Susil et al. 2004; Ménard
et al. 2004; Ares et al. 2009) (Fig. 7). More recently,
prototype robots have been developed to improve the
clinical workflow within the geometric and magnetic
constraints of high-field MRI (Song et al. 2010;
Stoianovici et al. 2007; van den Bosch et al. 2010).
2.2.4 Geometry
MR images suffer from system-related and patient-
induced distortions in geometry. This problem should
be addressed and solved in a manner specific to each
clinical application (Zhang et al. 2010; MacFadden
et al. 2010). As a first step, imaging protocols must be
designed to reduce contribution of susceptibility and
chemical shift in the imaging volume. In general, spi-
n-echo based sequences with high acquisition band-
width perform best in this regard. This is especially the
case at high field strength (e.g. 3 Tesla) and in tissues
prone to susceptibility such as air, fat, blood (hema-
toma), and implanted metal devices. In such instances,
dual acquisition with a gradient-reversal technique has
been proposed (Reinsberg et al. 2005), where an
accurate surface imaging reference required for precise
targeting (such as in stereotactic radiosurgery), phan-
tom-based methods for advanced 3D correction are
reported (Wang et al. 2004; Doran et al. 2005; Stanescu
et al. 2010). However, in the majority of applications
where MRI is registered to CT, concerns of geometric
integrity can be adequately addressed with current
Imaging in Radiation Therapy
Fig. 7 Case of a patient with brain metastasis treated with
radiosurgery, demonstrating value of frequent high-perfor-
mance MR imaging in early assessment and prediction of
response. Despite the absence of a volumetric response at day
3, rise in tumor ADC (third row) and reduction in Choline
vendor-provided solutions, established QA procedures,
and careful design of imaging protocols.
2.2.5 Predictive Biomarker of Response
to Radiotherapy
Dynamic changes in soft tissue structure through a
course of radiotherapy have been long appreciated in
head and neck cancer where responses can simply be
measured by clinical examination of surface anatomy.
For deep-seated tumors, such as cervix cancers, vol-
ume regression rates depicted on MRI have been
found to correlate with eventual clinical outcomes
(Mayr et al. 1996). However, for the majority of
cases, meaningful gross structural responses occur
73
(fourth row, arrow) were measured and predictive of a
subsequent dramatic volumetric response by Day 31. (Personal
communication, Drs. Cynthia Ménard and Caroline Chung,
Princess Margaret Hospital)
much later after a course of radiotherapy is com-
pleted. In this regard, MRI can provide spatial maps
of quantitative metrics which have biologic correlates
and show promise as early radiation response tools.
One of the most relevant MRI response biomarkers
is the apparent diffusion coefficient (ADC), which
measures water diffusion and varies with tumor cell
density (Zelhof et al. 2008). The mounting literature
supports a conclusion that tumor ADC rises during a
course of RT well before structural responses can be
ascertained (Eccles et al. 2009). ADC responses have
been found to correlate with subsequent clinical out-
comes in rectal cancer (Kim et al. 2009a), cervical
cancer (Liu et al. 2009), and head and neck tumors
74 C. Ménard et al.

(Kim et al. 2009b). In the brain, the Michigan group

demonstrated close association between ADC chan-
ges at 3 weeks with radiographic response at
10 weeks, time-to-progression, and overall survival
(Hamstra et al. 2005). A key approach in this study
was the definition of a ‘functional diffusion map’ or
fDM, as a spatial map of the ADC difference between
registered voxels across two time-points. However,
application of the fDM strategy necessitates confi-
dence that corresponding voxels are tracked accu-
rately, despite probable tumor deformation
compounded by voxel anisotropy and volume aver-
aging. Alternative analytic strategies include ROI-
based methods with histogram and summary statistics
of response.
Metrics of tumor microvascular physiology, glob-
ally termed perfusion, can be derived from dynamic
contrast enhanced acquisitions (DCE) following
exogenous administration of contrast agents, with
mounting evidence of a radiation dose relationship in
response. Reports of T1 contrast enhancement
dynamics in cervical cancer generally indicate that
tumors with high enhancement or an increase in
contrast enhancement intensity within the first
2 weeks of radiotherapy, independent of tumor vol-
ume, are later associated with superior tumor regres-
sion rates and local control outcomes (Mayr et al.
Fig. 8 Unexpected abdominal metastasis in a patient with
2000, Zahra et al. 2007). An apparent inconsistency esophageal cancer referred for neoadjuvant radio-chemotherapy
across reports can be partly attributed to substantial
heterogeneity in DCE-MRI methods in image acqui-
sition, model-based analysis of tissue permeability, with a measurable reduction in Choline only 3 days
and lacking calibration tools. Solutions to this prob- after radiotherapy for brain metastases (Fig. 8).
lem are the subject of active investigation across the
imaging community. A second technique, termed
dynamic susceptibility contrast (DSC), captures met- 2.3 Positron Emission Tomography
rics related to blood flow and blood volume through
the susceptibility effects of first-pass gadolinium During the last 20 years and across the field of
contrast on T2* as it courses through the compart- oncology, the impact of PET imaging has been
mentalized cerebral blood vessels. Response in blood explored. Today, PET or PET/CT contributes signif-
volume measured during the third week of radio- icantly to oncologic patient care through the addi-
therapy has been found to distinguish subsequent tional information provided towards staging and
tumor progression from confounding treatment effect restaging of cancer (Gambhir et al. 2001). The vast
(a phenomenon termed pseudoprogression) in patients majority of PET examinations are being performed
with high-grade gliomas (Tsien et al. 2010). with the glucose analog fluorodeoxyglucose ([18F]-
Magnetic resonance spectroscopy (MRS) can also FDG), which is avidly accumulated by most malig-
monitor metabolic responses that can predict for sub- nant tumors.
sequent clinical outcomes (Pickett et al. 2004). A case The basic principle of PET consists in the determi-
example of early metabolic response is shown in Fig. 7 nation of the three-dimensional distribution of the
Imaging in Radiation Therapy
radiopharmaceutical containing a positron emitter
within the patient (Chatziioannou 2002; Humm et al.
2003; Muehllehner and Karp 2006; Nutt 2002; Wieler
and Coleman 2000; Wienhard et al. 1989). In contrast
to other imaging methods like CT and MRI, the signal
originates from inside the patient and exhibits strong
time dependency. Due to the technical possibilities of
highly sensitive detection of the signal, very small
amounts of radiopharmaceutics are required during
PET scanning, which leads to radiation exposures of
only a few mSv and whose concentrations are far below
those associated with pharmacologic or toxic effects.
For technical reasons, PET imaging has limitations
due to its relatively low spatial resolution, restricted
anatomic localization of lesions, and the limited pos-
sibilities to coregister independently acquired PET and
e.g. CT studies. Therefore, PET-CT scanners have
been constructed to acquire both studies consecutively
on the same machine with unchanged patient posi-
tioning, which leads to improved anatomical orienta-
tion and allocation of pathological findings. Yet, there
is no simultaneous imaging and while CT rather gives
a snapshot image, the acquisition of a PET scan takes
some minutes per bed position. Therefore, the problem
of respiratory and other (heart, intestine etc.) motions
as well as possible movements of the patient during
acquisition have to be accounted for, especially as the
CT data are also used for attenuation correction of
PET data. Hence, artifacts can be found, e.g. in the
region of the diaphragm mimicking or erasing patho-
logical findings. For the use of PET image data in
radiotherapy, the absence of attenuation correction
artifacts and the correctness of image fusion must
therefore be verified against anatomical landmarks.
In clinical practice the standardized uptake value
(SUV) is commonly used for semi quantitative eval-
uation, e.g. of the FDG uptake in tumors. The SUV
resembles the relation of the activity concentration in
a given voxel compared to a hypothetically uniform
distribution of the tracer within the patient and is
therefore helpful in determining the intensity of
pathological uptake. However, the SUV is not a
constant value like laboratory findings or quantitative
measures. The determination of SUVs in whole-body
PET studies is significantly influenced by various
technical and biological factors (Lucignani et al.
2004). SUVs may vary considerably between centers
requiring standardisation before inter-institutional
75
comparison. Therefore, for the differentiation of
malignant versus benign lesions, or when contouring
target volumes, SUVs should be used with caution.
For correct image interpretation, it is necessary to
know the physiological distribution of the tracer used.
Thus glucose metabolism is depicted by FDG. After
i.v. injection, the small diffusible molecule is dis-
tributed in the body like glucose. It is taken up by the
physiologic glucose transport proteins and phospho-
rylized by the hexokinase according to the glucose
consumption of the cells. FDG does not take part in
further steps of the glucose metabolism, which leads
to an increase in trapping of the molecule over time,
especially in tumor cells which show an upregulation
of glucose transport and hexokinase (Abouzied et al.
2005; Weber et al. 2008). However, FDG-uptake is
not completely specific for tumor tissue, as e.g.
inflammatory lesions may also exhibit high glucose
consumption and therefore accumulate FDG.
Physiologically, the most intense FDG-uptake is
seen in brain tissue. Therefore, the tracer is not suit-
able for imaging of most intracerebral malignancies.
FDG shows a somewhat variable uptake in all kinds
of muscle cells (skeletal, myocardial, bowel) and is
mainly excreted by the kidneys. Overall, the physio-
logic distribution of the tracer allows rough anatom-
ical orientation in image data. Important for the
context of radiotherapy planning is the fact that a PET
examination—due to the need to sample a sufficient
number of counts—does last several minutes for each
of the 7–8 bed positions needed for a whole body
scan. In ungated acquisitions, this circumstance leads
to a blurring of various structures e.g. in the thorax
and upper abdomen.
Beyond the use of PET scanning for exact tumor
tissue detection and visualisation of malignant spread
and its vitality, there are more opportunities. In fact, it
only depends on the tracer injected, whose biological
property is depicted by the PET-scan. Apart from
FDG, other PET-tracers have been developed in recent
years, which can visualize biological pathways with
particular significance for treatment planning and
assessment of tumor response to treatment. Among
others, these are hypoxia, cell proliferation, apoptosis,
and angiogenesis (Plathow and Weber 2008).
It is a paradigm of medical science that new
imaging methods must be evaluated diagnostically
with histologic verification before becoming the base
76
Fig. 9 FDG-PET for radiotherapy planning in a patient with
left central NSCLC causing an atelectasis of the upper lobe
for therapeutic decisions. To date, several PET-tracers
have been adequately evaluated diagnostically in a
growing set of malignancies to consider their use in
staging, radiotherapy planning, and follow-up after
radiotherapy, e.g. for response assessment and
detection of recurrence.
2.3.1 PET in Radiotherapy Planning
The integration of a biological imaging method like
PET in the GTV delineation makes sense when it
shows a higher sensitivity and specificity for tumor
tissue in comparison to CT and MRI. This is the case
for FDG-PET in certain clinical situations e.g. in lung
cancer, head and neck cancer, gynecological cancers,
gastro intestinal malignancies, for AA-PET in brain
tumors, for choline-PET in prostate cancer and for
somatostatine-receptor PET in neuroendicrine tumors.
Beyond the depiction of primary tumors, PET may be
of great help in RT-planning for recurrent or pro-
gressive tumors after initial treatment (see below). A
detailed review on the state of the art inclusion of PET
in radiotherapy planning can be found in a recent issue
of ‘‘Radiotherapy and Oncology’’ (issue 96, 2010).
Primarily, the PET signal will be used for GTV
delineation, e.g. in tumors, whose edges cannot be
fully recognized in MRI or CT like lung cancer within
an atelectasis or recurrent glioma (Nestle et al. 1999)
(Fig. 9). Hereby, the intra-observer variation as
compared to CT- and/or MRI-based delineation
decreases significantly (Caldwell et al. 2001; Steen-
bakkers et al. 2006). However, due to the blurred and
sometimes fuzzy structure of the imaging signal,
PET-based GTV delineation needs some practice and
C. Ménard et al.
may be assisted by clinical protocols (MacManus
et al. 2007) and/or automatic or semiautomatic image
segmentation (Nestle et al. 2005; Nestle et al. 2009;
Schaefer et al. 2008). The consultation of the nuclear
medicine specialist for image interpretation will also
improve delineation.
Concerning the use of PET data for adjustments of
the CTV, it must be kept in mind that although
improved compared to CT and/or MRI, the diagnostic
accuracy of PET is never as high as 100%, e.g. for
mediastinal nodes in lung cancer patients it lies
between 85–90% (Hellwig et al. 2009). The respec-
tive figures differ depending from tracer, tumor entity,
and clinical situation and must be evaluated when
revising treatment algorithms, e.g. when discussing
the need for the prophylactic irradiation of lymph
node regions judged unaffected by PET.
A whole new world of radiotherapy planning and
delivery is envisioned by the term ‘‘dose painting’’,
i.e. radiotherapy adaptation within a given target
defined by biological properties of certain subvo-
lumes (Ling et al. 2000). Using modern IMRT tech-
niques, e.g. hypoxic regions within a tumor assumed
to be radioresistant, might be treated with integrated
boost concepts on the basis of hypoxia-PET imaging
etc. The first studies in head and neck tumors actually
address this vision, however, clinical outcome data
have to be awaited before introducing these tech-
niques into clinical practice.
2.3.2 PET for Response Assessment
There is growing evidence that PET may be very
interesting for the assessment of response to treatment
(Fig. 10). Beyond the morphologic criterion of
changing tumor size, which may need several weeks
or months to become evident, the biological proper-
ties of the tumor as imaged by FDG or other PET
tracers may change rapidly, even soon after the onset
of radiation and/or chemotherapy, indicating a future
benefit of the patient from the treatment initiated. PET
has been shown to predict response on radiation and/
or chemotherapy of lymphoma, lung cancer, sarco-
mas, colorectal, and esophageal cancers. While in
lymphoma, PET is likely to be the trigger for per-
sonalized chemotherapy in the near future, the aim in
solid tumors is rather the early identification of non-
responders in order to intensify or change treatment
approaches in due time (Weber 2009). This may be an
earlier or omitted operation as well as radiotherapy
Imaging in Radiation Therapy
Fig. 10 FDG-PET before
and 6 weeks after radical
radiochemotherapy for lung
cancer showing a complete
metabolic remission
dose escalation or change of the chemotherapy regi-
men. However, PET based response assessment is far
from being standardized and its clinical consequences
are not yet clearly defined. Therefore, PET-based
changes of running treatments should presently be
made within clinical studies, otherwise with high
caution.
3 Next generation of Online
Integration
Online imaging systems in radiation therapy are
typically defined as in-room systems whereby images
are acquired while patients are positioned (± immo-
bilized) on the treatment table. Historically, these
systems have focused on the geometry of radiation
delivery, and predominantly used to fit the patient on
any given day against the planned patient model and
delivery plan. A key advantage of online imaging
systems is their ability to perform frequent imaging
through a course of radiotherapy with minimal dis-
ruption. Clinical gains with the use of frequent online
imaging have been demonstrated in the realm of
IGRT (de Crevoisier et al. 2005; Kupelian et al. 2008;
Zelefsky et al. 2007), translating into widespread
clinical implementation across the cancer community.
However, the potential for timely assessment of bio-
logical response and adaptation has remained largely
untapped, in part due to the restricted imaging per-
formance of online systems.
77
Offline Online
Patient Model Patient
Biology Geometry
Imaging Performance Imaging Frequency
Computational Workflow Hardware Integration
Fig. 11 Idealized convergence of current strengths in offline
and online imaging models, whereby high performance in
image quality (including biological imaging) is physically
integrated with online radiation delivery systems
Despite this, online introduction of the state-of-
the-art imaging technology with external beam
radiotherapy has been slow and fragmented given the
cost and complexity of hardware integration. This is
especially true in the case of MRI. In the short term,
brachytherapy systems present fewer barriers and may
be more amenable to convergence with modern
interventional imaging environment (Ménard et al.
2004; Dimopoulos et al. 2006). In contrast, offline
imaging systems for radiotherapy (simulators) have
largely kept pace with diagnostic systems in terms of
imaging performance. The major strength of offline
systems therefore rests in an ability to recapture
image quality in radiotherapy with an emphasis on
computational (rather than physical) solutions in
workflow integration. Although offline images are of
higher quality and can provide a window of
78
Fig. 12 Online MR-Guided RT Systems are being developed
for higher precision and accuracy in radiation delivery.
a Fallone et al. have been building an integrated system that
relies on a permanent magnet and linear accelerator. b The
group in Utrecht led by Lagendijk has been developing an
integrated system with state-of-the-art superconducting 1.5 T
magnet. c Dempsey et al. at Viewray Inc. have made progress
on their combination of low-field and Cobalt irradiator. In
underlying biology, they are infrequently acquired
during a course of radiation therapy. (Fig. 11).
The potential for bringing the quality of offline
imaging to the online environment has been recog-
nized by the radiation community. Investigators in
Utrecht have been promoting the merits of high field
([1.5 T) imaging in combination with a linear
accelerator and have recently reported impressive
results in terms of image quality achieved during
irradiation (Raaymakers et al. 2004; Lagendijk et al.
2008). In addition to direct integration, there are
active projects to establish patient-transfer approa-
ches that bring many of the benefits of MR imaging
C. Ménard et al.
addition to integrated systems, there are two projects (Umea,
Sweden and Toronto, Canada) focusing on adjacent solutions
that minimize the time between MR imaging and treatment
delivery. The groups in Umea (d) have reported on their system
and the development in Toronto (e) chooses to move the
magnet to allow conventional devices to be exploited (linear
accelerator and brachytherapy afterloaders) in close proximity
to the patient
to the treatment room, but avoid the challenges of
direct integration (Karlsson et al. 2009). Recently,
the Radiation Medicine Program of the Princess
Margaret Hospital has embarked on the creation of a
multi-use facility that integrates an MRI scanner on
rails with both MR-guided brachytherapy and
external beam radiation therapy suites (Jaffray et al.
2010) (Fig. 12).
It is now clear that the potential impact of imaging
on patient outcomes in radiotherapy will be better
realized when high-quality images are acquired and
integrated more frequently in patient care. Such a
vision requires creative computational and hardware
Imaging in Radiation Therapy
solutions that will likely gravitate closer to the online
environment.
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 Physics of Radiotherapy Planning
and Delivery
James A. Purdy, Philip Poortmans, Carlos A. Perez,
and Seymour H. Levitt

Contents 4.4 Monitor Unit Calculation for Rotational Therapy ... 103
4.5 Monitor Unit Calculation for Irregular Fields.......... 103
4.6 Monitor Unit Calculation for Asymmetric
1 Introduction.............................................................. 86 Collimators................................................................. 104
4.7 Monitor Unit Calculation for MLC .......................... 104
2 Radiation Therapy Treatment Machines ............. 86
4.8 Monitor Unit Calculations for IMRT ....................... 104
2.1 Medical Linear Accelerators ..................................... 86
2.2 Tomotherapy IMRT................................................... 90 5 Dose Calculation Algorithms and Correction
2.3 CyberKnife................................................................. 91 Factors....................................................................... 105
2.4 Gamma Knife ............................................................ 92 5.1 Correction for Surface Obliquity .............................. 105
2.5 New Treatment Machines ......................................... 92 5.2 Correction for Tissue Heterogeneities ...................... 106
2.6 Proton, Heavy Particle Treatment Units................... 94 5.3 Interface Dosimetry ................................................... 108
5.4 Tissue Heterogeneities Corrections:
3 Dosimetry Parameters............................................. 95
Recommendations...................................................... 111
4 Monitor Unit and Dose Calculation Methods...... 101
6 Peripheral Dose, Whole Body Dose....................... 112
4.1 Equivalent Field Size ................................................ 102
6.1 Peripheral Dose-Linac MLC IMRT.......................... 112
4.2 Monitor Unit Calculation for Fixed Fields: SAD .... 102
6.2 Peripheral Dose-Helical Tomotherapy...................... 112
4.3 Monitor Unit Calculation for Fixed Fields: SSD..... 102
6.3 Peripheral Dose-CyberKnife ..................................... 112
6.4 Dose Due to Daily Imaging ...................................... 113
7 Treatment Planning: Combination of Treatment
Fields ......................................................................... 113
7.1 Parallel–Opposed Fields ............................................ 113
7.2 Multiple-Beam Arrangements ................................... 114
7.3 Rotational Therapy-Non IMRT................................. 116
7.4 Treatment Plan Comparisons .................................... 117
J. A. Purdy (&)
Department of Radiation Oncology, 8 Collimation and Field Shaping .............................. 119
University of California Davis Medical Center, 8.1 Asymmetric Collimator Jaws .................................... 119
Sacramento, CA 95817, USA 8.2 Multileaf Collimation ................................................ 120
e-mail: james.purdy@ucdmc.ucdavis.edu 8.3 Low Melting Alloy Blocks ....................................... 122
P. Poortmans 9 Separation of Adjacent X-ray Fields .................... 123
Department of Radiation Oncology, 9.1 Field Junctions........................................................... 123
Institute Verbeeten, Tilburg, The Netherlands 9.2 Orthogonal Field Junctions ....................................... 123
C. A. Perez, 10 Patients With Cardiac Pacemakers....................... 125
Department of Radiation Oncology,
Mallinckrodt Institute of Radiology, 11 Fetal Dose ................................................................. 127
Washington University School of Medicine,
12 Gonadal Dose ........................................................... 128
St. Louis, MO 63110, USA
References.......................................................................... 128
S. H. Levitt
Department of Therapeutic Radiation Oncology,
University of Minnesota, Minneapolis,
MN 55455, USA

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 85
DOI: 10.1007/174_2011_320, Ó Springer-Verlag Berlin Heidelberg 2012
86
Abstract
A solid foundation in the physics concepts used in
the planning and delivery of the cancer patient’s
radiation therapy is one of the fundamental
cornerstones for the practice of radiation therapy.
The essential concepts are discussed in this
chapter, including a brief review of modern
treatment machines, basic dosimetry parameters
used in treatment planning, monitor unit and dose
calculation methods, dose calculation algorithms
and correction factors for the effects of patient
topography and internal heterogeneities, isodose
distributions for various combined fields, periph-
eral dose, field junctions, field shaping and special
considerations including patients with cardiac
pacemakers, fetal dose and gonadal dose. These
topics are presented in detail suitable for practicing
radiation oncologists and physician residents.
1 Introduction
The radiation oncologist, when planning the treatment
of a patient with cancer, is faced with the difficult
problem of prescribing a treatment regimen with a
radiation dose that is large enough to potentially cure
or control the disease, but does not cause serious
normal tissue complications. This task is a difficult
one because tumor control and normal tissue effect
responses are typically steep functions of radiation
dose; that is, a small change in the dose delivered
(±5%) can result in a dramatic change in the local
response of the tissue (±20%) (Fischer and Moulder
1975; Herring 1975; Herring and Compton 1971;
Stewart and Jackson 1975). Moreover, the prescribed
curative doses are often, by necessity, very close to
the doses tolerated by the normal tissues. Because of
this small ‘‘therapeutic window’’, for optimum treat-
ment, the radiation dose must be planned and deliv-
ered with a high degree of accuracy.
One can readily compute the dose distribution
resulting from radiation beams of photons, electrons, or
mixtures of these impinging on a regularly shaped, flat-
surface, homogeneous unit density phantom. However,
the patient presents a much more complicated situation
because of irregularly shaped topography and many
tissues of varying densities and atomic composition
J. A. Purdy et al.
(called heterogeneities). In addition, some form of
beam modulation or beam modifier, such as wedges and
compensating filters or bolus, are most often inserted
into the radiation beam to achieve the desired dose
distribution. This chapter will review several of the
physics concepts used in the planning and delivery of
the cancer patient’s radiation therapy. As this textbook
is aimed at practicing radiation oncologists and physi-
cian residents, this topic is not treated in the detail
required for medical physicists. If interested, more
details on the topics covered can be found in the
references listed (Karzmark et al. 1993; Khan 2010).
2 Radiation Therapy Treatment
Machines
2.1 Medical Linear Accelerators
Today medical linear accelerators (referred to as
linacs) account for most of the operational mega-
voltage treatment units in clinical use (Podgorsak
et al. 1999). Figure 1 is a block diagram of a high-
energy bent-beam medical linear accelerator showing
the major components. The linac uses electromag-
netic waves of frequencies in the S-band microwave
region (2,856 MHz, ) to generate an electric field. The
microwave radiation is propagated through a device
called an accelerator structure and the electrons (used
to create the X-ray beam) are injected into the
structure and accelerated by the generated electric
field. The accelerator structure consists of a stack of
cylindrical metal cavities having an axial hole through
which the accelerated electrons pass. The accelerator
structure’s electric field produced by the microwaves
can be either a traveling wave (used e.g., in Elekta’s
linacs; Elekta, Crawley, UK) or a standing wave (used
e.g., in Varian’s linacs; Varian Medical Systems, Palo
Alto, CA). In a traveling wave design, the electrons
travel with the electric field as the field propagates
through the structure with time, somewhat in the
manner of a surfboarder riding the crest of an ocean
wave. In a standing wave accelerator, the reflected
microwave power is used to produce a standing wave
electric field. In that case, the microwave power is
coupled to the accelerator structure by side-coupling
cavities, rather than through the accelerator struc-
ture’s axial cavity apertures. Both methods have
proven to be robust design options for linacs.
Physics of Radiotherapy Planning and Delivery
Fig. 1 Schematic block
diagram showing major
components of high-energy
bent-beam medical linear
accelerator
Other important components of a linac are the mod-
ulator, microwave power sources, electron gun, and the
beam handling components. The modulator is the source
of pulsed DC (direct current) power needed for the
production of the microwave power. Pulsed DC power is
also supplied to the electron gun, (a hot wire filament
that serves as the source of the accelerated electrons).
The electrons are bunched together before acceleration
by a device called a buncher. The electron beam thus
consists of pulses of bunched electrons moving forward
in the form of a narrow pencil beam. The microwave
power is generated in some linacs using a magnetron,
which serves both as the source of the microwaves and as
a power amplifier. Other linac designs use a separate
microwave source (RF Driver) and the microwave
power is then amplified by a device called a klystron. The
microwave power coming from the magnetron or kly-
stron is transported to the accelerator structure via a
metallic pipe called a waveguide. Again, both methods
have proven to be robust design options for producing
the necessary microwave power to accelerate electrons
to the high energy needed for radiation therapy linacs.
Once accelerated, the high-energy electrons emerge
at the exit window of the accelerator structure in the form
of a pencil beam (about 2–3 mm in diameter) and are
directed to strike a metal target, when in photon mode.
This abrupt stopping of the electrons results in the con-
version of their kinetic energy partially to heat in the
metal target and partially to the production of brems-
strahlung X-rays. Because the accelerator structure is
87
typically placed horizontally or at some angle with
respect to the horizontal, the electrons must be bent
through a suitable angle, usually 90 or 270° between the
accelerator structure and the X-ray target. This is enabled
by a beam transport system, which consists of an ach-
romatic focusing and bending magnet, as well as steer-
ing and focusing coils. Several design options are in use
as shown in Fig. 2. It should also be noted that today’s
accelerator technology makes possible multiple high-
dose-rate photon beams of widely separated energies.
Important components located in the linac’s treat-
ment head (see Fig. 3a) include the X-ray target, fixed
primary collimator, scattering foils, flattening filter,
monitor ion chamber, movable secondary collimator
jaws, light field localizer, and optical distance indicator.
In addition, the treatment head contains a significant
amount of shielding material to minimize leakage
radiation.
The primary collimator is a fixed collimator located
just below the X-ray target, used to collimate the X-ray
beam in the direction of the patient treatment and to
reduce the leakage radiation emerging from the linac.
The angular distribution of the bremsstrahlung X-rays
produced by megavoltage electrons incident on a target
is forward peaked. To make the X-ray beam intensity
uniform across the field, a conical metal flattening filter
is inserted in the beam. Filters have been constructed of
lead, tungsten, uranium, steel, and aluminum (or some
combination of these), depending on X-ray energy.
The flattened X-ray beam then passes through a
88 J. A. Purdy et al.

Fig. 2 Schematic drawing

showing two types of beam
transport system, which
consists of an achromatic
focusing and a bending
magnet, as well as steering
and focusing coils. The slalom
approach (top of figure) is
used in Elekta linacs and the
270° bend approach (bottom
right) is used in Varian linacs

Fig. 3 Schematic cutaway

diagram of typical treatment
head for a high-energy bent-
beam medical linear
accelerator. a X-ray therapy
mode. b Electron beam
therapy mode

monitor ionization chamber. In most cases, this system
consists of several transmission-type parallel-plate
ionization chambers, which cover the entire beam.
These ion chambers are used to monitor the field
symmetry, dose rate, and the integrated dose per mon-
itor unit (MU).
After passing through the monitor chamber, the
beam can be further collimated by continuously
movable X-ray collimators, consisting of two pairs of
lead or tungsten jaws, which can move independently
and provide rectangular field sizes ranging from zero
to typically 40 9 40 cm at a distance of 100 cm.
Physics of Radiotherapy Planning and Delivery
Fig. 4 Modern medical accelerators come with multileaf col-
limator (MLC) systems. The leaf settings for each field are
computer controlled so as to shape the beam aperture to conform
to the patient’s target volume. Computer controlled MLC
systems are also used to create optimized modulated beam
fluence. This form of therapy is referred to as intensity modulated
radiation therapy (IMRT). (Varian Associates, Palo Alto, CA)
The field size is defined by a light localizer and a
mirror assembly. The independent jaw capability
allows simplified patient positioning and improved
safety by avoiding overlapping field abutments with-
out the necessity of using heavy beam-splitting alloy
blocks (Klein et al. 1994). Independent jaw technol-
ogy in conjunction with computer control of the dose
rate is also used in modern linacs to create a wedge-
shaped isodose pattern (Leavitt et al. 1990).
Modern medical accelerators come with multileaf
collimator (MLC) systems (Fig. 4) (AAPM 2001;
Klein et al. 1995). The leaf settings for each field are
computer controlled. Modern treatment planning
systems have the ability to configure MLC-shaped
fields and the patient’s MLC configuration files are
sent via a local area network to the linac’s MLC
computer. Most importantly, the computer controlled
MLC systems are used to create optimized modulated
beam fluence. This form of therapy is referred to as
intensity modulated radiation therapy (IMRT) and is
delivered at fixed gantry angles by (1) delivering
multiple field segments (called segmental MLC
(SMLC) or step-and-shoot IMRT), or (2) having the
89
leaf pairs move across the field at a varying rate with
the X-ray beam on (called dynamic MLC (DMLC) or
sliding window IMRT) (IMRTCWG 2001).
In the electron mode (Fig. 3b), the accelerator’s
beam current is reduced a 1,000-fold and the X-ray
target and flattening filter is retracted. An electron-
scattering foil is then moved into place on the beam
centerline so that the accelerated pencil electron beam
strikes it in order to broaden the beam and produce a
relatively uniform beam across the treatment field. The
scattering-foil system typically consists of multiple
lead foils, in which the thickness of the first foil ensures
that most of the electrons are scattered with only a
minimum of bremsstrahlung X-rays. The subsequent
foils are generally thicker in the central region and are
used to flatten the field. The bremsstrahlung produced
when the electrons strike the foils appears as an X-ray
contamination of the electron beam and is usually less
than 5% of the maximum dose. An electron applicator
is mounted below the movable collimator jaws to
provide the final field collimation.
Modern linacs now come with advance imaging
capabilities including cone beam CT (CBCT) capa-
bility. Such linacs are referred to as image-guided
radiation therapy (IGRT) linacs. The first commercial
CBCT IGRT linac was the Elekta SynergyTM (Elekta,
Crawley, UK) (Jaffray et al. 1999, 2002); other
medical linac manufacturers have also embraced
the IGRT concept, e.g., Varian TrilogyTM and
TrueBeamTM (Varian Medical Systems, Palo Alto,
CA) and Siemens ARTÍSTETM, (Siemens Medical
Solutions USA, Inc., Malvern, PA).
The Synergy (Fig. 5) IGRT system (referred to as
XVI) consists of a retractable kV X-ray source, an
amorphous silicon flat panel imager mounted on the
linac gantry perpendicular to the radiation beam direc-
tion, and a software module for processing the data and
tools for registering the images. The XVI system
provides for planar, motion, and volumetric imaging
capabilities. Registration software is provided for
comparing the daily patient set-up image with the stored
prescription CT planning image, after which table
adjustments can be made prior to treating the patient.
Most recently, manufacturers of medical linear
accelerators (linacs) and their associated planning
systems have introduced features that provide rota-
tional IMRT capability, e.g., Elekta VMAT (Rao
et al. 2010) and Varian RapidArc (Ling et al. 2008).
The linac-based rotational IMRT concept was first
90 J. A. Purdy et al.

Fig. 5 Elekta synergy IGRT

system (referred to as XVI)
consists of a retractable kV
X-ray source, an amorphous
silicon flat panel imager
mounted on the linear
accelerator perpendicular to
the radiation beam direction,
and a software module for
processing the data and tools
for registering the images.
The XVI system provides for
planar, motion, and
volumetric imaging
capabilities. (Elekta AB,
Stockholm, Sweden)

proposed by Yu (Yu 1995; Yu and Tang 2011) and

called intensity modulated arc therapy (IMAT), but
planning software was not commercially available at
that time. Rotational IMRT approaches on conven-
tional linacs may provide even more conformal dose
distributions delivered in a shorter treatment time,
compared with SMLC- or DMLC-IMRT approaches
that use only a limited number of gantry directions. In
addition, plan optimization is simpler since it elimi-
nates the planner’s iterative choices of beam number
and direction. The conventional MLC approach for
rotational IMRT is likely to improve the IMRT plan
quality and delivery efficiency (Ling et al. 2008),
although this remains somewhat controversial at
present (Ling et al. 2009; Mehta et al. 2009) and more Fig. 6 TomoTherapy HI-ART system installed at UC Davis.
A short in-line 6 MV linac rotates on a ring-gantry. IMRT
users will need to report their rotational IMRT treatment is delivered while the patient-support couch is
experiences over the next few years. translated through the gantry bore in the same way as a helical
CT study is conducted. The width of the beam in the patient
translated direction is defined by a pair of jaws that is fixed for
any particular patient treatment and laterally the treatment
2.2 Tomotherapy IMRT beam is modulated by a 64 leaf binary MLC. (TomoTherapy,
Inc., Madison, WI)
A completely different linac configuration design
is used in the TomoTherapy HI-ART system translated in the y-direction (toward gantry) through
(TomoTherapy, Inc., Madison, WI). Helical tomo- the gantry bore in the same way as a helical CT
therapy was first proposed by Mackie et al. (Mackie study is conducted. Thus, in the patient’s reference
et al. 1993). A short in-line 6 MV linac (Siemens frame the treatment beam is angled inwards along a
Oncology Systems, Concord, CA) powered by a helix, with the midpoint of the fan beam passing
magnetron rotates on a ring-gantry, at a source–axis through the center of the bore. Similar to helical CT,
distance (SAD) of 85 cm (Fig. 6). The IMRT treat- the treatment beam pitch is defined as the distance
ment is delivered while the patient-support couch is traveled by the couch per gantry rotation, divided by
Physics of Radiotherapy Planning and Delivery
Fig. 7 The CyberKnifeÒ
system couples an X-band
(*10,000 MHz) 6 MV linear
accelerator to a robotic
articulated manipulator and
allows for the delivery of both
stereotactic radiosurgery
(SRS) and stereotactic body
radiation therapy (SBRT).
(image used with permission
from Accuray Inc.,
Sunnyvale, CA)
the field width in the y-direction (typically between
0.2 and 0.5). The width of the beam in the
y-direction is defined by a pair of jaws that is fixed
for any particular patient treatment to one of three
selectable values (1, 2.5 or 5 cm). Laterally, the
treatment beam is modulated by a 64-leaf binary
MLC, whose leaves move rapidly between open and
closed states. Each leaf has a projected width of
6.25 mm at the bore center for a maximum possible
open lateral field length of 40 cm. Intensity modu-
lation is accomplished by varying the fraction of
time that individual leaves are opened. The individual
modulation pattern can change with angle (divided
into exactly 51 projections over a full revolution).
During the treatment, the gantry rotates at a constant
velocity with a period ranging between 10 and 60 s per
rotation. The extent to which a treatment beam
projection is modulated is characterized through what
is called, the modulation factor, defined as the ratio of
the maximum leaf open time to the average leaf open
time for the projection. Pitch and maximum permis-
sible modulation factor are new parameters needing to
be specified by the treatment planner. Highly modu-
lated treatments achieve greater conformality but they
inevitably take longer to deliver. A helical MVCT
image is acquired using the on-board xenon CT
detector system and the 6 MV linac (detuned to
3.6 MV) with the leaf fully opened when the patient-
support couch is translated in the y-direction through
the gantry bore. Registration software is provided to
91
compare the daily patient set-up image with the
stored prescription CT planning image. More details on
tomotherapy are provided in ‘‘Tomotherapy Image
Guided Radiation Therapy’’.
2.3 CyberKnife
The CyberKnifeÒ system couples an X-band
(*10,000 MHz) 6 MV linear accelerator to a robotic
articulated manipulator (Fig. 7), and allows for the
delivery of both stereotactic radiosurgery (SRS) and
stereotactic body radiation therapy (SBRT), both of
which are discussed in the later chapters. The system
was developed by Dr. John Adler Jr. (Adler et al. 1997,
1999), a neurosurgical trainee of Dr. Lars Leksell who
developed the Gamma Knife which is discussed next.
The robotic arm provides the capability for aiming a
narrowly collimated X-ray beam with any orientation
relative to the target volume. The system uses two
ceiling-mounted diagnostic X-ray sources and amor-
phous silicon image detectors mounted flush to the floor.
The treatment is specified by the trajectory of the robot
and by the number of monitor units delivered at each
robotic orientation. During the patient’s treatment, the
CyberKnife System correlates live radiographic images
with pre-operative CT or MRI scans in real time to
determine patient and tumor position repeatedly over
the course of treatment. More details are provided in
‘‘Robotic Image Guided Radiation Therapy’’.
92
2.4 Gamma Knife
The Elekta Gamma Knife is a dedicated stereotactic
radiosurgical device first developed in 1968, by Dr. Lars
Leksell, a Swedish neurosurgeon (Leksell 1968). This
machine made it possible to precisely deliver a single,
large dose of highly conformal radiation (c-rays) to any
number of intracranial sites using multiple fixed cobalt-
60 sources aimed at a center point. The Gamma Knife
has three basic components (spherical source housing,
four collimator helmets, and a couch with electronic
controls). The source housing contains 201 (models U,
B, and C) Cobalt-60 gamma-ray emitting sources dis-
tributed in a radial arrangement. The c-rays from each
source converge to the Unit Center Point (UCP), which
is 40 cm away from each source. The UCP is analogous
to the isocenter of a teletherapy machine and is the
location where the target volume must be positioned
during a treatment. This is accomplished by the three-
axis coordinate system on the Leksell stereotactic frame.
Each source has an activity of approximately 1.1 TBq,
when newly installed, and the 201 sources combined
provide a dose rate of approximately 3 Gy/min at the
UCP. Along the path to the UCP, the radiation beam
from each source is collimated twice, once by a primary
collimator, and then by one of four secondary collimator
helmets. For each helmet, 201 tungsten collimators
define specified circular apertures (4, 8, 14, or 18 mm
projected at the UCP). In order to conform the radiation
dose to the shape of the target in the patent, various
combinations of aperture diameters, aperture blocking
(plugging), irradiation times, and head positions are
utilized. A specific combination of these four parameters
defines what is referred to as a shot in Gamma Knife
terminology.
More recently, Elekta introduced the Gamma
Knife PerfexionTM (Fig. 8) which is a major change
in design from the previous models with several
advanced features including an enlarged internal
patient cavity for extended access to peripheral
cranial anatomy. Unlike the earlier models, the
Perfexion moves the entire patient on the couch to
each stereotactic x, y, and z coordinate. The sources
are arranged radially, and divided into eight moving
sectors with 24 sources each. Each sector is inde-
pendently selectable, thereby providing various sector
combinations for aperture size or blocking at each
shot position during treatment. With the introduction
of its associated Extend System accessory, the
J. A. Purdy et al.
Fig. 8 Elekta Gamma Knife (Elekta AB, Stockholm, Sweden) is
a dedicated stereotactic radiosurgical device first developed in
1968, by Dr. Lars Leksell, a Swedish neurosurgeon, to provide
highly accurate radiation ablative treatment of intracranial targets.
Shown above is the latest model, the Gamma Knife PerfexionTM,
which broadens both the techniques and the scope of treatments
including being able to treat lesions in the upper cervical spine
Perfexion has an increased reach to allow treatments
to the upper cervical spine. More details are provided
in ‘‘Cranial Stereotactic Radio Surgery’’.
2.5 New Treatment Machines
There are several other new treatment machine designs
that show significant promise. For example, the 4-D
IGRT system proposed by Kamino et al. is shown in
Fig. 9. It has a unique, gimbaled X-ray head that allows
the linear accelerator head to be pivoted (Kamino et al.
2006). By easily allowing non-coplanar beams without
couch rotations, new degrees of freedom are made
available for IMRT optimization, and even more con-
formal dose distributions may be possible.
A new device, Vero (Brainlab AG, Germany), for
SRS/SBRT was recently introduced that utilizes a rotat-
ing ring gantry to which an MV treatment head is
mounted on orthogonal gimbals (Fig. 10). Image guid-
ance systems include an EPID, and 2 fixed kV X-ray tubes
combined with 2 fixed flat panel detectors. This dual
imaging systems provides planer images, CBCT, and
real-time fluoroscopic monitoring (Depuydt et al. 2011).
Another highly promising IG-IMRT delivery sys-
tem on the horizon, which has significant potential to
improve one’s abilities to localize and track soft
tissue tumors, is the RenaissanceTM System 1,000
(ViewRay, Inc, Cleveland, OH, USA) (Fig. 11).
Physics of Radiotherapy Planning and Delivery
Fig. 9 Medical linac with gimbaled X-ray head mounted on
an O-ring with two kV X-ray tubes, two flat panel detectors
(FPDs), and an electronic portal imaging device (EPID). The
O-ring can be rotated 360° around the isocenter and can be
skewed + 60° around its vertical axis. The couch has motion in
Fig. 10 The vero system utilizes a rotating ring gantry to
which a MV treatment head is mounted on orthogonal gimbals.
Image guidance systems include an EPID, and 2 fixed kV X-ray
tubes combined with 2 fixed flat panel detectors. This dual
imaging systems provides planer images, CBCT, and real-time
fluoroscopic monitoring (courtesy Professor Dirk Verellen,
Dept. of Radiotherapy, UZ Brussel, Belgium)
93
X, Y, and Z. The X-ray head has a multileaf collimator to
control dose distribution. The pan and tilt rotations provide a
precise and quick beam motion around the isocenter. (Courtesy
Yuichiro Kamino, Ph.D.)
Fig. 11 Schematic of integrated MR-cobalt-60 IMRT system
(RenaissanceTM system 1,000, ViewRay Inc., Cleveland, OH)
that will provide real-time beam-on imaging and targeting of
the tumor and IMRT treatment delivery
94
This device utilizes a multi-headed Cobalt-60 rota-
tional IMRT system with MR image-guidance and
has the ability to image continually during treatment
even while the beam is on. In addition, MRI-linac
hybrid systems continue to be an important area of
research and development (Kirkby et al. 2008).
Also, it is important to be aware that several
investigators have pointed out the utility of very-high
energy (VHE) electron beams (150–250 MeV)
(DesRosiers et al. 2000; Fuchs et al. 2009). Such high
energy beams are not yet available so beam simula-
tion software has been used to demonstrate the use of
multi-VHE beams from opposite directions and the
ability to modulate VHE beam intensity (DesRosiers
et al. 2000; Fuchs et al. 2009). Such machines are
clearly some time away but these early planning
studies show promise.
2.6 Proton, Heavy Particle Treatment
Units
Proton beam radiation therapy (PBRT) and light ion
radiation therapy are seeing increasing interest
worldwide because their depth-dose characteristics
show advantages over photon beams (Schulz-Ertner
et al. 2006). In most proton facilities, cyclotrons are
used to accelerate proton beams to sufficient energy
(200–250 MeV) and beam intensity. Cyclotrons
produce continuous beams with a fixed energy, and
this makes their design quite simple. Beam spread-
ing mechanisms obtain suitable field sizes for radi-
ation therapy by passive modulation (scattering foil)
systems or by dynamic pencil beam spot-scanning
systems (Coutrakon et al. 1991), which allow dose
conformation not only at the distal edge of the
tumor, but also at the proximal edge. There are at
least 9 modern PBRT facilities specifically designed
for radiation therapy already operating within the
United States and approximately 10 more either in
development or scheduled to open over the next few
years.
There are only a few clinical facilities for light ion
radiation therapy (primarily carbon ion) currently
active (Henning and Shank 2010; Schulz-Ertner et al.
2006). Two are operational in Japan, with a third
coming on line shortly, and a fourth to begin con-
struction soon. Heidelberg, Germany now has the first
clinical center with multiple-ion capabilities from
J. A. Purdy et al.
protons to carbon, including the first gantry for carbon
beams, and two more are currently under construction
in Germany. The Centro Nazionale di Adroterapia
Oncologica (National Center for Oncological
Hadrontherapy, CNAO) in Pavia, Italy is scheduled to
begin treatments in 2011. In addition, a facility is
under construction in both France and Austria.
Light ion radiation therapy requires beams at much
higher energies than proton therapy. For example, a
proton beam of 150 MeV can penetrate 16 cm in water.
To achieve the same penetration with carbon ions,
energy of 3,000 MeV or 250 MeV/u (energy per
nucleon) is needed. Synchrotrons are currently the only
available sources for such high energy ion beams, and
they are large, complex machines requiring large
facilities and similarly large capital expenditures.
Interest in ion radiation therapy is due to its
combination of two important physical advantages:
(1) its depth dose characteristics and (2) high linear
energy transfer (LET) in the Bragg peak region of the
beam. For its depth characteristics, the ratio of the
Bragg peak dose to the entrance region dose is even
larger than for protons. In addition, unlike proton
beam therapy, there is a large increase in the radiation
LET in the Bragg peak region of the beam. The
combination of these two characteristics results in a
potentially unique advantage, a high LET region that
can be closely conformed to the target volume.
Hopefully, a heavy ion clinical facility will be built
in the USA in the next decade, but these types of
treatment facilities are more likely to remain in the
realm of promising research endeavors than in
mainstream radiation therapy systems in the foresee-
able future.
New technologies for the delivery of PBRT are
now emerging. Already, single gantry systems are
being designed and manufactured, including the
Monarch 250TM PBRT system (Still River Systems,
Littleton, MA, USA) shown in Fig. 12 and scheduled
to be installed at Washington University-St. Louis in
2010. In addition, Varian recently announced their
single-room PBRT system, which uses superconduc-
ting cyclotron technology and can be expanded into a
multi-room facility when needed.
A more futuristic design concept, depicted in
Fig. 13, has been reported by Caporaso et al. (2008).
This system is being co-developed by Compact Par-
ticle Acceleration Corp (CPAC) and TomoTherapy
Inc. The design is based on what has been called
Physics of Radiotherapy Planning and Delivery
Fig. 12 Rendering of next generation proton therapy system
(Monarch 250TM PBRT system, Still River Systems, Littleton,
MA). a Outer gantry holds the proton accelerator in the center,
pointing directly to the isocenter. Accelerator is a 250 MeV
cyclotron specifically designed (uses superconducting magnets)
for proton therapy (with IMPT capabilities, high dose rate, high
reliability and easy maintenance). b Treatment room depicting
inner gantry and 6° of-freedom robotic couch
dielectric wall accelerator (DWA) technology [under
development by the Lawrence Livermore National
Laboratory (LLNL) (Caporaso et al. 2008)] The goal
is to make a PBRT linac so compact that it can be
installed in a conventional linac treatment room. This
will require an average accelerating gradient of
approximately 100 MV/m to yield a linac of the order
of 2 m in length. If successful, the DWA PBRT
machine would produce a 200 MeV proton beam
composed of individual pulses that could be varied in
intensity, energy, and spot width. While the DWA is
still largely at a research level of development, the
realization of a compact, CT-guided PBRT system
that can provide rotational intensity modulated proton
therapy (IMPT) and be sited in a treatment room not
much larger than for a conventional linac which
would likely be a real ‘‘game-changer’’ for radiation
therapy.
95
Fig. 13 Artist’s rendition of a possible reduced size proton
therapy system being co-developed by Compact Particle
Acceleration Corp (CPAC) and TomoTherapy Inc. using the
dielectric wall accelerator (DWA) technology developed by the
Lawrence Livermore National Laboratory (LLNL)
3 Dosimetry Parameters
Several dosimetric parameters have been defined for
use in calculating the patient’s dose distribution and
the treatment machine settings to deliver the pre-
scribed dose. These parameters are only briefly
reviewed here, but more details can be found in the
text by Khan (2010).
Percentage depth dose (PDD) is defined as the
ratio, expressed as a percentage, of the absorbed dose
on the central axis at depth d to the absorbed dose at
the reference point dmax (Fig. 14).
Dd
PDDðd; do ; S; f ; EÞ ¼  100
Ddo
The functional symbols have been inserted in the
above expression to make it clear that the PDD is
affected by a number of parameters, including d, dmax,
field dimension S, source-to-surface distance f, and
radiation beam energy (or quality) E. S refers to the
side length of a square beam at a specified reference
96
Fig. 14 Schematic drawing illustrating definition of percent-
age depth dose where, d is any depth and do is the reference
depth, usually dmax
Fig. 15 Representative photon beam and electron beam cen-
tral axis percent depth dose curves for a 10 9 10 cm field for
selected energies
depth. Non-square beams may be designated by their
equivalent square. Field shape and added beam col-
limation also can affect the central axis depth dose
distribution.
Representative photon beam and electron beam
PDD curves are shown in Fig. 15 for conventional
source-to-skin distances (SSDs). As a rule of thumb, an
18 MV, 6 MV, and 60Co photon beam loses approxi-
mately 2, 3.5 and 4.5% per cm, respectively, beyond the
depth of maximum dose, dmax (values are for a
10 9 10 cm field, 100 cm SSD). There is no agreement
on what the single optimal X-ray beam energy is;
instead, institutional bias or radiation oncologist
training typically influences its selection, and it is
generally treatment site specific with higher beam
J. A. Purdy et al.
energies selected more often for deep seated target
volumes. Most modern medical linear accelerators
(linacs) are multimodality, and provide a range of
photon and electron beam energies ranging from 4 to
25 MV with 6 MV and 10, 15, or 18 MV X-ray beams
the most common. Due to the unwarranted generation
of neutrons by photon beams with energy exceeding
10 MV and the fact that modern day therapy beam
arrangements result in dose distributions that are only
marginally influenced by beam energy, many radiation
oncology departments now opt for linacs with photon
beam energies 6 MV and/or 10 MV.
Photon beam PDD for a specific depth increases
with increasing energy, SSD, and field size. The depth
of the 50th percentile increases from approximately
14 cm for 4 MV X-rays to nearly 23 cm for 25 MV
X-rays. The depth of maximum dose varies from
about 1 cm for 4 MV X-rays to over 3.5 cm for
25 MV X-rays. However, the depth of maximum dose
position is not unambiguously defined by the energy
of the X-ray beam, but depends on the field size and
on the treatment-head design of the particular
machine. This shift in dose maximum is principally
the result of electron scattering from the X-ray col-
limator. The specification of X-ray PDD in terms of
the maximum electron energy impinging on the X-ray
target is not sufficient to characterize the X-ray beam.
Various methods of specifying beam quality are now
in use, including the tissue phantom ratio at 20 cm
depth to that at 10 cm depth (TPR20 10 ), the PDD at
10 cm depth, and the depth of the 80% dose level.
The tissue–air ratio (TAR) is defined as the ratio of
the absorbed dose Dd at a given point in the phantom
by the absorbed dose in free space, Dfs, that would be
measured at the same point but in the absence of the
phantom, if all other conditions of the irradiation
(e.g., collimator, distance from the source) are equal
(Fig. 16). The TAR is expressed as:
Dd
TARðd; Sd ; EÞ ¼
Dfs
where d is depth, E is radiation beam energy, and
Sd is the beam dimension measured at depth d. TAR
depends on depth, field size, and beam quality but is
for all practical purposes independent of the distance
from the source.
The TAR at the depth of maximum dose is called the
peakscatter factor. It is perhaps better known as the
backscatter factor, but because of the finite depth do,
Physics of Radiotherapy Planning and Delivery
Fig. 16 Schematic drawing
illustrating the definition of
tissue-air ratio, where d is the
thickness of overlying
material
Fig. 17 Variation of peakscatter factor with beam quality
(half-value layer). [modified from Johns and Cunningham
(1983)]
this tends to be misleading. Figure 17 shows the peak-
scatter factors for various field sizes and beam qualities.
The concepts of tissue–phantom ratio (TPR) and
tissue–maximum ratio (TMR) were proposed for high-
energy radiation as alternatives to TAR in response to
arguments raised against the use of in-air measurement
for a photon beam with a maximum energy greater than
3 MeV (Holt et al. 1970; Karzmark et al. 1965). As
originally defined, TPR is given by the ratio of two doses:
Dd
TPRðd; dr ; Sd ; EÞ ¼
Ddr
where Ddr is the dose at a specified point on the
central axis in a phantom with a fixed reference depth,
dr, of tissue-equivalent material overlying the point;
Dd is the dose in phantom at the same spatial point as
before but with an arbitrary depth, d, of overlying
material, and Sd is the beam width at the level of
97
measurement (Fig. 18). In each instance, the under-
lying material is sufficient to provide for full back-
scatter. The TPR is intended to be analogous to the
TAR but has an advantage because the reference dose,
Ddr, is directly measurable over the entire range of
X-rays and c-rays in use, eliminating problems in
obtaining a value for the dose in free space when the
depth for electronic build-up is great.
The original TMR definition is similar to the defi-
nition of TPR, except that the reference depth, dr, is
specifically defined as the depth of maximum dose,
dmax. However, the dmax for megavoltage X-ray
beams varies significantly with field size and also
depends on SSD. Thus, the definition of TMR creates
measurement inefficiency because of the variable dr.
A modification by Khan and co-workers (Khan et al.
1980) redefines the TMR so that the reference depth,
dr, must be equal to or greater than the largest dmax;
this definition has now become the accepted practice.
The scatter-air ratio (SAR) can be thought of as
the scatter component of the TAR (Cunningham
1972). It is defined as follows:
SARðd; Sd ; EÞ ¼ TARðd; Sd ; EÞ  TARðd; 0; EÞ
SAR is the difference between the TAR for a field
of finite area and the TAR for a zero-area field size.
The zero-area TAR is a mathematical abstraction
obtained by extrapolation of the TAR values measured
for finite field sizes.
Similarly, the scatter-maximum ratio (SMR), the
scatter component of the TMR, is defined as follows:
Sp ðSd ; EÞ
SMRðd; Sd ; EÞ ¼ TMRðd; Sd ; EÞ 
Sp ð0; EÞ
 TMRðd; 0; EÞ
98 J. A. Purdy et al.

Fig. 18 Schematic drawing

illustrating definition of
tissue-phantom ratio and
tissue-maximum ratio, where
d is the thickness of overlying
material and dr is the
reference thickness

Fig. 19 Example of output

factor as a function of lower
and upper collimator settings
for a medical linear
accelerator18 MV X-ray
beam

where Sp is defined as the phantom scatter correction
factor, which accounts for changes in scatter radiation
originating in the phantom at the reference depth as
the field size is changed.
The output factor (denoted by Sc,p) for a given field
size is defined as the ratio of the dose rate at dmax for
the field size in question to that for the reference field
size (usually 10 9 10 cm), again measured at its
dmax. The output factor varies with field size (Fig. 19)
as a result of two distinct phenomena. As the
collimator jaws are opened, the primary dose, Dp at
dmax on the central ray per MU increases due to larger
number of primary X-ray photons scattered out of the
flattening filter. In addition, the scatter dose,
Ds(dmax,r), at the measurement point per unit Dp
increases as the scattering volume irradiated by pri-
mary photons increases with increasing collimated
field size. Note that these two components can vary
independently of one another if nonstandard treatment
distances or extensive secondary blocking is used.
Physics of Radiotherapy Planning and Delivery
Khan and associates (Khan et al. 1980) described a
method for separating the total output factor, Sc,p, into
two components, as given by the following formula:
Sc;p ðrÞ ¼ Sc ðrc Þ  Sp ðrÞ
The two components are the collimator scatter fac-
tor, Sc(rc), which is a function only of the collimator
opening, rc, projected to isocenter, and the phantom
scatter factor, Sp(r), which is a function only of the
cross-sectional area, or effective field size, r, that is
irradiated at the treatment distance. In practice, the total
and collimator scatter factors are both measured and the
phantom scatter factor calculated using the relationship
above. Sc(rc) is measured in air using an ion chamber
fitted with an equilibrium-thickness build-up cap and
given by the ratio of the reading for the given collimator
opening to the reading for a reference field (typically
10 9 10 cm) collimator opening. The overall output
factor is measured in-phantom using the standard
treatment distance and is given by the reading relative
to that for a 10 9 10 cm field size.
By carefully extrapolating this measured ratio to
zero-field size, the zero-field size phantom scatter
factor, Sp(o), is obtained. If a small ion chamber is
positioned axially in the beam, it is possible to mea-
sure Sc,p for field sizes as small as 1 9 1 cm. Because
of the loss of lateral secondary electron equilibrium
encountered near the edges of high-energy photon
beams, Sp deviates significantly from unity. Such an
extrapolation is needed to calculate SMR values
accurately from broad-beam TMR data. Consistent
separation of primary and scatter dose components
significantly improves the accuracy of dose predic-
tions near block edges and under blocks, overcoming
many of the dose-modeling problems presented by
use of extensive customized blocking.
An isodose curve represents points of equal dose.
A set of these curves, normally given in 10% incre-
ments normalized to the dose at dmax, can be plotted
on a chart (i.e., isodose chart) to give a visual rep-
resentation of the dose distribution in a single plane
(Fig. 20). Beam parameters, such as source size,
flattening filter, field size, and SSD, play important
roles in the shape of the isodose curve.
A dose profile is a representation of the dose in an
irradiated volume as a function of spatial position along
a single line. Dose profiles are particularly well suited
to the description of field flatness and penumbra. The
data are typically given as ratios of doses normalized to
99
the dose at the central axis of the field (Fig. 21). The
profiles, also called off-axis factors or off-center ratios,
may be measured in-air (i.e., with only a build-up cap)
or in a phantom at selected depths. The in-air off-axis
factor gives only the variation in primary beam inten-
sity; the in-phantom off-center ratio shows the added
effect of phantom scatter.
Wedge filters, first introduced by Ellis and
co-workers (Ellis and Miller 1944), are generally
constructed of brass, steel, or lead, and when placed
in the beam they progressively decrease in intensity
across the field, going from the thin edge to the thick
edge of the filter, causing the isodose distribution to
have a planned asymmetry (Fig. 22). Today, such
wedges have been largely replaced by either virtual
wedges (Klein et al. 1998), (i.e., wedge dose distri-
butions are created using a software feature that
drives a gradual movement of the collimator jaws
across the field), or by the use of a motorized wedge
fixed in the treatment head; when moved into the
beam it enables fields to have an angled isodose dis-
tribution simulating a wedge between 1 and 60°
depending on the combination of a fully wedged field
and an open field (Petti and Siddon 1985).
The wedge angle is defined as the angle the isodose
curve subtends with a line perpendicular to the central
axis at a specific depth and for a specified field size. The
current practice is to use a depth of 10 cm. Past defi-
nitions were based on the 50th percentile isodose curve
and, more recently, the 80th percentile isodose curve.
The wedge angle is a function of field size and depth.
The wedge factor is defined as the ratio of the dose
measured in a tissue-equivalent phantom at the depth
of maximum build-up on the central axis with the
wedge in place, to the dose at the same point with the
wedge removed. Wedge isodose curves are generally
normalized to the dose at dmax of the un-wedged
beam, resulting in percentiles greater than 100%
under the thin portion of the wedge. However, this
normalization is not always used. The normalization
and the use of the wedge factor in calculating
machine settings should be clearly understood before
wedges are used clinically.
Beam hardening occurs when a physical wedge is
inserted into the radiation beam, causing the PDD to
increase at depth. Differences in PDD of nearly 7%
have been reported for a 4 MV X-ray, 60° wedge
field, compared with the open field at a depth of
12 cm, and as much as 3% difference between the 60°
100 J. A. Purdy et al.

Fig. 20 Isodose distributions

for different quality
radiations. a 200 kVp,
SSD = 50 cm, HVL = 1 mm
Cu, field size = 10 9 10 cm.
b 60Co, SSD = 80 cm, field
size = 10 9 10 cm. c 4 MV
X-rays, SSD = 100 cm, field
size = 10 9 10 cm. d 10 MV
X-rays, SSD = 100 cm, field
size = 10 9 10 cm. (Khan
1994b)

wedge field and the open field for a 25 MV X-ray
beam (Abrath and Purdy 1980; Sewchand et al. 1978).
It should be noted that newer multi-modality/
multi-energy medical linacs are being introduced that
are capable of operating in a flattening filter free
(FFF) mode (Georg et al. 2010; Kouloulias et al.
2003; Kragl et al. 2009). Such linacs are able to
generate photon beams having significantly higher
dose rates; beam profile requirements for the patient’s
target volume are met by using the beam modulation
feature. Early studies do show reduced beam hard-
ening, but more work is needed to understand fully
the impact of FFF beams on the dosimetry parameters
discussed in this section.
Physics of Radiotherapy Planning and Delivery
Fig. 21 Dose profiles, also called off-axis factors (OAFs) or
off-center ratios (OCRs) for an 18 MV X-ray beam measured at
depths of 3 and 10 cm
All the parameters discussed above depend on the
precise and accurate measurement by the medical
physicist, typically done during the linac commis-
sioning process. Such commissioning beam data
are treated as reference data sets and are used to
commission the treatment planning system for plan-
ning patients to be treated on the linac. Hence, it is
essential that the collected data are of the highest
quality to avoid patient treatment dosimetric errors.
The AAPM Task Group 106 Report provides guide-
lines and recommendations on the data acquisition
procedures for acquiring specific photon and electron
beam parameters including proper selection of phan-
toms and detectors, and methods to reduce measure-
ment errors (Das et al. 2008a).
It is particularly important to appreciate the data
measurement issues for the advanced and specialized
radiation treatments such as IMRT, SBRT, SRS,
CyberKnife, and Gamma Knife, Traditionally, dosim-
etry data are measured for field sizes that range from
101
Fig. 22 Isodose curves for a wedge filter. a Normalized to Dmax.
b Normalized to Dmax without the wedge. 60Co, wedge angle =
45°, field size = 8 9 10 cm, SSD = 80 cm. (Khan 1994a)
4 9 4 cm2 to 40 9 40 cm2, but today’s advanced
treatment modalities require accurate measurements
for much smaller fields (as small as 1 9 1 cm2). Das
et al. has pointed out that measurements for such small
fields are problematic due to multiple reasons including
lack of lateral electronic equilibrium, overlap of the
geometrical penumbra due to the size of detector,
change in energy spectrum, and associated dosimetric
parameters and stopping power ratio (Das et al. 2008b).
Hence, the importance of small field beam measure-
ments and accurate beam modeling for the treatment
planning system cannot be emphasized enough.
4 Monitor Unit and Dose Calculation
Methods
Monitor unit (MU) calculations relate the dose at any
point on the central ray of the treatment beam,
regardless of depth, treatment distance, secondary
blocking configuration, or collimator opening selec-
ted, to the calibrated output of the treatment machine
(described in units commonly described as ‘‘dose per
monitor unit’’). This is accomplished by using
the various dosimetric quantities described in the
preceding section to relate the dose corresponding to
an arbitrary set of treatment parameters to a single
standard treatment setup where the output of the
machine is specified in terms of Gy/MU. The refer-
ence distance, field size, and depth of output specifi-
cation are denoted by the symbols SCD, rcal, and dcal,
respectively. Usually, but by no means universally, it
is assumed that
102
SCD ¼ SADðsource  axis distanceÞ þ dmax
rcal ¼ 10 cm 10 cm
dcal ¼ dmax
Normal incidence and open-beam geometry (i.e.,
absence of trays or any beam modifying filters) are
assumed. The above setup parameters are described as
fixed-SSD calibration geometry. Treatment machines
are also calibrated isocentrically with the point of MU
specification located at distance SAD rather than at
distance SAD ? dmax as described above. For the
isocentric calibration condition, SCD = SAD.
If the machine is a linear accelerator, it is cali-
brated by adjusting the sensitivity of its internal
monitor transmission chamber so that for the refer-
ence geometry
DðSCD; rcal ; dcal Þ=MU ¼ 1 Gy=1 MU
Several reports on monitor unit calculations and
their verification are now available (Dutreix et al. 1997;
Georg et al. 2001; Gibbons 2000; Stern et al. 2011).
4.1 Equivalent Field Size
All MU calculation formalisms require some means of
estimating the square field size, r, that is equivalent, in
terms of scattering characteristics, to an arbitrary rect-
angular field of width a and length b. Such equivalence is
of great practical importance because it reduces the
dimensionality of table lookups by one. In addition,
those formalisms that distinguish between overall and
effective field size require some means of estimating the
square or rectangular field size that is equivalent to an
arbitrary irregular field. Perhaps the most widely used
rectangular equivalency principal is the ‘‘A/P’’ rule. It
states that a square and a rectangle are equivalent if they
have the same area/perimeter ratio; that is:
2ða  bÞ
r ¼
ða þ bÞ
This relationship leads to remarkably accurate
PDDs, scatter factors, and isocentric dose ratios for
all but the most irregular elongated fields, where part
of the beam has a width reduced to a few cms.
Another widely used approach to reducing rect-
angular estimates of effective field size to square field
sizes is the equivalent square table published in the
British Journal of Radiology, Supplement 25 (BJR
J. A. Purdy et al.
1996). The problem of estimating the effective field
size equivalent to a clinical irregular field is most
accurately handled by irregular field calculations
(Cundiff et al. 1973).
4.2 Monitor Unit Calculation for Fixed
Fields: SAD
When the patient is to be treated isocentrically, the point
of dose prescription is located at the isocenter regard-
less of the target depth. The MU needed to deliver a
prescribed tumor dose to isocenter (TDiso) for a depth d
of overlying tissue on the central ray is given by
MU ¼
TDiso
SCD2
TMRðd; rd Þ  Sc ðrc Þ  Sp ðrd Þ  TF  WF  SAD
where TF and WF denote the tray and wedge factors,
respectively. They are defined as the ratio of the central
ray dose with the tray or wedge filter in place relative to
the dose in the open beam geometry. The collimated
field size is denoted by rc and is usually described as the
square field size equivalent to the rectangular colli-
mator opening projected to isocenter. The effective
field size is denoted by rd and is always specified to the
isocenter distance, SAD. The inverse-square law factor
accounts for the difference in distances from the source-
to-point of dose prescription relative to the point of MU
specification. When isocentric calibration is used, this
factor is unity. Note that collimator-defined field size is
used for lookup of Sc, whereas effective field size pro-
jected to isocenter is used for lookup of TMR and Sp. By
separately accounting for the effect of collimator
opening on the primary dose component and the
influence of cross-sectional area of tissue irradiated,
most of the difficulties in accurately delivering a dose in
the presence of extensive blocking are overcome.
4.3 Monitor Unit Calculation for Fixed
Fields: SSD
When a fixed distance between the target and entry
skin surface, SSD, is used to treat the patient, a dose-
calculation formalism based on PDD is used rather
than one based on isocentric dose ratios. The MU
needed to deliver a prescribed tumor dose to depth d
(TDd) on the central axis is given by
Physics of Radiotherapy Planning and Delivery
MU ¼
TDd  100
 2
SCD
PDDðSSD; d; rÞ  Sc ðrc Þ  Sp ðrÞ  TF  WF  SSD þ dmax
The field size (or its equivalent square) on the skin sur-
face at central axis is denoted by r and is used for lookup
of both PDD and Sp. The collimated field size rc at the
isocenter must be used for lookup of Sc. Note that when
an extended treatment distance is used, the collimated
field size at isocenter differs significantly from that at the
projected skin surface of the patient. Also, when this
dose calculation formalism for highly extended treat-
ment distances is used, such as encountered in admin-
istering total-body irradiation (TBI), care must be taken
to verify the validity of inverse square law at these dis-
tances. Because of the large scatter contribution to the
effective primary dose originating from the flattening
filter and other components in the treatment head, the
virtual radiation source position may differ significantly
(i.e., typically 2 cm) from the actual target position.
Also, it is recommended that an in vivo dosimetry check
be performed for each patient (Khan 2010).
4.4 Monitor Unit Calculation
for Rotational Therapy
MU calculations for rotation therapy can be computed
using the following expression:
ID
MU ¼  2
TARavg  D_ fs SCD
SAD
and the MU per degree setting is given by
monitor unit setting
MU=deg ¼
degrees of rotation
where the symbols have the previous meaning and
TARavg is an average TAR (averaged over radii at
selected angular intervals, e.g., 20°).
4.5 Monitor Unit Calculation
for Irregular Fields
For large, irregularly shaped fields and at points off the
central axis, it is necessary to take account of the off-
axis change in intensity (relative to the central axis) of
103
the beam, the variation of the SSD within the field of
treatment, the influence of the primary collimator on
the output factor, and the scatter contribution to the
dose. Changes in the beam quality as a function of
position in the radiation field should also be considered
(Hanson and Berkley 1980; Hanson et al. 1980).
The general method used for irregular-field calcu-
lations consists of summation of the primary and scatter
irradiation at each point of interest, with allowance for
the off-axis change in intensity (off-axis factor) and
SSD (Cundiff et al. 1973). The MUs required to deliver
a specified tumor dose at an arbitrary point in an
irregular field can be calculated as follows:
MU ¼
TD
   2
SSD þ dmax
TARðd; 0Þþ SARðdÞ  D_ fs ðSSD þ dmax ; rc ÞTFOAF  SSD þ g þd
where
TAR(d,0) zero-field size TAR at depth d
SAR(d) average SAR for point in question at depth d
determined using the Clarkson technique
D_ fs Gy/MU in a small mass of tissue, in air, on
the central axis at normal SSD ? dmax for
the collimated field size
SSD nominal SSD for treatment constraints
dmax depth of dose maximum
TF blocking tray attenuation factor
g vertical distance between skin surface
over point in question and nominal SSD
(beam vertical)
d vertical depth, skin surface to point in
question
OAF in-air off-axis factor
Several modifications to the original method have
been suggested. These include using the expanded
field size at a depth for the SAR calculation; deter-
mining the off-axis factor using the distance from the
central axis to the slant projection of the point of
calculation to the SSD plane along a ray from the
source; and determining the zero-area TAR using
the slant depth along a ray going from the source to the
point of calculation. It is generally accepted that the off-
axis factor should be multiplied by the sum of the zero-
area TAR and the SAR, as originally proposed.
Beam quality is a function of position in the field
for beams generated by linear accelerators (Hanson
and Berkley 1980; Hanson et al. 1980). The TAR0
104
may be expressed as a function of position in the
beam so that changes in beam quality can be incor-
porated into calculations, and it can be related to the
HVL of water by the following equation:
 (Gibbons 2000). Typically, one simply applies an off-
0:693ðd  dmax Þ
TARðd; 0; rÞ ¼ e
HVLðrÞ
where d is the depth of the point of reference, dmax is
the depth of maximum dose, r is the radial distance
from the central axis of the beam to the point of
calculation, e is the base of the natural logarithm, and
HVL(r) is the beam quality expressed as the HVL
measured in water.
One final point about irregular-field or off-axis
dose calculations concerns the off-axis factor. In some
computerized treatment planning systems, the calcu-
lation of dose to points off the central axis is based on
the assumption that the off-axis factor can be repre-
sented by a separable function given by
OAFðx; yÞ ¼ OAFðx; 0Þ  OAFð0; yÞ
where x and y are the symmetry axes perpendicular to
the beam axis and the functions OAF(x, 0) and
OAF(0, y) are equal for a square open field. For some
accelerator-generated beams, this assumption is
invalid because measured values differ from those
predicted by the above equation by as much as 20%
(Lam and Lam 1983).
4.6 Monitor Unit Calculation
for Asymmetric Collimators
Asymmetric X-ray collimators (also referred to as
independent jaws) allow independent motion of an
individual jaw and may be available for one jaw pair
or both pairs. Because MU calculations and treatment
planning methods generally rely on symmetric jaw
data, the dosimetric effects for asymmetric jaws must
be understood before being implemented into the
clinic. Several investigators have examined the effects
of asymmetric jaws on PDD, collimator scatter, and
isodose distributions; the reader is referred to other
sources for more details (Palta et al. 1988; Slessinger
et al. 1993). In general, the only change to MU
calculations for asymmetric fields is the need to incor-
porate an off-axis factor OAR(x) to account for off-axis
beam intensity changes. PDD is only minimally
J. A. Purdy et al.
affected, but isodose curve shape can be altered and must
be investigated for the particular treatment unit.
Monitor unit calculations for asymmetric jaws are
only slightly more complex than for symmetric jaws
axis ratio (OAR) or off-center ratio (OCR) correction
factor that depends only on the distance from the
machine’s central axis to the center of the independently
collimated open field (Palta et al. 1996; Slessinger et al.
1993). A more complex system that accounts for inde-
pendent jaw settings, field size, and depth has also been
described (Chui et al. 1986; Rosenberg et al. 1995).
Calculations for asymmetric wedge fields follow similar
procedures by simply incorporating a wedge OAR or
OCR (Khan 1993; Rosenberg et al. 1995).
4.7 Monitor Unit Calculation for MLC
Multileaf collimators (MLCs) have nearly completely
replaced conventional alloy field shaping in most
clinics around the world. Several investigators have
examined the effects of the Varian MLC design (ter-
tiary system) on PDD, collimator scatter, and isodose
distributions (Klein et al. 1995). The effects due to
field area shaped by the MLC on PDD and beam
output parameters are similar to those resulting from
Cerrobend field shaping. Thus, the dose/MU calcu-
lation methods discussed previously apply by simply
using the equivalent area defined by the MLC. The
collimator scatter factor is determined using the X-ray
collimator jaw settings, with an off-axis factor applied
for asymmetric jaw settings. However, Palta and
colleagues found that for the Elekta linacs (MLC
replacing the upper collimator jaws) the MLC field
shape was a determining factor in selecting the
appropriate output factor for their system (Palta et al.
1996). Their results showed that MLC dosimetry is
clearly dependent on machine design differences, and
so because treatment machine MLC designs are still
changing, each institution is advised to carefully study
the impact of the MLC on their basic MU calculation
procedure before introduction in the clinic.
4.8 Monitor Unit Calculations for IMRT
At present, independent verification of the MU settings
and dose calculation of IMRT treatment plans is mainly
based on experimental measurements, which are
Physics of Radiotherapy Planning and Delivery 105

time-consuming and labor intensive. While hand cal-

culations would not be practical, several groups have
reported on software developments specific to IMRT
MU verification (Georg et al. 2007; Kung et al. 2000;
Yang et al. 2005). Commercial software for IMRT MU
verification is now available e.g., RadCalc (LifeLine
Software Inc, Austin, TX) based on the work of Kung
et al. (2000) and IMSure (Standard Imaging, Middle-
ton, WI) based on the work of Yang et al. (2003).
Pawlicki et al. utilized the commercial software and
reported favorable results (Pawlicki et al. 2008).

5 Dose Calculation Algorithms

and Correction Factors

Current dose calculation algorithms can be broadly

classified into correction-based and kernel-based
models (Mackie et al. 1996). Correction-based models
correct the dose distribution in a homogeneous water
phantom for the presence of beam modifiers, contour
corrections (or air gaps), and tissue heterogeneities
encountered in treatment planning of real patients. The
homogeneous dose is obtained from broad field mea-
surements obtained in a water phantom. Kernel-based
models (also called convolution methods) directly
compute the dose in a phantom or patient. The convo-
lution methods take into account lateral transport of
radiation, beam energy, geometry, beam modifiers,
patient contour, and electron density distribution. The
reader is referred to review articles for more details
regarding the rigorous mathematical formalism of
these types of dose calculation algorithms (Ahnesjö and
Aspradakis 1999; Mackie et al. 1996).
2
Because basic dose distribution data are obtained
for idealized geometries (e.g., flat surface, unit den-
sity media), corrections are needed to determine the
dose distribution in actual patients. Typically, the
dose data calculated for idealized geometry are mul-
tiplied by a correction factor to obtain the revised
dose distribution. The methods commonly used to
correct for the air gap are discussed briefly.
5.1 Correction for Surface Obliquity
Figure 23 is used to illustrate both the effective SSD
method and the ratio of TAR (or ratio of TPR)
method (RTAR), for correcting for surface obliquity.
Fig. 23 Tissue–air ratio and effective SSD methods for the
correction of isodose curves under a sloping surface. (Interna-
tional Commission of Radiation Units and Measurements:
Report 24: Determination of absorbed dose in a patient
irradiated by beams of x or gamma rays in radiotherapy
procedures. Washington, DC, ICRU, 1976)
In the effective SSD method, the isodose chart to be
used is placed on the contour representation, posi-
tioning the central axis at the distance for which the
curve was measured. It is then shifted down along
the ray line for the length of the air gap, h. The PDD
value at point B is read and modified by an inverse-
square calculation to account for the effective
change in the dose at dmax. The CF can be expressed
as follows:
Pðd  h; do ; S; f ; EÞ f þ do
CF ¼ 
Pðd; do ; S; f ; EÞ f þ h þ do
In the ratio of TAR (or ratio of TPR) method
(RTAR), the surface (along a ray line) directly above
point A is unaltered, so the primary dose distribution
at this point is unchanged. For relatively small
changes in surface topography, the scatter component
is essentially unchanged. Thus, the dose at point A can
be considered as unaltered by patient shape. However,
for point B where there are considerable variations in
the patient’s topography, both the primary and scatter
components of the radiation beam are altered. The
correction factor (CF) may be determined using two
TARs or TPRs as follows:
106
Tðd  h; sd Þ
CF ¼
Tðd; sd Þ
where
h = air gap
5.2 Correction for Tissue
Heterogeneities
Most of the correction-based models used for clinical
dose calculations for radiation therapy treatment
planning still rely mainly on ‘‘one-dimensional’’
effective pathlength (EPL) approaches, some of which
were developed before the availability of X-ray
CT-scanning. These models consider the effect of
patient structure only along the ray joining the point of
computation and the source of radiation and are limited
in accuracy under some circumstances. It should be
well understood that in correcting water-based dose
calculations for tissue inhomogeneities, obtaining
correct anatomical information is as important, if not
more, than the type of dose algorithms used.
Patient tissues may differ from water by compo-
sition or density, which alters the dose distribution.
Four inhomogeneities are usually encountered in
treatment planning dose calculations: air cavities,
lung, fat, and bone. To correct fully for these inho-
mogeneities, it is necessary to know their size, shape,
and position and to specify their electron density and
atomic number. Manual correction methods for tissue
inhomogeneities closely resemble the three methods
discussed for correcting for patient contour changes
and are described below.
5.2.1 Ratio of Tissue–Air Ratio (RTAR)
Method
The ratio of TAR (RTAR) method of correction for
inhomogeneities is given by
Tðdeff ; Sd Þ
CF ¼
Tðd; Sd Þ
where the numerator is the TAR for the equivalent
water thickness, deff, and the denominator is the TAR
for the actual thickness, d, of tissue between the point
of calculation and the surface along a ray passing
through the point. Sd is the dimension of the beam
cross section at the depth of calculation. The RTAR
J. A. Purdy et al.
method accounts for the field size and depth of cal-
culation. It does not account for the position of the
point of calculation with respect to the heterogeneity.
It also does not take into account the shape of the
inhomogeneity, but rather assumes that it extends the
full width of the beam and has a constant thickness
(i.e., slab-type geometry).
5.2.2 Isodose Shift Method
Isodose lines are shifted by an amount equal to a
constant time the thickness of the inhomogeneity as
measured along a line parallel to the central axis and
passing through the calculation point. Values for the
shift constant empirically determined for 60Co and
4 MV X-rays are -0.6 for air cavities, -0.4 for lung,
+0.5 for hard bone, and +0.25 for spongy bone. The
isodose curves are shifted away from the surface for
lung and air cavities and toward the surface for bone.
5.2.3 Power Law TAR Method
The power law TAR method was proposed by Batho
(1964) and generalized by Young and Gaylord
(1970). This method, sometimes called the Batho
method, attempts to account for the nature of the
inhomogeneity and its position relative to the point of
calculation. However, it does not account for the
extent or shape of the inhomogeneity. The correction
factor for the point P is given by
Tðd2 ; Sd Þ q2 1
CF ¼
Tðd1 ; Sd Þ
where d1 and d2 refer to the distances from point P to
the near and far side of the non-water-equivalent
material, respectively, Sd is the beam dimension at the
depth of P, and q2 is the relative electron density of
the inhomogeneity with respect to water.
Sontag and Cunningham derived a more general
form of this correction factor, which can be applied to
a case in which the effective atomic number of the
inhomogeneity is different from that of water and
the point of interest lies within the inhomogeneity
(Sontag and Cunningham 1978). The correction factor
in this situation is given by
Tðd2 ; Sd Þðqb 1Þ ðlen =qÞa
CF ¼ ðqb pa Þ

Tðd1 ; Sd Þ ðlen =qÞb
where qa is the density of the material in which point
P lies at a depth d below the surface and qb is the
Physics of Radiotherapy Planning and Delivery 107

density of an overlying material of thickness (d2 - Ahnesjö showed that the point-spread function,
d1); (len/q)a and (len/q)b are the mass energy hðE; ~ r ~ sÞ; changes only slightly as a function of
absorption coefficients for the medium a and b. energy, and thus, can be replaced by hð~ r ~sÞ;
At an interface between two materials of different (defined as the average point-spread function weigh-
composition, there is a loss of equilibrium as a result ted by the spectral components of the beam) reducing
of changes in the electron fluence, that is, the number the basic convolution four-dimensional integral to a
of electrons generated from the photon interactions. three-dimensional inte-gral over all space (Ahnesjö
Therefore, the dose over a distance comparable with et al. 1987). Point-spread functions for mono-ener-
the range of the electrons is perturbed. For 60Co getic photons are generally pre-computed using
radiation, the alteration in the dose distribution occurs Monte Carlo methods (Ahnesjö et al. 1987). The
in only the few millimeters surrounding the interface. energy dependence of the TERMA, TE ð~ sÞ; can be
However, for high-energy photon beams, this region expressed by applying the inverse-square law and
extends for several centimeters depending on the exponential attenuation to the photon fluence at the
beam energy. surface of the phantom or patient.
The importance of verifying dose distributions The three-dimensional integral is typically evalu-
generated by a treatment planning system should not ated in a two-step process. The first step takes into
be understated. Modern systems are extremely com- account the properties of the accelerator (including
plicated and require well-defined dose calculation the finite source size, primary collimator, flattening
verification techniques. Traditional 2D type correc- filter, collimator jaws, multileaf collimators and any
tion factor methods using depth doses and selected beam-modifying devices used for the treatment, such
profiles are difficult to apply in the 3D situation. It is as wedges, alloy blocks, compensating filters, etc.) to
the task of the clinical physicist to be aware where compute the energy flu-ence at the phantom or patient
these calculations may fail and to take proper pre- surface, and the second step of the calculation takes
cautions, such as verifying with measurements in into account the inverse-square law and exponential
those situations where the errors will lead to unde- attenuation to this incident fluence to determine the
sirable clinical outcome. TERMA, TE ð~ sÞ; at each point within the phantom or
patient and convolve the result with the point-spread
function, hð~ r ~ sÞ:
5.2.4 Advanced Dose Calculation
The convolution equation is strictly valid only for
Algorithms: Accounting for Tissue
homogeneous media [i.e., hð~ sÞ must be spatially
Heterogeneities
invariant]. To account for the effects of tissue hetero-
The convolution/superposition dose calculation algo-
geneities, all physical distances in the convolution
rithm is based on the following equation (Ahnesjö and
integral are replaced with radiological distances, i.e.,
Aspradakis 1999):
the physical distance multiplied by the average density
ZZZZ along the line in question (Ahnesjö et al. 1987; Mackie
Dð~rÞ ¼ TE ð~
sÞhðE;~r ~ sÞd3 sdE et al. 1985). Hence, the convolution/superposition
algorithm accounts for the effects of heterogeneities
where D represents the dose at some point ~ r; TE ð~
sÞ anywhere in the vicinity of the calculation point in
represents the total energy released by primary photon three dimensions. In contrast, most correction factor-
interactions per unit mass (or TERMA), and hðE;~ r ~ sÞ based dose-calculation tech-niques require only a
is the point-spread function (also called dose spread simple one-dimensional evaluation of radiological path
array, differential pencil beam, and energy deposition length, and can thus account for the effects of only
kernel). The point-spread function represents the frac- those tissue heterogeneities that lie along a ray con-
tion of the energy deposited (per unit volume) at point~ s necting the radiation source to the calculation point.
that is subsequently transported to the calculation point, Several investigators have tested the convolution/
~
r. Hence, the dose at point~r is computed by integrating superposition algorithm against measurements and
over all space the contributions from photons and Monte Carlo–generated data for complex phantom
electrons pro-duced at all other points in the phantom geometries including both homogeneous and hetero-
or patient. geneous phantoms and found that the convolution/
108
superposition model gave accurate results, even
in parts of the build-up region and penumbra
(Ahnesjö 1989; Lydon 1998).
Monte Carlo is, in principle, the only method
capable of computing the dose distribution accurately
for all situations encountered in radiation therapy,
including being able to accurately predict the dose
near interfaces of materials with very dissimilar
atomic numbers, such as near metal prostheses, or
different densities such as tumors in lung tissue
(Siebers et al. 2005). The Monte Carlo method uses
the known cross sections for electron and photon
interactions in matter and follows individual photons
and the associ-ated electrons set in motion through the
entire heterogeneous phantom or patient. By calcu-
lating the trajectories and interactions of a very large
number of photons and electrons, one can accurately
model the dose distribution. Recently, several Monte
Carlo codes have been devel-oped for radiotherapy
treatment planning (Cygler et al. 2004; Fraass et al.
2003; ICRU , Report No. 42, Use of Computers in
External Beam Radiotherapy Procedures with High
Energy Photons and Electrons 1987; Verhaegen,
Seuntjens 2003). The reader is referred to the review
article by Siebers et al. for more details on Monte
Carlo calculations for external beam radiation therapy
(Siebers et al. 2005).
5.3 Interface Dosimetry
The dose distribution within the patient in transition
zones (interfaces of different media) depends on
radiation field size (scatter influence), distance
between interfaces (e.g., air cavities), differences
between physical densities and atomic number of the
interfacing media, and the size and shape of the dif-
ferent media. Near the edge of the lungs and air
cavities, the reduction in dose can exceed 15%
(Kornelsen and Young 1982). For inhomogeneities
with a density larger than water, there will be an
increase in dose locally due to the generation of more
electrons. However, most dense inhomogeneities have
atomic numbers higher than that of water so that the
resulting dose perturbation is further compounded by
the perturbation of the multiple coulomb scattering of
the electrons. Near the interface between a bony
structure and water-like tissue, large hot and cold
dose spots can be present.
J. A. Purdy et al.
Measurements are generally done with parallel-
plate ionization chambers. Corrections should be used
to account for plate separation, energy (ionization
ratio), and guard width (Gerbi and Khan 1990).
Thermoluminescent dosimeters (TLDs) and film have
also been used for transition zone measurements, but
the problems associated with thickness and atomic
number and the associated QA needed make mea-
surements with these dosimeters more laborious, and
the results typically have a greater uncertainty. Sev-
eral benchmark measurements have been reported for
various geometries simulating clinical situations such
as air cavities (larynx), lung (mediastinum), bone
(femur), and prostheses (steel for hip and silicon for
breast), and are discussed below.
5.3.1 Dose at Skin Surface: Build-up Region
When a photon beam strikes the tissue surface, elec-
trons are set in motion, causing the dose to increase
with depth until the maximum dose is achieved at
depth dmax. As the energy of the photon beam
increases, the thickness of the build-up region is
increased. The subcutaneous tissue-sparing effects of
higher energy X-rays, combined with their great
penetrability, make them well suited for treating deep
lesions. In general, the dose to the surface and in the
build-up region for megavoltage photon beams gen-
erally increase with increasing field size, with the
insertion of blocking trays made of plastic or other
materials in the beam (Fig. 24). The blocking trays
should be at least 20 cm above the skin surface
because skin doses are significantly increased for
lesser distances. Copper, lead, or lead glass filters
beneath the blocking tray can be used to remove the
undesired lower energy electrons that contribute to
skin dose, but this is nowadays rarely done routinely
in the clinic (Purdy 1986; Rustgi and Rodgers 1985).
As the angle of the incident radiation beam
becomes more oblique, the surface dose increases,
and dmax moves toward the surface (Fig. 25). This is
primarily due to more secondary electrons contribu-
tion from the media below the surface along the
oblique path of the beam (Gerbi et al. 1987).
5.3.2 Dose-Beam Exit Region
The skin and superficial tissue on the side of the
patient from which the beam exits receive a reduced
dose if there is insufficient backscatter material
present. The amount of dose reduction is a function of
Physics of Radiotherapy Planning and Delivery
Fig. 24 Relative surface dose versus field size with blocking
tray in place for 6 and 18 MV photons. (Klein and Purdy 1993)
X-ray beam energy, field size, and the thickness of
tissue that the beam has penetrated reaching the exit
surface. For a 6 MV beam, Purdy measured a 15%
reduction in dose with little dependency on field size
(Purdy 1986). This work was repeated for 18 MV
beams by Klein and Purdy, who reported a 11%
reduction in exit dose (Klein and Purdy 1993).
Generally, the addition of a thickness of tissue-equiv-
alent material on the exit side equivalent in thickness to
about two-thirds of the dmax depth is sufficient to pro-
vide full dose to the build-down region on the exit side,
as happens with traditional treatment tables and inserts.
Figure 26 shows the effects of various backscattering
media when placed directly behind the exit surface for 6
and 18 MV X-rays.
The exit dose is frequently calculated by multiplying
the maximum dose by the central axis PDD value
corresponding to the patient’s thickness; sometimes the
thickness value is reduced by the depth of the maximum
dose. However, this technique overlooks the fact that
there is insufficient material beyond the exit surface to
provide the total scatter dose in many situations. Thus,
the actual dose received by the tissues at or near the exit
surface is less than that calculated using this method. It
has been shown that if there is no backscatter material,
the dose to the skin at the exit surface (&4 mg/cm2
depth) is 15 to 20% less for 60Co c-rays and about 10%
less for 25 MV X-rays than the dose with full back-
scatter (Gagnon and Horton 1979). The skin dose
109
Fig. 25 The variation of surface dose and depth of maximum
dose as a function of the angle of incidence of the X-ray beam
with the surface (4 MV, 10 9 10 cm)
increases sharply as the thickness of material is
increased beyond the exit surface, until full backscatter
conditions are obtained with about 0.5 g/cm2 of added
material.
5.3.3 Dose-Air Cavities
Nillson and Schnell used even thinner LiF disks
(10 mm) and reported data for 6 and 42 MV photons,
with the higher energy beam showing fewer effects
(Nillson and Schnell 1976). Epp and colleagues
reported a 14.5% loss at the distal interface for
10 MV photons with a build-up curve that leveled off
within 20 mm behind the interface (Epp et al. 1977).
Beach and associates measured losses at the distal
interfaces with an extrapolation chamber and recom-
mended minimum field sizes to be used in irradiation
of the larynx to balance losses due to forward scatter
(Beach et al. 1987). Klein and colleagues measured
distributions about air cavities for 4 and 15 MV
photons with a parallel-plate chamber in both the
distal and proximal regions (Klein et al. 1993). They
combined the distributions in a parallel–opposed
fashion and observed a 10% loss at the interfaces for
an air cavity of 2 9 2 9 20 cm for 4 9 4 cm paral-
lel-opposed fields for either energy. They also
observed losses at the lateral interfaces perpendicular
to the beam on the order of 5% for the 4 MV beam.
Finally, Ostwald used TLD for measurements in
simulated larynx geometries (Ostwald et al. 1996).
110
Fig. 26 Enhancement of exit dose for (a), 6 MV and (b),
18 MV photons for a 15 9 15 cm field at 100 cm SAD versus
backscatter depth for various backscattering materials. (Klein
and Purdy 1993)
5.3.4 Dose-Lung Interfaces
Although the problem of reestablishing equilibrium
for lung interfaces is not as severe as with air
cavities, a transition zone region at the lung–tissue
interface still exists over the range of typical clinical
J. A. Purdy et al.
photon beam energies. Rice and colleagues measured
responses within various simulated lung media for 4
and 15 MV X-rays using a parallel-plate ion chamber
and a phantom constructed of solid water and simu-
lated lung material (average lung material density,
q = 0.31 g/cm3; some additional measurements made
with materials having densities of 0.015 g/cm3 and
0.18 g/cm3) (Rice et al. 1988). Figure 27a, b show
their results in terms of measured correction factors
(CFs) for the 15 MV beam. A considerable build-up
curve was observed (10% change in CF) for small
fields (5 9 5 cm2) for the 15 MV beam, which began
in the distal region of the lung and plateaus about
5 cm beyond the simulated lung interface.
5.3.5 Dose-Bone Interfaces
Das and colleagues measured dose perturbation
factors (DPFs) proximal and distal for simulated
bone–tissue interface regions using a parallel plate
chamber for both 6 and 24 MV X-ray beams (Das
et al. 1990; Das and Khan 1989). They reported DPFs
of 1.1 for the 6 MV beam and 1.07 for the 24 MV
beam at the proximal interface. A 7% enhancement
(build-down) was measured for the 24 MV beam at
the distal interface, whereas the 6 MV beam exhibited
a new build-up region distally with a DPF of 0.95 at
the interface. Klein and co-workers made similar
measurements for 4 and 15 MV photons with similar
results except that the 15 MV beam exhibited no
enhancement (Klein et al. 1988). These build-up or
build-down regions dissipated within a few millime-
ters in the tissue-like media. The perturbations were
independent of the thickness and lateral extent of the
bone or radiation field size.
5.3.6 Dose-Prostheses (Steel and Silicon)
Das and associates measured forward dose perturbation
factors (FDPFs) following a 10.5 mm thick stainless-
steel layer simulating a hip prosthesis geometry
(Das et al. 1990). They measured a dose enhancement
of 19% for 24 MV photons, but only 3% for 6 MV
photons. They also measured backscatter dose pertur-
bation factors (BDPFs) for various energies for many
high-Z materials, including steel. They reported an
enhancement of 30% for steel due to backscattered
electrons independent of energy, field size, or lateral
extent of the steel. These interface effects dissipated
within a few millimeters in polystyrene. Other reports
dealing with dosimetry perturbations due to metal
Physics of Radiotherapy Planning and Delivery
Fig. 27 Dose correction factors. a As a function of depth for a
transition zone geometry that simulates a lung–tissue interface
for three different field sizes and a lung thickness of 10 cm for
15 MV X-rays. Modification to the primary dose only on the
central axis (shown by the dashed curve) is independent of field
objects are included in the references (Sibata et al.
1990; Thatcher 1984).
Klein and Kuske reported on interface perturba-
tions with silicon breast prostheses (Klein and Kuske
1993). Such prostheses have a density similar to
breast tissue but have a different atomic number. They
observed a 6% enhancement at the proximal interface
and a 9% loss at the distal interface.
5.4 Tissue Heterogeneities Corrections:
Recommendations
In 2004, the AAPM published Report 85, (Task
Group 65) on tissue inhomogeneity corrections from
megavoltage photon beams (Papanikolaou et al.
2004). The task group recommended an accuracy goal
for tissue heterogeneity corrections of 2% in order to
achieve an overall 3% accuracy in dose delivery. The
AAPM Report recommended that heterogeneity cor-
rections be applied to plans and prescriptions, with
the condition that the algorithm used for calculations
be reviewed and rigorously tested by medical physi-
cists. It must be fully appreciated that not all hetero-
geneity corrections are equal. Some are much better at
providing a representation of the truth as compared to
others. The physician should work closely with the
medical physicist to better appreciate these issues.
111
size. b As a function of depth for a transition zone geometry
that simulates a lung–tissue interface for three different
densities, 5 9 5 cm field, and a lung thickness of 10 cm for
15 MV X-rays. Modification to the primary dose only on the
central axis is shown by the dashed curve. (Rice et al. 1988)
A brief summary of the site-specific recommen-
dations is presented here (Papanikolaou et al. 2004).
For the head and neck region, a one-dimensional path
correction algorithm for point dose estimations
beyond mandible and ear cavities was thought to be
reasonable. However, for soft tissue regions and
volumes that are adjacent to these heterogeneities,
superposition/convolution or Monte Carlo algorithms
should be used. For the larynx, specifically, if the
target volume was adjacent to the air cavity or severe
case of disease in the anterior commissure, then the
superposition/convolution or Monte Carlo algorithms
should be used. For treatment of lung cancer, for
interest points well beyond the lung interface, one-
dimensional path corrections were thought to be
reasonable. However, accounting for doses at tumor
lung interfaces, the superposition/convolution or
Monte Carlo algorithms should be used. Also, the
report recommended that photon energies of 12 MV
or less should be used for treatment of lung cancer in
order to minimize non-equilibrium conditions that
exist with higher energies. For breast cancer treatment
(particularly if the dose of interest of the target
volume is considered to be chest wall), it is recom-
mended that calculations be performed with super-
position/convolution or Monte Carlo algorithms.
However, for simple intact breast planning, one-
dimensional algorithms are adequate. For the upper
112
GI, one-dimensional corrections were adequate.
However, one should be leery of high-Z (e.g., barium)
contrast used that can erroneously call for increased
dose due to interpretation of the high atomic number
material. In terms of the pelvis and prostate, one-
dimensional corrections were quite reasonable except
in the presence of high-Z implanted hip prosthesis.
(Note, the dosimetric considerations for patients with
hip prosthesis undergoing pelvic irradiation are dis-
cussed in a latter section). The study by Frank et al.
provides a clear methodology for safely transitioning
clinical use from one based on planning that assumes
a homogeneous unit density patient, to one using a
heterogeneous patient model (Frank et al. 2003).
6 Peripheral Dose, Whole Body Dose 6.2
It should be appreciated that modern day radiation
therapy techniques (while greatly improving dose
conformality to the target volume) generally result in
an increase in the volume of normal tissues receiving
a low dose (including the whole body), which has the
potential to increase the risk of inducing secondary
malignancies, and thus should not be ignored (Purdy
2008). In this section, a brief review of peripheral
dose (PD) from the different external beam techniques
and the dose delivered to normal tissues outside the
patient’s treated volume is given. For more details on
this subject, the reader is referred to the comprehen-
sive review article by Xu et al. on dosimetry studies
for external-beam treatment modalities including
classical radiation therapy, 3DCRT, IMRT, tomo-
therapy, and proton therapy (Xu et al. 2008).
6.1 Peripheral Dose-Linac MLC IMRT
Several investigators have shown that IMRT tech-
niques result in an increase in the dose outside the
boundary of the primary collimator as a result of
increased leakage and scattered radiation (Followill
et al. 1997a, b; Williams and Hounsell 2001). This
is due primarily to the increase in the number of MUs
(a factor of 2–3 for MLC-IMRT).
Klein et al. reported on PD for pediatric patients
(Klein et al. 2006). They reported that PD was higher
for low energy and larger field size and when MLC
was not deployed for points close to the field edge.
J. A. Purdy et al.
For points more distant, the PD was higher for high-
energy beams. MLC orientation was found to be
inconsequential for the small fields tested. The thyroid
dose was lower for IMRT delivery than that predicted
for conventional RT (the ratio of IMRT/conventional
RT ranged from 0.47 to 0.94 (doses approximately
(0.4–1.8 cGy)/(0.9–2.9 cGy)/fraction, respectively.
They concluded that PD in close proximity (10 cm
from the field edge) is dominated by internal scatter,
and therefore, field-size differences overwhelm
phantom size affects and increased MUs. However,
distant PD is dominated by treatment head leakage.
The ratio of the testes dose ranged from 3.3 to 5.3 for
IMRT/conventional RT.
Peripheral Dose-Helical
Tomotherapy
Ramsey et al. reported on peripheral doses for the
HI-ART (HA) helical tomotherapy system (Ramsey
et al. 2006). At 20 cm, the HA tomotherapy PD
dropped to 0.4% of the prescribed dose. Leakage
radiation accounted for 94% of the in-air dose at
distances greater than 60 cm from the machine’s
isocenter. It should be noted that because the helical
tomotherapy treatment delivery requires significantly
longer beam-on times than those used by conven-
tional linacs, it was designed to minimize radiation
leakage. Hence, the PD is equal to or less than the
published PD for conventional MLC IMRT delivery.
Also, Aoyama and collaborators (Aoyama et al. 2006)
reported that helical tomotherapy results in a lower
radiation dose to the non-target volumes compared to
conventional SMLC or DMLC IMRT.
6.3 Peripheral Dose-CyberKnife
Petti et al. reported that PD for a CyberKnife ranged
from 0.16 to 0.041% (± 0.003%) of the delivered
number of MUs at distances between 18 and 71 cm
from the field edge (Petti et al. 2006). These values
are two to five times larger than those measured for
comparable Gamma Knife brain treatments, and up to
a factor of four times larger than those measured for
IMRT. They concluded that the CyberKnife PD is due
largely to leakage radiation, but for distances less than
40 cm from the field edge, entrance, or exit dose from
Physics of Radiotherapy Planning and Delivery
inferior- or superior-oblique beams can also contrib-
ute significantly. For distances larger than 40 cm from
the field edge, the CyberKnife PD is directly related
to the number of MU delivered, since leakage radia-
tion is the dominant component.
6.4 Dose Due to Daily Imaging
The implementation of IGRT treatment machines in
which kilovoltage (kV) cone beam CT (CBCT) ima-
ges or MV helical CT images can be acquired rou-
tinely is progressing rapidly. Such systems provide
volumetric images of the patient in the treatment
position, and using online software and hardware, the
patient position can be determined accurately with a
high degree of precision and, subsequently, set-up
parameters can be adjusted to deliver the intended
treatment. While the patient dose due to a single
volumetric imaging acquisition is small compared to
the therapy dose, repeated and daily image guidance
procedures can lead to an additional dose to normal
tissues that might result in a slight increase in the risk
of developing a second malignancy. The contribution
of the dose used for imaging should in general also be
incorporated into the treatment planning calculations
to avoid overdosing of the target area as well.
Islam et al. (2006) reported on the dosimetric
properties of the clinical CBCT system on an Elekta
linear accelerator (SynergyÒ, XVI system). Dose
measurements were performed at the center, periphery,
and surface of 30 and 16 cm-diam cylindrical-shaped
water phantoms, as a function of X-ray energy and
longitudinal field-of-view (FOV) settings of 5,10, 15,
and 26 cm. The measurements were performed for full
360° CBCT acquisition as well as for half-rotation
scans for 120 kVp beams using the 30 cm-diam
phantom. The doses at the center and surface of the
body phantom were determined to be 1.6 and 2.3 cGy
per scan for a typical imaging protocol, using full
rotation scan, with a technique setting of 120 kVp and
660 mAs. Dose to the patient from a CBCT depends
significantly on the scanning parameters used. Addi-
tionally, the dose across the patient may vary,
depending on scanning technique (i.e., some areas of
the patient will only be irradiated during parts of a 360°
scan, while the core of the scan, (and thereby parts of
the patient) will be irradiated at all times.
113
Forest and colleagues reported on the utility of MV
helical CT available on the TomoTherapy HI-ART
system (Forrest et al. 2004). The unit uses a xenon CT
detector system. The MVCT mode of the linear
accelerator reduces the nominal energy to about
3.5 MV and MVCT images can be obtained at a dose
level of about 3 cGy per scan. Acquisition time for a
MVCT image is approximately 3 min.
7 Treatment Planning: Combination
of Treatment Fields
7.1 Parallel–Opposed Fields
When only two unmodified X-ray beams are used
straightforward e.g., for palliative and low dose radia-
tion therapy, they usually are parallel–opposed beams
(i.e., directed towards each other from opposite sides of
the anatomic site with the central axes coinciding).
Figure 28 shows the normalized relative axis dose
profiles for parallel–opposed photon beams for a
10 9 10 cm field at an SSD of 100 cm and for patient
diameters of 15–30 cm in 5 cm increments. The weight
of a beam denotes a numerical value assigned to the
beam at some normalization point. For SSD beams, the
weight specifies the relative dose assigned to the beam
at dmax, and for isocentric beams, at isocenter.
For some treatment sites, the underdosing achieved
near the skin surface with very high-energy, parallel-
opposed X-ray beams is a highly advantageous fea-
ture, but in others it may be desirable to achieve a
higher dose nearer to the skin. With very high energy
X-ray beams traversing small anatomic thicknesses,
the exit dose can exceed the entry dose, and the exact
dose distribution in the regions beneath the entry and
exit surfaces from parallel–opposed high-energy
X-ray beams must be carefully evaluated to consider
properly the contribution from both entrance and exit
components.
Unequal beam weightings are advantageous if the
target volume is not at or near the midline. The
greater the unequal weighting, the greater will be the
shift of the higher dose region toward one surface and
away from the midline. Although in some anatomic
sites unequal weighting may be advantageous, special
attention must be directed to the anatomic structures
in the high-dose volume.
114 J. A. Purdy et al.

Fig. 28 Relative central-axis

dose profiles for parallel-
opposed beams as a function
of X-ray energy (60Co or 4, 6,
10, and 18 MV) and patient
thickness (15, 20, 25, and
30 cm). Beams are equally
weighted, and the profiles are
normalized to unity at mid-
line. Because of symmetry,
only half of each profile is
shown

A very commonly used parallel opposed technique is
the pair of tangential fields used in breast cancer treat-
ment, where most often the beam angles are inclined
slightly to obtain an alignment of the dorsal beam edges.
7.2 Multiple-Beam Arrangements
Figure 29 shows two commonly used coaxial 3-field
beam arrangements. A direct anterior field with two
anterior oblique fields can be used to generate a high-
dose region where the three fields overlap, whereas a
low-dose region exists beyond this intersection point.
For example, if this arrangement is used for treating
the mediastinum, the spinal cord might be included in
the anterior beam but spared by the anterior oblique
beams. Moving the anterior oblique fields laterally to
form a parallel–opposed pair yields a rectangular
isodose region with a more uniform dose gradient;
however, the magnitude of the dose gradient is
determined by the relative weighting of the beams and
the thickness of tissue traversed. An anterior field
with two symmetrically placed posterior oblique
beams yields elongated isodose curves. The degree of
Physics of Radiotherapy Planning and Delivery 115

Fig. 29 Dose distribution for two commonly used 3-field a Anterior field with two anterior oblique fields at 40° off the
beam arrangements using 6 MV X-ray beams, 8 9 10 cm, mid-line, all equally weighted. b Anterior field with a weight of
100 cm SSD. Isodose curves have been renormalized to show 0.8 with two equally weighted (1.0) posterior oblique fields
the 100% line almost encompassing the target volume. separated by 120°

elongation is determined by the relative thickness of

tissue that each beam traverses to the point of inter-
section and by the relative weights of the beams.
The use of a beam wedge influences the dose
distribution as well. Wedged fields are commonly
arranged such that the angle between the beams, the
hinge angle /, is related to the wedge angle h by the
following relationship (Fig. 30):
h ¼ 90 degrees  u=2
The use of angled beams is illustrated in Fig. 31
showing that 45° wedge fields orthogonal to one
another yield a uniform dose distribution.
Three-field non-axial (noncoplanar) arrangements
are readily achieved with linacs by rotating the table
and gantry. A common technique for treating pituitary
tumors uses two lateral fields and a vertex field with
the beam entering through the top of the head.
Astrocytomas are often treated with parallel–opposed Fig. 30 Parameters of the wedge beams: h is the wedge angle,
lateral fields and a frontal field entering through the / is the hinge angle, and S is separation. Isodose curves for
each wedge field are parallel to the bisector. (Khan 1994a)
forehead. A 90° couch rotation is used with the gantry
rotated laterally for the vertex or frontal fields.
The lateral fields are also rotated via collimator to technique for 6 and 18 MV X-ray beams. The central
ensure that the ‘heel’ of the wedge is in the plane of dose distribution is similar for all beam energies, but
the vertex/frontal field trajectory. the greater penetrability of the higher energy beams
Four-field techniques are typically used in such yields a lower dose to the region outside the box.
sites as the abdomen or the pelvis. In most instances Variations in the dose gradient are achieved by dif-
the arrangements consist of pairs of parallel-opposed ferential weighting of each pair of beams. Figure 33
fields, with a common intersecting point, which yield shows the dose distribution for oblique 4-field beam
a ‘‘box-like’’ isodose distribution. Figure 32 compares arrangements. Angulations of the beams yield a dia-
the dose distributions achieved with a 4-field boxlike mond-shaped dose distribution. A butterfly-shaped
116
Fig. 31 Isodose distribution
for two angled beams.
a Without wedges. b With
wedges. 4 MV, field
size = 10 9 10 cm,
SSD = 100 cm, wedge
angle = 45°. (Khan 1994a)
Fig. 32 Dose distribution for 4-field ‘‘box’’ technique with
equal beam weightings. a 6 MV X-ray beams. b 18 MV X-ray
beams. Note the improved dose distribution with the higher
distribution is achieved if each pair of beams has a
point of intersection lying on a common line but
separated by a few centimeters.
Treatments involving more than four gantry angles,
historically required with orthovoltage X-ray units to
treat deep, mid-line lesions, were originally rarely used
with high energy megavoltage therapy units. However,
with the broad introduction of three-dimensional
conformal radiation therapy (3DCRT) and intensity
modulated radiation therapy (IMRT), (see ‘‘Three-
Dimensional Treatment Planning and Conformal
Therapy’’ and ‘‘Linac Based Image Guided Intensity
Modulated Radiation Therapy’’) there has been an
increase in multi-field treatments such as the 3DCRT
six-field technique commonly used for the treatment of
prostate carcinoma. More recently, these beam
arrangements are further refined by adding segments of
fields with the same beam angle to either improve dose
J. A. Purdy et al.
energy beam technique (more uniform dose in the target region
and lower doses near the femoral head region of the lateral fields)
as a result of the increased percent depth for 18 MV X-rays
homogeneity or to intentionally generate an inhomo-
geneous dose distribution as with the simultaneous
integrated boost technique.
7.3 Rotational Therapy-Non IMRT
Rotational (or arc) therapy techniques, in which the
treatment is delivered while the gantry (and thus
the radiation beam) rotates around the patient, can be
thought of as an infinite extension of the multiple-
field techniques already described. This technique is
most useful when applied to small, symmetrically
shaped, deep-seated tumors, and is usually limited
to field sizes less than about 10 cm in width for the
treatment of centrally located lesions (i.e., have
approximately an equal amount of tissue in all
directions around the lesion).
Physics of Radiotherapy Planning and Delivery
Fig. 33 Dose distribution for 4-field oblique beam technique
for 6 MV X-rays with equal beam weightings. a With common
isocenter resulting in a diamond-shaped dose distribution.
Fig. 34 Dose distribution for 360° rotational therapy tech-
nique. a 6 MV X-ray beams. b 18 MV X-ray beams. Note that
there is little difference in the dose distribution when using a
Dose distributions generated by rotational tech-
niques are not very sensitive to the energy of the
photon beam. Figure 34 illustrates this fact, showing
the dose distribution achieved using a 6 MV X-ray
beam, and also the distribution using an 18 MV X-ray
beam. There is a little less elongation in the direction
of the shorter dimension of the patient’s anatomy for
the 18 MV beam and the dose distribution in the
periphery is slightly lower.
In arc therapy techniques, one or more sectors of
a 360° rotation are skipped to reduce the dose to
critical normal structures. When a sector is skipped,
the high-dose region is shifted away from the skip-
ped region. Therefore, the isocenter must be moved
toward the skipped sector; this technique is referred
to as past-pointing and examples are shown in
Fig. 35.
117
b Each beam pair intersecting at two different points
on a common line resulting in a butterfly-shaped isodose
distribution
higher-energy beam as a result of the offsetting effects of
increased percent depth versus higher exit dose
The prostate, bladder, cervix, and pituitary are
clinical sites that have been treated, either initially or
for boost doses, with rotation or arc therapy tech-
niques. Although the dose distributions achieved by
rotation or arc therapy yield high target volume doses,
these techniques normally result in a greater volume
of normal tissue being irradiated (albeit at low doses)
than fixed, multiple-field techniques. Moreover, the
dose gradient at the edge of the target volume is never
as sharp with a rotational technique as that achieved
with a multiple-field technique.
7.4 Treatment Plan Comparisons
There are numerous publications in which different
external beam radiation therapy techniques have been
118
Fig. 35 Dose distribution for arc therapy technique for
6 MV X-rays. a 240° arc. Note, that when a sector of the
full 360° rotation is skipped, the high-dose isodose curves
are shifted away from the skipped sector. b 240° arc, but
compared. These have been primarily treatment
planning studies for selected disease sites in which
3DCRT, IMRT, and proton beam therapy techniques
are compared against each other and sometimes
against conventional 2DRT techniques. For example,
Cella et al. (2001) published a study to assess the
potential benefit of intensity modulated proton beam
therapy (IMPT) in optimizing the dose distribution for
prostate cancer radiation therapy. In their study, four
treatment plans were compared using a single prostate
cancer patient CT data set in which the aim was to
deliver 81 Gy to the PTV: (Plan-1) 6-field, 18 MV
3DCRT; (Plan-2) 2-field, 214 MeV PB; (Plan-3)
5-field, 15 MV IMRT; and (Plan-4) 5-field, 177–
200 MeV IMPT. For all four treatment plans, the PTV
dose distribution was acceptable; however, the dose
homogeneity was slightly reduced in the 3DCRT and
IMRT plans. The low-to-medium doses delivered to
all OARs, and other normal tissues were significantly
reduced by both proton plans. Only the IMRT and
IMPT plans succeeded in predicting an acceptably
low NTCP for the rectum (\ 5%, Grade 3). The
integral non-target dose was significantly reduced
with IMPT (i.e., 3.1, 1.3, and 1.7 times less than Plans
1, 2, and 3, respectively).
Lomax et al. (2003) reported on a comparative
treatment planning study intended to show the
potential improvements that IMRT and protons could
bring for the loco-regional treatment of complex-tar-
get breast cancer. Using CT data from a single breast
cancer patient, treatment plans were computed
using the conventional 2DRT approach (photon/
J. A. Purdy et al.
patient positioned so that isocenter is 2 cm lower toward the
skipped sector (this technique is called ‘‘past-pointing’’).
Note high-dose isodose curves now encompass the target
volume
electron), IMRT, and a forward-planned proton
technique. A dose of 50 Gy was prescribed to the
target volume consisting of the involved breast,
internal mammary, supraclavicular, and axillary
nodes. The standard 2DRT plan was designed using
6 MV X-ray beams to the breast, axillary, and
supraclavicular areas and a mixture of 6 MV X-rays
and 12 MeV electrons for the internal mammary
nodes. Two IMRT plans (IMX1 and IMX2) were
calculated for nine evenly spaced beams using dose–
volume constraints to the OARs. For plan IMX1,
precedence was given to optimizing the reduction in
lung and heart dose while preserving target dose
homogeneity. For plan IMX2, an increased prece-
dence was given to the lungs, heart, and contralateral
breast to further reduce doses to these organs and to
study the effect on target coverage. The proton plan
consisted of two oblique, energy-modulated fields.
Target dose homogeneity and the doses to neighbor-
ing organs were both considered when comparing the
different plans. For the conventional RT plan, DVHs
of the target volumes showed severe dose heteroge-
neity, whereas target coverage for the IMRT and
proton plans was comparable. Mean doses to the
ipsilateral lung for the three plans were found to be
17, 15, and 13 Gy for the conventional RT, IMRT,
and proton plans, respectively. For the heart, the
IMRT plan delivered the highest mean dose (16 Gy),
reflecting the extra dose delivered through this organ
to spare the lungs. This was reduced somewhat by the
conventional RT plan (15 Gy), with the best sparing
being provided by the proton plan (6 Gy). When the
Physics of Radiotherapy Planning and Delivery
IMRT plan was reoptimized with an increased
precedence to the normal tissues, the mean doses to all
neighboring organs at risk could be reduced, but only
at the cost of substantial target dose heterogeneity.
They concluded that IMRT has the potential to greatly
improve the target dose homogeneity with only a small
increase in the doses delivered to the neighboring
critical structures. However, only the two-field, energy-
modulated proton plan had the potential to preserve
target dose homogeneity while simultaneously mini-
mizing the dose delivered to both lungs, heart, and the
contralateral breast.
Mock et al. (2004) reported on a paranasal sinus
carcinoma five-patient planning study comparing
proton and IMRT with conventional 2DRT and
3DCRT techniques. The evaluations analyzed DVH
findings of the PTVs and OARs, i.e., pituitary
gland, optical pathway structures, brain, and nontarget
tissue. The mean and maximal doses, dose inhomo-
geneities, and conformity indexes for the PTVs were
comparable for all techniques. Photon plans resulted
in greater volumes of irradiated non-target tissues
at the 10–70% dose level compared with the
corresponding proton plans. The volumes thereby
increased by a factor of 1.3–3.1 for conventional
2DRT, 1.1–3.8 for 3DCRT, and 1.1–3.7 for IMRT.
Compared with conventional 2DRT techniques,
3DCRT and IMRT options similarly reduced the
mean dose to the OARs. The use of protons further
reduced the mean dose to the OARs by up to 65 and
62% compared with the 3DCRT and IMRT tech-
niques, respectively. Compared with conventional
treatment techniques, 3DCRT and IMRT similarly
enabled dose reductions to the OARs.
8 Collimation and Field Shaping
A major constraint in the treatment of cancer using
radiation is the limitation in the dose that can be
delivered to the tumor because of the dose tolerance
to the tissue (critical organs) surrounding or near to
the target volume. Shielding normal tissue and critical
organs has allowed the radiation oncologist to
increase the dose to the tumor volume while main-
taining the dose to critical organs below some toler-
ance level. The frequently used tolerance doses for
these organs are not absolute and depend on a number
of clinical and treatment factors. Depending on the
119
predominantly serial or parallel organization of the
organ at risk, a large dose can sometimes be given to
fractional volumes of organs especially with a parallel
structure (liver; kidneys; lungs) (Emami et al. 1991;
Marks et al. 2010). Shielding is usually accomplished
using collimator jaws (with asymmetric feature) and
multileaf collimators, in which the beam aperture
(field shape) is customized for individual patients.
Low melting point alloy blocks are gradually being
abandoned.
8.1 Asymmetric Collimator Jaws
Field shaping and abutted field radiation techniques
have been made even more versatile with the asym-
metric jaw feature found on modern-day linacs. This
feature allows each set of jaws to open and close
independently of each other (Fig. 36). The collimator
jaw provides greater attenuation than the MLC leaf or
alloy block, thus providing an advantage (which is
readily apparent on portal films) in reducing the dose
to blocked regions.
Depth-dose characteristics for asymmetric fields
are similar to those of symmetric fields as long as the
degree of asymmetry is not too extreme. Clinical sites
where asymmetric jaws are typically used include
breast (Fig. 37), head and neck, craniospinal, and
prostate. In addition, the use of asymmetric jaws
as beam splitters, for field reductions, and with
MLC is helpful for most sites. Rosenow and col-
leagues(Rosenow et al. 1990) and later Marshall
(1993) described the use of a single set of asymmetric
jaws to match supraclavicular and tangential fields in
the longitudinal plane for breast irradiation. Klein and
co-workers described the use of dual asymmetric jaws
to create nondivergence along the chest wall for the
tangential beams (Klein et al. 1994). This technique
allows a single set-up point for all the treatment fields,
including the posterior axillary field. The Y-jaws can
beam split the caudal and cephalic regions for the
supraclavicular and tangential beams, respectively,
and the X-jaws are used to shield the ipsilateral lung
and contralateral breast. Hence, a common match
plane with one common isocenter can be used for all
portals, including a posterior axilla beam, eliminating
the need to move the patient between portals, thus
reducing the overall patient set-up time by almost a
factor of two. In addition, the increased attenuation by
120
Fig. 36 Independent or asymmetric collimators. a Conven-
tional symmetric pairs of collimators. b Asymmetric collima-
tors in which collimator jaws are allowed to move
independently of each other
Fig. 37 Treatment technique for breast cancer using indepen-
dent collimators. (Klein et al. 1994)
the jaws reduces the dose to the contralateral breast
and lung (Foo et al. 1993). A technique for matching
lateral head and neck fields and the supraclavicular
field using independent jaws was described by Sohn
and colleagues (Sohn et al. 1995).
J. A. Purdy et al.
8.2 Multileaf Collimation
MLC, first introduced in Japan in the 1960s
(Takahaski 1965), has now gained widespread
acceptance and has replaced alloy blocking as the
standard-of-practice for field shaping in modern
radiation therapy clinics. The different manufactur-
ers’ MLC systems vary with respect to MLC
location, leaf design, and field size coverage. The
leaves are typically carried on two opposed car-
riages that transport the leaves in unison. The
leaves have individual controls that are computer
assigned and positioned. Initially, most commercial
MLC systems were designed to serve as a block
replacement, but now provide for dynamic IMRT
delivery as well.
Elekta first introduced its MLC system in the late
1980s (Hounsell et al. 1992). Their current MLC
system is shown in Fig. 38. Note that the MLC
replaces the upper photon collimator jaws; and
therefore, the maximum field size can open to a full
40 9 40 cm. The MLC system is augmented by
parallel diaphragms, which increase the leaf’s atten-
uation by an additional two HVLs.
The Varian MLC system (Fig. 39) is placed below
the photon collimator jaws. The initial system con-
sisted of 52 tungsten leaves (26 on each side) with
rounded ends, non-divergent, and 5.65 cm thick
(Galvin et al. 1993b). That system was followed with
an 80-leaf version (40 on each side), increasing the
maximum field size to 40 9 40 cm. The latest Varian
MLC (non-SRS) is a 120-leaf (60 on each side), in
which the middle 20 cm consists of 0.5 cm wide
leaves, while the outer 20 cm leaves still project to
1.0 cm widths. This set of leaves projects to 16.0 cm
in length at isocenter, and the leaf span range (max-
imum–minimum positions on the same carriage) is
limited to 14.5 cm. The leaves move perpendicular to
the beam’s central axis. The distance from the X-ray
target to the bottom of the leaves (on central axis) is
54.0 cm. The leaves fan away from the central axis so
that their sides are divergent with the beam’s fan
lines. The leaves are interdigitated by a tongue-
and-groove design.
Siemens also introduced an MLC system in which
the lower collimating jaws are replaced with a double
focused leaf system (Das et al. 1998).
Galvin et al. (1993a) and Klein et al. (1995)
reported leaf transmission values of 1.5 to 2.0% for a
Physics of Radiotherapy Planning and Delivery
Fig. 38 Schematic
illustrating geometry of
multileaf collimator for Elekta
linacs. (Elekta AB,
Stockholm, Sweden)
Fig. 39 Schematic illustrating geometry of multileaf collima-
tor for varian linacs. The x-direction is the field width across
each leaf pair, and the y-direction is the field length. (Varian
Medical, Palo Alto, CA)
Varian 6 MV beam, and 1.5 to 5% for an 18 MV
beam. Transmission through the screw attachment
plane was 2.5%. These values are lower than those
found for alloy blocks (3.5%), but higher than those
121
for collimator jaw transmission (being less than
1.0%). Transmission through abutted (closed) leaf
pairs was as high as 28% for 18 MV photons on the
central axis. The abutment transmission decreased as
a function of off-axis distance to as low as 12%.
Figure 40 shows a comparison of MLC and alloy
blocks regarding penumbra. The discrete steps of the
MLC systems introduce undulations in the isodose
lines. This effect causes an apparent increase in pen-
umbra with wave patterns after the undulations. Single,
focused MLC systems have a slightly larger penumbra
than alloy shields and have an even larger difference in
comparison with collimator jaws. Boyer and colleagues
found the penumbra (80–20% isodose lines) generated
by leaf ends to be wider than those generated by upper
collimator jaws by 1.0–1.5 mm, and 1.0–2.5 mm
compared with the lower jaws, depending on energy
and field size (Boyer et al. 1992). Powlis and associates
compared MLC and alloy field shaping and found few
differences (Powlis et al. 1993). LoSasso and co-
workers found similar results and concluded that the
geometric accuracy is even improved with MLC
(LoSasso and Kutcher 1995).
The penumbras measured for the leaf sides are
comparable with those found for upper jaws due to their
122
Fig. 40 Comparison of beam’s eye view isodose curves at
10 cm depth for MLC (solid line) and cerrobend-shaped
(dashed line) beam apertures for 18 MV photons. (Klein
et al. 1995)
divergent nature. The penumbra increase and stair-
stepping effect are most prominent at dmax. The effects
diminish at depth due to the influence of scattered
electrons and photons as the scatter-to-primary ratio
increases with depth. Adding an opposed beam leads to
further smoothing of the undulations and penumbra
differences become less significant. For multibeam
arrangements, the differences in dose distribution
between MLC and alloy shields are negligible.
Two methods for designing the optimal MLC
configurations to fit the treatment plan’s field aper-
tures have evolved: (1) configuring the MLC based on
a digitized film image using a dedicated MLC work-
station (with or without automated optimization), and
(2) configuring the MLC using treatment planning
system software. The main limitation in optimizing
the MLC leaf settings to conform to the shaped field is
the discrete leaf steps. Most field shapes require only
minor adjustment of collimator angle to achieve
minimal discrepancy between the desired and resul-
tant field shape. The criteria for optimizing the MLC
leaf settings are governed by placing the most leaf
ends tangent to the field and also maintaining the
same internal area as originally prescribed. MLC
shaping systems typically provide an option to place
the leaf ends entirely outside the field (exterior),
entirely within the field (interior), or crossing the field
at mid-leaf (leaf-center insertion). The last is the most
widely used criterion because the desired field area is
more closely maintained. However, this choice leads
to regions in which some treatment areas are shielded
J. A. Purdy et al.
and some normal tissues are irradiated. Zhu and
colleagues reported on a variable insertion technique
in which leaves are placed only far enough into the
field to cause the 50% isodose contour to undulate
outside and up to the desired contour (Zhu et al.
1992). LoSasso and colleagues reported on a method
in which each leaf is inserted such that the treatment
area covered by the leaf equals the normal tissue area
that is not spared (LoSasso et al. 1993). Brahme also
demonstrates optimal choices for choosing a colli-
mator angle to optimize leaf direction, depending on
whether the field shape is convex or concave (Brahme
1988). Du and colleagues reported on a method that
defines optimal leaf positioning in combination with
optimal collimator angulation (Du et al. 1995).
Typically, the optimal direction for the leaf motion is
along the narrower axis. For a simple ellipse the
optimal leaf direction is parallel to the short axis.
Klein and co-workers studied the effects of tissue
heterogeneities on penumbra and resultant field defi-
nition and found lung to increase penumbra (espe-
cially for 18 MV photons) and bone to decrease
penumbra for both alloy blocks and MLC (Klein et al.
1995). When multibeam arrangements were used, the
summed doses consistently showed a superior dose
distribution for the MLC fields, despite the stair-
stepping effects, as opposed to alloy blocks.
As indicated previously, because MLC systems are
still evolving, a careful evaluation of the effect of
MLC on monitor unit calculations must be performed
before clinical use. Extensive testing over the clinical
range of field sizes and shapes should be undertaken
before the MLC system is used clinically.
8.3 Low Melting Alloy Blocks
While alloy blocks are rapidly disappearing from
clinical use, a short section is included in this chapter
for completeness. The Lipowitz metal (Cerrobend)
shielding block system was first introduced by Powers
et al. (1973). Lipowitz metal consists of 13.3% tin,
50.0% bismuth, 26.7% lead, and 10.0% cadmium. The
physical density at 20°C is 9.4 g/cm3 as compared with
11.3 g/cm3 for lead. Alloy blocks made from the
standard thickness (7.6 cm) of foam molds reduce the
primary beam intensity to 5% of its unattenuated value.
Increasing the block thickness any greater is generally
not worthwhile as it makes the block heavier, while the
Physics of Radiotherapy Planning and Delivery
scatter radiation contributes an equal or greater share of
the dose under the blocks. More details using this form
of field shaping can be found in the review article by
Leavitt and Gibbs (1992).
Computer-controlled adaptations of the hot-wire
cutting technique have evolved as an adjunct to 3D
treatment planning, in which the treatment field shape
is defined based on beam’s eye-view displays. The
shaped field coordinates are transferred directly to the
computer controlled block cutting system, thereby
eliminating potential errors in manual tracing, mag-
nification, or image reversal. The other steps in the
block-forming and verification process remain similar
to the manual procedure.
9 Separation of Adjacent X-ray Fields
9.1 Field Junctions
Different techniques for matching adjacent fields are
illustrated in Fig. 41. A commonly used gap calcu-
lation method for adjacent radiation fields is illus-
trated in Fig. 42. The separation between adjacent
field edges necessary to produce junction doses sim-
ilar to central-axis doses follows from the similar
triangles formed by the half-field length and SSD in
each field. The field edge is defined by the dose at
the edge that is 50% of the dose at dmax. For two
contiguous fields of lengths L1 and L2; the separation,
S, of these two fields at the skin surface can be cal-
culated using the following expression:
1 d 1 d
S ¼ 2 L1 þ 2 L2
SSD SSD
A slight modification of this formula is needed
when sloping surfaces are involved, as shown in
1 
Fig. 43 (Keys and Grigsby 1990). Typically, the skin
gap location is moved a number of times to reduce the
hot and cold spots that arise with this technique.
Figure 44 illustrates the dose distribution for three
different field separations (Johnson and Khan 1994).
Beam divergence may be eliminated by using a
‘‘beam splitter,’’ created using a five- or six-HVL
block over one half of the treatment field. The central
axes of the adjacent fields, where there is no diver-
gence, are then matched. As previously discussed, this
is a useful method on linacs with the independent jaw
123
feature. Match-line wedges or penumbra generators
that generate a broad penumbra for linac beams have
been reported but have not found widespread use
(Fraass et al. 1983). Here, the intent is to broaden the
narrow penumbra of the linacs so that it is not so
difficult to match the 50% isodose levels. The
resulting dose distributions are similar to those
obtained with a moving gap technique.
There are numerous reports of edge-matching
techniques based on the mathematical relationships
between adjacent beams and the allowed angles of the
gantry, collimators, and couch. Christopherson and
co-workers developed a useful nomograph for field
matching for treating cancer of the breast
(Christopherson et al. 1984).
9.2 Orthogonal Field Junctions
Figure 45 illustrates the geometry of matching abutting
orthogonal photon beams. Such techniques are neces-
sary, particularly in the head and neck regions where
the spinal cord can be in an area of beam overlap, in the
treatment of medulloblastoma with multiple spinal
portals (Van Dyk et al. 1977) and lateral brain portals. A
common method of avoiding overlap is to use a half-
block, as previously discussed, so that abutting anterior
and lateral field edges are perpendicular to the gantry
axis. In head and neck cancer, a notch in the posterior
corner of the lateral oral cavity portal is commonly used
to ensure overlap avoidance of the spinal cord when
mid-line cord blocks cannot be used on anteroposterior
portals irradiating the lower neck and matched to the
oral cavity portals. Other techniques rotate the couch
about a vertical axis to compensate for the divergence
of the lateral field (Siddon et al. 1981). The angle of
rotation is given by
field width
tan h1 ¼ 2
SAD
Another technique is to leave a gap, S, on the
anterior neck surface between the posterior field of
length L and lateral field edges (Gillin and Kline
1980; Williamson 1979). S can be calculated using
the formula below where d is the depth of the spine
beneath the posterior field:
1 d
S ¼ ðLÞ
2 SAD
124 J. A. Purdy et al.

Fig. 41 Different techniques

for matching adjacent fields.
a Beam’s central rays are
angled slightly away from one
another so that the diverging
beams are parallel. b Half-
beam block to eliminate
divergence. c Penumbra
generators (small wedges) to
increase width of penumbra as
illustrated in D1 and D2.
e Junction block over spinal
cord. f Moving gap technique.
(Bentel 1996)

The potential for the occurrence of radiation
myelopathy resulting from a potentially excessive
dose from misaligned overlapping fields is always a
concern when central nervous system tumors are
treated. Craniospinal irradiation is well established as
a standard method of treating suprasellar dysgermi-
noma, pineal tumors, medulloblastomas, and other
tumors involving the central nervous system. Uniform
treatment of the entire craniospinal target volume is
possible using separate parallel-opposed lateral cra-
nial portals rotated so that their inferior borders match
with the superior border of the spinal portal, which is
treated with either one or two fields, depending on the
length of the spine to be treated. Lim excellently
describes the dosimetry of optional methods of
treating medulloblastoma with diagrams (Lim 1985,
1986). Two junctional moves are made at one-third
and two-thirds of the total dose. The spinal field
central axis is shifted away from the brain by 0.5 cm
and the field size length reduced by 0.5 cm with
corresponding increases in the length of the cranial
field, so that a match exists between the inferior
Physics of Radiotherapy Planning and Delivery
Fig. 42 Standard formula for calculating the gap at the skin
surface for a given depth using similar triangles
border of the brain portal and the superior border of
the spine portal. To achieve the match, the whole-
brain portals are rotated by an angle given by the
following relationship:
1  arrest; most new ICDs can act as both pacemakers and
spinal field length
tan h1 ¼ 2
SAD
To eliminate the divergence between the cranial
portal and spinal portal, the table is rotated through a
floor angle
1  than the older models that utilized bipolar transistor
cranial field length
tan a1 ¼ 2
SAD
10 Patients With Cardiac Pacemakers
As the population ages, the likelihood of encountering
patients with either a pacemaker or an implantable
cardioverter defibrillator (ICD) that requires radiation
therapy for chest and lower neck neoplasms has
become commonplace. Pacemakers are electrical
devices that may stimulate either the atria, ventricles,
or both (single-chamber and dual-chamber models,
respectively) in order to regulate the heart’s natural
125
Fig. 43 Modified formula for calculating the gap for matching
four fields on a sloping surface. (Keys and Grigsby 1990)
rhythm (NHLBI 2011a). ICDs are generally larger
than pacemakers, and also actively shock the heart to
help control life-threatening, irregular heartbeats,
especially those that could cause sudden cardiac
defibrillators (NHLBI 2011b). Modern pacemakers
and ICDs incorporate complementary metal oxide
semiconductor (CMOS) circuitry into their generator
units (encompassing a sealed lithium battery pack and
circuitry only). Several groups have shown that these
modern devices are much more sensitive to radiation
circuitry (Hurkmans et al. 2005; Solan et al. 2004;
Sundar et al. 2005).
To safely and adequately treat such patients, it is
important to understand the potential effects of radi-
ation therapy on these devices’ operation and to take
steps to minimize any actions that could jeopardize
the cardiac health of the patient. The AAPM Task
Group 34 Report provides a list of widely accepted
clinical management guidelines (Marbach et al.
1994). Potential interactions between a functioning
pacemaker and the radiation therapy environment fall
into two categories: (1) electromagnetic noise inter-
ference (EMI) created by the treatment machine in the
course of producing high-energy photon and electron
126 J. A. Purdy et al.

Fig. 44 Dose distribution for

geometric separation of fields
with all four beams
intersecting at mid-point.
Adjacent field sizes:
30 9 30 and 15 9 15 cm;
SSD = 100 cm; AP
thickness = 20 cm; 4 MV
X-ray beams. a Field
separation at surface is
2.3 cm. A three-field overlap
exists in this case because the
fields have different sizes but
the same SSD. b The adjacent
field separation increased to
eliminate three-field overlap
on the surface. c Field
separation adjusted to 2.7 cm
to eliminate three-field
overlap at the cord at 15 cm
depth from anterior. (Khan
1994a)

beams, and (2) damage due to radiation. Most experts
now believe that category 1 is no longer a source of
concern. However, dose and dose rate are very much
a concern (Hurkmans et al. 2005; Mouton et al. 2002;
Sundar et al. 2005). Modern pacemakers are radio-
sensitive and have a significant probability of failing
catastrophically at radiation doses well below normal
tissue tolerance and, therefore, should never be irra-
diated by the direct beam. Also, several authors have
shown that recommended maximum doses obtained
from manufacturers have not proved to be reliable and
vary greatly among manufacturers (Hudson et al.
2010; Hurkmans et al. 2008; Mouton et al. 2002).
A recent review by Hudson et al. provides the latest
information and points out that radiation-induced
device malfunctions are rare, and death associated
with that malfunction is even more uncommon
(Hudson et al. 2010). However, they conclude that the
adequacy of published guidelines is not supported by
hard data. They recommend that it is important to
consider all aspects of radiation therapy treatment and
not just accumulated dose. These include the effect of
backscatter, dose rate, fractionation and potential EMI
interference with new technologies such as IMRT and
respiratory gating. They recommend that each radia-
tion oncology department employ their own policy for
the management of patients with pacemakers and
ICDs, potentially based upon an updated standard
national or international guideline similar to that
released by the AAPM in 1994.
Physics of Radiotherapy Planning and Delivery
Fig. 45 Some solutions for the problem of overlap for
orthogonal fields. a Beam splitter, a shield that blocks half of
the field, is used on the lateral and posterior fields and on the
spinal cord portal to match the nondivergent edges of the
beams. b The divergence in the lateral beams may also be
removed by angling the lateral beams so that their caudal edges
match. Because most therapy units cannot be angled like this,
11 Fetal Dose
Radiation therapy is the standard treatment for several
malignancies (e.g., Hodgkin’s lymphoma, breast
cancer) in which the population of women is often of
childbearing age. The issues are complex and the
patient along with the radiation oncologist must eval-
uate treatment risk to the fetus in such cases. Radiation
effects to the fetus are not fully understood and cannot
be comfortably predicted for each individual case. If
the decision is to irradiate, the dose levels outside the
treatment fields should be quantified, and every effort
should be made to lower the dose to the fetus. This may
require changes in irradiation technique (i.e., modified
mantle fields), elimination of double-exposure portal
127
the couch is rotated through small angles in opposite directions
to achieve the same effect. c A gap technique allows the
posterior and lateral field to be matched at depth using a gap S
on the skin surface. The dashed lines indicate projected field
edges at depth D, where the orthogonal fields meet. (Williamson
1979)
films, and the addition of special patient shields. An
AAPM report provides data and techniques to estimate
and reduce radiation dose to the fetus for beam energies
ranging from 60Co to 18 MV (Stovall et al. 1995).
Before the pregnant patient is treated, the pregnancy
stage should be known to estimate the size and location
of the fetus throughout the treatment. Dose-estimation
points should be selected that allow estimation of dose
throughout the fetus (e.g., fundus, symphysis pubis, and
umbilicus) (van der Giessen 2001).
Two methods are typically used to reduce the dose
to the fetus, namely, modification of treatment tech-
niques and the use of special shields. Modifications
include changing field angle (avoiding placement of
the gantry close to the fetus), reducing field size,
choosing a different radiation energy (avoiding 60Co
128
because of high leakage or energies of [10 MV
because of neutrons), and using tertiary collimation to
define the field edge nearest to the fetus. When shields
are designed, the shielding device must allow for
treatment fields above the diaphragm and on the lower
extremities. Safety to the patient and personnel is a
primary consideration in shield design.
12 Gonadal Dose
Many of the reports used to estimate peripheral dose
and fetal dose apply to dose estimations to both testes
and ovaries. Estimations by calculated methods
(Francois et al. 1988) and by extrapolated measure-
ments (van der Giessen 1996) have been reported
specific to gonadal dose. Simultaneously, there have
been studies to determine the genetically significant
dose (GSD) as it applies to peripheral radiotherapy
dosage to ovaries and testes. Niroomand-Rad et al.
(1993) combined measured data and GSD data to
determine the GSD for particular treatment tech-
niques that deliver peripheral dose to ovaries and
testes. They summarized that GSDs from conven-
tional therapies are minimal. However, there are cir-
cumstances, such as treatment of seminoma, when it
is necessary to use a testicular shield to surround the
testes to reduce head scatter and leakage, and some
internal scatter (Fraass et al. 1985).
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 Simulation in the Determination
and Definition of Treatment Volume
and Treatment Planning
Sasa Mutic, Mary Coffey, James A. Purdy,
Jeff M. Michalski, and Carlos A. Perez

Contents 5.3 Treatment Techniques ............................................... 154

6 Discussion.................................................................. 154
1 Introduction.............................................................. 134 References.......................................................................... 155
2 Technology Overview .............................................. 136
2.1 Conventional Simulator............................................. 137
2.2 CT (3D)-Simulator .................................................... 138 Abstract
2.3 MR Simulator ............................................................ 141 One of the cornerstones of modern radiation
2.4 PET/CT Simulator ..................................................... 142
therapy practice are volumetric patient image
3 Multi-Modality Imaging.......................................... 144 datasets from computed tomography (CT), mag-
4 Patient Positioning and Immobilization................ 146 netic resonance imaging (MRI), positron emission
tomography (PET), and ultrasound (US). Current
5 Simulation Process................................................... 148
5.1 3D Simulation............................................................ 148 radiation therapy imaging devices (simulators)
5.2 Conventional Simulation ........................................... 153 include (1) Conventional Simulators (based on
conventional x-ray radiography planar imaging);
(2) CT-simulators (based on CT scanners); (3)
S. Mutic (&)
J. M. Michalski PET/CT-simulators (based on PET/CT scanners
Department Of Radiation Oncology, and); (4) MR-simulators (based on MR scanners).
Washington University School of Medicine, The radiation therapy simulator has been an
Mallinckrodt Institute of Radiology,
integral component of the treatment planning
Siteman Cancer Center, 4921 Parkview Place,
St. Louis, MO 63141, USA process since the 1960s. Conventional simulators
e-mail: mutic@radonc.wustl.edu are designed to mimic the linear accelerator
M. Coffey geometry while providing a diagnostic-quality
Discipline of Radiation Therapy, x-ray beam for anatomic imaging. Due to the
School of Medicine, Trinity Centre for Health Sciences, increased use of 3D imaging for treatment plan-
St. James’ Hospital, Dublin 8, Ireland
ning, conventional simulators are less popular than
J. A. Purdy in the past. Still, this technology continues to be
Department of Radiation Oncology,
developed and retains its presence in most radia-
University of California, Davis,
4501 X Street, Suite G126, Sacramento, tion oncology departments. Shortly after the intro-
CA 95817, USA duction of clinical CT scanners in early 1970s it
C. A. Perez was realized that this imaging modality had much
Department of Radiation Oncology, to offer in a radiation oncology setting because
Washington University School of Medicine, they provided a volumetric view of the patient’s
Mallinckrodt Institute of Radiology,
normal and tumor anatomy with excellent spatial
Siteman Cancer Center,
4511 Forest Park Boulevard, St. Louis, accuracy. In response, CT simulators were devel-
MO 63141, USA oped during the 1980s and 1990s and today CT

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 133
DOI: 10.1007/174_2011_388,  Springer-Verlag Berlin Heidelberg 2012
134
simulator is the main imaging device in radiation
therapy. CT simulators have developed to a point
where CT scanner manufacturers are designing
scanners specifically for CT simulation purposes.
PET imaging can also provide valuable informa-
tion about tumors and PET/CT scanners have been
implemented as radiation therapy simulators and
can be found in many radiotherapy centers.
Finally, MRI scanners have also been implemented
and are used for treatment simulation in radiation
therapy. MRI scanners are less commonly found in
radiotherapy departments, but due to the imaging
advantages that MRI has to offer it is expected that
the use of MRI scanner for radiotherapy simulation
will experience significant growth. These devices
have enabled better delineation of treatment vol-
umes and critical structures while improving our
ability to image patients in better treatment
positions and with improved immobilization
devices. Successful radiation therapy imaging
(simulation) program must consider capabilities
of individual imaging equipment, immobilization
equipment, and the needs of individual techniques
and treatment sites. This chapter describes the
radiation therapy simulation process, design and
features of conventional, CT, PET/CT, and MRI
simulators, and their use for treatment planning.
1 Introduction
Radiation therapy is a continually evolving medical
specialty, especially considering the technology used
for treatment planning, treatment, and delivery veri-
fication. 3D Conformal radiation therapy (3D-CRT) is
now considered the standard of care for many treat-
ment sites and currently the vast majority of radio-
therapy treatment plans are based on volumetric study
sets. The four primary imaging modalities employed
in the modern radiation therapy treatment planning
process include computed tomography (CT), mag-
netic resonance imaging (MRI), positron emission
tomography (PET), and ultrasound (US). CT is by far
the most widespread imaging modality for this
application and as such has a focal point in this
chapter. Also described is the use of MRI and
PET as these two modalities are now commonly
found in many radiation therapy facilities. The use of
S. Mutic et al.
conventional simulator in the age of CT simulation
will be addressed accordingly.
The radiation therapy simulator, Fig. 1, has been an
integral component of the treatment planning process
for almost 30 years. Over the past ten to fifteen years it
has been rapidly replaced with CT simulation for many
reasons. CT images provide information not only about
target volumes but about critical structures as well.
Using CT images for radiation therapy treatment
planning has enabled us to improve dose delivery to
target volumes while reducing dose to critical organs.
CT images also provide density information for
heterogeneity-based dose calculations. A major
weakness of CT imaging is a relatively limited soft
tissue contrast. This limitation can be overcome by
using CT images in conjunction with MRI for treatment
planning. PET images can be used to add tumor met-
abolic and physiological information. The inclusion of
PET allows functional imaging to be incorporated into
the localization and planning process giving a further
level of accuracy to the definition of the tumor volume.
US has also been useful for imaging in brachytherapy.
As described elsewhere in this book, multi-
modality imaging-based treatment planning and target
and normal structure delineation offer an opportunity
to better define the anatomic extent of target volumes
and to define their biologic properties.
In 1983, Goitein and Abrams (1983) and Goitein
et al. (1983) further described multidimensional treat-
ment planning based on CT images. They described a
‘‘beam’s-eye-view’’ (BEV) function which ‘‘provides
the user with an accurate reproduction of anatomic
features from the viewpoint of a treatment source’’.
They also described how ‘‘projection through the CT
data from any desired origin provides an alignment film
simulation which can be used to confirm accuracy of
treatment, as well as help establish anatomic relation-
ships relative to the margins of a treatment field’’. In
reality, this was a description of the major character-
istics of a system that we know today as a CT simulator
or virtual simulator. An alignment film created from a
divergent projection through the CT study data is today
commonly known as a digitally reconstructed radio-
graph (DRR). Sherouse et al. (1990a) additionally
developed the use of DRRs in radiation therapy.
Sherouse et al. (1987, 1990b) went on to describe a
CT image-based virtual simulation process which
they referred to as a ‘‘software analog to conventional
simulation’’. This series of manuscripts described
Simulation in the Determination and Definition of Treatment Volume 135

Fig. 1 Modern version of a

conventional simulator. Image
courtesy of Varian Medical
Systems, Palo Alto,
California, copyright (c) 2002

Fig. 2 CT simulator room

layout. Image courtesy of
Philips Medical Systems,
Cleveland, Ohio

software tools and addressed technical issues that
affect today’s CT simulation process. The manu-
scripts pointed out the need for fast computers, spe-
cialized software, but also for improved patient
positioning, immobilization and setup reproducibility.
The radiation oncology community eagerly
embraced the concept of virtual simulation and in the
early 1990s commercial packages became available.
These systems consisted of a diagnostic CT scanner,
external laser positioning system, and a virtual sim-
ulation software workstation. A modern CT simula-
tion package is shown in Fig. 2. (Brilliance Big Bore,
Philips Medical Systems, Inc.)
CT simulators are one of the cornerstones of modern
radiation oncology facilities. Today’s systems incor-
porate specially designed large bore CT scanners,
136
Fig. 3 Place of CT simulation in radiotherapy treatment planning process. Reprinted with permission from Mutic et al. (2003)
multi-slice CT scanners, high quality laser positioning
systems, respiratory correlated imaging capabilities,
sophisticated virtual simulation packages, etc.
All these features with increased efficiency and
flexibility have enabled CT simulators to replace the
conventional simulators.
Figure 3 shows the place of CT simulation in the
treatment planning process. The implementation of
simulation and the treatment planning process varies
greatly between radiation oncology departments. This
diversity is in part driven by significant technical
differences between simulation and treatment plan-
ning systems offered by different manufacturers.
It would be impractical to address all the possible
variations in the implementation of these processes.
This chapter discusses the most common points
and describes the general differences between some
popular approaches.
Conventional simulators are still used in some
departments both for initial imaging and for verifica-
tion purposes. Conventional simulators are a combi-
nation of a diagnostic X-ray machine with fluoroscopic
imaging and certain components of a radiation therapy
linear accelerator (Fig. 1). The treatment table and
the gantry are designed to mimic the functions of a
linear accelerator. The gantry head is designed to
accommodate different beam modification devices
(blocks, wedges, compensating filters), similar to a
linear accelerator. The images are transmission radio-
graphs with field collimator setting outlined by delin-
eator wires. Using primarily bony landmarks, the
physician outlines areas to receive therapeutic radiation
doses.
S. Mutic et al.
A shortcoming of a conventional simulation process is
that very little anatomy, other than bony anatomy, is
available for design of treatment portals.
2 Technology Overview
The integration of new imaging modalities into the
treatment planning process has redefined volume
delineation and is now central to modern radiation
therapy practice. Image scanners used in radiation
therapy should have flat table tops, larger openings to
accommodate immobilization devices and patients in
conventional treatment positions, and software tools
that can improve patient positioning and target
delineation (Mutic et al. 2003). CT, MRI, and PET
scanners now commonly have major features
designed specifically for radiation therapy scanning.
These developments in volumetric scanning capa-
bilities have inevitably led to improvements in con-
ventional simulator design as well, as this technology
has to compete and keep up with other advances in
treatment planning and delivery techniques.
The specific requirements for radiation therapy
planning must be considered when a radiation therapy
department does not have its own imaging equipment
but acquires the images necessary for treatment plan-
ning in the diagnostic imaging department. Key to
maximizing the advantages of image acquisition is an
awareness of the modifications of the diagnostic
imaging equipment that must be made to ensure that the
images acquired are consistent with the requirements
for treatment planning. In this situation the diagnostic
Simulation in the Determination and Definition of Treatment Volume 137

Fig. 4 Digital image of a head from a modern conventional

simulator equipped with an amorphous silicon imager. Image
courtesy of Varian Medical Systems, Palo Alto, California,
copyright (c) 2002 Fig. 5 Digital image of a chest from an amorphous silicon
imager with MLC shape projected on the image. Image
courtesy of Varian Medical Systems, Palo Alto, California,
scanner should be modified to meet the radiotherapy copyright (c) 2002
needs with a flat tabletop insert and external patient
positioning lasers added to these scanners. Modern simulators have Digital Image Communica-
tions in Medicine (DICOM) standard (NEMA 1998)
import capabilities. Treatment field parameters can be
2.1 Conventional Simulator
imported directly from the treatment planning com-
puter. The software can then automatically set the
The conventional simulator, Fig. 1, consists of a fluo-
simulator parameters according to the treatment plan.
roscopic imaging chain [X-ray tube, filters, collima-
This facilitates efficient and accurate verification of
tion, image intensifier, video camera, etc., Bushberg
patient treatment setup on the conventional simulator.
et al. (2002)], generator, patient support assembly
These simulators also have DICOM export capabili-
(treatment table), laser patient positioning/marking
ties which enable the transfer of treatment setup
system, and simulation and connectivity software. The
parameters directly to a record and verify system or to
imaging chain and simulator software have undergone
a treatment planning computer. The ability to import
several improvements during the past few years.
and capture digital images enables conventional
Imaging Chain One of the major changes in the simulators to have tools for automatic correlation of
imaging chain design for the conventional simulator treatment planning and verification fields.
was the replacement of the image intensifier and
Vendors also offer solutions for some shortcom-
video camera system with amorphous silicon detec-
ings of older conventional simulators. For example,
tors. The new imagers produce high spatial and con-
older simulators were not equipped with tools to
trast resolution images which approach film quality
verify portal shapes created with multileaf collimators
(Fig. 4). More importantly, these images are distor-
(MLCs). Newer simulators have features that can
tion-free, a feature that is important for accurate
project MLC shapes directly on the patient’s skin or
geometric representation of patient anatomy. The
on the portal films (Fig. 5).
introduction of high quality digital imagers in con-
Another capability of modern conventional simu-
ventional simulation further facilitated the widespread
lation imaging is cone beam CT acquisition. This
implementation of filmless radiation oncology
feature allows volumetric imaging on a conventional
departments.
simulator and increases the utility of these devices.
Simulation Software The conventional simulation Figure 6 shows a cone beam CT image from a con-
software has also undergone many improvements. ventional simulator.
138
Fig. 6 Cone beam CT image of a head acquired on a
conventional simulator. Image courtesy of Varian Medical
Systems, Palo Alto, California, copyright (c) 2002
While it is often mentioned that conventional
simulators can be completely replaced with CT sim-
ulators, new features and usefulness of conventional
simulators are slowing down this process. The con-
ventional simulator continues to be an important
component of radiotherapy process even though its
use for treatment planning of many tumor sites has
been significantly reduced.
2.2 CT (3D)-Simulator
A 3D simulator consists of a CT scanner, laser patient
positioning/marking system, virtual simulation/3D
treatment planning software, and different hardcopy
output devices. The CT scanner is used to acquire the
volumetric CT scan of a patient which represents
the virtual patient and the simulation software creates
virtual functions of a conventional simulator. The
three most significant recent features of CT simula-
tion technology have been the introduction of a
larger gantry bore opening (Large Bore CT) (Garcia-
Ramirez et al. 2002), multi-slice image acquisition
(Multi-slice CT) (Klingenbeck et al. 1999), and the
addition of CT simulation software directly on the CT
S. Mutic et al.
scanner control console. These innovations improved
the efficiency and accuracy of the CT simulation
process. They also improved the patient experience
and reduced the simulation procedure time.
Large Bore CT Large bore CT scanners were spe-
cifically designed with radiation therapy needs in
mind. One of the requirements in the treatment of
several cancer sites (breast, lung, vulva, etc.) is for
extremities to be positioned away from the torso.
When acquiring a CT scan with a patient in such a
treatment position, extremities often cannot fit
through a conventional 70 cm diameter scanner bore
opening. In such situations, patient positioning needs
to be modified to acquire the scan. This can result in a
patient position which is significantly different from
that in which treatment will be planned and delivered.
Large immobilization devices (slant board, body
molds) are also difficult to fit through a conventional
diameter scanner. The first large bore CT simulator
was introduced in 2000, and numerous additional
models with enlarged bore opening have been intro-
duced since then.
Large bore scanners also have increased scan field
of view (SFOV). SFOV determines the largest
dimension of an object that can be fully included in
the CT image and it is typically 48–50 cm on most
conventional 70 cm bore opening scanners. For
treatment planning purposes it is necessary to have
the full extent of the patient’s skin on the CT image.
Lateral patient separation can often be larger than
48–50 cm and the skin is then not visible on CT
images. Increased SFOV available on large bore
scanners solves this problem.
Multi-Slice CT In 1992, Elscint introduced a scanner
which had a dual row of detectors and could acquire
two images (slices) simultaneously. Since then, multi-
slice CT scanners that can acquire 4, 8, 10, 16, 32, 40,
64, etc. slices (with sub-second rotation times) have
become the standard offering. The basic premise
behind the multi-slice CT technology is that multiple
rows of detectors are used to create several images for
one rotation of the X-ray tube around the patient. The
detector design and arrangement varies among the
vendors. Figure 7 shows an example of implementa-
tion for a 16 slice scanner available from a major
vendor. Although the scanner is considered a 16 slice
scanner, there are 24 rows of detectors or detector
elements. The center 16 have 0.75 mm collimated
Simulation in the Determination and Definition of Treatment Volume
Fig. 7 Schematic of a detector array for a 16 slice CT scanner
width at the isocenter and the outer four on either side
have 1.5 mm collimated width at the isocenter. The
total length coverage at the isocenter is then 24 mm.
The thinnest nominal slice thickness that the scanner
can produce is slightly larger than 0.75 mm, but for
practical purposes it can be considered here as
0.75 mm. With proper collimation (16 9 0.75) on the
X-ray tube side, signal from the center 16 detector
elements can be used to acquire 16 9 0.75 mm thick
images at a time. If the collimation is increased to
16 9 1.5 so that the X-ray beam includes the outer
eight detectors, 16 1.5 mm thick images can be
acquired. In this situation, signals from the adjoining
pairs of 0.75 mm detectors are combined to create
1.5 mm thick images. Similarly, larger slice thick-
nesses can be created by combining the signal from
multiple detector elements. The primary advantage of
multi-slice scanners is the ability to acquire image
studies many times faster than single slice scanners.
Multi-slice technology also facilitates respiratory-
correlated CT imaging (Keall et al. 2006). This
application of multi-slice CT in radiation has dra-
matically changed the approach to target definition for
many mobile tumors. AAPM TG-76 describes slow
CT, inhalation and exhalation breath-hold CT, and
four-dimensional (4D) or respiration-correlated CT as
three CT imaging techniques that can include the
entire range of tumor motion at the time of CT
acquisition.
Slow CT With this technique, the scanner couch is
slowed so that every anatomical location is scanned
through at least one respiratory cycle, thus allowing the
entire range of patient motion to be captured in a CT
image. Advantages of this imaging technique are that
no special equipment is needed and also that acquired
images enable dose calculation on geometry that is
more representative of patient geometry during treat-
ments. A major shortcoming of this technique is loss of
resolution and blurring which affects definition of
normal anatomy. Due to this limitation, the AAPM
TG-76 recommends this technique for lung tumors
139
which are not involved with mediastinum or chest wall.
The task group also does not recommend this technique
for other sites, like liver, pancreas, kidney, etc.
Inhalation and Exhalation Breath-Hold CT In this
technique two CT scans are acquired, one at inhala-
tion breath-hold and another at exhalation breath-
hold, thus effectively capturing the two extremes of
tumor motion. By combining tumor contours from the
two CT scans, a target representative of the tumor
motion can be created. An advantage of this technique
is a significantly improved resolution over slow CT.
Disadvantages include additional work associated
with processing two data sets. Another problem is that
the normal anatomy in either of two images is cap-
tured at extremes of breathing cycle and is thus not
very representative of normally observed anatomy as
the CT images captured at the extremes tend to over
estimate or underestimate lung volume.
Four-Dimensional CT/Respiration-Correlated CT This
process involves different imaging techniques which
allow imaging of individual or all phases of the respi-
ration cycle. The technique is performed with the
assumption that a patient’s breathing pattern remains
constant during the entire CT scan. The acquired ima-
ges allow individual phases of the breathing cycle to be
viewed one at a time or to be combined in movie
loops or derived images [MIP, Min-IP, average image
(Keall et al. 2006)]. Special hardware and software are
required to perform this imaging technique. The main
advantages of 4D CT are good resolution and a more
complete characterization of tumor motion. The limi-
tations include potentially large amounts of acquired
data and more importantly the susceptibility to artifacts
due to irregular breathing patterns during image
acquisition.
Multi-slice scanners are also capable of acquiring
thinner slices which result in better quality DRRs and
more accurate target delineation (better spatial resolu-
tion) (Fig. 8). Studies with thinner slices also result in
an increased number of images to process. Target
140
Fig. 8 a 0.8 and b 3 mm CT slice thickness DRRs. Image in figure a contains much more detail than image in figure b
volumes and critical structures have to be delineated on
an increased number of images and treatment planning
systems have to handle larger amounts of data. Cur-
rently, this can result in increased time and labor
required for treatment planning. Software vendors are
creating tools that will allow easier manipulation of
larger study sets but that will likely take several years to
implement. In the mean time, the number of CT images
that are acquired for a treatment plan needs to be bal-
anced between resolution requirements and the ability
to process a larger number of images.
CT Simulator Tabletop This section and discussion
about simulator tabletops applies equally to all sim-
ulators used in radiation therapy (conventional, MRI,
and PET) and treatment machines. Tabletops used for
patient support in radiation therapy during imaging or
treatment should facilitate easy, efficient, reproduc-
ible, and accurate patient. It is not only important that
a tabletop improves patient positioning on a single
device (i.e. treatment machine) but the repositioning
of a patient from one imaging or treatment device to
another also has to be considered. Tabletops used in
image acquisition should be consistent with the
tabletops on the treatment units to ensure accuracy
S. Mutic et al.
and reproducibility. They do not have to be neces-
sarily identical, but they should have the same
dimensions (primarily width), flex and sag under
patient weight, and they should allow registration
(indexing) of patient immobilization devices to the
tabletop. Figure 9 demonstrates this concept. The CT
simulator tabletop has the same width as the linear
accelerator used for patient treatment and both allow
registration of patient immobilization system to the
treatment couch. The ability to register the immobi-
lization device and the patient to a treatment table is
extremely important and improves immobilization,
setup reproducibility, accuracy, and efficiency. The
patient is always positioned in the same place on the
treatment machine and patient daily setup can be
facilitated using the treatment couch positions.
Actually, if the patient is registered to the treatment
couch, couch coordinates used for patient treatment
can become a part of parameters that are set and
tracked in the record and verify system. The tolerance
for the couch parameters can be set according to the
type of treatment that the patient is receiving. For
example, for conformal radiotherapy treatments the
coordinates should allow minimal deviations (com-
parable to margins used for target delineation) in daily
Simulation in the Determination and Definition of Treatment Volume
Fig. 9 Similarity in design
of simulator and treatment
machine tabletops allows
efficient and accurate
reproducibility of patient
positioning. Image courtesy of
MED-TEC, Inc, Orange City,
Iowa
couch positioning. The therapist can then first place
the treatment couch to the coordinates set in the
record and verify system and then evaluate patient
positioning. If the patient is well immobilized mini-
mal adjustments should be needed in patient setup.
Foam mattresses irrespective of thickness should not
be used as mattress depression can result in a change
in patient position in the AP/PA direction.
Patient Marking Lasers A laser system is necessary
to provide reference marks on patient skin or on the
immobilization device to ensure that the patient is
parallel to the treatment couch with no lateral rotation.
A centrally mounted laser with two lateral lasers is the
optimum arrangement allowing for accurate position
in all directions and avoiding rotational error. Figure 2
shows a laser system for a CT simulator:
Wall Lasers Vertical and horizontal, mounted to the
side of the gantry. These lasers can be fixed or
movable. The movable lasers allow automatic
movement to specific positions, this can improve the
efficiency of CT simulations and potentially reduce
errors due to manual control errors.
Sagittal Laser Ceiling or wall mounted single laser,
preferably movable. Scanner couch can move up/
down and in/out but cannot move left/right, therefore
the sagittal laser should move left/right to allow
marking away from patient mid line. Ceiling lasers
that can move in lateral as well as longitudinal
direction are commercially available and can also
improve the efficiency of CT simulations and poten-
tially reduce errors due to manual control errors.
141
Scanner Lasers Internally mounted, vertical and
horizontal lasers on either side of the gantry and an
overhead sagittal laser.
Lasers should be spatially stable over time and
allow positional adjustment. Properly aligned simu-
lator lasers greatly improve the accuracy of patient
treatments. Misaligned simulator lasers can introduce
systematic errors in patient treatments. Therefore,
simulator laser alignment should be checked daily and
the alignment tolerance should be within two milli-
meters Mutic et al. (2003). The quality of the lasers
should be consistent with those in the treatment units
and the intended technique to be applied. Green laser
lights are readily visible on all skin tones, give a very
high quality fine line, and should be used for maxi-
mum accuracy.
2.3 MR Simulator
MR images for radiation therapy treatment planning
are usually acquired in diagnostic radiology and very
few radiation oncology departments have a dedicated
MR scanner. Furthermore, the vast majority of MR
studies in radiotherapy are currently limited to brain
imaging. MR has a superior soft tissue contrast
compared to CT imaging and there are several ben-
efits that MR can offer for target delineation based on
this advantage. There have been several reports
describing the use of MR scanners for imaging and
treatment simulation in radiotherapy Potter et al.
(1992); Okamoto et al. (1997); Beavis et al. (1998);
142
Fig. 10 MR simulator. Image courtesy of Philips Medical
Systems, Cleveland, Ohio
Schubert et al. (1999) and Mah et al. (2002). Some of
these reports have suggested that MR studies can be
used alone for radiotherapy treatment planning.
Indeed, if spatial distortions (the geometry of imaged
objects is not always reproduced correctly), which is
the largest concern with MR imaging, can be removed
or minimized MR studies can be used as the primary
imaging modality for several treatment sites. Superior
soft tissue contrast provided by MR can also be an
advantage for treatment planning of certain extracra-
nial tumor sites like prostate, for example Lee et al.
(2003) and Chen et al. (2004).
Conventional MR scanners are not well suited for
extracranial imaging for treatment planning.
The main difficulty is the placement of the patient in
the treatment position with immobilization device in
the scanner. Small diameter and long length of con-
ventional MR scanner openings severely limits
patient positioning options for imaging. Open MR
scanners, Fig. 10, and scanners with bigger bores with
features designed specifically for radiation therapy are
commercially available. One of the major problems
with MR imaging for radiotherapy treatment planning
are geometric distortions in acquired images. MR
scanners are often equipped with correction algo-
rithms which will minimize geometrical distortions.
These corrections do not affect the entire image and
only the center portion of the image (center 20–35 cm
diameter) is adequately correct (within 2 mm).
S. Mutic et al.
Therefore, the representation of patient’s skin and
peripheral anatomy for larger body sections may be
inaccurate. The effect of these inaccuracies must
be evaluated if dose distributions and monitor units
are calculated directly on MR images.
Virtually all treatment planning system will allow
import of MR images and image registration with
CT study. Some treatment planning systems will
also allow design of treatment portals and display of
isodose distributions on MR images directly. If the
treatment planning system can calculate doses
directly on MR images and if it was determined that
geometric distortions are not significant, then there
may be no need for CT images and MR study may be
the only image set used for treatment planning. There
should be a way to create images from the MR study
which are equivalent to simulation radiographs for
comparison with port films from the treatment
machine. Another potential problem with MR images
is that they do not contain information that can be
related to the electron density of imaged tissues for
heterogeneity-based corrections. This is not a signif-
icant problem as bulk density corrections can be
applied in the majority of treatment planning systems.
Due to availability of CT images in modern radiation
oncology departments it may be easiest if a CT study
set is always acquired to complement the MR data
and facilitate easier and more accurate heterogeneity-
based dose calculations.
2.4 PET/CT Simulator
PET images for radiation therapy planning can
come from a standalone PET scanner or a combined
PET/CT unit. Combined PET/CT scanners have
replaced standalone scanners and the later technology
will not be addressed in this chapter. Combined PET/
CT scanners can be found in radiation oncology
departments and are used for PET scanning, these
machines can also be used for CT scanning but only
without PET acquisition. Due to this purpose, these
scanners can be classified as CT simulators, though
the term PET/CT simulator may be more appropriate.
Combined PET/CT The first combined PET/CT
prototype was introduced in 1998 at the University of
Pittsburgh, Beyer et al. (2000), since then all major
manufacturers have produced several commercial
Simulation in the Determination and Definition of Treatment Volume 143

Fig. 11 A combined PET/

CT scanner

models. The key description of PET/CT scanners is need for a time-consuming PET transmission scan,
that a PET and a CT scanner are ‘‘combined’’ in the Bailey (2003) and Bailey et al. (2003). The use of CT
same housing (Fig. 11). Meaning that there are two images to generate PET ACFs reduces the scan time up
gantries (PET and CT) combined in one housing to 40% and also provides essentially noiseless ACFs
sharing a common couch. Image reconstruction and compared with those from standard PET transmission
scanner operation is performed from one control measurements, Townsend et al. (2004). Shorter scan
console. times can benefit radiotherapy patients who are scan-
ned in treatment position which often can be uncom-
Combined PET/CT scanner design varies among
fortable and difficult to tolerate for prolonged amounts
different vendors with respect to PET detectors, image
of time. One of the concerns with ACFs generated from
quality and resolution, speed, image FOV; number of
CT images is mismatch or misalignment between CT
slices for the CT part, scanner couch design, gantry
and PET images. PET images are acquired during many
bore opening, and other considerations. Modern PET/
cycles offree breathing and CT images are acquired as a
CT scanners incorporate many features, including
snapshot in time at full inspiration, partial inspiration,
larger bore openings, which simplify their use for
or some form of shallow breathing. The breathing
patient imaging for radiation therapy treatment
motion will cause mismatch in anatomy between PET
planning.
and CT images in the base of lung and through the
The combined PET/CT technology offers two major
diaphragm region. This mismatch can result in artifacts
benefits for radiotherapy planning. First, because the
in these areas which may influence diagnosis and
images are acquired on the same scanner, provided that
radiotherapy target definition in this region. There are
the patient does not move between the two studies, the
various gating methods that can be used during image
patient anatomy will have the same coordinates in both
acquisition to minimize the motion component and
studies. These images are registered using hardware
essentially acquire true, motionless, images of patient
registration rather than software registration. The sec-
anatomy. 4D CT can be used to generate more reliable
ond benefit of the combined PET/CT units is that CT
ACFs and also for radiotherapy treatment planning
images are used to measure attenuation correction
where gated delivery methods are being used.
factors (ACFs) for the PET emission data, obviating the
144
Anatomy Physiology
CT
US
MRI
Nuclear
Fig. 12 Information content of current imaging modalities in radiotherapy. Adapted from Piwnica-Worms (2000)
Contrast-enhanced CT images can cause inaccu-
rate ACFs due to artificially increased attenuation
through anatomy which contains contrast material.
The most obvious way to avoid this problem is to
acquire a routine CT with contrast and another non-
contrast CT. There is also an option to use software
tools to correct for these artifacts. For radiotherapy
scanning, it is preferred to acquire two separate scans.
The attenuation correction CT can be a whole-body,
low-dose scan with greater slice thickness if desired.
The second CT would be a treatment planning scan
with thin slices for better resolution and DRR quality.
This scan is acquired only through the volume of
interest thus limiting the number of images and
memory requirements to manipulate these images in
the treatment planning computer. This second scan
can then be contrast enhanced if desired.
3 Multi-Modality Imaging
Imaging is involved in all steps of patient manage-
ment, disease detection, staging, treatment modality
selection (intra-modality and inter-modality), target
volume definitions, treatment planning, and outcome
estimation and patient follow-up. An overall goal of
imaging in radiotherapy is to accurately delineate
and biologically characterize an individual tumor,
select an appropriate course of therapy, and predict
the response at the earliest possible time. The
requirement to biologically characterize an individ-
ual tumor means that an imaging modality must be
capable of imagining not only the gross anatomy but
also recording information about physiology,
metabolism, and the molecular makeup of a tumor.
Therefore, the image information used in radiation
S. Mutic et al.
Metabolism Molecular
therapy can be classified as anatomical and/or bio-
logical. The four primary imaging modalities used in
radiation therapy are CT, MRI, US, and nuclear
medicine imaging.
No single imaging modality provides all the nec-
essary information for treatment planning and patient
management for several cancer sites, but multiple
imaging modalities can be used to complement each
other and improve disease detection, staging, therapy
selection, target design, outcome prognosis, and fol-
low-up. Figure 12 shows the information content
possibilities of the imaging modalities used in radia-
tion therapy. The maximum benefits may be realized
if anatomical and biological imaging modalities
complement each other.
Detection Imaging of disease with CT or MRI (non-
functional) is based on anatomic or physiologic
changes that are a late manifestation of molecular
changes that underlie the disease. By detecting
changes in the molecular and biochemical process,
biological imaging (PET or functional MRI) can
demonstrate disease before it becomes anatomically
detectable. Changes in tumor detection capabilities
can lead to modification in radiation therapy target
volumes and dose prescriptions.
Staging PET has improved patient staging in several
treatment sites (Dizendorf et al. 2003). Better
knowledge of the true extent of the patient’s disease
can significantly alter patient management. For some
patients, who would otherwise undergo curative
radiation therapy, PET may demonstrate distal disease
or alter the extent of local disease and indicate that a
palliative course of therapy is more appropriate.
These patients would not only be spared the side
effects of inappropriate high dose curative treatment,
Simulation in the Determination and Definition of Treatment Volume
but the overall health care costs could also be lowered
due to PET findings.
In addition to more accurate staging, PET may also
be able to provide information about individual tumor
biology (phenotype). This would allow further strat-
ification of patients within the same clinical stage. So
rather than basing therapy selection for an individual
patient on the stage alone, which is statistically
appropriate for a large group of patients, biological
properties of an individual tumor can then be used for
therapy selection. The tumor phenotype information
may affect inter-modality and intra-modality patient
management depending on suspected radiation or
chemotherapy sensitivity of an individual tumor. If
we know more about the biological properties of an
individual tumor, it may be possible to incorporate
biological response models in the therapy selection
process to maximize the therapeutic ratio.
Target Definition and Altered Dose Distributions
The true extent of the disease may extend beyond
anatomically defined volumes and biological imaging
with PET has already been shown to be valuable for
defining the extent of target volumes. Furthermore,
PET can be used to differentiate areas of biological
importance within the boundaries of target volumes.
Ling et al. (2000) have described a concept of bio-
logical target volumes (BTVs). In addition to rec-
ommendations for target volume definitions proposed
by the International Commission on Radiation Units
and Measurements (ICRU) reports 50 (ICRU 1993)
and 62 (ICRU 1999), portions of target volumes
would be identified as having increased growth
activity or radioresistance. Identification of these
volumes would be performed with biological imaging
and these volumes would be labeled as BTVs. BTVs
would then have a special consideration during the
treatment planning process and would be subject to
dose escalation and IMRT delivery.
For example, Chao et al. (2001) have shown how PET
imaging-based hypoxia measurement technique with a
Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-
ATSM) tracer can be used to identify a BTV for head and
neck tumors. Experiments have shown that increased Cu-
ATSM uptake can be used to identify hypoxic tissues,
which are also associated with increased radioresistance.
The proposed treatment technique is based on the idea
that Cu-ATSM can be used to identify the hypoxic BTV
145
and IMRT delivery can be used to deliver escalated doses
to overcome the radioresistance of the BTV.
Evaluation of Response to Therapy and Follow-Up
Currently, tumor control and effectiveness of radio-
therapy is evaluated in the weeks and months fol-
lowing the completion of treatments. The evaluation,
similar to detection and diagnosis, relies largely on
anatomical changes, which take time to manifest. If
the planned approach of radiotherapy is not effective
and the patient has a persistent disease or new
growth it is too late to make any modifications, as
the therapy has already been completed. Addition-
ally, by the time it is determined that a local tumor
control has not been achieved it may be too late to
initiate a second line of therapy. Biological imaging
may be used to detect response to therapy on a
molecular level and allow evaluation of therapy
effectiveness sooner after completion of treatments
(Young et al. 1999). Ideally, biological imaging may
be used shortly after initiation of treatments to image
tumor changes. This approach has had limited suc-
cess thus far, but research in this area is active and it
eventually may be possible to evaluate tumor
response after initiation of therapy.
We are just beginning to exploit the benefits of
multi-modality imaging in the management of radio-
therapy patients. With time, the use of several image
types will be commonplace for treatment planning of
many cancer sites. This has already, to an extent,
taken place for treatment planning of central nervous
system tumors where CT images are complemented
with MRI studies for a significant fraction of patients.
One concern with utilization of novel imaging data
for treatment planning and management of radiation
therapy patients is that the information contained in
the images may be misinterpreted or may be incorrect
resulting in inappropriate patient treatments. It is
imperative for radiation oncologists to understand the
potential pitfalls and shortcomings of individual
imaging modalities and also to realize that the best
results can be achieved if newer imaging techniques
are used to supplement existing staging and tumor
delineation processes. This is especially true if bio-
logical or functional information is used for target
delineation where the possibility of false positive or
negative findings exists. The correlation of biological
or functional signals with anatomic abnormalities
detected by CT or MRI can provide an important
146
validation in the target delineation and patient man-
agement process. Care and attention must be given to
accurate patient positioning when images are acquired
using different imagining modalities for the purpose
of fusion for treatment planning.
4 Patient Positioning
and Immobilization
The success of conformal radiation therapy begins
with accurate positioning and immobilization. In an
era of dose escalation care and attention to accurate
positioning and immobilization is essential. An
accurate and reproducible patient position is depen-
dent on several factors including patient physical and
psychological status, their knowledge and under-
standing, and the level of patient comfort that can
realistically be achieved. Patients who are uncom-
fortable may have poor treatment setup reproduc-
ibility or suffer unnecessarily during the course of
their treatment. Attaining good patient co-operation is
very important and the clarity of the information that
patients are given prior to commencement of simu-
lation is a crucial step in the procedure. A detailed
explanation should be given to patients on the posi-
tion they are expected to maintain and why and this
should include any instructions relating to bladder or
bowel preparation if appropriate. The patient should
be given time to clarify the information and should be
provided with written information as back up.
Care must be taken in achieving a balance between
maintaining patient privacy and not compromising
positioning. Trousers at low pelvic or thigh level, for
instance, do not maintain patient modesty and make
reproduction of the position very difficult. The addi-
tional thickness of material if it encroaches into the
treatment area will alter the dose distribution and can
act as bolus material. The NHS funded Lancashire
Teaching Hospital has developed an interfaith gown
which has been specifically developed to preserve
patient modesty during treatment [TrusTech Interfaith
Gown http://www.trustech.org/case-studies/inter-faith
-gown.htm]. This can be very useful but care must be
taken to ensure that the gown does not compromise
the treatment area.
The optimum patient position and method of
immobilization is based on the clinical site and the
extent of the tumor volume. Treatment protocols and
S. Mutic et al.
procedures should include details on positioning and
immobilization. This can be one of the most effective
methods of minimizing dose to the organs at risk
(OARs). The physical status of the patient and the
stage of disease should be considered when deciding
on the most appropriate immobilization method.
Patients may suffer with co-morbidities that may
affect their ability to achieve and maintain the
required position and this must be taken into account.
In the case of palliative treatment patient comfort may
be considered as a priority but accuracy, within
agreed parameters, must be maintained.
Patients should be aligned straight and parallel to
the imaging table and should not be rotated or slanted.
It is much easier to reproduce a straight patient
position than a rotated one. Patient setup design
should consider location of critical structures and
target volumes, patient overall health and flexibility,
possible implants and anatomic anomalies, and
available immobilization devices.
Immobilization devices significantly improve the
accuracy and reproducibility of the setup and mini-
mize the inter and intra fraction motion. In the era of
IMRT and multiple beam arrangements it is also
important to ensure that the immobilization device
does not limit beam entry positions. Standard immo-
bilization devices often do not provide an adequate fit
for all patients, they work for many but not for all
patients. This is well accepted and understood for
body molds, and also for thermoplastic masks for
immobilization of head and neck region. Where sur-
rogates such as the maxilla, bridge of the nose, and
top of the head are important for the stability of the
head and neck thermoplastic mask it is important to
ensure that the mask is fit for purpose e.g., where
treatment is to the neck area a five-field fixation mask
should be used to minimize shoulder movement and
avoid a thickened mask edge covering a section of the
treatment area.
One very important point that is often overlooked is
design of head supports (head cups) for treatment of
head and neck region. There is a tendency to use a
standard head cup and a custom thermoplastic mask.
An analogy could be made that the head cup is a
foundation for a house and thermoplastic mask is
framing for the walls. If the foundation is not appro-
priately constructed, the entire structure will be
unstable. Therefore, for conformal treatments of head
and neck region improved setup reproducibility can be
Simulation in the Determination and Definition of Treatment Volume
Fig. 13 Head and neck immobilization device with custom
headrest
achieved with custom head supports made from body
mold material as shown in Fig. 13. Care should also be
taken with standard head and neck supports as it has
been demonstrated in several studies that the shape of
the support can change over time and with variation in
usage. Studies have shown that head and neck supports
retained in either the simulator or treatment unit and
used for a number of patients have a significant change
in thickness over time. Supports in the treatment unit
are used more frequently and therefore subjected to
depression over time resulting in a change in position.
This change in thickness results in a variation of
position between the simulator and treatment unit and
it is recommended that individual head and neck
supports are used and that this support move with the
patient from simulation throughout treatment (van Lin
et al. 2003). Houweling et al. compared standard with
individual head supports and demonstrated a signifi-
cant improvement in reproducibility and stability
using the individual support. They found a decrease in
both systematic and random error of inter-fraction
variation with statistically significant reductions in
vertebral rotation at C1-3 (Houweling et al. 2010).
Similar approach and forethought can be applied to
other treatment sites and respective immobilization
devices. Figure 14 shows a body mold that is used at
the Washington University School of Medicine for
treatment of patients with breast cancer. This device
was designed to facilitate CT-based treatment plan-
ning and to improve patient reproducibility from the
simulator to the treatment machine. In the inside of
the body mold are Styrofoam wedges which elevate
147
Fig. 14 Breast treatment immobilization device. 1 Portion of
the mold removed on the ipsilateral side, 2 arm grip, 3 ear mold
made from dental wax, 4 non-skid surface
the patient and provide adequate positioning for the
breast or chest wall. A handle improves patient com-
fort by providing a solid grip point for the arm, and the
non-skid material prevents patients from sliding in the
body mold. The ear mold which is made from dental
wax improves the head position reproducibility. The
device also registers to the treatment table so that the
couch coordinates are tracked during patient treatment
in the record and verify system. Others have proposed
even more elaborate positioning devices for the breast,
like the prone breast board which has an opening for
the breast to hang freely beneath the patient. Swal-
lowing, respiration, and diaphragm motion can affect
the reproducibility in the thoracic region and breathing
control may be requested. The breathing cycle will
need to correlate with the image acquisition.
Positioning and immobilization in the pelvic region
is still a topic under active discussion with studies
demonstrating that patient comfort is one of the most
148
important factors in achieving stability in this region.
Lower leg immobilization with knee and foot fix is
commonly used. Debate relating to the effectiveness of
the belly board is also ongoing. The advantages of dose
reduction to the rectum and bowel using this position-
ing device are often negated by the instability of posi-
tion causing patient movement. A comfortable arm
position when patients are in a supine position helps to
maintain stability and it has been found that placing the
arms on the chest prevents the weight of the arms on the
trunk and subsequent distortion of surface contours and
marks (Griffiths et al. 2004). When using a vacuum cast
it should be long enough to fully support the patient’s
spine, it should not stretch the patient skin, and the sides
should be sufficiently low to ensure that lateral tattoos
are visible (Mubata et al. 1998).
5 Simulation Process
Like other areas of radiation therapy treatment plan-
ning and treatment, image acquisition for treatment
planning requires a team approach, involving physi-
cians, physicists, dosimetrists, therapists, nurses, etc.
The team needs to understand individual components
of the process and their specific technical requirements.
Well-informed and knowledgeable personnel are nee-
ded to fully exploit the benefits of modern treatment
simulation equipment. Furthermore, treatment site-
specific written procedures can significantly improve
efficiency, consistency, and accuracy of simulations.
Written procedures are also helpful for training of new
staff and performing simulations for less frequent
treatment procedures. A well-designed and simple
simulation process greatly increases treatment plan-
ning efficiency and improves patient setup reproduc-
ibility between the simulator and treatment machine.
This section describes CT simulation processes as this
is routine procedure in many departments, with a sub-
sequent section on conventional simulation.
5.1 3D Simulation
The 3D Simulation process consists of the following
steps:
• Patient positioning and immobilization
• Patient marking
• CT scanning
S. Mutic et al.
• Transfer to virtual simulation workstation
• Localization of initial coordinate system
• Localization of targets and placement of isocenter
• Marking of patient and immobilization devices
based on isocenter coordinates
• Contouring of critical structures and target volumes
• Beam placement design, design of treatment portals
• Transfer of data to treatment planning system for
dose calculation
• Prepare documentation for treatment
• Perform necessary verifications and treatment plan
checks.
Again, this process and its implementation vary
from institution to institution. The system design is
dependent on available resources (equipment and
personnel), patient workload, physical layout, and
location of different components and proximity of
team members. Communication channels need to be
well established to avoid errors and unnecessary re-
simulations. A simulation request form can be used to
communicate simulation specifics between the phy-
sician and other team members (Fig. 15). The fol-
lowing is a general description of the major steps in
the CT simulation process:
5.1.1 Scan and Patient Positioning
The CT simulation scan is similar to conventional
diagnostic scans. However, there are several differ-
ences. Patient positioning and immobilization are
very important. Scan parameters and long scan vol-
umes with large number of slices often push scanners
to their technical performance limits. CT simulator
staff must be aware of scanner imaging performance
capabilities and limitations and also the geometrical
accuracy limitations. Imagining capabilities should be
exploited to achieve high image quality and geomet-
rical limitations need to be considered when posi-
tioning and marking patients. The scanning length
should also reflect the requirements of radiotherapy
and should include the recognized routes of spread of
the tumor being imaged.
Patient Positioning and Immobilization General
patient positioning and immobilization considerations
are as described earlier in this chapter. Larger bore
scanners typically allow for imaging in the patient
treatment position with larger immobilization devices
and offer a definitive advantage over conventional CT
scanners. Pilot (scout) images are a very efficient tool
Simulation in the Determination and Definition of Treatment Volume 149

Fig. 15 A sample simulation request form

150
for evaluation of patient positioning prior to the actual
CT scan. After patient initial immobilization, a pre-
liminary pilot scan should be imaged to assure that the
patient positioning is straight. Immobilization devices
should not produce artifacts on CT images.
Scan Protocol The CT scan parameters should be
designed to optimize both axial and DRR image quality
and to account for patient motion (Curry et al. 1990;
Conway and Robinson 1997; Coia et al. 1995; Bahner
et al. 1999; McGee et al. 1995; Yang et al. 2000; Keall
et al. 2006). The parameters influencing axial and DRR
image quality include: kVp, mAs, slice thickness, slice
spacing, spiral pitch (Kalender and Polacin 1991; Ka-
lender et al. 1994), data acquisition, reconstruction
algorithms, scanned volume, total scan time, field of
view (FOV), and size of image reconstruction matrix.
Modern scanners come with preset protocols. Often,
these include ‘‘oncology’’ protocols which take the
needs of virtual simulation process into consideration.
Preset protocols should be evaluated for adequacy and
modified according to treatment planning needs. Phy-
sicians, dosimetrists, therapists, and physicists should
be involved in protocol parameter selection. This is a
very important component of the CT simulation
implementation process. The quality of images from
the same scanner can vary significantly and the infor-
mation contained in these images may be inadequate if
care is not taken to properly select scan acquisition
parameters. Suboptimal scan protocols can cause sig-
nificant inefficiencies and potential errors in treatment
planning. The best protocol selection can only be
implemented with a thorough understanding of the
properties of individual scan parameters and recon-
struction algorithms.
Scan Limits Scan limits should be specified by the
physician and should encompass an area at least 5 cm
away from the anticipated treatment volumes. An ana-
tomical drawing can help when designing scan limits.
Contrast For several treatment sites contrast can be
used to help differentiate between tumors and sur-
rounding healthy tissue. Contrast is not always useful
and should be used carefully. Care should be taken to
identify any contraindications. For heterogeneity-
based calculations, contrast can cause dose distribu-
tion errors due to artificial CT numbers and corre-
sponding tissue densities. For implementation of
contrast in radiotherapy scanning, especially if the
S. Mutic et al.
scanner is located in the radiation oncology depart-
ment, a diagnostic radiologist should be consulted.
Special Considerations and Instructions Each treat-
ment site has unique considerations. These should be
specified in CT scan procedures. Special considerations
include: individual physician preferences, wiring of
surgical scars for identification on CT images, refer-
ence marks, scanning of patients with peacemakers and
other implants, scanning of pediatric patients, patients
under anesthesia, etc. A communication chain and
responsibilities should be established for new problems
and scans of patients with special needs.
Reference Marks During the CT scan a set of refer-
ence marks must be placed on the patient so that the
patient can be positioned on the treatment machine.
When and in relationship to which anatomical land-
marks the reference marks are placed can be done in
two different ways.
No Shift Method For this method the patient is
scanned and, while the patient is still on the CT
scanner couch, images are transferred to the virtual
simulation workstation. The physician contours the
target volume and the software calculates the coor-
dinates for the center of the contoured volume. Dur-
ing this time, the patient should remain still on the
couch in the treatment position. The calculated
coordinates are transferred to the CT scanner, the
couch and the movable lasers are placed at that
position, and the patient is marked. On the first day of
treatment, the patient will be positioned using these
marks on the treatment machine.
This method requires the physician to be present
during the CT scan and the patient scan procedure is
longer. However, the marks placed during the CT scan
can be used for patient positioning without any shifts.
This system reduces the risk of error during subsequent
treatment setup. This method can be greatly simplified
if the virtual software is located directly on the CT
scanner control console, obviating the need to transfer
the CT study set to another computer. If the software is
located on the scanner, the physician can start con-
touring the preliminary set of target contours directly
on the scanner console as soon as images are recon-
structed. This minimizes the time between the CT scan
and the time when the patient is marked. This is pre-
ferred as the patient must remain still in the treatment
position on the scanner couch while the physician
Simulation in the Determination and Definition of Treatment Volume 151

contours target volumes. If the patient moves between target volume. With asymmetric jaws, the initial ref-
the scan and the time when alignment marks are placed erence may be used as the isocenter eliminating the
on the skin, the marks will not correspond to contoured need for shifts.
tumor volumes resulting in potentially significant
treatment errors. Contouring on the CT scanner ensures
the shortest possible time between the CT scan and 5.1.2 Image Transfer and Registration
placement of alignment marks. Also the scanner soft- The CT study set is almost always the primary data on
ware is aware of absolute scanner couch coordinates which the isodoses are computed and displayed due to
relative to target volumes contoured by the physician. If its high spatial resolution and fidelity. The exceptions
the contouring is performed on the scanner console, are some stereotactic radiosurgery and brachytherapy
absolute couch coordinates can be used for patient applications where MRI or US, respectively, are used
positioning for placement of alignment marks. If as the primary studies. When properly calibrated
independent software package is used for contouring, and free of image artifacts, CT images can provide
the patient marking usually involves relative shifts to electron density information for heterogeneity-based
some initial set of reference marks. Relative shifts can dose calculations. As previously described, CT ima-
be inaccurate and can also result in significant errors if ges do have shortcomings and other imaging modal-
shifts are applied in the wrong direction or magnitude. ities can offer unique information about tumor
volumes. If other imaging modalities are used in the
Shift Method This method does not require physi-
treatment planning process, they are typically con-
cians to be present for the CT scan. Prior to the scan
sidered secondary data sets and must be spatially
procedure, based on the diagnostic workup (CT, MRI,
registered to the CT study to accurately aid in tumor
PET, palpation, etc.), the physician instructs CT
volume delineation.
simulator therapists where to place reference marks
One of the important functions of a CT study set is
on the patient. For example, ‘‘place reference marks at
definition of the patient/treatment coordinate system.
the level of carina, 4 cm left from patient midline and
Usually the, orientation of the coordinate system (X, Y,
midplane’’. The intention is to place these initial
and Z) is predetermined by the treatment planning
marks as close to the final isocenter as possible. Prior
software. However, the origin of the coordinate system
to the CT scan, the reference marks are marked on the
is defined, in most instances, by the location of the
patient and then radiation opaque markers are placed
reference marks which were placed on the patient
over the skin marks. The radiation opaque markers
during the simulation scan as described in the previous
allow the reference marks to be visible on the CT
section. If the patient was marked during the simulation
study. The markers can be constructed from thin
using the ‘‘No Shift’’ method, there will not necessarily
solder wire, aluminum wire, commercial markers, etc.
be any visible landmarks on the patient’s scan which
After the CT scan, the patient can go home and
correlate with the location of the origin of the coordi-
images are transferred to the virtual simulation
nate system. In this situation, the accuracy of the
workstation. Later, the physician contours target
treatment relies on the ability to accurately transfer
volumes and determines the treatment isocenter
coordinates from the simulation software to the treat-
coordinates. Shifts (distances in three directions)
ment planning software. This feature should be thor-
between the reference marks drawn on the CT scanner
oughly tested during commissioning for all scanners
and the treatment isocenter are then calculated. On the
and for different patient orientations on the scanner
first day of treatment, the patient is first positioned to
(supine, prone, head-first, feet-first, etc.). Errors in
the initial reference marks and then shifted to the
transfer can result in significant treatment errors. If the
treatment isocenter using the calculated shifts. Initial
patient was marked using the ‘‘Shift’’ method, a set of
reference marks are then removed and the treatment
radiation opaque markers that are placed on top of the
isocenter is marked on the patient.
skin marks can be seen on CT images and the location
This method is commonly used when a dedicated
of the coordinate system can be defined using these
radiation oncology CT scanner is not available. With
marks. Figure 16 shows a CT image with such marks.
proper planning (from diagnostic workup), the initial
Transfer of image studies and registration of
marks can be placed very close to the center of the
multimodality images is a several-step process
152
Fig. 16 CT image with radiation opaque markers on patient’s
anterior and left and right sides
requiring multi-function software capable of image
set transfer, storage, coordinate transformation, and
voxel interpolation. These features enable image
study registration (transforming images into a com-
mon reference frame and resampling to a common
pixel grid) and fusion (the display of a combination of
pixel intensities from registered image studies).
Registered and ‘‘fused’’ image studies can then be
used for radiotherapy treatment planning.
Images and other treatment planning data are
transferred between modern systems using DICOM
standard. DICOM is a standard for representing and
exchanging medical imaging data. This standard has
greatly simplified image exchange between scanners
and software manufactured by various vendors. Some
limitations still exist but are being eliminated
gradually.
There are several methods for image registration.
Surface-based registration requires contouring of the
same structure (internal or external) on the two data
sets and the studies are then registered by aligning the
contours. This method is well suited for CT–CT or
CT–MR registration. Edges of organs on PET images
are poorly defined and surface-based registration
typically cannot be used for image registration.
Image-based registration involves displaying CT data
set in background, in grayscale, and superimposing
the other study set image in color-wash or in gray-
scale on top of the CT study. The two studies are
typically simultaneously viewed in transverse, sagit-
tal, and coronal orientation. The studies are then
registered by manipulating the secondary study set
images in three displayed planes. Point-based regis-
tration is based on identifying a set of at least three
S. Mutic et al.
corresponding points in both data sets and performing
image transforms to align these points. Point-based
registration works well for CT and MRI as there are
numerous anatomical points which are identifiable on
both studies. Point-based registration with PET, using
anatomic points, is virtually impossible due to poor
image resolution. However, point-based registration
of PET images with external fiducial markers is
extremely useful (Mutic et al. 2001).
As a part of initial implementation of multimo-
dality imaging-based radiation therapy treatment
planning, tests should be performed to verify that
transferred images have correct geometry (e.g., pixel
size, spatial fidelity, slice thickness and spacing),
orientation (e.g., prone/supine, head–foot orientation,
and left–right orientation), scan text information, and
grayscale values (Mutic et al. 2001; Lavely et al.
2004). For routine treatment planning, images should
always be inspected for any distortions, misalign-
ments, and artifacts. This should be a part of the
routine quality assurance program, Mutic et al.
(2003).
5.1.3 Target and Normal Structure
Delineation
Virtual simulation typically consists of contouring
target and normal structures, computation of the iso-
center, manipulation of treatment machine motions
for placement of the beams, design of treatment
portals, generation of DRRs, and related treatment
setup information. This process is largely dependent
on the virtual simulation software capabilities. Target
and normal structure delineation requirements for
conformal radiation therapy have been addressed by
the ICRU (1993, 1999) and are described throughout
this book for various treatment sites. This is often the
most time-consuming portion of the virtual simulation
process and care should be taken to simplify this task
as much as possible. Well-designed contouring soft-
ware package is a prerequisite and should be one of
the main concerns when selecting virtual simulation
software. Another important component is to prede-
fine which structures are to be contoured for indi-
vidual treatment sites. This will avoid unnecessary
work. Also important is to predefine the anatomical
extent of each structure to be contoured. Uniform
extent of critical structures makes outcome and
complication analysis more meaningful.
Simulation in the Determination and Definition of Treatment Volume
5.2 Conventional Simulation
As described earlier in this chapter the dependence on
conventional simulators has decreased over the past
several years as conformal radiation therapy has
become the standard of care, and many radiation
oncology departments have replaced conventional
simulators with CT simulators. Other institutions have
reduced the number of conventional simulators and/or
number of conventional simulations. For example,
during the 1990s, the Department of Radiation Oncol-
ogy at Washington University School of Medicine
operated with three conventional simulators and one
CT simulator. In 2000, the department replaced two of
the conventional simulators for another CT simulator
for a total of one conventional simulator and two CT
simulators, while treating the same number of patients.
In 2005, the department also added an MR simulator.
The conventional simulator remains largely unused, as
IGRT capable machines are now used to perform most
of the functions which were once performed on the
conventional simulator.
One of the advantages of conventional simulators is
that there are virtually no limitations on available
patient positions and on the size and shape of immo-
bilization devices used for simulation. If a patient
cannot lie down, the sitting position in a special treat-
ment chair can be accommodated with a conventional
simulator where CT scanner would not be an option.
For some treatments of hands and arms it may be
desirable for the patient to stand next to the treatment
table. Again, this type of simulation can only be per-
formed with the conventional simulator. With better
imaging capabilities, cone beam CT, and better con-
nectivity with the treatment planning system and
treatment machine, conventional simulators are actu-
ally becoming more valuable than in the past.
The conventional simulation process consists of:
• Patient positioning and immobilization
• Verification of patient positioning using fluoro-
scopic imaging
• Determination of isocenter location
• Beam placement design
• Marking of patient and immobilization devices
based on isocenter coordinates
• Acquisition of X-ray films
• Outlining of treatment portals on the X-ray films
• Transferring or acquiring of patient setup data for
the record and verify system
153
• Transfer of simulation data to dosimetry for treat-
ment planning and monitor unit calculation
• Prepare documentation for treatment
• Perform necessary verifications and treatment plan
checks.
Patient Positioning and Immobilization The goals
for patient positioning and simulation described ear-
lier should be followed for conventional simulation.
The flexibility in size of immobilization devices
greatly simplifies patient positioning for treatment. If
the patient’s conventional simulation is to be followed
with a CT scan, then the limitations of the CT scanner
should be considered in patient positioning and
immobilization.
Verification of Patient Position Using Fluoroscopic
Imaging Prior to construction of the immobilization
device the patient should be aligned to lay straight on
the treatment table. This means that the patient’s
head, vertebra, and possibly extremities should be
parallel with the longitudinal axis of the treatment
table. The patient should also lay flat on the table with
no rotation. It is much easier to reproduce a straight
patient position on the treatment table than if the
patient is rotated. The verification of patient position
is performed under fluoroscopic guidance. After it is
verified that the patient is straight, an initial set of skin
marks should be placed on the patient so that this
position can be reproduced throughout the simulation.
Patient alignment should be monitored throughout the
simulation procedure.
Determination of the Isocenter Location Treatment
isocenter is typically placed based on physician
instructions. For the majority of the standard treat-
ments, the isocenter placement should be predeter-
mined and outlined in treatment and simulation
policies. It is desirable to place the isocenter on a
stable location on the patient where the skin or patient
anatomy does not move significantly. If the treatment
isocenter must be placed in a position where the
overlaying external anatomy does move, then a
treatment setup point should be used. Treatment setup
point is a set of marks which are placed on a stable
position on the patient’s anatomy (like sternum).
Accurate marking of reference points and field
delineation, whether directly on the patient skin or on
the immobilization device, is essential. The difficulty
of overreliance on skin marks is their inherent
154
unreliability. Skin, particularly in the more obese
patient, is mobile with respect to the underlying
organs, and a shift in skin mark position can lead to a
failure to adequately cover the treatment volume.
Many centers routinely use couch height for posi-
tioning rather than relying on skin marks and lateral
lasers.
The moisture content of skin also varies with time
and this can cause marks to become blurred or faded.
Tattoos are an excellent alternative but with some
limitations. Tattoos on darker skin may be difficult to
distinguish and even on light skin may be difficult to
differentiate from skin blemishes; additionally, tattoos
may not be acceptable in some cultures. Various
commercial products are now available that can help
to overcome this problem.
Marks on both skin and immobilisation devices
must be clear and not too thick. Thick lines are open
to error in field positioning and over a course of
treatment can lead to a significant shift in field bor-
ders. Thick lines are also problematic when remarking
is required and shifts from the initial field definition
can be easily introduced. Tape used to mark field
information on the immobilisation devices must be
secured with minimum creasing to facilitate clear
marking.
Where there is a second phase or integrated boost
care must be taken to differentiate the two phases.
For treatment, the patient is first aligned to the
setup point and then shifted to the isocenter location
using the shifts which were determined during the
simulation. Other considerations for the placement of
isocenter include limitations/capabilities of treatment
machines and desired dose distributions. These con-
siderations are beyond the scope of this text.
Beam Placement Design Beams should be placed
according to the treatment policies. Fluoroscopic
capabilities of the conventional simulator are used for
this purpose. Other chapters in this book outline
common treatment techniques.
Outlining of treatment portals based on simulation
X-ray films is also better addressed in some other
chapters in this book.
Transfer of Simulation Information for Treatment
Planning and Treatment The final step in the sim-
ulation process is the transfer of patient setup data to
dosimetry for calculation of monitor units and possi-
bly for some simple treatment planning. The setup
S. Mutic et al.
information is also transferred to the linear accelera-
tor. Depending on the connectivity of the conven-
tionally simulator and its ability to acquire patient
setup information electronically, some or all of the
patient setup data can be exported from the simulator
electronically. The integrity of captured and exported
electronic data should be verified through a periodic
quality assurance process.
5.3 Treatment Techniques
Treatment techniques for individual cancer sites are
described throughout this book. Implementation of
these treatment techniques also requires simulation
procedures. Simulation techniques for these individ-
ual sites greatly depend on the available simulation,
treatment planning, and treatment technology and
staff expertise and understanding of this technology.
Therefore, the actual simulation processes can vary
significantly among radiation oncology facilities and
description of these processes is beyond the scope of
this text. The goal is to implement treatment and
simulation techniques which best serve individual
institution’s patients based on the available equipment
and staff. When developing simulation processes, it is
important to understand the capabilities of local
resources. Simulation techniques will inevitably
continually evolve as these resources change.
6 Discussion
Simulation is a critical step in the radiation therapy
process, and the Radiation Oncologist must be inti-
mately involved in its design and execution, as it lays
the foundations for the complex treatment planning
and delivery currently used in radiation therapy.
As radiation therapy treatment planning and
delivery technology and techniques evolve, so does
the treatment simulation. The most significant change
in the recent past has been the wide adoption of CT
simulation to support conformal radiation therapy and
3D treatment planning. 3D simulation has gone from
a concept practiced at few academic centers to several
available sophisticated commercial systems located in
hundreds of radiation oncology departments around
the world. The acceptance of virtual simulation comes
from improved technology and training of radiation
Simulation in the Determination and Definition of Treatment Volume
oncology professionals, better outcomes, and
increased efficiency associated with conformal radi-
ation therapy. Image-based treatment planning is
necessary to more precisely treat a multitude of can-
cers and CT simulation is a key component in this
process. Due to the demand for CT images, CT
scanners are commonly found in radiation oncology
departments. As CT technology and computer power
continue to improve so will the simulation process,
and it may no longer be based on CT alone. In the
radiation oncology department at Washington Uni-
versity, there are two CT simulators and a large
number of our patients are also scanned using MR and
PET scanners located in the diagnostic radiology
department. Several authors have described MR
Simulators where the MR scanner has taken the place
of the CT scanner. A PET/MR device has rently been
made commercially available. It is difficult to predict
what will happen over the next ten years, but it is safe
to say that image-based treatment planning will con-
tinue to evolve.
A great opportunity for an overall improvement of
radiation oncology in cancer management is better
understanding of tumors through biological imaging,
which has been shown to better define the extent
of disease than anatomical imaging and also to
better characterize individual tumor properties (i.e.
Hypoxia, cellular proliferation, etc.). Improved target
volumes definition can optimize the full potential of
IMRT and particle modulation delivery. Biological
imaging can also allow evaluation of tumor response
and possibly modifications in therapy plan if the
initial therapy is deemed not effective. Future develop-
ments in radiation therapy treatment planning simula-
tion will involve integration of specific biological
imaging.
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 Clinical Applications of High-Energy
Electrons
Bruce J. Gerbi, Youlia M. Kirova, and Roberto Orecchia

Contents 6 Effect of Inhomogeneities on Electron

Distributions ............................................................. 166
6.1 Lungs.......................................................................... 167
1 Introduction.............................................................. 158 6.2 Bones.......................................................................... 168
6.3 Air Cavities................................................................ 168
2 Historical Perspective.............................................. 158
7 Clinical Applications of Electron Beams .............. 170
3 Electron Interactions............................................... 158
7.1 Target Definition ....................................................... 170
4 Central Axis Percentage Depth-Dose 7.2 Therapeutic Range: Selection of Beam Energy ....... 170
Distributions ............................................................. 159 7.3 Dose Prescription: ICRU 71 ..................................... 170
4.1 Central Axis Percentage Depth–Dose Dependence 7.4 Field Shaping and Collimation ................................. 172
on Beam Energy ........................................................ 160 7.5 Internal Shielding ...................................................... 173
4.2 Central Axis Percentage Depth–Dose Dependence 7.6 Chest Wall Irradiation ............................................... 174
on Field Size and SSD .............................................. 161 7.7 Intracavitary Irradiation............................................. 182
4.3 Flatness and Symmetry: Off-Axis Characteristics ... 162
8 Special Electron Techniques .................................. 186
4.4 Determination of Absorbed Dose Under Reference
8.1 Electron-Arc Irradiation ............................................ 186
Conditions .................................................................. 163
8.2 Craniospinal Irradiation............................................. 188
5 Isodose Curves ......................................................... 163 8.3 Total Skin Electron Therapy..................................... 190
5.1 Change in Isodose Curves versus SSD .................... 164
9 Total Limb Irradiation ........................................... 193
5.2 Change in Isodose Curves versus Angle of Beam
Incidence .................................................................... 164 References.......................................................................... 193
5.3 Irregular Surfaces ...................................................... 165

Abstract
High-energy electron beams have been used suc-
cessfully in radiation therapy for several decades.
Their primary application has been in the treatment
B. J. Gerbi (&) of skin and superficial lesions and also play an
Department of Therapeutic Radiology, important role in the treatment of head and neck
Radiation Oncology, University of Minnesota,
and breast disease. Many applications where
Mayo Mail Code 494, 420 Delaware St SE,
Minneapolis, MN 55455, USA electrons have been used historically have been
e-mail: gerbi001@umn.edu replaced by the modem techniques of intensity
Y. M. Kirova modulated radiation therapy (IMRT) or Tomo-
Department of Radiation Oncology, Therapy but there is still a distinct role for
Institut Curie, 26 Rue d’Ulm, electrons in the treatment of the total skin, other
75005 Paris, France
superficial regions, or as a unique boost modality
R. Orecchia to treat the skin surface while protecting sensitive
Department of Radiation Oncology,
underlying normal structures.
European Institute of Oncology and
University of Milan, Milan, Italy

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 157
DOI: 10.1007/174_2011_321,  Springer-Verlag Berlin Heidelberg 2012
158
1 Introduction
The basic physics of electron beams has been discussed
in several books and in several excellent chapters of
standard radiation therapy textbooks (Khan 2003;
Hogstrom 2004; Strydom et al. 2003). As with many of
these previous works, the purpose of this chapter is to
discuss the role of electron beams in radiation therapy,
describe their physical characteristics, and describe
how this information is relevant to clinical practice in
radiation therapy. In addition, several techniques using
electron beams that have been found to be useful in
clinical settings will also be presented.
2 Historical Perspective
In modern radiation therapy departments, high-energy
electrons are a useful and expected modality.
Although, they have been available for many years, it
was not until the 1970s when linear accelerators
became widely available that electrons moved into the
mainstream in radiation therapy. Similar to advances
in photon beam treatments in radiation therapy, there
have been several key advances in the 1970s that
improved dramatically the ability to deliver optimized
electron-beam treatments. These developments were:
(1) computed tomography (CT) scanners that paved
the way for CT-based treatment planning, (2)
improvements in electron treatment-planning algo-
rithms (electron pencil beam algorithms) to calculate
accurately and display dose deposition using CT data,
and (3) improvement in linac designs resulting in
improved depth dose, off-axis uniformity, and the
physical characteristics of electron beams. Central to
these latter improvements were the development of
dual scattering foil systems and improvements in
electron-beam applicators (Hogstrom 2004).
Modern linear accelerators are capable of produc-
ing several electron-beam energies in addition to two
or more photon energies. Electron beams in the range
of 6–20 MeV are most clinically useful with the
intermediate beam energies being the most commonly
used. The energy designation of a clinical beam is
described using the most probable energy at the sur-
face of the phantom at the standard treatment or
source–skin distance (SSD). This most probable
energy is the energy possessed by the majority of the
B. J. Gerbi et al.
incident electrons and is represented on the linear
accelerator console by the closest integer value to the
actual electron-beam energy. Figure 1 shows the
nature of the electron energy spectrum as a function
of location in the beam. Before the accelerator beam
exits window, the electrons are fairly monoenergetic
in nature. The spectrum of electron energies in the
beam is spread more widely as it hits the surface of
the phantom with the spectrum centered on the most
probable energy. As the beam penetrates into the
patient, the width of the energy spectrum increases
while the average energy of the beam decreases with
increasing depth in the medium. The rate of this
decrease is about 2 MeV/cm in unit density material
such as muscle.
3 Electron Interactions
Two basic properties of electrons are that they possess
a negative charge (we are not considering positrons at
this time) and that they are low in mass having
approximately 1/2,000 of the mass of a proton or
neutron. Being charged particles, they are directly
ionizing, meaning that they interact directly with the
material on which they are incident. They are attrac-
ted to charges of opposite sign and are repelled by
charges of like sign as they travel through a medium.
These forces of attraction or repulsion are called
Coulomb force interactions and lead directly to ion-
izations and excitations of the absorbing material.
Due to their relatively low mass, their direction of
travel can be changed easily during these interactions.
When electrons pass through a medium, their mean
energy decreases with depth and they scatter to the
side of their original path. Thus, the locations to
which electrons scatter dictates where bonds are
broken and ultimately where dose is deposited.
Interactions undergone by electrons can be either
elastic in which no kinetic energy is lost or inelastic in
which some portion of the kinetic energy is changed
into another form of energy. Elastic collisions occur
with either atomic electrons or atomic nuclei, result-
ing in elastic scattering. These interactions are char-
acterized by a change in direction of the incident
electron with no loss of energy. In the collision pro-
cess between the incident electron and atomic elec-
trons, it is possible for the ejected electron to acquire
enough kinetic energy to cause additional ionizations
Clinical Applications of High-Energy Electrons 159

Fig. 1 Representation of the

energy of electrons in a linear
accelerator beam as a function
of the location in the beam.
Ep,o represents the most
probable energy at a depth
 o is the
of zero, the surface, E
average mean energy at the
surface, and Ep,z is the most
probable energy at the depth,
z. [Reprinted with permission
from Brahme and Svensson
(1976)]
Φ

of its own. These electrons are called secondary
electrons or delta rays and they can go on to produce
additional ionizations and excitations. Inelastic colli-
sions can occur with electrons resulting in ionizations
and excitations of atoms or inelastic collisions of
nuclei that result in the production of Bremsstrahlung
X-rays (radiative losses). The energy of these X-rays
can be as high as the maximum accelerating potential
of the beam and contribute dose to tissues deep within
the body. The magnitude of this photon contamination
component can range from about 1% to as high as 5%
for 6 MeV and 20 MeV electron beams, respectively.
The typical energy loss in tissue for a therapeutic
electron-beam, averaged over its entire range, is about
2 MeV/cm in water. The rate of energy loss for colli-
sional interactions depends on the energy of the elec-
trons and on the electron density of the medium. The
rate of energy loss per gram/cm2 is greater for
low atomic number (low Z) materials than for high
Z materials. This is because high Z materials have fewer
electrons per gram than low Z materials. In addition, the
electrons in high Z materials are more tightly bound and
are thus not available for these types of interactions.
Keeping the above types of interactions of electrons in
mind will help to explain many of the clinical situations
presented later. The most important of these is scat-
tering at edges of tissue or lead-shielding materials.
4 Central Axis Percentage
Depth-Dose Distributions
The shape of the central axis depth–dose curve of
electron beams depends on many factors, most nota-
bly the beam energy, field size, source surface dis-
tance, collimation, depth of penetration, and angle of
beam incidence. A typical central axis percentage
depth–dose curve for high-energy electrons is shown
in Fig. 2. This figure represents some of the quantities
used to describe electron beams. Ds represents dose at
the surface and is defined at a depth of 0.05 cm. Dm is
the dose maximum at depth while Dx is the dose due
to X-ray contamination. R100 is the depth of the
maximum dose while R90 is the depth of the 90%
depth dose. R50 is the depth of the 50% depth–dose
curve. Rp is the practical range, which is close to the
most probable energy of the electron-beam at the
surface, E0, divided by two in centimeters. Thus, a
20 MeV electron-beam would have a practical range
of 10 cm in tissue. Rp is determined by taking the
160
Fig. 2 Centralaxis depth–dose curve for an electron-beam
with parameters indicated that can be used to characterize
electron beams. The therapeutic range is at the 90% depth-dose
level and all other parameters are discussed in ICRU (1984)
depth of intersection of the straight line descending
portion of the central axis percentage depth–dose
curve with a line drawn representing the photon
contamination. G0, as shown in the figure, gives what
has been termed the reduced dose gradient. This is a
measure of how quickly the dose decreases beyond
the therapeutic range. This factor depends on the
quantity Rq, which is the depth at the tangent of the
central axis percentage dose curve as the inflection
point meets the level of dose maximum, Dmax, and its
relationship to the practical range, Rp. As shown in
the figure, Go = Rp/(Rp–Rq).
The portion of the central axis percentage depth–
dose curve at depths deeper than the practical
range, Rp, represents the photon contamination
present in the electron-beam. Photon contamination
results from electron interactions with the exit
window of the linear accelerator, the scattering
foils, beam ion chambers, the collimator jaws, the
cones, and intervening air which produce Brems-
strahlung X-rays. Additional X-rays are also pro-
duced within the patient, although this is a small
source of photon generation. Photon contamination
varies with both beam energy and type of linear
accelerator. The amount of photon contamination
is low for low-energy beams usually less than
approximately 1% and increases to approximately
5% at 20 MeV. In the past, linear accelerators
B. J. Gerbi et al.
Fig. 3 Central-axis percentage depth-dose as a function of
beam energy from 4 to 20 MeV
employing scanning electron beams did not use
scattering foils to spread the beam and thus pro-
duced the least amount of photon contamination.
For safety reasons scanning electron beams have
been abandoned and that modality is no longer
available on current commercial linear accelerators.
In most cases, the magnitude of the photon con-
tamination is very acceptable for patient treatment.
It does become a consideration when performing
total skin electron irradiation where multiple elec-
tron fields and patient positions are required.
Consequently, techniques designed to treat the total
skin using high-energy electrons must strive to keep
the magnitude of the photon contamination as low
as possible and ideally less than 1%. Thus, the
total-body dose can be held as low as possible,
since treating the skin surface is the primary
objective of this particular treatment regimen.
4.1 Central Axis Percentage Depth–Dose
Dependence on Beam Energy
Figure 3 shows the change in the central axis per-
centage depth–dose curves as a function of beam
energy. With modern linear accelerators, the per-
centage depth–dose at the surface for 6 MeV elec-
tron beams is approximately 70–75%. The surface
dose increases with increasing beam energy to about
Clinical Applications of High-Energy Electrons 161

Table 1 The percentage depth dose at the surface and in superficial regions of high-energy electron beams for a Varian 2300CD
for a 10 9 10 cm2 cone at 100 cm source–skin distance (SSD)
Depth (cm) Electron percentage depth dose
6 MeV 9 MeV 12 MeV 15 MeV 18 MeV 22 MeV
0 70.8% 76.5% 82.0% 86.6% 88.4% 89.1%
0.5 82.5% 84.7% 89.5% 93.7% 96.0% 97.0%
1.0 94.0% 90.0% 92.6% 96.4% 98.7% 98.9%
The data were taken using an Attix plane-parallel chamber

Table 2 Depths at which Dmax and D90 occur for various electron-beam energies
6 MeV 9 MeV 12 MeV 15 MeV 18 MeV 22 MeV
Dmax depth (cm) 1.4 2.2 2.9 2.9 2.9 2.2
D90 depth (cm) 1.8 2.8 3.9 4.8 5.4 5.8
2
The data were taken using a Varian 2300CD for a 10 9 10 cm cone at 100 cm source–skin distance (SSD)

95% for 20 MeV beams. Tables 1 and 2 show the

dose at the surface and at 0.5 and 1.0 cm depths for
a Varian Clinac 2300CD for a 10 9 10 cm2 cone at
100 cm SSD. This characteristic of clinical electron
beams where low-energy electrons have a lower
surface dose than high-energy electrons exists
because low-energy electrons scatter into wider
angles than higher energy electrons. Thus, in com-
parison with the amount of scatter exhibited at the
surface, at the depth of Dmax lower energy electrons
scatter more than higher energy electrons. Knowl-
edge of the dose at the surface is important clinically
because the target to be treated using electrons often
includes the skin, and adequate dosage must be
ensured in these areas. Fig. 4 Change in percentage depth dose versus field size for a
(a) 7 MeV and (b) 18 MeV electron-beam for 2x2–25x25 cm2,
The depth of both D90 and the Rp increases with 100 cm SSD field sizes produced from a Siemens Mevatron 80
increasing beam energy. Additionally, the central axis accelerator. [From Meyer et al. (1984) with permission]
percentage depth doses for lower energy electron
beams decrease more rapidly beyond the depth of D90
than do higher energy beams. As a result, when using
higher energy electron beams, more distance must be energy (Meyer et al. 1984). There is little change in
placed between the target to be treated and sensitive the percentage of depth–dose curve for field sizes
structures than when using lower-energy beams. greater than the practical range. The reason for this
field size dependence is loss of side scatter equilib-
rium with decreasing field size. Figure 4 shows the
4.2 Central Axis Percentage Depth–Dose change in percentage depth dose with change in field
Dependence on Field Size and SSD size for 7 and 18 MeV electron beams for field sizes
ranging from 2 9 2 to 25 9 25 cm2. As shown,
There is a significant change in the central axis there is greater change in the percentage depth dose
percentage depth dose for electron beams with for higher beam energies when the field size is
change in field size when the field size decreases to decreased below the practical range. For all beam
less than the practical range for that electron-beam energies where this situation exists, there is a shift in
162
Fig. 5 Comparison of central-axis depth–dose curves for
9 MeV and 20 MeV electrons using a 10 9 10 cm2 cone at
100 and 115 cm SSD. Data are taken on a Varian 2100C linac
using Kodak XV2 film in a solid-water phantom and scanned
using a Wellhofer-scanner running WP700 software
both the depth of dose maximum and the D90 dose
toward the surface with decreasing field size. The
surface dose increases with increasing amounts of
field restriction for lower energy electrons while
there is no change in the surface dose for the higher-
energy beams with field restriction. The practical
range, Rp, is unchanged by field restriction since the
overall beam energy is not affected by a change in
field size.
The central axis percentage depth–dose curve for
high-energy electron beams is only slightly dependent
on SSD. Figure 5 shows no discernable difference in
the central axis data for 9 MeV electrons at 100 cm
versus 115 cm SSD. For the 20 MeV beam, the 80–95
isodose lines are only a few millimeters deeper at
115 cm SSD than their depth at 100 cm SSD. Isodose
curves lower than 80% are negligibly more pene-
trating at extended SSDs since inverse square effects
are not that great for electrons over their short depth
of penetration.
B. J. Gerbi et al.
Fig. 6 Electron-dose profile showing both field flatness and
symmetry. Data are for a 20 MeV, Varian 2100C, 25 9 25 cm2
cone in place. Data are taken using Kodak XV2 film in a solid-
water phantom and scanned using a Wellhofer scanner running
WP700 software
4.3 Flatness and Symmetry: Off-Axis
Characteristics
A typical dose profile is shown in Fig. 6. A dose
profile represents a plot of the beam intensity as a
function of distance off axis. The variation in the dose
distribution in the direction perpendicular to the
central axis can be described by the off-axis ratio.
The off-axis ratio is defined as the ratio of dose at a
point away from the central axis divided by the dose
at the central axis of the beam at the same depth.
Specifications for flatness are given by the IEC
(International Electrotechnical Commission) at the
depth of maximum dose. The flatness specification
consists of two requirements: (1) the distance between
the 90% dose levels and the geometric beam edge
should not exceed 10 mm along the major axis and
20 mm along the diagonals of the beam and (2) the
maximum value of the absorbed dose anywhere within
the region bounded by the 90% isodose contour should
not exceed 1.05 times the absorbed dose on the axis of
the beam at the same depth. The specification for
symmetry according to the IEC at the depth of Dmax for
high-energy electron beams is that the crossbeam pro-
file should not differ by more than 2% for any pair of
symmetric points with respect to the central axis value.
The AAPM has also made recommendations (TG-25;
American Association of Physicists in Medicine 1991)
Clinical Applications of High-Energy Electrons
concerning field flatness and symmetry. They specify
that the flatness be specified in a plane perpendicular to
the central axis at the depth of the 95% isodose line
beyond the depth of dose maximum. The variation in
the beam at this depth should not vary by more
than ± 5% versus the value at the central axis and
optimally should be within ± 3% at a point 2 cm
within the geometric field edge (the 50% isodose width)
for fields greater than or equal to 10 9 10 cm2.
Knowledge of the beam flatness is important from a
clinical standpoint in determining an adequate field size
to treat a particular region, particularly in setting an
adequate margin around the target.
4.4 Determination of Absorbed Dose
Under Reference Conditions
There are three basic methods used at Primary
Dosimetry Laboratories (PSDLs) for the absolute
determination of absorbed dose to water: graphite or
water calorimetry, chemical (Fricke) dosimetry and
ionization chamber dosimetry. In the clinical practice
that is at the user’s level ionization chambers are the
most frequently used dosimeters for the determination
of this dose and beam calibration. Currently, proto-
cols giving recommendations for reference dosimetry
in electron-beam clinical practice are represented by
the AAPM’s TG-51 (Almond et al. 1999) and IAEA
TRS-398 (IAEA 2000) codes of practice. They are
based on a calibration factor in terms of absorbed
dose to water for an ionization chamber in a reference
quality beam (60Co gamma radiation or an electron-
beam), at a standards laboratory or by cross-calibration.
Plane-parallel chambers are always recommended for
the calibration of electron beams, while cylindrical
chambers may be only used for electron-beam ener-
gies higher than 10 MeV. Water is the recommended
reference medium for full calibration measurements.
If a plastic phantom is used, all depths must be
properly scaled. The beam quality index is repre-
sented by the half-value depth in water, R50. The
reference conditions include the specification of field
size, that should not be less than 10 cm x 10 cm at
the phantom surface, and the reference depth at a new
defined zref, (dref in TG-51) which is different from the
depth of the absorbed-dose maximum recommended
in previous protocols, to gain accuracy and reduce
machine-to-machine variations in chamber calibration
163
factors. The recommended source-skin distance
(SSD) is 100 cm. Under the specified reference
conditions, the absorbed dose to water is given by
the product of three factors: (a) the reading of the
dosimeter, corrected for air density, polarity, and ion
recombination effects and electrometer calibration;
(b) the calibration factor of the dosimeter for the
reference quality, in terms of absorbed dose to water;
(c) a chamber-specific factor, correcting for differ-
ences between the reference and the actual beam
qualities. Values for the latter factor, for the most
commonly used ionization chambers calibrated in
60
Co, are given in the above-mentioned protocols.
5 Isodose Curves
Isodose curves are generated by connecting points of
equal dose. The curves are usually drawn at intervals
of absorbed dose separated by 10% and expressed as a
percentage of the dose at the reference point com-
pared with that at the Dmax point on the central axis of
the beam. The shape of individual electron isodose
curves varies with beam energy, field size, beam
collimation, SSD, and the level of the isodose curve.
Typical isodose curves are shown in Fig. 7 for both a
6 9 6 cm2 and 15 9 15 cm2 12 MeV, 100 cm SSD
electron-beam. The 6 9 6 cm2 field is overlaid on the
15 9 15 cm2 field to illustrate that the shape of the
isodose curves in the penumbra region, the distance
from the 80% to the 20% isodose curve, changes very
little as a function of field size. An investigation of
these isodose curves shows that the 50% isodose
curve penetrates almost straight down perpendicular
to the surface, assuming a flat patient surface. The
edge of both the 90 and 80% isodose curves moves in
toward the central axis, while that in the isodose
curves less than 50% spreads out from the 50% iso-
dose line. Keeping these beam characteristics in mind
is important to ensure adequate field size coverage of
the specific target region by the 90% isodose curves.
Usually a 1 cm margin around the desired treatment
area provides an adequate margin for electron beams
at standard treatment distances. When electron fields
are abutted with other electron or photon fields, the
widening of the penumbra exhibited by the lower
value isodose curves influences the dose in any
overlap regions or in fields adjacent to the electron
field.
164
Fig. 7 Isodose curves for a 6 9 6 cm2 field overlaid on a
15 9 15 cm2 field for a 12 MeV, 100 cm SSD electron-beam
from a Varian 2100C Clinac. The central-axis percentage depth–
dose values are the same for the 6 9 6 and 15 9 15 cm2 fields as
The overall shape of isodose curves can be influ-
enced by many factors. These include patient curva-
ture, inhomogeneous materials such as air, bone, lung,
and high Z materials, and the effects of extended SSDs
and field-shaping devices. These field-shaping devices
include cerrobend inserts, lead shields or cutouts on the
patient’s skin surface, and internal shields designed to
protect underlying sensitive or normal tissue.
5.1 Change in Isodose Curves
versus SSD
Figure 8 shows the change in the shape of isodose curves
with changing SSD. The data is for a 10 9 10 cm2 cone
at 100 and 115 cm SSD, creating an 11.5 9 11.5 cm2
field at 115 cm SSD, the reason that the right side of the
figure is wider than the left side. It can be seen at both
9 MeV and 20 MeV that the shapes of the isodose
curves change dramatically at extended distance. Near
the surface, the isodose lines less than 50% extend much
farther outside the field edge than at 100 cm SSD. Iso-
dose lines greater than 50% also are changed markedly
from what is exhibited at the standard 100 cm SSD. In
general, the 90% field width is decreased at extended
SSDs while more dose is contributed outside of the field
edge at extended SSDs. This change in the shape of the
isodose curves is important to keep in mind so that the
target is adequately covered at extended distances and
for field abutment at extended SSDs. As was shown in
B. J. Gerbi et al.
is the shape of the isodose curves in the penumbral region.
Isodose values represented are the 98, 95, and 90–10 by steps of
10 levels. Data are taken using Kodak XV2 film in solid-water
phantom, scanned using a Wellhofer WP700 system
Fig. 5, there is very little change in the central axis
percentage depth dose with increasing SSD.
5.2 Change in Isodose Curves
versus Angle of Beam Incidence
Many times in clinical situations, electrons are incident
on the patient’s surface at oblique angles. This is most
notable when treating the chest wall, the scalp, or
extremities of the body. For obliquely incident beams
whose angle of incidence is greater than 30, there is a
significant change in the shape of the central axis per-
centage depth dose. With reference to Fig. 9, as the
angle of beam incidence increases, the depth of the dose
maximum decreases. At slightly increased angles of
beam incidence, the slope of the central axis percentage
depth–dose curve and the practical range remain
unchanged. As the angle of incidence increases beyond
60, the shape of the central axis percentage depth–dose
curve changes significantly, and the Dmax increases
dramatically when compared with the dose at dmax for
normally incident beams (Ekstrand and Dixon 1982;
Khan et al. 1985; Khan 2003). Table 3 gives a
numerical description of the change in the central axis
dose distribution as a function of oblique beam inci-
dence for different electron-beam energies as a function
of depth for a 20 9 20 cm2 field (Khan et al. 1985).
Clinical examples where sloped or curved surfaces
are encountered include chest wall treatments,
Clinical Applications of High-Energy Electrons
Fig. 8 Isodose curves for 9 MeV (top) and 20 MeV (bottom)
electron beams, 10 9 10 cm2 at both 100 cm and 115 cm SSD.
Isodose values represented are the 98, 95, and 90–10 by steps of
10 isodose levels. Data are taken using Kodak XV2 film in
solid-water phantom, scanned using a Wellhofer WP700 system
treatment of the limbs, and treatments of the scalp.
Figure 10 shows the isodose distributions for a beam
of electrons incident vertically on a curved surface,
such as the chest wall. The isodose curves follow
roughly the curvature of the contour but there is sig-
nificant change in the beam coverage due to the
attenuation of the beam, loss of scatter, inverse
square decrease due to distance, and obliquity effects.
The magnitude of these changes also depends on the
radius of curvature of the surface to be treated.
5.3 Irregular Surfaces
Irregular skin surfaces involving abrupt changes in
the patient surface are encountered primarily during
the treatment of the nose, eye, ear and ear canal, and
165
Fig. 9 Change in dose versus depth for 9 MeV electrons
incident on water. The curves are normalized to the 100% point
for the zero degree incident beam. [From Ekstrand and Dixon
(1982) with permission]
in the groin area. Surgical excisions can also create
treatment areas with abrupt changes in the surface of
the body. For areas of the body where sharp surface
gradients exists (nose, ear), there will be a loss of side
scatter equilibrium resulting in a hot spot beneath
the distal edge of the step and a cold spot beneath the
proximal surface. This is illustrated in Fig. 11 for an
experimental situation. Figure 12 shows a clinical
example treating a region around the nose and the
high-dose areas to the side of the nose (Chobe et al.
1988). This figure shows that the magnitude of the
high-dose region can be increased as much as 20%
with a low-dose region directly adjacent. In clinical
practice, the potential for the creation of these types
of high-dose regions has to be monitored constantly
so that this effect can be minimized by the use of
bolus material when possible to smooth out the sur-
face irregularity.
166 B. J. Gerbi et al.

Table 3 Obliquity factors for electron beams

E0(MeV)
Zb/R 22 18 15 12 9 6
(a)h = 30
0.0 1.00 0.98 0.98 1.00 0.94 1.01
0.1 1.00 1.00 1.00 1.00 1.00 1.08
0.2 1.00 1.00 1.01 1.02 1.05 1.11
0.3 1.01 1.00 1.02 1.03 1.05 1.06
0.4 1.01 1.01 1.02 1.00 1.00 0.96
0.5 1.00 1.00 0.98 0.96 0.92 0.86
0.6 0.95 0.94 0.92 0.90 0.86 0.79
0.7 0.92 0.90 0.87 0.86 0.86 0.83
0.8 0.93 0.85 0.82 0.90 1.00 0.96
0.9 1.09 1.00 1.20 1.11 1.44 1.00 Fig. 10 Measured (solid lines) and calculated (dashed lines)
1.0 1.42 1.54 1.50 1.50 1.30 1.00 isodose distribution for an electron-beam incident on a
cylindrical polystyrene phantom. [Reprinted with permission
(b)h = 45 from Khan (1984)]
0.0 1.03 1.02 1.03 1.05 0.98 1.14
0.1 1.03 1.04 1.04 1.06 1.10 1.14
0.2 1.05 1.06 1.07 1.11 1.12 1.12
0.3 1.06 1.07 1.09 1.09 1.05 1.07
6 Effect of Inhomogeneities
on Electron Distributions
0.4 1.04 1.04 1.04 1.01 0.93 0.92
0.5 1.00 0.99 0.92 0.92 0.80 0.77
Commissioning data for electron beams is performed
0.6 0.93 0.90 0.86 0.82 0.70 0.69 using a flat, homogeneous, water phantom. This idealized
0.7 0.84 0.84 0.82 0.77 0.70 0.76 data set provides a good starting point for clinical
0.8 0.87 0.83 0.85 0.86 0.83 1.10 dosimetry for electron beams. However, the presence of
0.9 1.30 1.00 1.43 1.20 1.40 1.46 inhomogeneous material in the body is a fact of life in
1.0 2.17 2.31 2.19 2.50 2.00 2.14 real-world situations. The inhomogeneities of greatest
(c)h=60 concern are air cavities (primarily in the head and neck
region), lung, and bone. Electron depth–dose distribu-
0.0 1.06 1.06 1.10 1.14 1.14 1.30
tions in a medium are dependent on electron density
0.1 1.10 1.12 1.17 1.20 1.23 1.21
(electrons/cm3). Since the number of electrons per gram
0.2 1.12 1.14 1.15 1.16 1.17 1.08 is the same for all materials (except hydrogen which has
0.3 1.07 1.07 1.07 1.0 0.98 0.90 about twice the number of electrons per gram), the
0.4 1.00 0.96 0.93 0.86 0.79 0.70 physical density (g/cm3) of the material determines the
0.5 0.87 0.84 0.79 0.74 0.67 0.56 depth of penetration of the beam. Therefore, the depth of
0.6 0.75 0.74 0.69 0.63 0.58 0.51 penetration of the beam of electrons can be determined
0.7 0.70 0.68 0.67 0.62 0.57 0.56 by scaling the depth of penetration in water by the
0.8 0.75 0.71 0.67 0.74 0.77 0.87
physical density of the inhomogeneous medium. This can
be represented by the following equations:
0.9 1.21 1.00 1.29 1.14 1.60 1.40
1.0 2.31 2.46 2.75 3.0 3.2 2.45 Zwater ¼ Zmed qmed ð1Þ
These factors show the relative change in the beam intensity
at angle h compared with that at normal beam incidence. where z is the depth in the indicated material, water or
(Reprinted with permission from Khan et al. 1985) medium, and qmed is the physical density of the medium
Clinical Applications of High-Energy Electrons 167

Fig. 11 High-dose regions

produced by an electron-beam
incident on a water phantom
have sharp, step-like
irregularities in the surface
contour. [Reprinted with
permission from Dutreix
(1970)]

or inhomogeneity in this example. For beams passing

through lung material of density 0.25 g/cm3, the depth
of penetration of the beam in the lung would be:

Zlung ¼ Zwater =qlung  ð2Þ

Thus, a beam that would penetrate 1 cm of normal,

unit density material such as water would penetrate to
a 4 cm depth in lung having a density of 0.25 g/cm3.
This is a quick rule of thumb that can be applied in the
clinic to determine the amount of penetration into
materials, the density of which differs from that of
normal tissue. The actual situation is more compli-
cated due to scattering of the electron-beam and
interface effects.

6.1 Lungs
Figure 13 illustrates the increased penetration of
electron beams into lung tissue. Figure 13a shows a
12 MeV beam incident on the chest wall of a patient
without taking the density of the lung into account
(Khan 2003). Figure 13b shows the dramatic increase
in dose to the lung when this inhomogeneity is taken
into account in the calculation. For simplicity, the
effects of the ribs have not been considered in this
illustration. As mentioned above, the energy of the
Fig. 12 Effect of the abrupt change in contour by the nose and
the effect on the final isodose distribution. The plan is done
assuming unit density material and not taking into account the
air cavities particular to this region of the body [from Chobe
et al. (1988)]
beam is selected to place the 80% isodose line at the
lung–chest wall interface rather than using the 90%
isodose line. Insuring that this 80% isodose line lies at
the interface often requires the use of a bolus or
compensating bolus plus a judicious selection of the
168 B. J. Gerbi et al.

Fig. 13 The effect of lung corrections on the overall dose tissue. Bolus was used to maximize the dose on the surface.
distribution a without correction for lung, b with bulk 10 MeV, 100 SSD (68 SSD effective) electrons were used.
correction for lung using a density of 0.25 g/cm3 for lung [From Khan (2003) with permission]

best electron energy to employ. For complicated chest

wall anatomy or for patients with surgical defects post
mastectomy, a second layer of bolus or custom
compensating bolus (Sect. 6.1) may be required.

6.2 Bones

Inhomogeneities in the form of bones are often

present within the electron treatment field. Bone
density can range from 1.0 to 1.10 g/cm3 for the
spongy bone of the sternum to 1.5–1.8 g/cm3 for hard
bones such as those of the mandible, skull, and other
bones that provide structural support for the body.
Additionally, the density of bone is not uniform
throughout their cross section. Figure 14 illustrates Fig. 14 The effect of hard bone on electron isodose curves.
the effect of hard bone on electron isodose curves [From Hogstrom (2004) with permission]
(Hogstrom and Fields 1983). Beneath the bone, the
electron isodoses are shifted toward the surface due to
extra attenuation or the shielding effect of the bone. capsules that at 9 MeV the intercostal doses in dogs
In addition, the dose outside or at the edge of the were increased by an appreciable amount. This effect
bone–tissue interface is increased by about 5%, while is even more dramatic when using 6 MeV electrons.
that at the edge of the interface but beneath it is
decreased, by approximately the same amount. This is
due to the loss of side scatter equilibrium. It should be 6.3 Air Cavities
noted that actual bone–tissue interfaces are more
rounded than those depicted in the figure, which Because of the low physical density of air (0.0013 g/cm3),
would lead to lesser deviations than those indicated. electrons pass easily through this medium. In addi-
However, some investigators (Boone et al. 1967, tion, complicated scatter situations are created at the
1969) showed, using thermoluminescent dosimeter interface between air cavities and other tissues.
Clinical Applications of High-Energy Electrons
Fig. 15 a Dosimetry without heterogeneity correction gives
false impression of isodose distribution. b Dosimetry with
heterogeneity correction shows more accurate isodose distribu-
tion. c Improved isodose distribution with use of internal and
external bolus. d Actual treatment fields, with bolus placed in
Figure 15 shows the dose distribution using an ante-
rior electron field to treat the nasal region using high-
energy electrons. The first illustration (Fig. 15a)
shows the dose distribution neglecting corrections for
inhomogeneities. Figure 15b shows the dramatic
difference in the dose distribution when air cavities
and bone are taken into account. Very high doses
169
nostrils and intraoral stent in place. [Reprinted with permission
from McNeese and Sinesi (1986)]. e Completion of treatment
setup with external wax bolus and lead eyeshield in place. f Two
years after completion of therapy. [Reprinted with permission
from McNeese and Sinesi (1986); Chobe et al. (1988)]
penetrating into the brain and other underlying tissues
can easily be seen from this diagram. If this increased
dose is not considered, large doses to these underlying
structures can result. It is common practice when
treating this region to put bolus into the nose to help
counteract this increased penetration. Figure 15c
shows the improvement in dose distribution by the
170
use of both internal and external bolus placement.
However, the bolus can be difficult to place so that it
fills completely the internal cavity especially if
immobilization masks are used. Thus, protection of
underlying structures from increased penetration
through these air cavities might be assumed by the
placement of this bolus, when, in actual fact, little
protection is actually provided. Verification of bolus
placement should be verified using CT scans to
ensure that it is producing the desired effect.
Figure 15d–f shows an example of the actual field
and bolus placement along with clinical results
obtained at 2 years post treatment (McNeese and
Sinesi 1986).
Another significant effect is the reduction in the
dose to the tissues directly adjacent to the air cavities.
Electrons scatter preferentially into low-density
regions (air cavities), and electrons scattering from
the adjacent tissue into air are not replaced because
the air is not able to scatter an equal number of
electrons back to the higher density tissues. This can
lead to clinical under dosing of the tissues in this area
by approximately 10% which could result in the loss
of control of the primary target site.
7 Clinical Applications of Electron
Beams
7.1 Target Definition
As with photon beam treatments, the first step in the
initiation of electron therapy is to determine accu-
rately the target to be treated. All available diagnostic,
operative, and medical information should be con-
sulted to determine the extent and the final planning
target volume (PTV) with appropriate margins to be
treated before simulation and placement of the
electron fields is initiated. Treatment-planning CT
scans may be helpful and even required to make this
determination along with the determination of the
optimum beam placement and energy selection.
The clinical target volume (CTV) and PTV must be
defined by the radiation oncologist in close collabo-
ration with the physicist. With the advent of
techniques and new imaging modalities, the definition
of the various target volumes has become increasingly
important.
B. J. Gerbi et al.
7.2 Therapeutic Range: Selection
of Beam Energy
The depth of the 90% isodose level (D90) is a very
common therapeutic depth for electron-beam therapy.
The electron energy for treatment should be selected
such that the depth of the 90% isodose line covers the
distal or deepest portion of the region to be treated in
addition to an approximate 5 mm additional depth
beyond the treatment region. This depth of R90 can be
approximated by dividing the energy of the electron-
beam in MeV by four (Eo/4) in centimeters of water.
The 80% isodose level (D80) is also frequently used as
a treatment parameter for defining the therapeutic
treatment range. It is most commonly used for chest
wall treatments where the D80 would be placed at the
lung–chest wall interface. The 80% point is chosen in
this region since it adequately covers the chest wall
without depositing an excessive amount of radiation
in the underlying lung and heart tissue. The depth of
D80 is approximately equal to Eo/3 in centimeters of
water.
7.3 Dose Prescription: ICRU 71
In 2004, the International Commission on Radiation
Units and Measurements (ICRU) published Report 71
detailing new recommendations for ‘‘Prescribing,
Recording, and Reporting Electron-Beam Therapy’’
(Gahbauer et al. 2004). They recommended the same
general approach for dose prescriptions for electron
treatments as those taken for photons as specified in
the previous reports ICRU 50 and 62 for photon
beams (International Commission on Radiation Units
and Measurements 1993, 1999). For treatment-plan-
ning purposes and to maintain consistency with the
previous ICRU reports dealing with photon beam
treatments, the concepts of gross tumor volume
(GTV), clinical target volume (CTV), planning target
volume (PTV), treated volume, organs at risk (OAR),
and planning organ at risk volume (PRV) are defined
as in previous reports and are to be used.
They indicated that the treatment should be spec-
ified completely, including time–dose characteristics
and making no adjustments in the relative biological
effectiveness differences between photons and elec-
trons. Specifically, they recommended the selection of
Clinical Applications of High-Energy Electrons
a reference point for reporting electron doses which is
referred to as the ‘‘ICRU reference point’’. This point
should always be selected at the center (or central
part) of the PTV and should be clearly indicated. In
general, the beam energy is selected so that the
maximum of the depth–dose curve on the beam axis is
located at the center of the PTV. If the peak dose does
not fall in the center of the PTV, then the ICRU
reference point for reporting should be selected at the
center of the PTV and the maximum dose should also
be reported. For reference electron irradiation condi-
tions, they recommend that the following dose values
be reported (Gahbauer et al. 2004):
• The maximum absorbed dose to water.
• The location of and dose value at the ICRU refer-
ence point if not located at the level of the peak-
absorbed dose.
• The maximum and minimum doses in the PTV, and
dose(s) to OARs derived from dose distributions
and/or dose–volume histograms.
For small and irregularly shaped beams, the peak
absorbed dose to water for reference conditions
should be reported. It is also recommended that when
corrections for oblique incidence and inhomogeneous
material are applied, the application of these correc-
tions should be reported.
7.3.1 ICRU 71 Recommendations:
Intraoperative Radiation Therapy
ICRU Report 71 also provides direction for the spe-
cial electron-beam techniques of intraoperative radi-
ation therapy (IORT) and total skin irradiation (TSI).
In IORT, high-energy electrons are used to deliver a
large, single-fraction dose to a well-defined anatom-
ical area after surgical intervention. The CTV is
defined as accurately as possible by both the surgeon
and the radiation oncologist during the procedure.
All devices specific to IORT need to be recorded
such as the IORT applicator system including type,
shape, bevel angle, and size of the applicator. The
ICRU reference point for reporting is always selected
in the center or central part of the PTV and, when
possible, at the level of the maximum dose on the
beam axis.
The ICRU recommended that the following dose
values be reported for IORT (Gahbauer et al. 2004):
• The peak-absorbed dose to water, in reference
conditions, for each individual beam (if the beam
axis is perpendicular to the tissue surface).
171
• For oblique beam axis, the maximum absorbed
dose in water on the ‘‘clinical axis’’ (i.e., the axis
perpendicular to the surface of the tissues, at the
point of intersection of the central axis of the beam
with the tissue surface).
• The location of and dose value at the ICRU refer-
ence point (if different from above).
• The best estimate of the maximum and minimum
doses to the PTV. Usually the irradiation conditions
(electron energy, field size, etc.) are selected so that
at least 90% of the dose at the ICRU reference
point is expected to be delivered to the entire PTV.
• In addition to the ICRU recommendations, specific
guidelines for IORT can be found in the AAPM
TG-48 (Palta et al. 1995) and TG-72 reports,
(Beddar et al. 2006)
7.3.2 ICRU 71 Recommendations: Total Skin
Irradiation
For total skin irradiation (TSI), the aim is to irradiate
the total skin surface as homogeneously as possible.
For patients with superficial disease, TSI can be
delivered with one electron energy. In other clinical
situations, the thickness of the skin disease may vary
with stage, pathology, and location on the body
surface. For such cases, several CTVs need to be
identified and different beam penetrations have to be
used. For each anatomical site, an ICRU reference
point for reporting at or near the center of the PTVs/
CTVs has to be selected. The reference point may be
at the level of the peak dose if it is located in the
central part of the PTV. In addition, an ICRU refer-
ence point, clinically relevant and located within the
PTV, can be selected for the whole PTV.
For TSI treatments, reporting of the following dose
values are recommended:
• The peak-absorbed dose in water for each individ-
ual electron-beam.
• The location of and dose value at the ICRU refer-
ence point for each anatomical area (the ICRU
reference point may or may not be at the level of
the peak dose).
• The best estimate of maximum and minimum dose
to each anatomical area.
• The location and absorbed dose at the ICRU point
for the whole PTV, and best estimate of the max-
imum and minimum doses for the whole PTV.
• Any other dose value considered as clinically
significant.
172
Fig. 16 The effect of collimating with a field defining device at 10 cm from the skin surface (a), as opposed to defining the field at the
skin surface (b) for a 6-MeV, 3 9 3-cm2 electron field at 100 cm SSD. [Modified from Hogstrom (1991) with permission]
7.4 Field Shaping and Collimation
Cerrobend or lead cutouts are used to restrict the
cone-generated electron fields to the desired area to be
treated. Cerrobend is the material of choice for these
field restriction devices due to the ease by which they
can be constructed. After the field has been defined on
the surface of the patient, it is extremely easy to
outline on a clear piece of acrylic the insert to be
constructed that will be inserted into the electron cone
in exactly the orientation in which it will be used for
treatment. This design process can be done in either
the simulator or in the linac treatment room. Alter-
natively, a lead cut out can be manufactured from
commercially available sheets of lead. They are more
difficult and time consuming to construct and require
that a store of lead sheets be kept in house. Lead
cutouts are placed directly on the patient’s surface to
define the treatment area and offer the advantage of
producing a field with sharper edges than what can be
accomplished with cerrobend inserts. Lead cutouts
should be considered for small fields, low-electron
energies, when critical areas lie directly adjacent to
sensitive structures, to sharpen the field edge either at
standard or extended treatment distances, or when
electron-arc treatments are employed. Figure 16
shows the difference in the isodose curves for a
6 MeV, 3 9 3 cm2 electron field when a cerrobend
insert is placed 10 cm above the skin surface to define
the field as opposed to lead blocking placed directly
on the skin surface (Hogstrom 1991).
The thickness of lead required to stop the primary
electrons has been investigated by Giarratano et al.
B. J. Gerbi et al.
(1975), who concluded that a lead with thickness in
millimeters equal to the most probable electron energy
at the surface (in MeV) divided by two is adequate to
provide shielding. An extra millimeter of lead can be
added to provide an additional margin of safety. Thus, a
20 MeV electron-beam would require a lead shield
thickness of 10 mm of lead plus 1 mm for safety for a
total thickness of 11 mm. Sheet lead is commercially
available in 1/16 inch increments, so the conversion
needs to be made between inches and millimeters.
Required thicknesses of cerrobend for electron
shielding have been studied by Purdy et al. (1980). Since
low-melting point alloy has approximately 82% of the
density of lead (9.3 g/cm3 versus 11.34 g/cm3, respec-
tively), 20% additional thickness needs to be employed
for adequate shielding. In the example above for lead
shielding of 20 MeV electrons, the required thickness of
cerrobend would be 13 mm. It is interesting to note that
the addition of high-Z material for electron shielding
slightly increases the amount of photon contamination
in the beam when treating the patient thus increasing the
deep dose (Purdy et al. 1980; Zhu et al. 2001).
When lead cutouts are placed directly on the skin
surface, electrons scattered from the edges of the lead
into the treated field create a region of high dose at the
inside edge of the field. Figure 17 shows the isodose
distribution at the edge of a lead shield placed at the
water surface. Shown in Fig. 17a are the angles a and
b, which represent the angles of maximum and min-
imum dose changes, respectively. Figure 17b shows
the change in a and b as a function of the energy of
the incident electron-beam. In general, both a and b
decrease with increasing beam energy since electron
Clinical Applications of High-Energy Electrons 173

Fig. 17 Isodose distribution

at the edge of a lead shield
placed at the water surface.
a shows the angles a and b
which represent the angle of
maximum and minimum dose
change, respectively. b shows
how a and b are affected by
the energy of the incident
electron-beam. [From Pohlit
and Manegold (1976) with
permission]

scatter becomes more forward directed as the beam

energy increases (Pohlit and Manegold 1976).

7.5 Internal Shielding

In some instances, internal shields need to be used to

protect underlying sensitive structures. This is most
commonly seen when using fields to treat the lip,
buccal mucosa, and eyelid lesions. Internal shields are
also commonly used for intraoperative radiotherapy
treatments. Important considerations when designing
internal shields are to ensure an adequate shield
thickness at the depth of shield placement, to ensure
that the electrons that are backscattered from the lead
surface do not dangerously increase dose at the Fig. 18 Increase in the dose upstream from a lead shield
interface, and to consider the high-dose edge effects thickness = 1.7 mm) at various depths in polystyrene. [From Khan
mentioned above. Lead is the most common material et al. (1976)]
used for the production of internal shields because of
its availability and ease of use. The required thickness cheek to protect the oral cavity would have to be
of the shield depends on the energy of the electron- 4.5 mm thick. This is because the electrons would
beam at the location of the internal shield, the fact decrease to 7 MeV after penetrating 1 cm of tissue,
that electrons decrease in energy by 2 MeV/cm for and that 3.5 ? 1 = 4.5 mm of lead would be required
every 1 cm that they travel in unit density material to shield 7 MeV electrons. For final shield design, the
(water or muscle), and that 1 mm of lead is required backscatter of electrons from the lead surface has to
as shielding for every 2 MeV of electron energy (plus be taken into account. As shown in Fig. 18, the
1 mm for safety, as mentioned above). Thus, if amount of electron backscatter that would be pro-
9 MeV of electrons are used to treat the buccal duced by placement of a shield made solely of lead
mucosa of 1 cm thickness, a shield placed beneath the would produce an increase in dose of approximately
174
Fig. 19 Isodose distribution
produced using a Varian
2100C, 12 MeV, 5 cm
diameter circular electron field
incident on a 2 cm thick,
1.2 cm diameter cylindrical
cerrobend pencil eye shield
in contact with a solid-water
phantom. The data is taken
using Kodak XV2 film and
scanned using a Wellhofer
scanning densitometer system
running WP700 software
50% at the lead–tissue interface (Klevenhagen et al.
1982; Klevenhagen 1985). Reduction of the increased
dose due to backscatter from the lead surface can be
accomplished by the addition of some low-Z mate-
rial—dental acrylic, bolus material, or, in some cases,
aluminum. We find it convenient to apply a coating of
dental acrylic to the surface of the lead followed by
layers of dental boxing wax to the surface of the lead
facing the beam. The dental acrylic seals the lead,
which is itself toxic, and makes cleaning and sterili-
zation much easier to accomplish between treatments.
Using two half-value layers of wax is usually suffi-
cient to reduce the amount of backscatter to an
acceptable level. At 6 MeV, one half-value layer is
approximately 3.5 mm of unit density material
(Lambert and Klevenhagen 1982). Thus, the final
intra-oral shield would consist of 4.5 mm lead, a
coating of dental acrylic, plus about 7 mm of wax.
Internal shields placed under the eyelid to protect
the underlying eye are particularly challenging to
design and manufacture because of the limited space
for shield placement beneath the lid and the required
thicknesses of materials to provide adequate protec-
tion. In some instances, an effective shield cannot be
designed that will allow the use of the desired electron
energy while making the shield sufficiency thick and of
the proper combination of materials. By substituting
tungsten (Z = 74, density = 17.3 g/cm3) for lead
(Z = 82, density = 11.34 g/cm3) in the design of the
eyeshield, acceptably thin eye shields can be made to
fit under the eyelid that are capable of shielding 9 MeV
electrons (Shiu et al. 1996; Weaver et al. 1998). An
added benefit is that tungsten is of a lower Z value than
lead which leads to a slightly lower amount of
backscatter from the surface of the tungsten shield.
B. J. Gerbi et al.
Commercially available eye shields (Radiation Products
Design, Inc., Albertville, MN) made from tungsten and
aluminum have also been shown to provide excellent
protection for the underlying eye (Weaver et al. 1998).
Pencil eye shields can be utilized to protect the lens
of the eye when the eyelid is involved and needs to be
irradiated using electrons. A cerrobend shield 1.3 cm in
diameter and at least 1 cm-thick was shown to be
adequate in protecting the lens when 6 MeV or 9 MeV
of electrons were used for the treatment (Rustgi 1986).
Protection of the lens was optimal when the shield was
placed 1 cm or closer to the surface of the eye. In our
clinic, we use a 1.2 cm diameter, 2 cm thick cerrobend
shield coated with acrylic to reduce electron scatter
from the side of the shield into the eye. An acrylic
support rod is attached perpendicular to the side of the
cylindrical shield so that a small ring stand can be used
for daily shield placement. This arrangement allows for
very easy placement of the shield to less than the
desired 1 cm distance from the surface of the eye.
Figure 19 shows that the 2 cm thick shield is effective
in reducing even 12 MeV electrons to an acceptable
level of protection for the lens.
7.6 Chest Wall Irradiation
The benefit of adjuvant radiotherapy to the chest wall
has been controversial for many years. Recently pub-
lished data showed that the radiotherapy regimens
produced moderate but definite reductions not only in
breast-cancer mortality but also in overall mortality
(EBCTCG 2005; Gebski et al. 2006). The benefit
of post-mastectomy radiotherapy independent of the
effects of systemic treatment was also shown in the
Clinical Applications of High-Energy Electrons
Danish Breast Cancer Cooperative Group and British
Columbia study (Overgaard et al. 1997; Overgaard
et al. 1999; Ragaz et al. 1997). However, the first meta-
analysis report did not find any advantage in overall
survival at 10 and 20 years (EBCTCG 2000). One
explanation for the increase of non-breast-cancer
deaths is particularly due to cardiac disease associated
with old irradiation techniques (Cuzick et al. 1994;
Giordano et al. 2005). In response, electron beams have
been extensively used in recent years especially in
treatment of the chest wall (Perez and Brady 1992;
Gaffney et al. 1997, 2001; Magee et al. 1991; Hehr et al.
1999; Feigenberg et al. 2003). It has already been
shown that this technique yields similar loco-regional
control, disease-free survival, and overall survival
rates as are experienced using standard photon-beam
irradiation (Feigenberg et al. 2003; Gez et al. 2004).
Other important potential dose concerns arise at the
junction of internal mammary chain fields, supracla-
vicular fields, and chest wall electron-beam field.
Improved techniques were developed to address these
concerns (Salguero et al. 2009; Kirova et al. 2007).
These ‘‘new’’ techniques provide improved target
homogeneity and conformality over the standard or
previous techniques (Kirova et al. 2007). However,
modern electron dose calculation algorithms must be
extensively tested to ensure that the data that they
produce accurately reflects the electron dose distribu-
tion being delivered to the patient (AAPM TG25;
AAPM TG 70; AAPM TG53). With these new tech-
niques, a conformal and homogeneous dose distribu-
tion is achieved from the skin surface to the costal wall.
The position of the 20 Gy and 40 Gy isodoses relative
to the sternum and the homolateral lung are routinely
assessed as warnings to limit useless heart and lung
irradiation. The new technique shows better sparing of
the underlying normal tissue, the 20 Gy isodose being
about 0.7 cm shallower in the heart, and the 40 Gy
isodose 0.4 cm less deep in the lung. These factors are
only used as relative metrics to compare two treatment
plans for the same patient (Kirova et al. 2007).
7.6.1 Bolus
Bolus is used for several reasons in electron-beam
treatments: to increase the dose on the skin surface, to
replace missing tissue due to surface irregularities,
and as compensating material to shape the coverage
of the radiation to conform as closely as possible
to the target volume while sparing normal tissue.
175
For modern linear accelerators, the surface dose can
be quite low (see Table 1) and, to treat to the 90%
isodose line, a bolus would be required to cover
adequately the superficial regions of the body.
The ideal electron bolus material would be equiva-
lent to tissue in both stopping power and scattering
power. Additionally, it should be flexible and easy to
conform to the variations in surface topography of the
patient. This is an important requirement since small air
gaps between the bolus and skin surface can promote
in-scattering of electrons into the lower density air
spaces resulting in local high-dose regions. Figure 20
shows the effect of an acrylic plate placed at a distance
of 5 cm from a flat surface (Hogstrom 1991). The
reduction in dose to the patient and decreased field
coverage from what would be desired is quite dramatic
and would lead to a significant decrease in the delivered
dose and insufficient treatment of the target area.
Several commonly available materials can be used
as bolus material. These are paraffin wax, polystyrene,
acrylic (PMMA), Super Stuff, Superflab, and Super-
flex. Additionally, solid sheets of thermo-plastics
(3 mm thickness per sheet) can be used. When hot,
the material can be held in contact with the skin
surface so that it conforms almost perfectly to the
underlying contours. Additional layers of bolus can be
added to this initial layer to produce the final desired
thickness. An additional benefit of thermoplastic
material is that it is transparent when hot. The trans-
parency of the material makes it easy to transfer any
marks made on the skin during setup to the surface of
the bolus so as to aid in the accurate placement of the
bolus.
7.6.2 Custom, Compensating Bolus
A custom compensating bolus can be designed for
complex situations to eliminate or decrease the
effect of tissue heterogeneities, irregular patient
surface structure, distance or curvature effects, or
other parameters that would affect the production of
an optimal dose distribution. A custom bolus can be
designed by hand using individual CT scans of the
region to be treated (Archambeau et al. 1981). The
electron energy is selected by choosing the electron
energy that would penetrate to cover the deepest
extent of the target to be treated. A bolus is added
to the top of the CT scans to create an equal depth
of penetration along fan lines on all scans to cover
the target (Fig. 21). A grid describing the bolus
176
Fig. 20 The effect of location of an acrylic plate on the shape and
magnitude of the dose distribution. An acrylic plate placed on the
surface of a phantom (a), preserves both the shape of the original
isodose curves and the magnitude of the delivered dose. An acrylic
Fig. 21 Schematic representation of the patient contour, target
volume, and compensating bolus designed to optimize the
coverage of the target while minimizing the dose to the underlying
critical structure (with permission from Low et al. (1992))
B. J. Gerbi et al.
plate placed at a distance of 5 cm from the surface (b) produces
not only a significant change in the shape of the isodose curves but
also a large decrease in the overall delivered dose to the skin
surface and at depth. [Modified from Hogstrom (1991)]
Fig. 22 Compensating bolus diagram for construction and
placement of the bolus for patient treatment (with permission
from Low et al. (1992))
location on the patient and the thickness of the
bolus at those locations is produced and the com-
pensator is made to these specifications (Fig. 22).
The proposed bolus is added to each individual CT
scan and a computerized treatment plan is com-
pleted to ascertain the accuracy of the bolus design
(Fig. 23). The technique is repeated until a final
Clinical Applications of High-Energy Electrons
Fig. 23 a Custom compensating bolus in place on a transverse
CT scan. Multiple layers may be needed so that the target is
covered by the prescription isodose line and the underlying
lung is spared. b A computerized 3-dimensional view of the
custom bolus in place
acceptable bolus design and plan is achieved. The
grid also serves as an alignment tool so that the
compensating bolus can be placed accurately on
the patient from one treatment to the next. This
hand technique has several limitations: it is iterative
in nature, time consuming, and one-dimensional
which neglects multiple Coulomb scattering, and it
does not account for the full three-dimensional
nature of the problem unless full 3D treatment
plans with the bolus in place are computed (Low
et al. 1992; Antolak et al. 1992).
Computer-based techniques (Low et al. 1992) have
been devised to address these difficulties and limita-
tions. The distribution in Fig. 24 gives an idea of the
177
Fig. 24 Isodose distribution (in Gy) using the custom 3D
electron-bolus technique. A dose of 50 Gy was prescribed to
100% of the given dose using 16 MeV electrons. The bolus was
designed to deliver 90% of the given dose to the target volume.
The plan shows the outline of the bolus above the skin surface
(in yellow), along with dose minimization to the ipsilateral lung
and underlying cardiac tissues. [from Perkins et al. (2001) with
permission]
capabilities of these approaches in covering the target
volume and limiting the high-dose regions (Perkins
et al. 2001; Kudchadker et al. 2002). The computer-
ized-bolus technique has been paired with electron
intensity modulation to produce theoretical dose dis-
tributions for challenging target locations, although
currently there is no easy way to deliver the treatment
(Kudchadker et al. 2003).
Sophisticated customized bolus can be designed in
order to realize electron conformal therapy. Custom
bolus is usually used to shape the 90% isodose surface
to the planning-treatment volume, maintaining an
adequate level of dose homogeneity. The proper
design of this kind of bolus requires the use of a 3-D
TPS. A CT scan with the bolus in place should be
obtained and a verification treatment plan should be
performed to ensure that this complex bolus is acting
to shape the isodose curves to cover the target.
7.6.3 Field Abutment
Field abutment is employed in most instances either
to cover a larger treatment area or region or to change
electron energy in a particular region to more ade-
quately cover the target at depth. Alternatively,
electron fields are abutted to photon fields so that a
superior dose distribution can be achieved. In any
case, optimal coverage of the target area is the goal of
treatment and complicated field arrangements may be
178
Fig. 25 Isodose curves showing the dose at the junction
location for matching electron beams of the same energy
incident on a flat surface as a function of different gap widths,
0.5 cm gap on bottom, 1.0 cm gap middle figure, 1.5 cm gap
top figure. [From Almond (1976), with permission]
required to treat the patient properly. Since most
targets where electrons are used involve the surface of
the patient or are very close to the patient’s surface,
no gaps in the dose coverage at the surface can be
allowed. With field abutment, hot spots beneath
the surface will be created which may be acceptable
depending on the size, the magnitude of the high-dose
region, and the location in the patient of the high-dose
region. Figure 25 shows the resultant isodose distri-
butions when gaps of 0.5, 1.0, and 1.5 cm are placed
between two electron fields of the same beam energy
with parallel central axes incident on a flat surface.
With a 0.5 cm gap, high-dose regions of 140–150%
result. As the gap is increased, the magnitude of the
B. J. Gerbi et al.
Fig. 26 Electron field matching isodose curves for different
electron-beam energies for a Varian 2100C, 10 9 10 cone,
100 cm SSD, 16 MeV electrons on the left, and 12 MeV fields
on the right. No gap on the skin surface (top), 0.5 cm gap on the
surface (middle), and 1.0 cm gap on the surface (bottom). Data
taken using Kodak XV-2 film in a solid-water cassette and
scanned using a Wellhofer isodensitomer and WP700 software
high-dose region decreases to a more acceptable
level, but low-dose regions that may be clinically
important start to become evident near the surface.
Figure 26 shows the effect of field matching with
different electron-beam energies incident on a flat
surface as a function of different gap widths on the
Clinical Applications of High-Energy Electrons
a b
Fig. 27 A collection of abutment geometries. a Diverging
central axes form a common edge with the least amount of
beam overlap. The central axes are angled away from each
other by the angle h = tan-1 (0.5 w/SSD) where w is the
skin surface (0, 0.5, and 1.0 cm gaps). The magnitude
of dose in the overlap region is not as severe as when
identical beam energies are employed but the high-
dose regions can still lead to significant high-dose
regions.
Figure 27 shows a comparison of several abutting
beam configurations. As shown in 7.27a, the extent
and magnitude of the high-dose region can be mini-
mized by angling the central axis of each beam away
from each other so that a common beam edge is
formed. Figure 27b represents the dose overlap that
can occur when the central axis of the beams are
parallel and the beams impinge on a flat surface and
match without a gap at the junction point. Figure 27c
shows converging beam central axes that result in the
greatest amount of overlap beneath the surface with
the highest doses and largest high-dose regions.
7.6.4 Electron–Electron Field Matching:
Sloping, Curved Surfaces
Matching electron fields on a curved surface, such as
those that exist in clinical situations, only tends to
exaggerate the magnitude and size of the overlap
region. This occurs since each of the electron fields is
usually positioned perpendicular to the skin surface.
Figure 28 shows a clinical example of abutting
electron fields in chest wall treatment (Hogstrom
2004). For Fig. 28a, the dose homogeneity is accept-
able at the border of the internal mammary chain and
medial chest wall fields because central axes are par-
allel and field widths are small. However, the dose
homogeneity is unacceptable at the border of the
179
c
common field width. b Parallel central axes lead to overlapping
fields and high-dose area beneath the patient surface. c Con-
verging beam axes resulting in the highest dose regions and the
greatest amount of overlap
medial and lateral chest wall fields because the central
axes are converging which produces a +49% high-dose
region at the junction. Figure 28b shows the smoothing
effect of moving the junction by 1 cm twice during the
treatment. A 49% high-dose region can be reduced to
+27% by moving the junction in this manner. A shift in
the junction of 1 cm is adequate in most instances but
the absolute amount depends on the size of the overlap
region and the total dose. It is recommended that the
amount of the shift and the number of junction changes
be made to ensure that the high-dose region does not
exceed the prescription dose by more than 15–20% in
any region, if possible.
Figure 29a shows a treatment field arrangement for
a post-mastectomy patient. The chest wall is usually
treated with 6–9 MeV electrons with a 0.5–1 cm
bolus to ensure an adequate skin dose. The internal
mammary chain is treated with mixed photons and
9–12 MeV electrons depending on the thickness of
the chest at this location. An additional 6 MeV elec-
tron fields is added for the lower part of the mastec-
tomy scar using adequate bolus to ensure that a high
skin dose is achieved. The supra-clavicular and infra-
clavicular area is treated with photons, with the depth
depending on the anatomical characteristics of the
patient and the depth of treatment for the supra cla-
vicular nodes.
A treatment field arrangement for a post-mastec-
tomy patient (Institut Curie technique) is shown in
Fig. 29b. The chest wall and internal mammary chain
(IMC) volumes are included into one unique field at a
gantry angle of 20–30 from the vertical. During the
180
Fig. 28 Clinical examples of abutting electron fields in chest
wall treatment. a Dose homogeneity is acceptable at the border
of the internal mammary chain and medial chest wall fields
because central axes are parallel and field widths
are small. Dose homogeneity is unacceptable at the border of
the medial and lateral chest wall fields because central axes are
converging. b Dose homogeneity is improved in this region by
moving the match line twice during treatment by 1 cm.
[From Hogstrom (2004)]
simulation, the radiation oncologist determines the
clinical volume of the chest wall to be irradiated and
also delineates the IMC target volume (Kirova et al.
2007).
The dose in the overlap region increases with
decreasing radius of curvature of the external body
contour. Situations such as those illustrated in Fig. 30
should be closely monitored in the clinic, and the
location of the junction should be repositioned with
sufficient frequency to limit the risk of a complication.
7.6.5 Electron–Photon Field Matching
Often in clinical situations, a combination of electron
and photon fields yields a dose distribution superior
B. J. Gerbi et al.
to that obtained using electron fields exclusively.
Adjacent photon and electron fields are commonly used
in treatment of the head and neck region and again, for
post-mastectomy chest wall situations. It is extremely
challenging to treat extensive regions of the chest wall
using electron fields alone. A combination of 6 MV
X-rays and electrons is often used for chest wall and
IMN treatments (Fig. 31a). The delivery of additional
dosage to the site of excision following breast-
conserving surgery and whole-breast irradiation redu-
ces the risk of local recurrence by up to 40%. All age
groups benefit, however the greatest one is conferred to
women under the age of 50 (Bartelink et al. 2007).
Accurate targeting of the clinical target volume (CTV)
is, perhaps the weakest link in the irradiation of the
conserved breast (Whipp and Halliwell 2008).
Originally tumor bed localization was done by taking
account of operative notes, pre-operative imaging, scar
position, and palpation of the surgical defect. Currently
CT-based localization of the tumor bed (TB) with
titanium clips inserted preoperatively at the margins of
the cavity has been the gold standard (Coles et al.
2008). There is limited information on the role of MRI
in localizing the tumor bed. It may be that MR-based
TB outlining overestimates the actual TB by including
hematoma and hemorrhage which does not lie within
the cavity itself (Kirby et al. 2009). In addition, most of
the patients had undergone full thickness cavity closure
resulting in difficulty in clearly defining the original
excision cavity.
The treatment positioning of the patients generally
does not differ from the previous whole-breast irra-
diation. The boost is given with a proper selected
electron energy (up to a maximum of 16 MeV), to a
total dose ranging from 10 to 20 Gy with conven-
tional fractionation, with a margin of at least 2 cm of
margins around the tumor bed. The 90% prescription
isodose line is limited to the chest wall, in order to
decrease the dose to the organ at risk in the thorax
(Fig. 31b).
The benefit of tumor bed boost in conservative
breast-cancer treatment has been supported by
two randomized studies (Romestaing et al. 1997;
Bartelink et al. 2007). In recent years, the definition of
the tumor bed boost volume has been delineated
accurately with the use of CT scans and daily images
registration using clips to define with accuracy the
volume of the tumor bed boost (Kirova et al. 2008;
Kirova et al. 2010; Benda et al. 2003; Graham and
Clinical Applications of High-Energy Electrons 181

Fig. 29 a Treatment field

arrangement for post-mastec-
tomy patient. The chest wall is
usually treated with 6–9 MeV
electrons with a 0.5–1 cm
bolus to ensure an adequate
skin dose. The internal
mammary chain is treated with
mixed photons and 9–12 MeV
electrons depending on the
thickness of the chest at this
location. Additional 6 MeV
electron fields are added to
cover the lower part of the
mastectomy scar. The supra
clavicular and infra clavicular
area is treated with photons,
the depth depends on the
anatomical characteristics of
the patient and the depth of
treatment for the supra ± infra
clavicular nodes. b Treatment
field arrangement for
post-mastectomy patient
(Institut Curie technique): The
chest wall and IMC volumes
are included in one unique field
at a gantry angle of 20–30
from the vertical. During the
simulation, the radiation
oncologist determines the
clinical volume of the chest
wall to be irradiated and also
delineates the IMC target
volume (Kirova et al. 2007)

Fourquet 2006a, b; Al Uwini et al. 2009) (Fig. 32).
High-energy electrons are still the preferred option to
boost the tumor bed (Romestaing et al. 1997).
Electron–photon field matching is the other possibil-
ity to boost adequately the tumor bed volume.
Figures 33 and 34 illustrate possible combinations
of photon and electron fields to treat extensive regions
of the chest wall. The use of combined photon and
electron fields with moving junctions allows for the
treatment of a large amount of chest wall with
acceptable high-dose regions. These approaches could
be extended to treat the entire periphery of the chest
wall if necessary.
Treatments of the head and neck region commonly
use abutted photon and electron fields where right/left
lateral 6 MV fields are used to treat the anterior neck
and electrons are used to treat the posterior neck
nodes. A high-dose region is created at the junction
location in the photon field and a corresponding
low-dose region is created in the electron field. Since
the posterior neck electron fields are often treated at
an extended distance of 110 cm SSD instead of the
nominal 100 cm, changes in the electron field brought
about by this increased distance cause the high-dose
region in the photon fields to be larger while the
coverage in the electron fields is decreased over what
182 B. J. Gerbi et al.

Fig. 30 Representation of the magnitude of the high-dose

regions when two electron fields abut at the skin surface. Both
beams are perpendicular to the skin surface. Represented are
12 MeV electron fields using Varian CadPlan beam model

is achieved at the usual 100 cm electron-treatment

distance. This effect is shown in Fig. 35.
Total scalp treatments present a particularly chal-
lenging situation where the entire periphery of the
scalp needs to be treated while sparing underlying
brain tissue. Electron beams alone have been used to
treat this area but involve very extensive field
matching, special lead shielding, and junctioning
techniques (Tapley and du 1976; Able et al. 1991).
A simpler and dosimetrically superior technique using
right/left lateral 6 MV photon fields to treat the rind
of skin of the scalp while avoiding the brain plus
matched electron fields to treat the lateral surface
of the scalp was developed at the University of
California, San Francisco (Akazawa 1989) and later
modified by Tung et al. (1993). Figure 36 shows the
photon and electron field arrangement used for the
technique. In the technique by Tung et al., the outer
edge of the electron field overlaps the inner edge of
the photon field by 3 mm to account for the diver-
gence of the contralateral 6 MV photon field whose
central axis is placed approximately in the middle of
the brain. The border of the photon field is placed
initially 0.5 cm interior to the inner table of the skull.
Midway through treatment, the junction between the
fields is shifted by 1 cm toward the central axis to
improve the dose homogeneity. To ensure that the
Fig. 31 a A combination of tangential 6 MV photons matched
with 9 MeV electrons to treat a large portion of the chest wall
and internal mammary chain. b a boost to the IMC completes
the dose to a total of 50 Gy. To better spare the skin where the
additional dose is delivered at the IMN, the boost field is
delivered with photons (6MV). It is treated by fractions of
0.5 Gy (prescribed at dmax), once or twice a week, depending
on the complement dose to be delivered (distribution using
Eclipse TPS) (Courtesy N. Fournier-Bidoz 2009)
dose to the scalp is maximized, a 6 mm wax bolus is
used for both the photon and electron treatments.
7.7 Intracavitary Irradiation
7.7.1 Intraoral and Transvaginal Irradiation
Intracavitary radiation is performed for treatment of
intra-oral or trans-vaginal areas of the body. Addi-
tionally, IORT can be considered an intracavitary
electron technique. Intracavitary electron irradiation is
primarily used as a boost for particular sites offering the
advantage of delivering a high dose to a specific and
Clinical Applications of High-Energy Electrons 183

Fig. 33 Combination of tangential 6 MV photons with

12 MeV electrons to cover a large portion of the chest wall.
Varian CadPlan beam models

Fig. 32 a Tumor bed boost volume definition in 3D after pre-

and post-operative images registration. The PTV (green)
includes the GTV (red) and CTV clips ? 1 cm margins. The
breast volume is defined by the pink lines. b The boost using
9 MeV electrons is shown superimposed on the original
treatment volume. (Varian Eclipse TPS)

well-defined area and allowing the sparing of closely-

adjacent normal or sensitive tissue. In the case of
intraoperative radiotherapy, the sensitive structures are
exposed and then physically moved from the beam
before delivery of the radiation. The use of intraoral
cones for boost treatments has been described in the
literature indicating a benefit for the treatment of oral
lesions presenting in the floor of the mouth, tongue, soft
palate, and retromolar trigone. Even though not a ran-
domized prospective study, the data presented showed
that intraoral cone electron- beam boost technique was
superior to interstitial implant and kilovoltage intra-
oral treatments for boosting early carcinoma of the
tongue (Wang 1989, 1991).
Fig. 34 An alternate combination of tangential 6 MV photons
matched with 12 MeV electrons to treat a large portion of the
chest wall. Varian CadPlan beam models
For all intracavitary irradiation, specially designed
treatment cones are required. In addition, an adapter
to attach the cone to the linear accelerator has to be
available which should incorporate a good system
to visualize the area being treated. Figure 37
shows a commercially available intraoral/intrava-
ginal cone system (Radiation Products Design, Inc.,
184
Fig. 35 Composite isodose distribution created by abutting
photon and electron fields. 9 MeV electron-beam; field
size = 10x10 cm2, 6 MV photon beam, SSD = 100 cm.
a Electron-beam at standard SSD of 100 cm. b Electron-beam
at extended SSD of 120 cm. (Reprinted with permission from
Johnson and Khan (1994))
Albertville, MN). Cones are available with internal
diameters from 1.9 to 9.5 cm and bevel angles from
no angle to 60 angulation in steps of 15. In
clinical practice, the cone size and bevel angulation
are chosen to provide adequate field coverage with
the best contact between the end of the cone and
the treated surface.
Special dosimetry for the electron cones has to be
performed before initiating an intracavitary electron
treatment program. The size of the opening of the
adjustable linac jaws has a large impact on both the
output and on the flatness of the electron field ema-
nating from the end of the cone. A jaw size that yields
a uniform field for all available cones is required to
be set as the default size when the cone adapter is
inserted into the treatment head. For each cone to be
used clinically, isodose curves in the direction of the
B. J. Gerbi et al.
Fig. 36 Combination of right–left lateral photon fields with
abutting electron fields to treat the entire scalp region. The
overlap between the photon and electron fields is approximately
3 mm. Both the photon and electron fields have a common
central axis placed approximately in the center of the brain.
[From Tung et al. (1993) with permission]
beam and perpendicular to the beam have to be
obtained. These data are required to determine accu-
rately the depth of penetration of the beam, the depth
of the 90% isodose line, and to ensure that the treat-
ment field is large enough to cover the target with a
sufficient margin. Figure 38 shows 6, 12, and 16 MeV
electron isodose curves for a 5 cm diameter cone
designed for use in IORT. For comparison, isodose
curves in the plane of the beam for a 5 cm diameter
cone with a 0 and 22.5 bevel are shown. The depth
of penetration for the angled beam is significantly
different from the normally incident beam showing
less penetration perpendicular to the skin surface
(Nyerick et al. 1991).
7.7.2 Intraoperative Radiation Therapy
IORT is a very involved technique that requires a great
deal of time and effort to create a dedicated program
for large volumes of patients. The specifics of this
program development are presented in great detail in
AAPM Task Group Report 48 (Palta et al. 1995). It is
important to emphasize that IORT relies not only on
Clinical Applications of High-Energy Electrons
Fig. 37 Intraoral/intravaginal
cone system showing an
assortment of cone sizes and
bevel angles (a), vaginal
obturators to aid in insertion
of the cone (b), the docking
assembly showing the
periscopic visualization system
(mirror, light pen holders,
periscope) (c), and cone mated
to the periscopic attachment
system (d). (Radiation
Products Design, Inc.,
Albertville, MN)
new technological developments, but also on a multi-
disciplinary team with clear roles and responsibilities,
the establishment of a program of quality assurance
with appropriate guidelines and a comprehensive
staff development program. Either a dedicated linear
accelerator room that can meet the requirements of
operating room (OR) sterile conditions or new mobile
electron linacs (Ellis et al. 2000) that can be transported
to a shielded OR need to be used. Dedicated linacs
deliver electron beams with a range of beam energies
from 4 to 12 MeV. A radiation survey to determine
photon leakage and scatter consisting of air kerma
measurements is strongly recommended. The values
outside the OR are generally lower than 1 mSv for an
annual workload of 200 patients. Because of the need to
have the patient under anesthesia, efficient field posi-
tioning and convenient dosimetry need to be available at
the time of the operation. Thus, isodose tables and graphs
for each applicator and energy combination should be
readily available in the OR, as well as output factors for
each possible clinical condition. Real-time in vivo
dosimetry using micro-MOSFET detectors during IORT
is an effective method to evaluate the agreement between
measured and expected dose (Ciocca et al. 2006).
A clinical team needs to be assembled consisting of
surgeons, radiation oncologists, physicists, therapists,
185
and engineering and support staff. Each of these mem-
bers must be thoroughly familiar with their role and how
their role affects other members of the team. If a dedi-
cated unit is not available in the OR suite, which is the
usual situation, then the route of travel from the OR to the
treatment unit must be chosen to minimize distance
while ensuring maintenance of sterility, security, and
patient confidentiality. In general, a major advantage of
IORT is the administration of a large dose of radiation
(from 10 to 21 Gy) directly to the tumor bed, as an
anticipated boost dose or as sole treatment. Accurate
localization and precise definition of the CTV is essen-
tial to avoid geographic miss and to achieve maximal
effects in terms of local control while minimizing
unnecessary damage to the normal surrounding tissues
(Orecchia and Veronesi 2005). Compared to other intra-
operative techniques, electrons appear to deliver the
most homogeneous dose distribution. The linear qua-
dratic model used to calculate the biological equivalence
of such a large single dose for both tumor and normal
tissue effects is not considered totally reliable. The main
concern is the potential increase in severe late effects.
7.7.3 Orbital Tumors
The use of electrons in the treatment of ocular tumors
is well-known (Donaldson and Findley 1991).
186
Fig. 38 Isodose curves for a 5 cm inner diameter IORT cone for 6, 12, and 16 MeV electron beams angled (a), perpendicular to
the surface of the phantom and (b) at an angle of 22.5 [From Nyerick et al. (1991)]
The rapid depth dose decreases with depth with
electrons and the ease with which the beam can be
intercepted suggests that an electron-beam with an
eye shield may offer advantages (Wilson et al. 1992).
For treatment involving the entire eye and orbit,
multi-electron field arrangements yield a favorable
dose distribution. Figure 39 shows the isodose dis-
tribution in multiple planes for a three field arrange-
ment of 10 MeV electron beams.
Radiation therapy is an accepted treatment for
orbital lymphoma, alone for low-grade disease, or
combined with chemotherapy to consolidate the
remission for more aggressive disease. For anterior
lesions limited to the eyelid or conjunctivae, electron-
beam therapy is adequate. Energies ranging from 6 to
9 MeV, with a 0.5–1.0 cm bolus, usually cover the
target. The field size should be no less than 4 cm, in
order to reduce large inhomogeneity in dose distribu-
tion. If allowed by the tumor location, a shield should
B. J. Gerbi et al.
be used to cover the lens. Tungsten or lead shields are
commercially available with thickness varying from
1.5 to 3 mm. Reduction in deep dose is significant with
a 50% or more reduction to the surface of the cornea
using lead shields, and up to 90% reduction with
tungsten shields (Shiu et al. 1996; Weaver et al. 1998).
8 Special Electron Techniques
8.1 Electron-Arc Irradiation
Electron-arc therapy is employed in the treatment of
post-mastectomy chest wall and other areas of the
body such as the ribs and limbs. This technique can
provide an excellent dose distribution in these areas.
It is most effective when a constant radius of curva-
ture is present for the patient to be treated since the
isocenter needs to be placed at a constant distance
Clinical Applications of High-Energy Electrons
Fig. 39 The isodose distribution in multiple planes (a), transverse (b), sagittal and (c), coronal for a (d) three field arrangement of
10 MeV electron beams (courtesy Dr. Dendale)
from the surface of the patient. Electron-arc therapy is
seldom employed at the University of Minnesota due
to the difficulty of fabricating the necessary tertiary
shielding, the amount of time to perform dosimetric
verification of the technique, and competing tech-
niques for covering large areas of the chest wall or
limbs that are much easier to accomplish. In addition,
the depth–dose distribution is such that the dose to the
skin surface is significantly lower for electron-arc
treatments than for a single stationary electron-beam.
This is due to the ‘‘velocity effect’’ where a deeper
point is exposed to the beam longer than a shallower
point resulting in a higher dose at depth than for a
static field. Because of this, a bolus is often required
so that an adequate dose is delivered to the skin sur-
face. Finally, treatment-planning computers lack the
ability to perform electron-arc calculations and the
distribution has to be approximated using several
stationary beams placed around the arc track or by
direct measurement. An excellent and detailed
description of all aspects of electron-arc therapy is
given in the AAPM 1990 Summer School Proceed-
ings (Leavitt et al. 1992).
187
For the electron-arc technique, three levels of
beam definition are required: the opening of the
adjustable X-ray collimators, a secondary cerrobend
insert placed below the adjustable collimators, and
tertiary shielding placed on the patient’s surface to
define sharply the area of treatment. The adjustable
X-ray collimator setting is usually determined by the
linac manufacturer and it automatically selected when
electron-arc mode is selected. The secondary cerro-
bend insert is placed at a distance from the patient’s
surface so that it does not collide with the patient
during the rotation of the gantry during arc treatment.
Any field width can be used on the secondary cerro-
bend insert but geometric field widths of 4–8 cm at
the isocenter are most suitable for clinical situations.
It must be kept in mind that the smaller the field at
isocenter, the lower the overall dose rate resulting in
higher photon contamination. The radius of curvature
usually decreases superiorly from the curvature at the
isocenter. This decreased radius of curvature leads to
a higher dose in this region. The width of the defined
field using the secondary collimator can be tailored to
make the dose more uniform throughout the treatment
188
Fig. 40 Isodose distributions showing the difference in the
sharpness at the ends of the electron-arc when lead is in place.
Data is taken in Rando phantom using 10 MeV electrons, an arc
length of 236 and average radius of curvature of 10 cm. [With
permission from Khan et al. (1977)]
region taking these changes in radius of curvature into
account.
Since the secondary cerrobend insert is far from the
patient’s skin surface, the dose falloff at the treatment
field borders is gradually relative to ordinary static
electron fields due to air scatter. To re-establish a
sharper dose falloff at the ends of the treatment arc, the
electron-arc is extended approximately 15 beyond
each end of the treatment arc. A tertiary shield is fab-
ricated not only to sharpen the edges of the treatment
area but also to protect the uninvolved regions that
would be irradiated by the extended arc. Figure 40
shows an example of an electron-arc distribution both
with and without a lead tertiary shield in place (Khan
et al. 1977). Typically, the shield is made from sheets of
lead of the requisite thickness. Due to the large area to
be covered, the thickness of the shield, and the extra
B. J. Gerbi et al.
shielding needed beyond the edge of the field, the shield
is not only time consuming to produce but also very
heavy to use.
Calibration of the dose rate for electron-arc ther-
apy can be done either by integrating stationary beam
profiles or by direct measurement. Direct measure-
ment using an ionization chamber in a cylindrical
phantom of polystyrene (acrylic or solid water) pro-
vides a direct means by which to determine the dose
rate. Holes are drilled at dmax in the phantom to
accommodate the chamber and standard corrections
are applied to convert the integrated charge into dose
(Khan 2003). Thermoluminescent dosimeters can be
placed on the surface of the phantom to quantify
the surface dose for the treatment. For dosimetry, the
depth of the isocenter has to be the same as for the
treatment, even though the radius of curvature of
the phantom needs only to be approximately that of
the patient (Khan 1982).
8.2 Craniospinal Irradiation
Craniospinal irradiation is used to manage brain
tumors that seed along the entire length of the cere-
bral spinal fluid. Medulloblastoma, malignant epen-
dymoma, germinoma, and infratentorial glioblastoma
are all candidates for this irradiation approach.
Commonly employed techniques treat the patient in a
prone position and use right/left lateral photon beams
to treat the brain in addition to a posteriorly directed
photon beam to treat the spinal cord. Replacement of
the posterior photon field with a high-energy electron
field can reduce greatly the exit dose to the upper
thorax region, especially the heart, and the lower
digestive tract. This is especially important for pedi-
atric patients and results in reductions of both acute
and late complications. Key challenges in the use of
this technique involve matching of the right/left lat-
eral photon fields with the posterior electron spine
fields, selection of the proper electron energy to cover
adequately the spinal canal all along its length, and
the production of a posterior electron field of adequate
length to treat the entire involved region. Techniques
have been published addressing these concerns with
consequent solutions to the above-stated problems
(Maor et al. 1985, 1986; Roback et al. 1997). The first
two techniques using high-energy electrons employ
conventional treatment distances for the posterior
Clinical Applications of High-Energy Electrons
Fig. 41 Isodose curves demonstrating therapeutic and penum-
bra widths at the depth of dose maximum (dmax = 2.5 cm). Top
illustrations is for the field without tertiary collimation, while
the bottom is with tertiary collimation. Data are for 16 MeV
electrons at 120 cm SSD using Kodak XV2 film [with
permission from Roback et al. (1997)]
spine field of 110 and 115 cm SSD and use two
adjacent electron fields if one field is not adequate.
The technique of Roback et al. (1997) for production
of a larger posterior electron field uses an extended
SSD of approximately 120 cm. Special consider-
ations in the application of this technique hinge on
the change in the isodose distributions exhibited at
the extended SSD. Figures 41 and 42 show the dif-
ference in the sharpness of the electron field both
with and without tertiary collimation at the depths of
Dmax and 4 cm, respectively. This approach can be
extended to larger treatment distances (140 cm SSD)
providing that adequate dosimetry is performed at
this distance.
Figure 43 shows the basic field arrangement for
the M.D. Anderson technique (Maor et al. 1985). The
lateral photon fields are rotated through an angle h to
match the divergence of the posterior electron field.
The central axis of the photon beams is placed as
close to the junction region as possible to eliminate
divergence in the superior–inferior direction. The
superior field edge of electron field ‘‘e1’’ is not moved
during the treatment but the inferior border of the
photon fields is shifted 9 mm to feather the junction
location (positions y1, y2, and y3). To achieve the most
uniform dose per fraction in the region of the junc-
tion, one-third of the photon treatments are delivered
with the inferior border of the two photon fields
coincident with the electron field edge. The next
189
Fig. 42 Isodose curves demonstrating therapeutic and penum-
bra widths at the approximate deepest depth of a child’s spinal
cord (4 cm). Top illustrations is for the field without tertiary
collimation, while the bottom is with tertiary collimation. Data
are for 16 MeV electrons at 120 cm SSD using Kodak XV2
film [with permission from Roback et al. (1997)]
one-third of the photon treatments are delivered with
the edge of one photon field moved 9 mm superior to
the electron field edge and the edge of the second
photon field moved 9 mm inferiorly to the electron
field edge. The final one-third of the photon treat-
ments are delivered with the edges of the photon
fields reversed from their previous position. Specifi-
cally, the photon field that was shifted 9 mm superior
to the electron field edge is now positioned 9 mm
inferior to the electron field edge while the photon
field edge that was 9 mm inferior to the electron field
edge is now 9 mm superior to the electron field edge.
The overall length of the cord to be treated often
exceeds the field size that can be covered using a
25 9 25 cm2 cone at either 110 cm or 115 cm SSD.
A small increase in overall field size can be accom-
plished by rotating the collimator 45 to produce a field
size of approximately 30–35 cm in length. If the entire
length of the cord cannot be covered in one electron
field, then a second posterior field must be abutted to the
inferior border of the first electron field. The addition of
this second field requires that the couch be rotated 90
and that the angle of the two electron fields be rotated by
an angle h (Fig. 43) to account for the divergence of
each of these electron fields and to produce a common
field edge (Maor et al. 1985).
190
Fig. 43 Craniospinal field arrangement showing the prone
patient treatment position and the arrangement of the right/left
lateral photon fields and the posterior electron fields. Two
electron fields are shown in the diagram but some patient’s are
small enough such that one posterior electron field covers
adequately the entire spine. The lateral photon fields are rotated
through an angle h to match the divergence of the posterior
electron field. The superior field edge of electron field ‘‘e1’’ is
not moved during the treatment but the inferior border of the
photon fields is shifted 9 mm to feather the junction location
(positions y1, y2, and y3). The central axis of the photon
beams is placed as close to the junction region as possible to
eliminate divergence in the superior–inferior direction. From
Maor et al. (1985)
A simulation of the patient is done to establish the
treatment position and properly place the photon and
electron fields and to provide documentation for sub-
sequent patient treatment. A lateral radiograph is taken
to define the depth of the cord along its entire length and
to show the changes in the SSD along the length of the
cord. A computerized treatment plan of this sagittal
plane can be done easily using this information.
The electron energy is selected so that the 90%
isodose surface covers the target to be treated. The
energy should be selected such that the 90% isodose
should exceed the maximum depth of the cord by
7–4 mm to account for the increased absorption of bone
and 3 mm for a margin of error to ensure coverage of
B. J. Gerbi et al.
Fig. 44 Diagram illustrating total skin electron-treatment
position. Beam angulation provides a larger superior-to-inferior
treatment field, along with extended treatment distance. The
scatter plate (3/8-inch-thick acrylic) is placed approximately
20 cm from the patient surface while the treatment stand is
designed to place the average-height patient at about the middle
of the overall treatment field
the target. If the depth of the spinal cord or the SSD to
the patient skin surface varies significantly, then a bolus
can be added to the spinal cord to conform the 90%
isodose surface to the anterior border of the cord. With
modern 3D-treatment-planning computers, the overall
plan can be calculated before treatment is begun.
8.3 Total Skin Electron Therapy
Total skin electron treatments are employed in the
management of mycosis fungoids (Marinello and
Le Bourgeois 1992; Kirova et al. 1998, 1999a, b;
Duvic et al. 2003). Numerous techniques for treating
the entire skin surface using electron beams have been
devised and each has its particular advantage. For all
techniques, the objective is to deliver as uniform a dose
to the entire skin surface as possible. This is quite a
challenging goal considering the various surfaces and
individual variations that may be encountered. Report
23 of the AAPM (American Association of Physicists
in Medicine 1987) goes into great detail on the various
techniques, the dosimetry, and the proper steps required
to initiate successfully a total skin electron treatment
program. Many different total skin electron techniques
have been developed (Sewchand et al. 1979; Gerbi et al.
1989; Le Bourgeois et al. 1986) that allow the patient to
be treated lying down rather than standing, which is
difficult for many patients who either start treatment in
a weakened condition or become weaker as their
Clinical Applications of High-Energy Electrons 191

Fig. 45 Four of the six

standard treatment positions
for the modified stanford
technique for total skin
electron-beam treatments.
The anterior (a), left-posterior
oblique (b), left anterior-
oblique (c), and right
posterior- oblique (similar to
(c) but for the right posterior)
are treated on day one, while
the posterior (d), and the
right-anterior oblique (similar
to (d) but for the right-
anterior) are treated on
day two

treatment progressed. Our preferred technique is the
modified Stanford technique, while others have been
devised for patients unable to stand for the entire course
of therapy. We use 9 MeV for our treatments and the
high-dose rate total skin electron insert for our linac
which automatically sets the standard linac jaws to
36 9 36 cm2 and allows the unit to operate at between
800 and 900 monitor units per minute.
The first requirement for total skin electron treat-
ments is a uniform electron field large enough to
cover the entire patient in a standing position from
head to foot and in the right-to-left direction. This is
accomplished by treating the patient at an extended
distance (410 cm), angling the beams superiorly and
inferiorly (h = ± 16.78), and using a large sheet of
plastic (3/8 inch thickness acrylic at 20 cm from the
patient surface) to scatter the beam (Fig. 44). This
beam angulation not only produces a large treatment
field but also limits the amount of photon contami-
nation that is directed onto the patient. This is because
192
Fig. 46 The six-field cycle for total skin electron treatments
for the positions indicated in Fig. 45
the lateral scattering of the electrons at the patient
surface extends beyond the edges of the diverging
photon field. In addition, the acrylic plate decreases
the energy of the beam from 9 MeV at the exit win-
dow to about 6 MeV at the surface of the patient. The
scatter produced by the acrylic sheet aids in providing
a more uniform dose around the periphery of the
patient. The beam angulation of ± 16.78 is specific
to this accelerator, the treatment distance and the
thickness and distance of the scatterer from the
patient. The optimum angulations have to be deter-
mined for each linear accelerator and set of treatment
parameters.
Several different patient positions need to be used
to ensure that the entire surface of the body is covered
uniformly. This is accomplished using the six differ-
ent patient positions indicated in Fig. 45. Each of the
positions is rotated at a 60 interval from the other.
Only three of the six fields are treated per day to help
expedite the treatment on a per day basis (Fig. 46).
Thermoluminescent dosimeters are placed at multiple
locations on the third and fourth treatment days to
measure the dose uniformity at those locations. Pub-
lished material (Weaver et al. 1995; Antolak et al.
1998) gives an indication of the amount of variation
that should be expected for various measurement
locations. The usual areas of low dose—the perineum,
under breast tissue, the top of the head—need to be
boosted with separate electron fields to make up for
the dose deficit experienced from the normal total
skin treatment. In contrast, high-dose areas such as
the finger tips, toes, and tops of the feet receive too
B. J. Gerbi et al.
Fig. 47 Resultant dose distribution obtained for total limb
irradiation using six equally spaced 17 cm wide, 5 MeV
electron fields on a 9 cm diameter phantom. From Wooden
et al. (1996)
much dose and need to be shielded for a large portion
of the treatment. The fingers and toes receive a higher
dose since they are irradiated by more than three of
the six electron fields and their lack of thickness for
the fingers.
Eye shields are very often used (the tungsten/alu-
minum shields described above) for the entire treat-
ment to shield the eyes while treating the overlying
eyelid. The eye is first anesthetized, a non-prescrip-
tion contact lens is inserted to protect the cornea from
the shield, and then the tungsten/aluminum eye shield
is placed under the lid. Once the eye shield is in place,
extreme caution and constant monitoring of the
patient must be conducted to ensure that they do not
lose their balance and fall from the treatment stand.
Total skin electron treatments involve a sub-
stantial amount of time and effort on the part of the
department. Commissioning of the technique requires
numerous hours from the physics staff while actual
treatments require more than 30 min of linac time for
the six-field treatment to be completed. Once the
boost fields are added, an hour of linac time can be
consumed in the treatment of one patient. However,
total skin electron-beam therapy has been shown to be
highly effective in the treatment of early-stage
mycosis fungoids without adjuvant therapy. In addi-
tion, the management of relapses with local radio-
therapy or using second total skin electron treatment
is an effective means of treatment for this disease
(Hoppe 2003; Ysebaert et al. 2004).
Clinical Applications of High-Energy Electrons
9 Total Limb Irradiation
Treatment of the entire periphery of body extremities
can be accomplished using electron fields spaced
uniformly around the limb. The advantage of using
electrons over treating simply with parallel opposed
photon fields is that the central uninvolved regions of
the limb can be spared from unnecessary radiation.
The disadvantages of the technique lie in a more
complicated field arrangement, additional dosimetry
to verify the accuracy of the technique, and more
treatment time on the linear accelerator per day to
deliver the treatment. Figure 47 illustrates a technique
described in the literature (Wooden et al. 1996) using
six equally spaced 5 MeV electron beams to treat a
9 cm diameter cylinder. Each beam is wide enough to
cover the entire width of the limb and provide grazing
radiation to all surfaces. The resultant distribution
shows that a surface dose of 90% of the average
maximum is delivered compared with 70% for a
single electron-beam, and that the depth of the 90%
isodose decreases to a depth of 8–10 mm versus
15 mm for a single beam.
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 Proton Therapy
Nancy Price Mendenhall and Zuofeng Li

Contents
1 Rationale ................................................................... 197
2 The State of Particle Therapy ............................... 199
3 Current Proton Therapy Technology Options
and Issues..................................................................
3.1 Sources, Accelerators, and Delivery Modes.............
3.2 Treatment Delivery Systems: Gantries, Fixed
Beams, and Patient Positioners .................................
3.3 Treatment Targeting ..................................................
3.4 Treatment Planning ...................................................
3.5 Integration ..................................................................
3.6 Technology Summary ...............................................
4 Proton Therapy Economics .................................... 203
5 Proton Therapy Applications .................................
5.1 Choroidal Melanomas and Other Eye Lesions.........
5.2 Sarcomas ....................................................................
5.3 Central Nervous System Tumors ..............................
5.4 Head and Neck Malignancies ...................................
5.5 Thoracic Tumors .......................................................
5.6 Pancreas and Other Gastrointestinal
Malignancies ..............................................................
6 New Horizons ........................................................... 216
7 Summary................................................................... 216
References.......................................................................... 216
Abstract
Dose distribution is the most powerful factor in
determining the therapeutic ratio in radiation oncol-
ogy. Developments in diagnostic imaging and
computerized treatment planning justified the drive
199 for increasingly conformal X-ray-based radiation
199 therapy over the past two decades. The end of
substantive improvements in X-ray dose distribu-
200 tions is near, however, because of the inherent
201
202 problems of entrance and exit dose with X-rays. The
203 unique pattern of dose deposition with protons has
203 long made them a promising source for radiation
therapy and recent developments in technology have
made proton therapy applicable to almost all
204
206 cancers. While proton therapy is likely to improve
206 the therapeutic ratio in all radiation indications, the
209 highest priorities currently include cancers requir-
211 ing radiation doses that exceed the tolerance of
212
critical adjacent structures and cancers of childhood
213 and young adults, for which the inevitable entrance
and exit dose of X-ray-based radiation produces a
low-dose radiation bath resulting in early functional
loss in most childhood tissues as well as a lifelong
risk for second malignancies and other radiation-
related dysfunctions. This chapter discusses the
rationale, technical basis, and potential applications
for proton therapy.

N. P. Mendenhall (&)
Z. Li 1 Rationale

University of Florida Proton Institute,
2015 North Jefferson Street, The rationale for proton therapy lies in three basic
32206 Jacksonville,
FL, USA principles of radiation therapy: First, radiation effects
e-mail: menden@shands.ufl.edu are nonspecific—both normal tissues and cancer cells

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 197
DOI: 10.1007/174_2011_266, Ó Springer-Verlag Berlin Heidelberg 2012
198 N. P. Mendenhall and Z. Li

may be injured or destroyed. Second, the likelihood of

damage is both dose- and volume-related. Third, the
most important factor in achieving the highest thera-
peutic ratio—that is, the greatest probability of disease
eradication with the smallest probability of normal-
tissue damage—is the dose distribution. While biologic
modifiers and fractionation impact the effects of radi-
ation, the most powerful method for achieving a higher
probability of disease control with the least probability
of normal-tissue complication is in maximizing the
dose to the tumor target while simultaneously mini-
mizing the dose to the normal tissues.
X-rays, the predominant source of external-beam Fig. 1 Depth dose curves for electron, photon, and proton
beams. Note that the proton beam deposits much less dose
radiation, have a particular pattern of dose deposition
along the entrance path and no exit dose compared to the
in tissue that is problematic. Most of the X-rays in a photon and electron beams. Courtesy: Z Li, PhD
therapeutically applied beam pass through the patient.
Along the beam path, X-rays are absorbed by normal
tissues, placing those tissues at risk for radiation
complications through normal-cell damage and/or
loss. As X-rays are absorbed, the beam is attenuated;
thus, more radiation energy is deposited in tissues
along the entrance portion of the beam than in the
target. With external-beam X-ray therapy, much more
radiation is deposited in the non-targeted entrance and
exit tissues than in the targeted cancer. This is a basic
fact, regardless of how many beam paths or what type
of beam shaping or modulation are used.
With protons, the pattern of radiation dose depo-
sition in tissue differs significantly from that of Fig. 2 The spread-out Bragg peak (SOBP). An SOBP is used
X-rays. As charged particles, protons do not travel an for clinical applications to achieve the optimal target coverage.
infinite distance, but stop at a distance in tissue that is The one shown in this figure is comprised of 9 separate pristine
proportional to their acceleration and to the ‘‘stopping Bragg peaks. The deepest Bragg peak contributes some dose
along its entrance to the shallower portion of the SOBP.
power’’ of the tissues they traverse. A small per- Therefore, the weighting of the individual Bragg peaks
centage of protons are lost through nuclear interaction decreases with depth to create a relatively flat dose distribution
with atoms along the path. Most protons, however, do within the SOBP. Courtesy: Z Li, PhD
not go through such interactions, but rather lose
energy gradually through multiple Coulomb interac-
tions with atoms along the beam path. These gradual acceleration energy of the protons (Fig. 1). A
energy losses are small in the beam-entrance region ‘‘spread-out Bragg peak’’ (SOBP) can be created by
where the protons have high energy. As the protons using a range of proton energies (Fig. 2). Whereas most
traverse deeper into tissue, their energy is further of the radiation dose in a patient with external-beam
reduced, and the rate of energy loss, or linear-energy photons is deposited outside the target, most of the
transfer (LET), quickly increases. At the end of the radiation dose with a proton beam can be placed inside
proton range, the LET of protons increases signifi- the target, affording a significant opportunity to
cantly, resulting in a rapid loss of energy in a short decrease normal-tissue damage. A decrease in normal-
distance. Thus, most of the radiation energy from a tissue damage allows for an increase in radiation dose
proton is deposited near the end of its range in a sharp or dose intensity to the target, thereby improving dis-
peak called the ‘‘Bragg peak.’’ The depth of the Bragg ease control. A decrease in normal-tissue damage also
peak in tissue can be controlled by varying the allows for dose intensification, i.e., a decrease in the
Proton Therapy
number of treatment fractions required and the overall
treatment time, thereby decreasing treatment cost.
Thus, the rationale for proton therapy is the potential for
improvement in normal-tissue toxicity, disease control,
and ultimately overall treatment costs.
2 The State of Particle Therapy
With the development of three-dimensional (3D)
imaging, potential applications for highly conformal
radiation dose distributions have increased, leading to
interest and adoption of highly conformal X-ray ther-
apy techniques such as stereotactic radiosurgery and
radiation therapy, 3D conformal radiation therapy,
intensity-modulated radiation therapy (IMRT), image-
guided IMRT, robotic radiosurgery, and volumetric arc
therapy as well as setting the stage for increased
application of particle therapy. The relative biologic
effectiveness (RBE) of protons is generally considered
to be about 1.1 that of X-rays, similar enough to make
tumor and normal-tissue effects with protons predict-
able based on X-ray experience. Heavier ions, such as
carbon, also produce sharp Bragg peaks, but appear to
have a much higher RBE than protons, making their
tumor and normal-tissue effects somewhat less pre-
dictable. In addition, the costs of heavy ion delivery
systems are much higher than the costs of proton
facilities, so most of the current interest in particle
therapy is focused on proton therapy.
Barriers for the development and proliferation of
proton therapy facilities include the significant cost
and complexity of delivery systems; the requirement
for more intense physics, dosimetry, and engineering
support in treatment planning; quality assurance;
equipment operation and maintenance; and, finally,
the immaturity of treatment planning and delivery
systems currently available.
3 Current Proton Therapy
Technology Options and Issues
3.1 Sources, Accelerators, and Delivery
Modes
In a proton accelerator, protons are produced by
applying an electric field to hydrogen gas to break the
hydrogen atoms into their constituent electrons and
199
protons. Accelerator systems for protons include both
synchrotrons and cyclotrons. Synchrotrons produce a
variety of proton energies in pulses, the lengths of the
pulses being dependent on the extracted proton
energy. Cyclotrons produce a continuous mono-
energetic beam that can be degraded to the desired
energy. The maximum proton energies typically
produced range from 250–270 MEV, yielding a
potential depth-in-tissue penetration of approximately
28–35 cm. Once a proton beam of the desired energy
is produced, it is delivered to a treatment room in a
steel vacuum tube, steered by a series of magnets that
align, focus, and bend the beam (Fig. 3).
There are two basic methods for increasing the
cross-section of the pencil beam transported through
the beam line to a clinically useful size sufficient
for covering a typical radiation treatment field of
10–25 cm: scattering and scanning. Currently, most
proton therapy is delivered through a double-scattered
mode (Fig. 4) in which the narrow beam of protons is
scattered twice and flattened to produce a clinically
useful beam size and intensity. As in X-ray therapy,
the lateral edge of the beam is custom-shaped with
patient-specific apertures or multi-leaf collimators.
In contrast to X-rays, the distal edge of the beam is
also shaped through a compensator placed in the
beam path after the aperture. Most systems employing
the double-scattered mode for sizing the proton beam
can deliver a dose of approximately 2 Cobalt Gray
Equivalent (CGE) to a moderately sized target vol-
ume within 1 min. Field sizes of up to 25 cm in
diameter are achievable with current double-scatter-
ing delivery modes.
In contrast to the scattering mode, the scanning
mode for creating a useful field size requires magnets
to steer the pencil beam, like a paint brush, across
single layers of the target (Fig. 5). Generally, the
deepest layer is dose-painted first,and then the energy
of the beam is decreased to permit the painting of a
series of increasingly shallower layers to create a 3-D
dose distribution. Most strategies employ multiple
paintings of each layer to create a more homogeneous
dose distribution in the actual target and mitigate
minor variations in set-up and intra-fraction target
motion. The dose may be delivered in variously sized
step-and-shoot ‘‘spots’’ (called spot scanning) or in a
continuous beam (called pencil-beam scanning). The
dose delivered at each spot or layer is adjustable,
resulting in a modulated dose distribution at each spot
200 N. P. Mendenhall and Z. Li

Fig. 3 Major components of

a proton delivery system. In
this system, protons are
injected into the cyclotron
then accelerated to a
maximum accelerating
energy. They pass through the
energy degrader which slows
the protons to the desired
patient-specific energy. The
beam energy is refined
through the energy-selection
system and then passes along
the beam line, steered by
magnets, into the nozzle in the
treatment room. Courtesy:
R Slopsema, PhD

or layer as well as between layers, which is known as
intensity-modulated proton therapy (IMPT).
An intermediate method of proton therapy delivery
techniques is uniform scanning, which, instead of
using physical scattering devices, scans the beam
laterally to achieve larger field sizes than can be
achieved by scattering techniques. Uniform scanning
delivers doses layer by layer similar to spot or pencil-
beam scanning. The beam intensity within each layer
is not modulated, so the total dose distribution is
similar to that achieved by a scattering technique. The
omission of physical scattering devices minimizes
proton-beam degradation in these devices, so that
beam quality in a patient, in terms of lateral penumbra
and distal fall-off, is improved. Neutron production in
the uniform-scanning technique is also reduced
compared to the scattering technique, as there are no
proton interactions in the scattering devices.
The advantages of the scanning mode of delivery
include improved dose-distribution conformality,
resulting in less integral dose to non-targeted tissues;
less reliance on beam-scattering hardware devices,
which may reduce patient neutron exposure and sub-
sequent long-term secondary malignancies and less
need for patient-specific apertures and compensators,
potentially resulting in greater efficiency and less cost.
Other potential advantages may be increased field size
and penetration depth. Potential disadvantages of
scanning delivery modes include a greater demand for
accuracy in target localization; reduced speed in
treatment delivery increasing the risk of errors related
to intra-fraction organ motion; and increased com-
plexity of the dose-delivery control system and sub-
sequent quality assurance needs. Treatment delivery
time is impacted by various factors in both the scat-
tering and scanning mode, including beam intensity,
beam tuning time, and room-to-room beam-switching
time. Dose-delivery time impacts the degree of locali-
zation and monitoring strategies required, such as
patient immobilization, internal-organ stabilization,
and external-beam gating strategies. The faster the
delivery time, the lesser the need for volume expansion
and for intra-fraction assessments.
3.2 Treatment Delivery Systems:
Gantries, Fixed Beams, and Patient
Positioners
Protons may be delivered from the beam line to the
treatment area via a gantry or a fixed beam. The
advantages of the gantry system over a fixed beam
Proton Therapy
Fig. 4 A nozzle for double-scattering mode. Key components
of the double-scattering nozzle are the fixed beam scatterer, the
range-modulator wheel, the second beam scatter and flattening
Fig. 5 The spot-scanning technique. A set of focusing magnets
is used to further reduce the diameter of the proton pencil beam.
Scanning magnets then scan the beam in the lateral directions.
Range-shifter plates are inserted into the beam path after
delivery of the distal-most layer of proton doses for treating the
include an increase in possible beam angles, simpler
strategies for patient immobilization and internal-
organ motion tracking, and general flexibility in
applications. For example, with a gantry system,
patient position remains constant throughout a multi-
ple-field treatment. Thus gravitational forces impacting
internal-organ position are constant. If patient position
is changed relative to gravitational forces between the
treatment simulation and treatment delivery or between
treatment fields in a daily treatment, internal-organ
position may change because of changed position rel-
ative to the force of gravity and thus may be difficult to
model. In addition, movement of the patient rather than
the beam may require more time in the treatment room,
impacting operation efficiency. The disadvantage of the
201
filter, and the patient-specific aperture and compensator.
Courtesy: R Slopsema, PhD
second-most distal and subsequently increasingly more-super-
ficial layers. Open circle: beam-off for spots outside of the
target. Black circle: the higher dose. Gray circle: the lower
dose. Courtesy: R Slopsema, PhD and Z Li, PhD
gantry system over a fixed beam, though, is a sub-
stantial increase in equipment cost, shielding material,
and space required. Current patient positioners in pro-
ton facilities are tables with six degrees of freedom and
robotic chairs. In general, the lesser the flexibility in the
beam-delivery system, the more the flexibility will be
required in the patient positioner.
3.3 Treatment Targeting
Increasing the conformality of the dose distribution
to the target volume demands increased precision in
patient simulation, treatment planning, targeting, and
daily delivery.
202
With respect to targeting, all current facilities use
orthogonal X-ray imaging sets for target localization.
Cone-beam computed tomography (CT) for proton
systems is under development, but not in clinical use
as yet. Many centers employ fiducial markers to
enhance target localization. However, the size, com-
position, and placement of the fiducial markers must
be considered in the treatment planning process to
avoid a clinically significant impact on the dose dis-
tribution in the target volume. Radiofrequency fidu-
cial emitters for target localization and tracking are
also under investigation.
3.4 Treatment Planning
Treatment planning in particle therapy differs from
X-ray planning in several important aspects.
First, the absence of an ‘‘exit’’ dose with proton
therapy has several implications. ‘‘New’’ beam angles
typically not used with X-ray therapy can be utilized.
The absence of an exit dose, however, mandates more
precise knowledge of tumor location along the beam
path to avoid distal target under-dosage or overshoot.
Since Bragg-peak location depends not only on the
length but also on the composition of the entrance
tissue, more precise knowledge of the composition of
the beam’s entrance path is also necessary with pro-
tons than with X-ray treatment planning. With IMRT,
the two most important determinants when selecting
the beam angle are avoiding entering or exiting
through a critical structure and maximizing the
number of beams used to achieve the most conformal
target dose distribution. Principles in selection of
proton-beam angles include the following:
(1) Avoid angles that require stopping the beam
immediately in front of a critical structure
because of both range and RBE uncertainties.
(2) Use angles with the shortest entrance-path length.
(3) Select angles to produce the most favorable cross-
sectional target, e.g., angles that produce the
smallest cross-section and/or the most homoge-
nous target thickness.
(4) Choose angles that match the beam path to the
primary axis of target motion—e.g., an anterior
en face field in a thoracic tumor may require a
smaller planning target volume (PTV) expansion
than a lateral field if there is more target motion
along the anterior-posterior axis.
N. P. Mendenhall and Z. Li
(5) Prioritize angles that result in the most stable and
predictable length and composition of entrance
path, producing a ‘‘robust’’ or reliable treatment
plan—e.g., avoiding angles that pass the beam
through distensible organs, such as the bowel or
bladder, if possible.
The second difference between X-ray treatment
planning and proton treatment planning is the reduc-
tion in entrance dose relative to target dose with
protons, meaning that simpler treatment plans with
fewer fields are possible and often preferable com-
pared with those typically used with X-rays. For
example, it is often possible, with a fairly regularly
shaped target, to achieve standard target coverage
goals with a single field (e.g., 95% of the target
receiving 100% of the prescription dose and 100% of
the target receiving a minimum of 95% of the pre-
scription dose) with acceptable fractional and often
total normal-tissue doses along the entrance path. To
further minimize the entrance tissue dose, if desired,
or to increase ‘‘robustness’’ of the overall treatment
plan (Albertini et al. 2010), additional fields can be
added at the price, of course, of low-dose exposure to
additional normal tissues.
Generally, a minimum number of beam angles are
used to achieve the desired target conformality, plan
robustness, and acceptable fractional and total doses
to tissues along the entrance path. Adding unneces-
sary fields expose additional tissue to the effects of
low-dose irradiation and increases treatment delivery
time. To minimize the opportunity for intra-fraction
organ motion (and its attendant prescribed target-
volume expansion), it may be acceptable and prefer-
able with proton therapy to treat a single alternating
field or field combination each day, rather than all
possible fields every day. This option would rarely
occur with X-ray therapy because of the increased
normal-tissue dose along the entrance path relative to
the target dose, which would mandate the treatment of
multiple fields each day. The biological effect of such
beam arrangements, however, needs to be carefully
considered (Engelsman et al. 2011).
The third difference in treatment planning is found
in the early prototype treatment planning systems that
were developed and validated internally by proton
facilities. Currently, only a few commercial treatment
planning systems are available. To date, all are based
on algorithms that convert CT Hounsfield units to
proton stopping power. In all cases, there is a small
Proton Therapy
degree of uncertainty related to actual tissue stopping
power. There is also uncertainty about how to model
the stopping power at the interface between tissues of
different stopping powers. Thus, proximal and distal
margins are applied to the PTV to account for the
stopping power uncertainties.
In addition to the stopping power uncertainty, there
is also a subtle but real difference in the application of
treatment planning safety margins or PTV expansions
between X-ray and proton planning. With IMRT
treatment planning, multiple fields are delivered
sequentially during each daily fraction and a single
PTV expansion, based on the maximum target motion
in any axis is generally applied to all fields. With
protons, the target motion, proximal and distal mar-
gins, and necessary PTV expansion are considered
separately for each beam in the treatment plan. Target
motion along the axis of the beam path is not
important if the entrance path is stable (in length and
composition); therefore, a smaller PTV expansion
along the beam axis may be necessary for protons
compared with IMRT. Since each beam contribution
is planned separately and then summed, each beam
angle has its own proximal and distal margin as well
as its own PTV expansion, potentially leading to
smaller overall PTV expansions than necessary with
multi-field integrated X-ray plans.
Another difference in treatment planning is related
to RBE, which is higher in high linear-energy-transfer
(LET) irradiation than in low-LET irradiation. The
LET is higher near the end of a proton-beam range.
An average RBE value of 1.1 is used for dosimetry
calculation of CGE dose units. It is likely that there is
some variation in RBE along the beam path not
modeled by the current treatment planning systems
(e.g., the RBE may be greater at the end of the range
than along the entrance path where LET is lower).
Currently, it is common in treatment planning for
targets near critical structures to ‘‘pull back’’ some
dose from the distal edge of the target to account for
the probable increase in RBE at the distal range.
To summarize, new and fewer beam angles can be
used with proton therapy to generate a comparable
conformal radiation dose distribution with much less
normal tissue exposed to the integral radiation dose.
These simpler plans may also result in shorter beam-
delivery times, reducing the time available for intra-
fraction organ motion and the attendant necessity
of PTV expansions. Factors considered in beam
203
selection with proton planning differ from those
emphasized in IMRT planning. New treatment plan-
ning systems are under development that may prove
more accurate and reliable, further refining and
improving dose-distribution predictions in the treat-
ment planning process.
3.5 Integration
Contemporary X-ray delivery systems are highly
integrated and even automated, with treatment plan-
ning systems, daily targeting and patient-positioning
devices, quality assurance procedures, and even
facility-management systems. Not all proton facilities
are so fully integrated; some components may have
been developed internally and/or piecemeal. While
these systems work extremely well in the hands of
their developers, not all of the internal integration and
quality assurance measures that may be somewhat
automatic in a conventional radiation therapy practice
are always in place. Therefore, at this point in proton
therapy development, it is particularly critical that
each user understands all the processes necessary to
assure accuracy in delivery of the actual treatment
plan and develop internal quality assurance processes
that minimize the possibility of error.
3.6 Technology Summary
A variety of new approaches to proton production and
delivery, patient immobilization and positioning, and
target localization, tracking, and treatment planning
systems, in addition to integration tools, are under
development and may provide even more cost-
effective, efficient, and accurate processes for proton
therapy.
4 Proton Therapy Economics
The economics of proton and particle therapy have been
much discussed in the academic and public domains over
the past decade as the potential promise of proton therapy
in most radiation applications has been widely recog-
nized. Currently, proton technology is significantly more
expensive than the X-ray technology necessary to treat
a comparable number of patients on a daily basis.
204
The expense is due to the higher system cost as well as
operating and maintenance staffing needs. However,
operations associated with X-ray technology historically
have differed substantially from those commonly
employed with proton technology and the durability of
the equipment appears to be substantially different as
well, making economic comparisons complex. Most
X-ray equipment in the U.S. is operated one shift a day,
5 days a week, and lasts about 10 years, but it is typically
depreciated over 7 years in most hospitals. In contrast,
most proton equipment is operated for extended or double
shifts each day and the oldest clinically dedicated facility,
that of Loma Linda University Medical Center, has been
in continuous operation for more than 20 years without
requiring substantial upgrades. Cyclotrons have typically
lasted for clinical and other purposes for up to 40 years.
It is very likely that proton technology will be more
durable than X-ray equipment, capable of longer daily
treatment hours and more years of production, supporting
different operational models and warranting different
models for investment returns. In addition, because of the
reduction in normal-tissue exposure achievable with
proton therapy, it is highly likely that there will be mea-
surable differences in clinical outcomes that impact
overall health-care costs: shorter more intense treatment
schedules, decreased treatment complications and side
effects, decreased disease recurrences, and ultimately
higher quality of life and thus more productivity in cancer
survivors. Finally, because of the recognized significant
potential benefits, it is likely that demand, competition,
and innovation will drive the development of less costly
and more-efficient proton therapy systems.
5 Proton Therapy Applications
In general, tumors occurring in areas where potentially
curative doses cannot safely be delivered with
acceptable toxicity using photons have been an
accepted province for proton therapy—for example,
clivus chordomas and chondrosarcomas, which are
immediately adjacent to the brainstem and optic chi-
asm, but require radiation doses that greatly exceed the
tolerance of these critical structures. Another example
is sarcomas of the spine, adjacent to the spinal cord.
Malignancies occurring in children, youth, and
young adults have been widely endorsed as a special
priority for proton therapy because even low-dose
radiation can have a profound effect on maturing
N. P. Mendenhall and Z. Li
tissues, likely due to the higher proportion of stem
cells present and the significant impact of radiother-
apy on future growth and development. In addition to
the long-recognized effects of low-dose irradiation on
musculoskeletal development in children, recent
studies have demonstrated a significant risk for sec-
ond malignancy with doses as low as 4 Gy (Travis
et al. 2002, 2003; Tukenova et al. 2010), and an
increased risk of heart disease with doses as low as
4–15 Gy (Mulrooney et al. 2009). Investigators from
St. Jude Children’s Hospital have demonstrated a
strong relationship between radiation dose and vol-
ume parameters and subsequent neurocognitive,
neuroendocrine, and auditory functional loss in chil-
dren treated with radiation for brain tumors (Merchant
et al. 2006, 2008, 2009; Hua et al. 2008; Merchant
2009). Furthermore, they have documented the
absence of a low-dose threshold for impairment of
neurocognitive and neuroendocrine function. These
findings suggest that all efforts should be made to
reduce radiation dose to non-targeted brain tissue in
children and youth (Merchant 2009; Hoffman and
Yock 2009). It is quite likely that similar investiga-
tions with similarly sensitive tools would show sim-
ilar findings in other tissues in children and adults.
It has long been understood that the volume of
lung and liver tissue receiving a high dose of irradi-
ation as well as the volume receiving low radiation
doses were both important predictive factors for the
likelihood of acute and late organ injury. There have
been similar findings in radiation exposure to the
rectum for prostate cancer (Kuban et al. 2008;
Mendenhall et al. 2010). A potential explanation for
the importance of both large-volume low-dose expo-
sure and small-volume high-dose exposure in pre-
dicting tissue injury is that the primary injury occurs
with the high-dose exposure, but rapid and optimum
healing of the injury is related to the health of sur-
rounding tissues. It is possible, for example, that low-
dose exposure to a large volume of tissue around the
primary injury may reduce the number of stem cells
available for recruitment to the healing process,
making the manifestation of the primary injury more
severe or longer in duration. Regardless of the
explanation, these findings suggest that the volume of
surrounding tissue exposed to low-dose irradiation
may impact the risk of radiation complications and
thus the degree of radiation dose escalation and/or
intensification possible in any given tumor system.
Proton Therapy
Fig. 6 A comparison of intensity-modulated radiation therapy
(IMRT) and proton therapy plans for a base of skull chordoma.
Note the reduction in dose to the optic apparatus, the brainstem,
and whole brain with the proton plan. With comparable target
coverage, the maximum and mean doses to the brainstem are
57.4 and 35.2 Gy with IMRT compared to 30.2 and 3.6 CGE
with proton therapy, respectively. The maximum and mean
doses to optic chiasm are 40.3 and 36.3 Gy with IMRT
At the outset, when considering proton therapy
applications, it is important to appreciate that with
comparable delivery and treatment planning technol-
ogy, proton therapy would deliver equivalent target
coverage with substantially less dose to non-targeted
tissues than X-ray therapy, an obvious goal in radiation
therapy. Thus, potentially, any application for X-ray
therapy could be an application for proton therapy. The
absence of a dose threshold for injury in many tissues
now studied with more-sophisticated tools and the dual
importance of the volumes of non-targeted tissue
exposed to both high-dose and low-dose irradiation in
predicting a clinical manifestation of tissue injury
establish the rationale for considering more extensive
application of proton therapy across the world.
205
compared to 36.8 and 32.1 CGE with proton therapy, respec-
tively. The mean whole-brain dose is 16.6 Gy with IMRT and
8 CGE with protons, respectively. The volumes of brain
receiving 10 and 30 Gy or CGE are 66.8 and 11.2% with
IMRT compared to 32.2 and 6.3% with protons, respectively.
Courtesy: R Malyapa, MD, PhD, Craig McKenzie, CMD, and
D. Louis, CMD
Compared to various applications of X-ray ther-
apy, profound reductions in integral dose with proton
therapy have been demonstrated by many investiga-
tors in many clinical sites. With the limited number of
facilities providing proton therapy, the relatively
immature delivery and treatment planning technol-
ogy, and the relative costs, however, protons have not,
as of yet, been applied to all X-ray indications, nor
have randomized clinical trials or prospective com-
parative effectiveness studies been feasible. The
applications discussed below do not in any way
constitute a complete list of all possible proton
applications, but are selected because they demon-
strate a variety of potential improvements achievable
with proton therapy.
206
Fig. 7 A comparison of intensity-modulated radiation therapy
(IMRT) and proton therapy plans for Ewing sarcoma of the rib.
Note the reduction in dose to the lung, heart, and overall body
with the proton plan. The mean lung dose, lung V20, and lung
V4 are 23.5 Gy, 44.2%, and 98.2% for the IMRT plan
compared to 11.2 CGE, 23.1%, and 46.9% with the proton
5.1 Choroidal Melanomas and Other Eye
Lesions
One of the first sites treated with proton therapy was
the eye. Eye treatments could be provided with rela-
tively low-energy protons delivered through a fixed
beam available in physics research centers. Large
numbers of patients have been treated across the
world for choroidal melanomas, in particular
(Gragoudas et al. 2002; Damato et al. 2005).
5.2 Sarcomas
Sarcomas occur in soft tissues and bones throughout
the body, often involving the trunk or extremities.
While surgery is the preferred local treatment, it is
frequently not feasible to completely resect both
N. P. Mendenhall and Z. Li
plan, respectively. The maximum and mean spinal cord doses
are 53.3 and 42.8 Gy with the IMRT plan compared to 49.0 and
35.4 CGE with the proton plan, respectively. The heart V4 and
V20 are 100% and 86.7% with the IMRT plan compared to
10.6% and 0.4% with the proton plan, respectively. Courtesy: D
Indelicato, MD, D Louis, CMD, Z Su, PhD
macroscopic and microscopic tumor. Thus, radiation
is often used as an adjuvant before or after surgery
and in some cases as the sole local therapy. Often,
critical organs adjacent to the sarcoma are the reason
why the tumor cannot be completely eradicated with
surgery, and these organs also make the delivery of
optimal radiation doses difficult. Established and
potential roles for proton therapy include clivus,
sacrum, and spine sarcomas, sarcomas of the rib case,
and retroperitoneal sarcomas. Three examples follow.
5.2.1 Base of Skull and Spine Sarcomas
The doses required for sarcoma eradication with
radiation alone exceed the doses tolerable in adjacent
brainstem, optic structures, and spinal cord, often
precluding the delivery of adequate radiation doses
for tumor eradication with conventional X-ray-based
radiation therapy. However, investigators from
Proton Therapy
Fig. 8 A comparison of intensity-modulated radiation therapy
(IMRT) and proton therapy plans for a retroperitoneal sarcoma.
Note the reduction in dose to the spinal cord, bowel, and overall
body with the proton plan. The mean bowel dose with IMRT is
15.8 Gy compared to 3.2 CGE with protons. The maximum and
Massachusetts General Hospital (Boston, MA) have
reported the delivery of very high doses of proton
therapy to these tumors with unprecedented disease
control rates without significant damage to the brain-
stem, optic structures, or spinal cord (Munzenrider
and Liebsch 1999; Schoenfeld et al. 2010; Delaney
et al. 2009; Hug et al. 2002). These applications of
proton therapy have resulted in the only reasonable
chance of tumor control without an unacceptable risk
of severe normal-tissue morbidity or mortality.
Figure 6 shows a dosimetry comparison between
IMRT and protons in a patient treated for chordoma;
with comparable target coverage, the maximum and
mean doses to the brainstem are 57.4 and 35.2 Gy
with IMRT compared to 30.2 and 3.6 CGE with
proton therapy, respectively. The maximum and mean
doses to the optic chiasm are 40.3 and 36.3 Gy with
IMRT compared to 36.8 and 32.1 CGE with proton
207
mean spinal cord doses are 26.2 and 17.8 Gy with IMRT
compared to 20.3 and 0.9 CGE with proton therapy, respec-
tively. Courtesy: D. Indelicato, MD, D. Louis, CMD, and R.
Slopsema, PhD
therapy, respectively. The mean whole-brain dose is
16.6 Gy with IMRT and 8 CGE with protons. The
volumes of brain receiving 10 and 30 Gy or CGE are
66.8 and 11.2% with IMRT compared to 32.2 and
6.3% with protons, respectively. The primary advan-
tage in this particular case was in the brainstem and
whole-brain dose.
5.2.2 Ewing Sarcoma
Ewing sarcoma is a common sarcoma of bone and
soft tissue. Once considered universally fatal, it is
now highly curable with combined radiation therapy
and chemotherapy. While the doses required for local
control in Ewing sarcoma appear to be less than those
required for other sarcomas, these tumors often
present in bones near critical organs that are prone to
serious, potentially life-threatening radiation injury
with sufficiently effective doses of radiation for
208
Fig. 9 A comparison of intensity-modulated radiation therapy
(IMRT) and proton therapy plans for craniopharyngioma. Note
the reduction in dose to the cochlea, temporal lobes, optic
structures, and overall brain dose with the proton plan. The
mean dose to the temporal lobe is 18.0 Gy with IMRT
compared to 5.4 CGE with proton therapy. The maximum
tumor control. Figure 7 shows a comparison between
IMRT and protons for a Ewing sarcoma of the rib
cage. The proton plan results in significantly less
radiation dose to the lung, heart, and total body. The
mean lung dose, lung V20, and lung V4 are 23.5 Gy,
44.2% and 98.2% for the IMRT plan compared to
11.2 CGE, 23.1%, and 46.9% with the proton plan.
Maximum and mean spinal cord doses are 53.3 and
42.8 Gy with the IMRT plan compared to 49.0 and
35.4 CGE with the proton plan, respectively. The
heart V4 and V20 are 100 and 86.7% with the IMRT
plan compared to 10.6 and 0.4% with the proton plan,
respectively. In this case, the proton plan provided a
substantially reduced risk of both acute and late
serious and potentially fatal side effects, such as,
acute pneumonitis, pulmonary fibrosis, spinal cord
injury, and cardiac disease.
N. P. Mendenhall and Z. Li
and mean doses to the optic chiasm are 55.2 and 54.9 Gy with
IMRT compared to 56.4 and 56.1 CGE with proton therapy,
respectively. The mean whole-brain dose with IMRT was
9.0 Gy compared to 4.7 CGE with proton therapy. Courtesy D.
Indelicato, MD and D Louis, CMD
5.2.3 Retroperitoneal Sarcomas
Retroperitoneal sarcoma presents challenges to both
the surgeon and the radiation oncologist because of its
proximity to kidney, liver, bowel, and spinal cord.
Figure 8 shows a dosimetry comparison between
IMRT and proton therapy in such a tumor, demon-
strating the substantial reduction in radiation dose to
bowel and spinal cord. The mean bowel dose with
IMRT is 15.8 Gy compared to 3.2 CGE with protons.
The maximum and mean spinal cord doses are 26.2
and 17.8 Gy, respectively, with IMRT compared to
20.3 and 0.9 CGE with proton therapy. In this case,
the proton plan again provides a substantially reduced
risk of both acute and late effects, such as nausea and
second malignancies. In other retroperitoneal sarco-
mas, substantial sparing of the kidney and liver is
possible.
Proton Therapy
Fig. 10 A comparison of intensity-modulated radiation ther-
apy (IMRT) and proton therapy plans for an ependymoma.
Note the reduction in dose to the cochlea, hypothalamus,
pituitary gland, and overall brain with the proton plan. The
mean and maximum doses to the left cochlea, located close to
the expanded target volume, were 59.8 and 55.6 Gy with IMRT
compared to 45.3 and 32.4 CGE, respectively, with protons.
5.3 Central Nervous System Tumors
The compelling radiation dose-modeling data from
Merchant et al. discussed above mandate maximum
reduction of integral dose to the hypothalamus and
pituitary axis, the temporal lobes, the cochlea, and all
the non-targeted brain tissue in children (Merchant
et al. 2006, 2008; Merchant 2009; Hua et al. 2008).
Thus there is a strong rationale for consideration of
proton therapy in tumors involving the central ner-
vous system (MacDonald et al. 2008, 2011; Krejcarek
et al. 2007; Cochran et al. 2008; Yock et al. 2005).
Below are three examples demonstrating different
advantages to be gained from proton therapy: a cen-
tral suprasellar tumor, a posterior fossa tumor, and a
high-grade brain tumor requiring craniospinal
irradiation.
209
The mean and maximum doses to the right cochlea were 33.6
and 30.9 Gy with IMRT compared to 4.4 and 1.6 CGE with
protons, respectively. The mean and maximum doses to the
hypothalamus with IMRT were 26.2 and 18.0 Gy with IMRT
compared to 1.9 and 0.3 CGE with proton therapy, respec-
tively. Courtesy: D Indelicato, MD and D Louis, CMD
5.3.1 Craniopharyngiomas
Craniopharyngiomas occur in the suprasellar region
of the supratentorial brain. They are comprised of
solid and cystic components thought to be remnants
of Rathke’s pouch. They are usually detected in
children and young adults because of presenting
symptoms such as headaches, nausea and vomiting,
diabetes insipidis, cranial nerve deficits, precocious
puberty, and other signs of growth disturbance.
Although the tumors are highly curable with moder-
ate-dose irradiation, the side effects and complications
of radiation to non-targeted tissue, such as the
cochlea, temporal lobes, optic nerves and chiasm, and
pituitary gland and stalk, have been substantial,
leading to delays in therapy or multiple surgeries
fraught with significant sequelae. Figure 9 is a com-
parison between an optimized IMRT plan and a
210
Fig. 11 A comparison of
intensity-modulated radiation
therapy (IMRT) and proton
therapy plans for the
craniospinal axis. Note the
reduction in dose to the
thyroid, heart, lung, gut,
gonads, and overall body with
the proton plan. The mean
cardiac doses are 19.7 Gy
with IMRT and 1.2 CGE with
protons. Courtesy: R Marcus,
MD, A Chellini, CMD, and D
Louis, CMD
proton plan for a typical craniopharyngioma showing
the significant reduction in mean brain dose, temporal
lobe dose, and optic apparatus with proton therapy.
The mean doses to the temporal lobes are 18.0 Gy
with IMRT compared with 5.4 CGE with proton
therapy. The maximum and mean doses to the optic
chiasm are 55.2 and 54.9 Gy with IMRT compared to
56.4 and 56.1 CGE with proton therapy, respectively.
The mean whole-brain dose with IMRT was 9.0 Gy
compared to 4.7 CGE with proton therapy. In this
case, the reduced doses to the temporal lobes and
whole brain with protons are likely to result in less
neurocognitive loss and a reduced risk of second
malignancy than with IMRT.
5.3.2 Ependymomas
Ependymomas arise from the ependymal cells lining
the ventricles and may occur in either the supraten-
torial or the infratentorial brain. They typically occur
in young children. Presenting symptoms can include
nausea, vomiting, headaches, and other signs of
obstructive hydrocephalus. Figure 10 shows a com-
parison between IMRT and protons to an infraten-
torial ependymoma. The mean and maximum doses
to the left cochlea, located close to the expanded
target volume, were 59.8 and 55.6 Gy with IMRT
N. P. Mendenhall and Z. Li
compared to 45.3 and 32.4 CGE with protons,
respectively. The mean and maximum doses to the
right cochlea were 33.6 and 30.9 Gy with IMRT
compared to 4.4 and 1.6 CGE with protons, respec-
tively. The mean and maximum doses to the hypo-
thalamus with IMRT were 26.2 and 18.0 Gy with
IMRT compared to 1.9 and 0.3 CGE with proton
therapy, respectively. In tumors of the posterior
fossa, protons typically yield a reduced risk of
hypothalamic injury, reduced dose to one or both
cochlea leading to a lower risk of ototoxicity, and
less whole-brain dose leading to a lower risk of
neurocognitive compromise.
5.3.3 Medulloblastoma
Medulloblastoma is the most common of several
central nervous system tumors that shed tumor cells
into the cerebrospinal fluid and require craniospinal
irradiation for tumor control. Treatment of the spinal
canal with X-rays results in substantial dose to the
thyroid, heart, gut, and gonads leading to thyroid
dysfunction, late cardiac disease, second malignan-
cies, and infertility in survivors. Figure 11 demon-
strates the remarkable reduction in dose to these
organs with protons. The mean cardiac doses are
19.7 Gy with IMRT and 1.2 CGE with protons.
Proton Therapy
Fig. 12 A comparison of intensity-modulated radiation ther-
apy (IMRT) and proton therapy plans for a maxillary sinus
carcinoma. The maximum and mean doses to the chiasm are
48.5 and 40 Gy with IMRT and 36.2 and 15 CGE with protons,
respectively. The maximum and mean doses to the left optic
5.4 Head and Neck Malignancies
There are several sites in the head and neck likely to
benefit from proton therapy: nasopharynx, orophar-
ynx, paranasal sinus tumors, periorbital carcinomas,
and skin cancers with perineural invasion requiring
treatment to the nerve track up to the base of skull.
Each of these sites presents at least one outcome with
photon therapy that offers an opportunity for
improvement with a better radiation dose distribution;
perhaps the one with the greatest opportunity and
challenge is the paranasal sinus tumor.
5.4.1 Paranasal Sinus Tumors and Skin
Tumors
Paranasal sinus tumors and skin tumors that track to
the base of skull are difficult sites for conventional
radiation therapy because of the optic structures—
211
nerve are 50.6 and 37.8 Gy with IMRT and 42.2 and 27.9 CGE
with protons, respectively; similarly, the maximum and mean
doses to the right optic nerve are 49.7 and 41.3 Gy with IMRT
and 44.9 and 27.2 CGE with protons, respectively. Courtesy: R
Malyapa, MD, C McKenzie, CMD, D Louis, CMD
the retina, optic nerves, and chiasm in particular.
Most series reporting a high cure rate also report a
significant rate of unilateral or bilateral blindness
(Mendenhall et al. 2009). Significant dosimetric
improvements can be made with protons compared
with optimized IMRT, likely to lead to improve-
ments in clinical outcomes (Chera et al. 2009a;
Weber et al. 2006; Pommier et al. 2006; Lomax
et al. 2003). Figure 12 shows a comparison between
IMRT and protons. The maximum and mean doses
to the chiasm are 48.5 and 40 Gy with IMRT and
36.2 and 15 CGE with protons, respectively. The
maximum and mean doses to the left optic nerve
are 50.6 and 37.8 Gy with IMRT and 42.2 and
27.9 CGE with protons; similarly, the maximum
and mean doses to the right optic nerve are 49.7 and
41.3 Gy with IMRT and 44.9 and 27.2 CGE with
protons, respectively.
212
Fig. 13 A comparison of intensity-modulated radiation ther-
apy (IMRT) and proton therapy plans for a non-small cell lung
carcinoma. Note the reduction in dose to the non-targeted lung,
the heart, the esophagus, and bone marrow with the proton plan.
5.5 Thoracic Tumors
5.5.1 Lung Cancer
Lung cancer is a prevalent cancer that is frequently
inoperable. Historically, control rates with radiation
have been poor while radiation side effects and
complications have been common. In 1999, investi-
gators from Loma Linda University (Loma Linda,
CA) reported unprecedented control rates with few
significant complications with an extremely hypo-
fractionated radiation regimen in which the typical
course of 8 weeks had been compressed to 2 weeks
(Bush et al. 1999). The experience has now been
duplicated in other programs outside the U.S. and is
currently under investigation at several proton centers
in the U.S. (Sejpal et al. 2011; Chang et al. 2011).
Because of target motion and entrance tissues with
significantly variable stopping powers, the delivery of
proton therapy to lung cancers is more difficult than to
N. P. Mendenhall and Z. Li
The mean lung dose, lung V20, and lung V4 are 22.1 Gy, 34.5,
and 70.8% with the IMRT plan compared to 18.3 CGE, 33.7,
and 43.2% with the proton plan, respectively. Courtesy: R
Nichols, MD, and S Huh, PhD
some other sites (Hui et al. 2008; Chang et al. 2011).
However, the significant opportunity for clinical gains,
because of the significant reduction in mean lung dose,
dose to the esophagus, heart, and bone marrow is likely
to facilitate the delivery of higher, more-effective
cancer doses with lower, less-toxic normal-tissue
exposures. Both early and more-advanced lung cancers
are therefore a priority for proton therapy. Figure 13
shows a comparison between IMRT and protons in an
inoperable stage I lung cancer. The significant reduc-
tion in mean lung dose and V4 may facilitate the
delivery of more dose-intense irradiation and also
result in fewer late effects of treatment.
5.5.2 Hodgkin Lymphoma
Hodgkin lymphoma might seem at first consideration
an unlikely application for proton therapy because of
the extremely high control rates with low to moderate
dose irradiation. However, the relatively young age of
Proton Therapy
Fig. 14 A comparison of intensity-modulated radiation ther-
apy (IMRT) and proton therapy plans for Hodgkin lymphoma.
Note the reduction in dose to the heart, lung, breast, and overall
body with the proton plan. The volume of breast tissue
receiving 4 Gy or CGE with IMRT is 78.8% compared to
45.7% with protons. The volumes of heart receiving doses of 4
and 20 Gy or CGE are 100 and 81% with IMRT compared to
most Hodgkin’s patients and the excellent cure rates
result in a long life span during which many late
effects of radiation are manifested, most importantly
secondary malignancies and cardiac disease. The
emerging literature documenting increased second
malignancies and cardiac disease at doses as low as 4
and 5 Gy provides the compelling rationale to reduce,
as in children, as much dose as possible to as much
tissue as possible in Hodgkin’s patients. As docu-
mented and shown in Fig. 14, substantial reductions
to mean heart, lung, breast, and body dose can be
achieved with proton therapy compared with both
conventional radiation therapy and IMRT (Chera
et al. 2009b; Hoppe et al. 2010). It is likely that these
reductions in dose to the breast, heart, lung, and body
will result in fewer late effects of radiation including
second malignancies and heart disease.
213
61.4 and 53.1% with protons, respectively. The volumes of lung
receiving 4 and 20 Gy and CGE are 89.5 and 20.6% with IMRT
compared to 38.4 and 24.5% with protons, respectively. The
volume of total body receiving a dose of 4 Gy or CGE is 63.1%
with IMRT compared to 22.6% with protons. Courtesy: B
Hoppe, MD, S Flampouri, PhD, and D Louis, CMD
5.6 Pancreas and Other Gastrointestinal
Malignancies
Most of the tumors in the gastrointestinal tract present a
window of local disease progression before distant
metastases and thus afford an opportunity for cure with
effective local therapy. With the exception of early
colorectal cancers, surgery is often unsuccessful as it is
difficult to irradiate both macro and microscopic dis-
ease without compromising patient function. Radiation
alone to the esophagus, biliary tract, pancreas, stomach,
colon, or rectum carries the risk of damage to adjacent
normal tissue, thus doses to these tumors, even with
definitive radiation frequently must be limited to what
is tolerable rather than what would be effective. Many
sites in the gastrointestinal track offer potential oppor-
tunities for a therapeutic advantage with proton therapy.
214
Fig. 15 A comparison of intensity-modulated radiation ther-
apy (IMRT) and proton therapy plans for a pancreatic
carcinoma. The volume of liver receiving 10 Gy or CGE is
46.7% with IMRT and 33.6% with protons. The volume of
A significant and positive experience in treating
hepatocellular carcinoma in Japan has been reported
(Mizumoto et al. 2010; Kawashima et al. 2011;
Nakayama et al. 2009). There are currently ongoing
investigations in the U.S. in hepatocellular, esophagus,
anal canal, and pancreatic carcinoma. The pancreas
represents perhaps the greatest challenge and, thus, the
greatest opportunity.
5.6.1 Pancreas
Pancreas tumors are often not completely resectable
and have very poor local control rates with conven-
tional radiation, in part because the doses must be
limited to avoid damage to critical normal tissues
such as the kidney, liver, and bowel. Nichols et al.
have demonstrated significant reductions in the dose
to non-targeted tissues, such as the liver, kidney, and
bowel, with protons compared to optimized IMRT
plans in pancreatic cancer (Nichols 2010). Figure 15
shows an IMRT and proton comparison. It is probable
that these reductions in dose to the liver and bowel
N. P. Mendenhall and Z. Li
bowel receiving 20 Gy or CGE is 27.5% with IMRT and 8.2%
with protons. The mean bowel dose is 17.1 Gy with IMRT and
4.4 CGE with protons. Courtesy: R Nichols, MD, D Louis,
CMD, and S Huh, PhD
with protons will facilitate more dose escalation and/
or intensification in pancreatic cancer than what can
be achieved with IMRT, hopefully impacting cure
rates in the future. It is likely that other sites in the
gastrointestinal tract, such as the esophagus, liver, and
rectum, will also benefit.
5.6.2 Prostate
Prostate cancer is the most prevalent cancer in males
in the U.S., even more common than breast cancer in
females in the U.S. There are a variety of manage-
ment strategies, ranging from active surveillance in
favorable presentations in the elderly and infirm to
surgery, brachytherapy, and external-beam irradiation
with 3-D conformal radiation therapy, IMRT, or
protons. External-beam irradiation offers the most
flexibility and general applicability. Dose-escalation
trials show clear improvements in disease control
with higher and/or more-intense radiation regimens,
but also increased toxicity. There is intriguing data to
suggest that low-dose exposure to non-targeted rectal
Proton Therapy
Fig. 16 A comparison of intensity-modulated radiation ther-
apy (IMRT) and proton therapy plans for a low-risk prostate
carcinoma. Note the reduction in dose to the bladder, rectum,
and soft tissues of the pelvis with the proton plan. The rectal
tissue may increase the likelihood of rectal injury
(Kuban et al. 2008). Protons offer dosimetric
advantages in minimizing the dose to non-targeted
rectal tissue in prostate cancer patients over IMRT,
and thus creating a rationale for proton therapy as
the preferred external-beam radiation option in
prostate cancer (Vargas et al. 2008; Chera et al.
2009c). Early technology precluded the use of
protons alone in prostate cancer, but excellent out-
comes were reported with protons used in con-
junction with X-rays as a ‘‘boost’’ to the prostate in
both advanced disease and early disease (Zietman
et al. 2010; Shipley et al. 1995). In contrast to other
contemporary dose-escalation trials (Dearnaley et al.
2007; Peeters et al. 2006; Kuban et al. 2008), dose
escalation with protons as the boost was accom-
plished without a significant increase in grade-3
toxicity (Zietman et al. 2010). Reports from proton-
only experiences in prostate cancer thus far have
215
wall V30 and V70 are 51 and 12.6%, respectively, with IMRT
compared to 19.8 and 10.4%, respectively, with proton therapy.
Courtesy: R. Nichols, MD, B. Carter, CMD, Z Su, PhD
shown extremely low toxicity rates, suggesting that
the dosimetric advantages of proton therapy in
prostate cancer may translate into measurable
improved clinical outcomes (Slater et al. 2004; Rossi
et al. 2004; Mendenhall et al. 2010). Figure 16
shows a comparison between an optimized IMRT
plan for prostate cancer and a proton plan. Note that
the dose to the anterior wall of the rectum is similar
for IMRT and proton therapy because of the prox-
imity of the anterior rectal wall to the prostate tar-
get; but there is a substantial reduction in dose to the
non-targeted rectal tissue with proton therapy com-
pared to IMRT, potentially an important prognostic
factor for manifestation of rectal injury (Kuban et al.
2008; Mendenhall et al. 2010). There is also a
substantial reduction in total-body exposure, which
may translate into lower second-malignancy rates for
younger prostate cancer patients (Fontenot et al.
2009).
216
6 New Horizons
It is expected that the early dosimetric and clinical
benefits associated with proton therapy will increase
with better treatment planning and delivery systems in
the future. It is also likely that new applications for
proton therapy will be identified in other malignancies
(Ares et al. 2009). Finally, it is anticipated that proton
therapy will be investigated as an ablation option for
other non-malignant conditions in the future.
7 Summary
Proton therapy provides an opportunity to substan-
tially improve the radiation dose distribution in most
clinical situations. Radiation oncologists expect that
the dosimetric improvement will translate into clinical
benefits: increased disease control, reduced toxicity,
and increased opportunity for dose intensification.
These three benefits will likely translate into
improved overall health-care costs, despite the
increased expense of this technology.
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 Physical, Biological and Clinical Background
for the Development of Light Ion Therapy
Anders Brahme
Contents
1 Introduction.............................................................. 220
1.1 Radiation Therapy Treatment Strategy..................... 222
2 Therapeutic Characteristics of Light
Ion Beams .................................................................
2.1 High Dose to the Tumor and Low Dose to Healthy
Normal Tissues ..........................................................
2.2 Small Cell Cycle Variation and Dose Rate Effect
on Cell Survival.........................................................
2.3 High Relative Biological Effectiveness in the Tumor
and Low in the Normal Tissues ...............................
2.4 Low Dependence on the Presence of Oxygen
in the Tumor ..............................................................
2.5 Simultaneously Low OER and High Dose, LET
and RBE in the Tumor..............................................
2.6 High Apoptotic Cell Kill in the Tumor
but not in Normal Tissue ..........................................
2.7 Fewer Microscopic Cold Spots and Higher
Microscopic Uniformity of the Energy Deposition
at Intermediate LETs.................................................
2.8 Summary of the Clinical Value of Different Light
Ions Species ...............................................................
3 Clinical Indications..................................................
3.1 Radiation Resistant and Hypoxic Tumors................
3.2 Targets Located Close to Organs at Risk.................
3.3 Tumors of Complex Local Spread ...........................
3.4 Potential Number of Patients ....................................
3.5 Improved Diagnostic Imaging of Tumor
Responsiveness and Dose Delivery by PET-CT ......
3.6 Accurate Patient Fixation and Registration of Organ
and Tumor Movements .............................................
3.7 Physically and Biologically Based Treatment
Optimization ..............................................................
A. Brahme (&)
Department of Medical Radiation Physics,
Karolinska Institutet, Box 260,
SE-171 76 Stockholm, Sweden
e-mail: anders.brahme@ki.se
S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_265,  Springer-Verlag Berlin Heidelberg 2012
4 Development of Comprehensive Cancer Centers
and Biologically Optimized Radiation Therapy... 243
5 Equipment and Building Design............................ 246
5.1 Patient Recruitment and Treatment Capacity........... 246
5.2 Conventional Radiotherapy and Biologically
Optimized IMRT ....................................................... 247
225 5.3 Connection to Conventional Radiotherapy............... 247
5.4 Number of Patients.................................................... 248
225 5.5 Beam Delivery System, Treatment Rooms
and Gantries............................................................... 248
227
6 Economical Aspects ................................................. 249
228 6.1 Capital Expenditure ................................................... 249
6.2 Cost per Patient for Different Types of Cancer
228 Treatments ................................................................. 249
7 Conclusion ................................................................ 250
230
References.......................................................................... 250
231
Abstract
231
The light ions have a unique role in the develop-
233 ment of modern radiation therapy where biological
optimized radiation quality and intensity-modu-
236
236 lated radiation therapy are increasingly coming
237 into clinical interest, not least through a systems
239 biology approach to therapy optimization. The
239 traditional dose distributional qualities of light ions
241 like penumbra and depth dose are ideally suited for
high-quality radiation therapy, and their radiation
243 biological properties are even more important for
eradicating large complex generally radiation
243
resistant and/or hypoxic tumor volumes with
minimal damage to surrounding normal tissues.
The remaining challenge to a more wide spread
clinical use of light ions are to improve the
sensitivity and specificity of Molecular Tumor
Imaging to more accurately localize the tumor
219
220
tissues and their biological characteristics as well as
to develop fast scanning systems that preserve the
fundamental biological and physical advantages of
the light ions. For optimal application it is essential
to modulate the ion beams and select the best
possible ion species depending on the molecular and
anatomic properties of the tumor and that is where
systems biology will play a key role in the future.
For small hypoxic tumors the high-apoptotic induc-
tion at the Bragg peak of lithium ions is ideal,
whereas large tumor masses may require carbon and
sometimes even oxygen ions and large microscop-
ically invasive tumors may be best treated by
photons, electrons, protons and helium ions.
1 Introduction
Biologically optimized intensity-modulated photons,
electrons and light ions represent the ultimate devel-
opment of radiation therapy where the absorbed dose
and biological effect to normal tissues can be adjusted
to be as low as possible from a radiation physical’s
point of view, at the same time as the therapeutic
effect on radiation resistant tumor cells is as high as
possible from a radiation biological point of view.
With light ions the border region between the clinical
target volume and surrounding healthy normal tissues
can be set as narrow as physically possible, the
required number of treatment fractions can be sub-
stantially reduced and the curative gain factor for
hypoxic tumor cells can often be more than doubled
as compared to photon, electron and proton beams (cf
Figs. 1, 2, 3, 4, 5, 9 and 14). Taking all this infor-
mation into account, the cost effectiveness for light
ions per patient cured is similar to that of advanced
intensity-modulated radiation therapy (IMRT), and
about 2–3 times higher than that for proton therapy.
The only problem with the light ions is the large
capital cost requiring an initial investment in the order
of 100–150 M€ (cost level 2005). Beside the
increased therapeutic efficiency with in average 12
treatment fractions, the major clinical advantages of
light ion therapy are an increased therapeutic outcome
in terms of improved local tumor control and quality
of life, and a substantially increased patient survival
as well as a significantly reduced risk for adverse
A. Brahme
normal tissue reactions not least for deep target vol-
umes (cf Fig. 5).
As our knowledge about the molecular biology of
cancer is rapidly improving, we continuously need
better tools for diagnostic molecular imaging to match
the improved treatment accuracy and therapeutic effi-
ciency with light ion therapy. Malignant tumors are our
major life-threatening disease at least up to the age of
about 65 years and as many as 50% of the young gen-
eration today may be diagnosed with cancer sometime
during their life. A Comprehensive Cancer Center and a
Center of Excellence for Advanced Radiation Therapy
should therefore be focused on two unique develop-
ments that will considerably improve our ability to cure
cancer patients and maximize their quality of life.
First, the sensitivity, resolution and field of view of
modern PET-CT cameras should be improved as far as
possible so that they really become a unique, sensitive
and fast tool in the early detection of tumor spread.
Furthermore they should also be used to evaluate the
radiation resistance of the tumor in vivo by repeated
PET-CT imaging during the first week of therapy
(Brahme 2003). Even if the sensitivity is lower
Magnetic Resonance Spectroscopic Imaging (MRSI)
could be used for screening purposes since the dose to
normal tissues is really minimal. A third potential
diagnostic development could be mentioned here
namely stereoscopic phase contrast (SP) X-ray imaging
since it has a very interesting potential in tumor diag-
nostics due to the improved resolution and contrast at
significantly lower doses compared to diagnostic CT. It
has also the potential to allow advanced molecular
imaging of tumor properties and treatment responses
(Zhou and Brahme 2008, 2010). With any of these
diagnostic approaches the initial image of tumor spread
should be used as the base for treatment response
monitoring during the early phase of therapy and allow
accurate in vivo predictive assay of radiation respon-
siveness and consequently allow biologically based
adaptive therapy optimization (Brahme 2003, 2009).
Secondly, to maximize the therapeutic response of
the tumor and minimize eventual adverse normal
tissue reactions biologically optimized photons,
electrons and light ions are the ultimate therapeutic
modalities delivering high densities of DNA lesions
in genetically unstable tumor cells and only induce a
low density of easily repairable lesions in genetically
stable normal tissues (Brahme 2004). To maximize
the therapeutic outcome it is important to be able to
Physical, Biological and Clinical Background 221

b Fig. 1 a With a 5 cm thick tumor located between 10 and

15 cm depth the energy of the proton and helium ions have to
be modulated over a 110–150 MeV/u energy range, whereas
electrons and photons can be used directly as seen in (a). With
range modulation the total dose distribution to the tumor
volume is better covered with less dose to surrounding normal
tissues, even though the skin spearing is best with the high
energy photon beam. b If the tumor is of low-oxygen content
(hypoxic) the effective dose with photons, electrons and protons
will be reduced between 2 and 3 times due to reduced toxicity
since less oxygen radicals are being formed (cf Figs. 9b and
10). This effect is much lower with carbon ions where the direct
cell kill dominates due to the much higher ionization density
(cf Fig. 2) and there is less dependence on oxygen radical
mediated cell kill and thus tumor oxygenation. As seen in (b) the
higher OGF of carbon ions makes them significantly more
effective (cf Fig. 14b) in hypoxic and otherwise radiation
resistant tumors generally requiring fewer beam portals (gen-
erally two are sufficient) rather than 3–5 with low-LET beams
(cf also Figs. 1c, 19, 20, 21 and 22). c Comparison of the
biologically effective dose distributions when irradiating a deep-
seated tumor using parallel opposed photon, electron and light
ion beams. It is clearly seen that the normal tissues surrounding
the tumor are considerably less damaged with the lightest ions
around lithium (cf also Figs. 2, 3, 4 and 9). For hypoxic
radiation resistant tumors the clinical advantage is even larger
for the light ions beyond helium. For well-oxygenated tumors
the difference is less significant and protons and electrons can be
used with rather small differences in clinical response since both
generally deliver doses that are well below the threshold for
severe normal tissue damage as shown by the schematic dose-
response curves in the left panel. In both panels a vertical
effective dose scale is used in GyE and %, respectively. In
addition to the longitudinal dose distribution shown here and in
Fig. 3, also the lateral penumbra (Figs. 4, 5 and 6) and the
biological effectiveness (Fig. 2) should be considered when
selecting the optimal treatment energy and modality depending
on the location of the tumor and organs at risk

accurately quantify the therapeutic properties of

the beams in terms of linear energy transfer (LET),
relative biological effectiveness (RBE), oxygen
enhancement ratio (OER), oxygen gain factor (OGF),
apoptotic fraction (AFr) and the dose response relation
(DRR) for the tumor and affected normal tissues (cf
Figs. 1, 3, 7, 14, 15, 16 and 17).
Since both the diagnostic and therapeutic methods
have mm resolution a comprehensive cancer center
with light ion therapy will represent a quantum leap in
our ability to accurately treat malignant tumors. It is
very important that such centers will be realized as
soon as possible to make full use of the clinical
advantages and fast developments of light ion therapy
222
Fig. 2 a Comparison of the RBE and LET ranges of protons,
lithium, carbon and neon ions. It is seen that the range from lithium
to carbon ions is most interesting especially for hypoxic tumors.
(Modified from Blakely and Chang 2009). It is important that not
too large part of the dose delivery should fall in region beyond RBE
maximum where the excessive energy only makes extra normal
tissue double-strand breaks and not sufficient tumor cell kill
(‘‘overkill region’’). The dotted curves describe the probability for
two or more double-strand breaks based on Poisson statistics.
b Variation of the Relative Biological Effectiveness (RBE) as a
function of the ionization density or LET (in eV/nm) of light ion
beams. The highest biological effectiveness is seen for ionization
densities between 25 and 200 eV/nm (=keV/lm), which is
as well as of molecular genomics and proteomics of
cancer and to make them clinically available for the
benefit of our cancer patients. It is one of the few
areas where a substantial investment in new diag-
nostic and therapeutic methods is cost-effective and
rapidly bringing improved quality of life to our
patients and significantly better treatment results into
the health and cancer care system.
1.1 Radiation Therapy Treatment
Strategy
The increasing number of patients, particularly at an
old age, as well as the increasing indications to treat
with radiation creates an increasing need for efficient
radiation therapy facilities with IMRT and light ions,
presently at a rate of several percent per year. The
principle of Radiation Therapy is to deliver as high
dose as possible to the target (that is to the tumor plus
A. Brahme
achieved by track-end electrons and Bragg-peak carbon ions as
illustrated in the diagram. The broad peaks are based on
microdosimetric inversion of jujenal crypt cell survival and are
based on a wide set of neutron data. Analytical ion-specific
response data from Furusawa (2000) are also included based on his
analytical formula, which has wider spread than the track segment
data of Cera et al. (1997). It is seen that the microdosimetric data
cover partly the hydrogen influence since it is largely based on
neutron beam irradiations that generate many secondary protons.
The proton data pertain to low-energy protons with negligible
range straggling and a high RBE contrary to high-energy protons
(cf Fig. 2a). The data of Tilikidis cover a wider range of particle
species resulting in a broader RBE peak similar to Fig. 2a
an internal margin taking into consideration the diag-
nostic accuracy and positional uncertainties of internal
organ motions) and as low dose as possible to healthy
tissues to avoid severe side effects. A compromise
between these two mutually conflicting goals must
generally be found. Improved imaging techniques
make it possible to determine the location of the tumor
volume more accurately. New treatment techniques
must be found that can increase the dose to the tumor
and restrict radiation effects in surrounding normal
tissues as far as possible. Furthermore, the tumor cells
are often resistant to conventional photon, electron and
proton radiation. Light ion beams are therefore the
ultimate treatment modality since they are more
effective than other types of radiation to concentrate
the absorbed dose and the therapeutic effect to the
tumor. More importantly, the biological effect to
eradicate hypoxic and otherwise radiation resistant
tumors is considerably increased with light ions hea-
vier than protons with reduced risk of damaging
Physical, Biological and Clinical Background 223

Fig. 4 Variation of the penumbra width and longitudinal range

straggling for light ions of increasing nucleon number. A sharp
reduction to 50% of the half width value of protons is seen for
helium and almost one-third for lithium and beyond. Interest-
ingly the lateral scattering and penumbra decrease in almost the
same fashion as the longitudinal straggling measured as the
60% width of the high-LET region of the Bragg peak. The 60%
width is approximately the half width of these latter quantities
as seen in the insert. The dotted line approximately gives the
value of the quantity in question for nuclei with N Nucleons
relative to that for protons

Fig. 3 a Comparison of the energy deposition density distri-

butions when irradiating with broad plane parallel electron, and
light ion beams. The dose distributions are here normalized to
the absorbed dose at dose maximum showing the close
similarity between lightest ions from protons to carbon. With
increasing atomic number the LET in the entrance or plateau
region as well as in the deep Bragg peak and beyond increases
as seen in Figs. 2 and 6. The optimal therapeutic effect ratio
between tumor and normal tissue is generally obtained between
helium and carbon ions (cf Figs. 3b, 14 and 15). b The
biological advantage of lithium to boron ions is illustrated more
clearly here by combining the energy deposition in a with the
biological effectiveness in Fig. 2b and normalizing to the Fig. 5 The increase in penumbra as a function of tumor depth.
obtained biologically effective dose at the Bragg peak. For a With electrons and protons it is better than for photons at
given dose in the tumor and Bragg peak the lowest biological shallow depths (\5 cm), whereas light ions from helium and
effect in the plateau region with normal tissues is obtained by beyond are needed to get significant improvements compared to
lithium and beryllium ions. (cf also Fig. 14) photons at large depths. On top of these multiple scatter
contributions (rr, cf Figs. 4 and 6) the part from the initial
normal tissue as it can be seen from Figs. 1, 2, 3, 4, 5 effective source size (r0) of the beam should be added in
and 6. Similar to biologically optimized IMRT with quadrature. This part is included in Fig. 6 where r0 = 2.5 mm
(1/e width = 5 mm). The insert shows the clinical advantage of
photons and electrons the best form of therapy opti- a sharp penumbra in the neighborhood of organs at risk. The
mization with light ions has as treatment objective to brainstem in this case is almost totally avoided with carbon ions
maximize the quality of life by maximizing the but not with protons
224 A. Brahme
Physical, Biological and Clinical Background 225

Fig. 6 a Illustration of the clinical value of different 5 mm 1/e

width light ion pencil beams for biologically optimized therapy
planning. With protons the dose to normal tissues in front of the
tumor is almost twice the tumor dose due to significant multiple
scatters (cf Figs. 4 and 5) whereas it is only a small fraction of
the tumor dose for the light ions from lithium and above. The
color scale illustrates to some extent the ionization density and
thus the additional increased biological effect in the tumor and
comes as an equally important advantage on top of the physical
dose distributional advantage shown in the figure. From carbon
and higher the increasing LET in the entrance region have to
also be considered when maximizing the complication free
cure. b Comparison of photon and ions beam radial dose
profiles for elementary point mono-directional pencil beams as
well as for 2p and 4p steradian rotated convergent pencil
beams. It is seen that ions from about lithium and heavier (cf
Figs. 4, 5 and 6) always allow a much more accurate dose
delivery than photons and protons with a penumbra which is
reduced to between half and one-third of present values for
photons. The longitudinal range straggling is shown in Fig. 4
and the fragmentation tail in Fig. 3 and result in a longitudinal
deterioration of the beam quality, setting in mainly from
beryllium and higher as also seen in Fig. 3a. To get ion pencil
beam kernels that are sharper than 60Co photons ions heavier
than helium are needed for deep therapy as photons have
generally sharper penumbra than proton beams as seen in the
Fig. 5. The ion kernels were derived by Brahme et al. (1989)
and the photon kernels by Eklöf et al. (1999)
Fig. 7 a The cell survival is varying quite a lot with cell cycle
phase with sparsely ionizing photons, electrons and protons.
probability to cure the patient from his tumor without The Synthesis phase and Gap1 are very radiation resistant
inducing severe normal tissue morbidity (P+ strategy where as the late Gap2 and the Mitotic phases are generally
the probability for a truly positive outcome) or even very sensitive. Instead, all phases are almost equally sensitive
with densely ionizing light ions and tumor cells cannot escape
simultaneously maximizing the cure and minimizing cell kill as they do with photons and protons in for example the
the probability of injury (P++ optimization strategy). S phase, which is commonly occupied by rapidly dividing
With severely hypoxic tumors a single beam portal is tumor cells. b The variation of the initial linear cell survival
never sufficient and 2–3 light ion beam portals or 3–5 curve slope a with LET illustrating the LET dependence in
Fig. 7a more clearly. The large variability in a at low LET is
photon beams will generally be needed for curative clearly shown to be reduced to negligible amounts as the LET
treatment as seen by comparing Figs. 1a and b with reaches 50–200 eV/nm for lithium ions and beyond (Modified
Fig. 1c. from Hall and Giaccia 2006)

2.1 High Dose to the Tumor and Low

2 Therapeutic Characteristics
of Light Ion Beams
Compared to low LET photon, electron and proton
beams the clinical properties of light ion beams for
radiation therapy are much more versatile and com-
plex as discussed in more detail in the following
sections. A large part of the detailed information is
presented in graphical form in Figs. 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14 and 15.
Dose to Healthy Normal Tissues
Light ions are charged nuclear particles with rest
masses several thousand times higher than that of
an electron. A much higher accelerating potential is
therefore needed for ions than for the electrons pres-
ently dominating in therapy accelerators of today.
The six lightest ions from protons to carbon ions are
of major clinical interest (cf Fig. 6a) even though ions
up to neon and argon have been used at Berkeley.
226
Fig. 8 a Since most of the lethal cell kill with densely ionizing
ions is along single ion tracks there is practically no dose rate
dependence on the cell survival, contrary to what is generally
seen for sparsely ionizing photons and electrons. b For carbon
ions, as expected from Fig. 8a, there is no significant dose rate
dependence between 0.01 and 10 Gy/min. (Modified from Hall
and NIRS, respectively)
Light ions have dose distributional properties, which
are very advantageous for radiation therapy as seen in
Fig. 1. When they pass through superficial tissues
much less energy is absorbed locally than at the end
of the range. The peak initial energy of the ions is
therefore selected so that the distal part of the tumor is
located at the end of the particle range. Figs. 1, 2, 3
and 4 show the dose, energy deposition density and
biologically effective dose distribution for conven-
tional photon and electron beams compared with the
distribution using different light ion beams. Not only
is the penumbra getting narrower but also the longi-
tudinal range straggling is lower so more of the
energy is deposited in the tumor by light ions of
increasing atomic weight (cf Figs. 2, 3, 4, 5 and 6).
The high-energy deposition at the end of the ion range
A. Brahme
Fig. 9 a The relative biological effectiveness is measured as
the dose ratio at a given survival level and may reach values
between 3 and 5 around the Bragg peak of light ions but is only
around 1.5 in the plateau region. At LET values beyond 150 eV/
nm the cell kill is reduced again as seen in Fig. 2. b Cell survival
for high-LET (Bragg peak helium ions) and low-LET (X-rays)
radiations under well- oxygenated (O2) and hypoxic conditions
(N2). The reduced dependence on the oxygenation status of the
tumor when using Bragg peak light ions versus sparsely ionizing
electrons, photons and protons are clearly seen (Modified from
Raju 1980). The OER is almost unity for Bragg peak helium
ions whereas X-rays need to deliver about 2.6 times more doses
for the same cell survival and tumor response under hypoxic
conditions at the 10% survival level
is due to a velocity resonance causing a high-energy
transfer to the tumor cells when the speed of the ion is
almost equal to the speed of the electrons in the tumor
cells and there is a very high probability that energy is
transferred from the multiply charged ions to the
electrons as they travel long distances together toward
the end of the range (The Bragg peak, cf Figs. 2, 3
Physical, Biological and Clinical Background
and 6). When the atomic weight gets too high, the
ionization density in the entrance region becomes too
high and the amount of particle fragments increases
so the dose, ionization density and effect beyond the
Bragg peak also gets too high as seen in Figs. 2 and 3.
Therefore particles heavier than carbon should be
used very carefully with sensitive structures located in
front of and beyond the tumor depth.
In Figs. 4 and 5 the fast reduction in lateral pen-
umbra and longitudinal range straggling when going
from protons to helium and more slowly going from
helium to lithium and carbon. Since the penumbra of
helium ions (a-particles) is already half of that for
protons, helium ions are really the particle of choice in
the low-LET region. The influence of these effects on
the Bragg peak of pencil beams is shown in Fig. 6,
demonstrating that for each dose addition to a small
part of the tumor require that about four times higher
doses have to be given to normal tissues with protons
as compared to light ions from lithium to carbon.
This is a severe dose delivery drawback for small
radiation-resistant tumors and perhaps less of a dose
delivery problem for large tumors where the broad
beam Bragg peak is reestablished. However, large
tumors often have extensive hypoxic regions so pro-
tons are not generally the radiation modality of choice,
since lithium to carbon ions are more often indicated
for larger hypoxic tumors. The clear improvement in
tumor coverage and normal tissue avoidance is seen in
Figs. 3, 4, 5 and 6 where also the reduction in pen-
umbra width is seen beyond helium ions.
One may ask why there are such a large difference
in biological effect between protons and other light
ions (cf Figs. 2, 3 and 4) even though their normal-
ized dose distributions are fairly similar (cf Fig. 3a).
This is partly due to the same phenomenon that
reduces their Bragg peaks in narrow beams as seen in
Fig. 6 and increases their range straggling as seen in
Fig. 4. The stopping power along a proton path
increases as it slows down. It is only during the last
45 lm or so (or 3–5 cell diameters) that the LET is
above 20 eV/nm and a true high-LET effect is
obtained with protons. However, in a high energy
proton beam the range straggling is about 1% of the
range and is generally about 2–3 mm (cf Fig. 4) and
thus the range straggling almost completely erases the
high-LET regions of the individual protons. The mean
LET of the remaining Bragg peak in Figs. 4 and 6
is only about 4 eV/nm for protons but as high as
227
20 eV/nm for helium, 45 eV/nm for lithium and about
150 eV/nm for carbon ions.
To compare the dose-delivery ability of the light
ion beams with those of low-LET photons and elec-
trons some of the key dose-distribution kernels are
compared in Fig. 6b. It is seen that even the most
systematic use of narrow photon beams for IMRT in
co-planar 2p or stereotactic 4p geometries cannot
produce as accurately confined dose distributions as
narrow light ion beams beyond helium. Furthermore,
their dose distributions are not only sharper and more
well-confined, so are their biological effectiveness as
seen from the Bragg peaks in Fig. 3, their unique
biological effects in Fig. 2 and their apoptotic induc-
tion in Fig. 13. It is also seen that low-energy photons
generally have a sharper penumbra than protons par-
ticularly for deep target volumes (cf also Fig. 5).
2.2 Small Cell Cycle Variation and Dose
Rate Effect on Cell Survival
With low-LET radiation, the effect on the cell is very
much dependent on the phase of the cell cycle at
which the cells are irradiated, as shown in Fig. 7a, b.
Many tumor cells are in the radiation resistant
S-phase during the irradiation and are therefore dif-
ficult to eradicate by low-LET electrons, photons and
protons. High-LET radiation, such as at the end of the
range of light ions, gives almost the same cell survival
independent on the cell cycle phase as seen in Fig. 7.
The light ions are therefore more efficient for eradi-
cating tumor cells since they can no longer hide for
example in the radiation resistant late S- and early G-2
phase or in the mid G-1 and S-phases.
This is a very important property since rapidly
growing tumor cells have a significant portion of their
cells in these resistant phases where sister chromatin
exchange is an effective high fidelity repair process.
Quite similar to the cell cycle dependence, the dose
rate effect at low LET protects cells exposed at
low-dose rates as seen in Fig. 8.
This dose rate effect is due to a more efficient
removal of sub-lethal damage when the damage is
afflicted at a lower rate so there is less risk for damage
interactions. With high-LET radiation this effect is
almost entirely gone as seen in Fig. 8b. This is quite
clear from a radiobiological point of view since all the
dose delivery of light ions occurs at an extremely
228
high-dose rate especially at the core of the ion path
where 106 Gy are delivered in a fraction of a pico-
second (1020 Gy/min). At a low mean dose rate in
an ion beam just a lower number of ions deliver the
dose but all of them at the same high local dose rate.
Therefore no observable dose rate effects are expected
with light ions as seen from the experimental data in
Fig. 8b. From this point of view light ions are ideally
suited for IMRT since the intensity modulation is
well-translated into a biological effect modulation.
At extremely high doses and dose rates there may be
dose rate phenomena when the ionization density is so
high that individual ion tracks interact. This is gen-
erally not the case during light ion radiation therapy.
2.3 High Relative Biological
Effectiveness in the Tumor
and Low in the Normal Tissues
Particle radiations such as light ions transfer energy to
tissue through low-energy secondary electrons of
varying density that locally cause a very high-ioniza-
tion density in irradiated tissues. For light ions, the
ionization density increases about 4- to 5-fold at the
end of range, cf Figs. 2 and 3. Photons, electrons and
protons produce a rather low and uniform ionization
density at all depths, and are generally considered to be
low- LET radiations even though each proton posses a
narrow Bragg peak with elevated LET (cf Fig. 2b) and
the above discussion. High-LET radiation increases
the Relative Biological Effectiveness (RBE, cf
Figs. 2b and 9) particularly at the end of the range at
the so called Bragg peak, cf Figs. 2, 3, 6 and 13. The
RBE is around 2–5 for light ions at the Bragg peak
with an ionization density of around 50–150 eV/nm
and this densely ionizing region should only be located
in the tumor during therapy, to avoid damage to nor-
mal tissues. This means that for a given effect in the
tumor the dose requires to be higher by a factor of
about 3 with low LET radiations such as photons,
electrons or protons to get a similar therapeutic effect.
With light ions the most favorable situation occurs
with radiation resistant tumors (for low LET beams)
since the RBE is then high at the tumor depth, and as
low as possible in the plateau region when passing
through normal tissues as clearly seen particularly for
lithium and beryllium ions in Figs. 1c, 2b, 3, 11 and
13. From a therapeutic point of view a high-LET and
A. Brahme
RBE is not a strong therapeutic advantage on its own
as was seen for the neutrons since an increased ther-
apeutic efficiency in the tumor was counteracted by an
increased damage to normal tissues unless combined
with low LET photons in mixed treatment schedules.
To make a beam as useful as possible from a thera-
peutic point of view (Brahme et al. 1980, 1982, 1983) a
high and uniform LET is desired in the target volume
at the same time as these quantities should be as low as
possible in the normal tissues. These goals are best
fulfilled by lithium and beryllium ions at least for
small tumors (cf Figs. 3b, 13) whereas for larger
hypoxic tumors boron, carbon and sometimes even
oxygen ions may be more suitable.
The new RCR model (potentially repairable and
conditionally repairable damage, Lind et al. 2003)
describes the interaction of different types of DNA
damage very well. The model is based on the interac-
tion of the two major DNA damage and repair pathways
of mammalian cells: the most severe damage resulting
in dual double-strand breaks and multiple damaged
sites require Homologous Recombination (HR)
whereas most plain double-strand breaks at low dos-
erates can be handled by Non-Homologous End Joining
(NHEJ). The potentially repairable lesions are thus
easily repaired by NHEJ, however with low fidelity,
whereas the conditionally repairable lesions also
require the high-fidelity repair of HR (Lind and Brahme
2010; Brahme 2011). This is the case for a large part of
the high-LET damage causing multiple damaged sites
such as dual double-strand breaks (as shown in
Fig. 12), and they have a high risk of misrepair,
requiring HR to step in during the G2M phase to really
make sure that the misrepair is eliminated and corrected
by HR. Interestingly, the RCR model also describes the
presence of a low-dose hypersensitivity as indicated in
Fig. 9b and the presence of a normal tissue fraction-
ation window causing minimal damage in normal tis-
sue around 2 Gy per fraction (Brahme et al. 2001a, b).
2.4 Low Dependence on the Presence
of Oxygen in the Tumor
The biological effect of low to medium LET radiation
is strongly dependent on the local oxygen concentra-
tion in the cell since a substantial part of the cell kill is
then mediated by oxygen radicals. The OER might be
defined as the increased radiation resistance in absence
Physical, Biological and Clinical Background
Fig. 10 With increasing hypoxia the low-LET dose, D37 (and
D50), causing 37 (and 50)% tumor cure increases rapidly.
However, the normalized slope of the DRR (c37) first decreases
at low-LET values as the hypoxic fraction increases due to the
increasing tumor heterogeneity and a dominating small hypoxic
compartment, and then increases as most of the tumor
clonogens become hypoxic. The upper left panel shows that
the degree of hypoxia in a glioblastoma is much larger than in
the normal brain which is contributing to the radiation
resistance of these tumors and make light ions the modality
of choice at least for the primary tumor. The upper right panel
shows how a small hypoxic compartment can totally dominate
of oxygen in the cell. The OER is generally between 2
and 3 for low-LET photons, electrons and protons (cf
Fig. 9b). Tumors are often heterogeneous (Fig. 10)
and tumor cells divide frequently and are therefore
often living under hypoxic conditions and at least some
of these cells are thus more resistant to conventional
low-LET radiations. Often 2.5–3 times more low-LET
dose is therefore needed for eradicating hypoxic tumor
cells as compared to well-oxygenated tumor cells (cf
229
a low-LET treatment whereas with high-LET carbon ions there
are no problem and one may only marginally increase the dose
needed for cure. The loss in c37 and increase in D37 and D50 are
substantially smaller with high-LET lithium or carbon ions as
shown in the lower pair of panels. The D37 value rises steadily
and may be increased 2–3 times whereas the c37 value first is
reduced due to the increased heterogeneity and then reverse and
increase as the tumor becomes less heterogeneous and totally
hypoxic. Many clinical tumors are close to the lowest c value
(&2) and carbon ions bring this low-point back up to the
c & 3.5 region (cf Figs. 16 and 17)
Figs. 1b and 9b). The OER is lower for high-LET
radiation, which favor the use of light ions with hyp-
oxic tumors (OER &1.5–1.7). Because the number of
double-strand breaks is approximately proportional to
the absorbed dose, more damage is inflicted to sur-
rounding normal tissues by a curative dose of low LET
than by high-LET radiation.
In Fig. 9b the reduced dependence on oxygen and
more general radiation resistance is clearly shown for
230 A. Brahme

Fig. 11 Comparison of the

type of damage and repair
induced by low- (right
column) and high-LET beams
(left column). It is seen that
much more of the sub-lethal
damage is repaired at low
LET and that the apoptotic
cell kill is higher with a high
LET (cf also Fig. 13a) due
to higher probability of dense
ionization clusters along the
ion tracks (second row of
panels). The high-LET
portion and RBE is rapidly
increasing beyond protons
(essentially low LET) going
to helium, lithium and carbon
ions (cf Fig. 2)

Bragg peak helium ions and schematically for high-
LET ions in general. In Fig. 10 it is shown how the
low-vascular density and high-vascular heterogeneity
of a tumor (right panel and Nilsson et al. 2002) is
producing a high number of poorly oxygenated tumor
cells as seen in Fig. 10 (solid curves) in good agree-
ment with experimental Ependorf data (tumors: gray
histogram, normal tissues: open histograms; Lind and
Brahme 2007). In Fig. 10 it is also seen how the
oxygenation curves are converted to dose-response
curves requiring higher doses as the hypoxic fraction
increases. It is furthermore shown how a small hyp-
oxic fraction in a tumor significantly reduces the slope
of the DRR with low-LET beams (electrons, photons
and protons) but not so much with lithium and carbon
ions since a small hypoxic fraction is more effectively
eradicated by the medium to high-LET dose
fraction whereas the hypoxic cells totally dominates
the response for low-LET radiations. Finally the
improvement of the effective DRR in terms of D37
and c37 when going from low-LET photons
(&0.2 eV/nm) to medium and high-LET ions in tis-
sues of increasing hypoxic fraction are shown
(Fig. 10 lower panels).
2.5 Simultaneously Low OER and High
Dose, LET and RBE in the Tumor
From the above discussion (Figs. 1, 2, 3, 4, 5, 6, 7, 8
and 9) it is clear that the light ions from lithium to
carbon possess very interesting therapeutic properties
as they combine in the Bragg peak all the properties
one would like in a hypoxic tumor at the same time as
they mainly have a low dose and LET in the sur-
rounding normal tissues producing a low level of
easily-repairable damage. For tumors in organs where
an intact internal normal tissue stroma is important for
survival the lightest ions with low to slightly elevated
LET are most advantageous. A high LET may be less
advantageous for young patients when there is a
considerable life expectancy after therapy because
there may be a marginally increased risk of a sec-
ondary malignancy. The high-LET Bragg peak should
then be used only in the gross tumor which should be
exposed to a high dose level from each beam so even
if a secondary tumor is induced, there is a high
probability that it will also be sterilized by the same
high local dose level that is used to sterilize the pri-
mary tumor. To understand the unique clinical
Physical, Biological and Clinical Background
properties of light ions their radiation biological
effects are of key importance. With conventional low-
ionization density or low-LET radiations the micro-
scopic dose distribution on the sub-cellular scale is
fairly uniform except for the effects of single low-
energy electron track ends or d-rays as seen in
Figs. 11 and 12. With ions the central ion path
functions as a source of low energy d-electrons and at
the Bragg peak they are produced at a very high
density so multiple d-electrons contribute to the very
high local energy deposition density reaching the
MGy region.
The severe damage on super coiled DNA first
wound two times around nucleosomes in the cell
nucleus is shown in close up in Fig. 12. Most toxic are
the &700 eV electrons which deposit a dose in the
neighborhood of the track of around 106 Gy. This
phenomenon explains why the medium-LET beams
are most efficient in inducing apoptosis as seen in
Fig. 13a and thereby eradicating hypoxic tumor cells.
With a low LET too few severe direct cell kill events
are obtained and at high LETs too few ions are
available at a given dose even though they produce
very severe damage. Figure 12 shows that the most
probable DNA fragment length at high doses is around
78 base pairs, corresponding to a single turn around
the nucleosome. This is obtained by d-electrons or
track ends that randomly hit any point on the periphery
of the nucleosome and thus produces dual double-
strand breaks, that always make one DNA fragment of
close to a single nucleosomal DNA turn in length.
During repair the four DNA ends have to be correctly
legated which is difficult for the cell and the 78 base
pair segments may be misrepaired or lost as almost
invisible micronuclei.
2.6 High Apoptotic Cell Kill in the Tumor
but not in Normal Tissue
With intermediate LET ions the fluence, with suffi-
ciently high LET and lethality to maximize the apop-
totic cell kill, is highest at a given dose level as seen in
Fig. 13a, b. This is advantageous from a clinical point
of view since tumor cell kill by apoptosis does not
cause as large an inflammatory response in normal
tissue. Similar to the RBE in Fig. 2 the apoptosis has a
peak at around 30–80 eV/nm that is at lower LET
values than that of the RBE peak at 100–200 eV/nm as
231
seen in Fig. 13a. This is due to the fact that the number
of high-LET events that are needed to induce apoptosis
at a given dose level decreases rapidly with increasing
LET due to the decreasing number of apoptotic events
per unit dose at high-LET values. In Fig. 13b a very
interesting property of the medium LET light ions like
lithium and beryllium is illustrated. These ions induce
a local apoptotic response (programmed cell death)
only in the Bragg peak region where the LET is suffi-
ciently high. Therefore they eliminate tumor cells
with natures own method of programmed cell death
characterized by highest possible local efficiency
and minimal side effects. At the same time the
DNA-damage in the plateau region and the fragmen-
tation tail beyond the Bragg peak is instead triggering
cell cycle arrest and DNA-repair as indicated in the
upper left corner. Thus normal tissue will generally
repair between treatment fractions whereas the tumor
cells are directly eradicated by apoptosis. In tumors
with a mutant P53 pathway the apoptotic fraction is
lower. However, with light ions there still is a signifi-
cant apoptotic fraction due to other apoptotic pathways
normally not active with low-LET radiations. In P53
proficient tumor cells the lithium and beryllium ions
will induce local apoptosis mainly at the Bragg peaks
as seen in Fig. 13b. Lighter ions do not produce much,
whereas carbon and heavier ions produce a significant
level of apoptosis both in front of and behind the Bragg
peak. The lithium–boron ions thus possess a unique,
geometrical molecular precision in their apoptotic
potential.
2.7 Fewer Microscopic Cold Spots
and Higher Microscopic Uniformity
of the Energy Deposition
at Intermediate LETs
The standard deviation of the microscopic energy
deposition increases with LET beyond the lightest ions
and results in a shallower normalized dose-response
gradient at high LETs (Brahme 1984, 2001a and Lind
et al. 2001). This is caused by the microscopic hetero-
geneity which increase the risk that some tumor cells
are missed due to microscopic coldspots even at high
normally curative doses. The increased randomness
may also cause increased cell kill along the tracks at
low doses due to random high-dose events (cf Lindborg
and Brahme 1990, Tilikidis and Brahme 1994).
232
Fig. 12 Molecular close-up view showing that most of the
lethal cell damage of densely ionizing ions is induced by low-
energy d-electrons in the 200–1 keV range that can generate
severe difficult to repair DNA damage in the cell nucleus such
as dual double-strand breaks at the periphery of the nucleosome
(cf Brahme et al. 1997). The lower panel shows that at high
doses of low LET the most common DNA segment length
corresponds to a single turn of the DNA around the nucleosome
as expected from a dual double-strand break at the periphery of
a nucleosome. Interestingly, the 78 base pair fragments are
more than twice as common as all other fragment sizes and they
should be expected to be even more common with high LET
beams having substantially more secondary d-electrons in the
keV- to sub-keV energy range with very high probability of
inducing dual double-strand breaks. The low RBE of low-LET
radiation in the late S-phase may be due to a more open
chromatin with fewer nucleosomes and thus less dual double-
strand breaks as well as a more efficient repair using fully
developed sister chromatid exchange when most alleles are
present in 4 copies (cf Fig. 7)
Based on the different dose distributional and biologi-
cal properties of light ions discussed above it is clear
that their optimal usage requires some careful consid-
erations as discussed in Figs. 14 and 15. For example
should the Bragg peak dose delivery mainly be located
in the gross tumor so that negligible high-LET dose
falls on sensitive normal tissues outside the tumor.
Furthermore, it is better from a microdosimetric point
A. Brahme
of view to generate a rather uniform microscopic
energy deposition density on the cellular scale in the
tumor as discussed in Figs. 12 and 13 starting with a
slightly lower LET at the distal tumor edge as shown in
Fig. 14a. This could basically be done in two different
ways by starting with a suitable Bragg peak at the distal
tumor edge and gradually increase the atomic weight
and Bragg peak LET of the ion used or by just mixing
two different ions species so the mean LET stays
approximately constant. This latter approach requires
that most of the Bragg peak dose is of very high LET,
such as carbon ions, in the anterior part of the tumor
whereas the distal part mainly requires a lower LET
such as helium or lithium ions. In fact, mixing lithium
and carbon ions may be a very good way to achieve
close to ideal microscopic energy deposition density
distribution for medium to large size tumors whereas
small oligo metastasis are best treated by lithium ions
alone as shown in Fig. 13b.
Both the biological and dose-distributional proper-
ties of different radiation modalities from low-energy
photons through high-energy electrons and photons to
neutrons and light to heavier ions are summarized in
Figs. 14 and 15 indicating that the intermediate LET
light ions are most advantageous in most respects.
The quite complex Fig. 14b summarizes the depen-
dance on LET (upper horizontal scale) or high-LET
dose fraction (lower scale) of a number of biological
parameters showing that most of the high-LET
advantages are obtained already at around 30–50 eV/
nm or with as little as about one-third of the dose in the
form of very high-LET neon ions. This is so not only
with the OGF, the OER, RBE and AFr but also with the
physical quantities like rl the microscopic standard
deviation in absorbed dose delivery, the D50 dose
causing 50% probability of tumor cure and the maxi-
mum clinically observed normalized steepness of the
DRR cClin is still high. The clinically most useful LET-
range is thus in this intermediate region and not at very
high- or low-LET values. Within an extended Bragg
peak region the LET is reduced as by necessity some
parts of the target volume will receive low-LET plateau
ion dose. With a rather uniform tumor with regard to
cell density and sensitivity it is thus desirable to pro-
duce a rather uniform LET distribution with a mean
LET value around 40 eV/nm. Interestingly, this inter-
mediate LET-region also maximizes the apoptotic cell
kill so that tumor cells are more effectively eliminated
without too much inflammatory response in normal
Physical, Biological and Clinical Background
tissues as shown by the dotted (10B) and shaded (12C)
curves in Fig. 14b. The lower LET at the Bragg peak
with boron ions as compared to carbon ions indicate the
importance of the fluence density of ions with suffi-
ciently high LET for this type of process (see also
Fig. 13a).
In Fig. 15 it is furthermore seen that these ions are
also among the most cost efficient ones in clinical
use, since the energy needed is lower and the number
of treatment fractions are quite low, commonly about
1/2–1/3 of the number required with low-LET
photons electrons and protons. Optimal particle spe-
cies are found between helium and carbon for most
tumor sites. Figure 15 is based on data from Figs. 1, 2
and 5 indicating the penumbra width, the biological
advantage in a hypoxic or radiation resistant tumor, as
well as the tumor to the whole tissue dose ratio,
respectively, on three independent, perpendicular axis.
The associate cost of an the whole installation and the
associated cost per treatment for a single patient are
also included. Obviously, treatment modalities with a
good tumor to normal tissue dose ratio are most
advantageous (deep part of the figure) and so are those
with a low penumbra (to the right in the figure) and
fairly high biological effectiveness in the tumor region
(high up in the figure) so hypoxic tumors can be
effectively eradicated. Too high biological effective-
ness results in few ions and a high microscopic
randomness in energy deposition with resulting lower
apoptotic yield and shallower DRR. It is clear that the
group of ions from helium to carbon is most interesting
for radiation therapy both from a clinical dose distri-
butional, biological and economical cost effectiveness
point of view.
2.8 Summary of the Clinical Value
of Different Light Ions Species
The clinical value of different ions depends both on
their dose-distributional and their radiobiological
properties as summarized below and in Figs. 2, 3, 4,
5, 6, 14 and 15.
Dose-distribution properties. With light ions con-
siderably improved physical dose distributions are
obtained compared to photons, electrons and protons
• About 3-fold reduction in longitudinal range
straggling between protons and lithium ions
(Fig. 4).
233
• About 3-fold reduction in lateral scatter (Fig. 5).
• This results in the possibility to have a 3-fold
reduction in penumbra and dose outside well-
defined tumor volumes (Figs. 4, 5, 6 and 7).
• A lower effective dose and biological effect is
deposited in front of and distal to a small tumor
with the lightest ions (Figs. 1, 3, 4 and 13).
• For 5 mm half width pencil beams ideally suited
for biologically optimized energy and intensity-
modulated light ion therapy, the tumor dose addi-
tion is approximately twice the entrance dose for
the light ions, whereas it is only half the entrance
tissue dose for protons (cf Fig. 6).
• To increase the tumor dose in a small tumor vol-
ume (*10 mm), about four times higher proton
dose thus needs to be delivered to anterior dose
limiting normal tissues by protons compared to
light ions from lithium to carbon (Fig. 6). Even if
this may be a small problem for large tumors it is
the dose kernels in Fig. 6 that determine the effi-
ciency when using biologically optimized inverse
treatment planning.
• Lower biologically effective doses are delivered to
normal tissues in parallel to opposed light ion beam
techniques (Li–C, cf Fig. 1):
8-times lower compared to photons.
2–3 times lower compared to electrons.
1–5 times lower compared to protons.
• PET-CT imaging allows for more accurate 3-D in
vivo dose delivery verification and radiation
responsiveness imaging both with light ions and
high-energy photons. 8B and 11C are the lightest
PET emitter ion beams allowing 50 increased in
vivo specificity in Bragg peak detection.
Biological response properties. Light ions have
considerably improved biological selectivity due to:
• Co-localization of high dose, high LET and high
RBE (cf Figs. 2, 3 and 6).
• Co-localization of high dose, high RBE and low
OER is obtained in the Bragg peak for ions from
lithium to carbon and above (cf Fig. 13).
• This results in a more than doubled therapeutic
effect or OGF in hypoxic and radio resistant tumors
(Fig. 14).
• Many radiation-resistant tumors can be locally
controlled with reduced normal tissue morbidity and
increased cure due to the simultaneously improved
biological and physical selectivity (Figs. 1, 2, 3, 6
and 13b).
234
Fig. 13 a The fraction of cells that are lost by an apoptotic
response (Afr) or so-called programmed cell death is maximal
at intermediate LET. This is due to the fact that the highest
number of lethal track ends or d-electrons per unit absorbed
dose is generated at intermediate-LET values (&25–50 eV/nm)
as indicated by the lower scale panels. b The DNA damage in
the cell is recognized by proteins that signals their results by
phosphorylation on the P53 gene product. Low-ionization
density damage generally phosphorylates the serine 15 and 20
sites on P53 which leads to a cell cycle block and initiation of
DNA-repair by P21 and GADD45. With lithium ions this
mechanism dominates in normal tissues in front of and behind
the tumor. At the Bragg peak the ionization density is high
which leads to more severe unrepairable DNA damage which
• Negligible variation in sensitivity with cell cycle
phase (Fig. 7a, b).
• A considerably steeper DRR is seen in hypoxic,
and/or radiation-resistant tumors and consequently
often an increased therapeutic window between
tumor cure and normal tissue complications can be
obtained, cf Fig. 16.
• Considerably reduced variation in radiation
sensitivity between oxic and hypoxic and
otherwise radiation resistant tumor cell lines
(Figs. 7, 8 and 9).
• Light ions between lithium and carbon deliver the
ideal LET spectrum for eradication of hypoxic and
low-LET radiation resistant tumor cells and for
preferential induction of apoptosis in the tumor
(cf Figs. 12 and 14).
• Maximum apoptotic cell kill probability per unit
dose at a given cell survival level is obtained for
intermediate LET ions (Figs. 13 and 14) (Vreede
and Brahme 2009).
A. Brahme
commonly phosphorylates the serine 46 site on P53 and thereby
triggers an apoptotic response, eliminating tumor cells with too
severe DNA damage for the repair system (Nakamura 2004).
With lithium ions a high LET is only present in the Bragg peak
where tumor cells are effectively eliminated by apoptosis
whereas in all normal tissues the low-ionization density triggers
a cell cycle block and DNA damage repair. With protons a too
low-ionization density is reached at the Bragg peak whereas
carbon ions have a high LET already 5 cm in front of the Bragg
peak and also in the fragmentation tail behind it, so a too little
or too wide apoptotic region is obtained with these ions.
Lithium and beryllium ions are therefore optimal for this new
form of molecular radiation therapy
• The low-fractionation sensitivity of light ions
reduces the need for a high number of radiation
therapy sessions typically 4–12 are used instead of
25–35 for low-LET beams (Fig. 16).
• Negligible dose rate effect and high-therapeutic
efficiency makes biologically optimized few field
light ion IMRT the preferred treatment for many
advanced tumors (Fig. 8c).
• More generally, light ions are ideally combined to
make radiation Quality Modulated Radiation
Therapy (QMRT) for example combining helium
or lithium and carbon (Brahme 2011) (cf Figs. 19,
20, 21 and 22).
• With lower doses in intensity-modulated dose
delivery, light ions will deliver a more linear ther-
apeutic response whereas low-LET beams suffer
from the double or triple trouble effect, since when
the dose is low, so is the dose rate and the dose per
fraction giving a more strongly nonlinear response
with photons, electrons and protons. Expressed
Physical, Biological and Clinical Background
Fig. 14 a Different light ion dose-distribution kernels are
advantageous in different regions of the target volume (here
cervix cancer with locally involved lymph nodes). Helium and
protons may be most useful in the periphery of the clinical target
volume due to their lower LET in a region where the tumor cell
density is low. Lithium ions may be best in the distal Gross Tumor
region where rectum is down stream of the target volume and may
otherwise receive the more toxic fragmentation tail of carbon
ions. Finally the gross tumor core should preferably receive
Bragg peak carbon ions so that a uniform medium LET (&40 eV/
nm) could be reached throughout the tumor. In order to get a more
uniform biological effect distribution in the target region (10–
15 cm depth) it is better to start with a lower distal LET such as
lithium or helium ions and increase the Bragg peak LET toward
the anterior part of the tumor using carbon ions ( Brahme 2011).
differently: the ions always have the same high
dose rate along their tracks largely independent of
the mean dose level and thus instead triple advan-
tage (cf Figs. 7, 8, 9 and 10).
Clinical properties. As a consequence of the
significant physical and radiobiological advantages
several clinical advantages can be identified.
• The sharp penumbra and small range straggling
makes local high dose and effect treatments possi-
ble with minimal side effects in normal tissues
(cf Figs. 4, 5, 6 and 16).
• The whole treatment can often be delivered in a week
or two so that there is no time to develop severe side
effects during the treatment, largely due to advanta-
geous dose distribution and clinical advantages of
high fractional tumor doses (cf Fig. 16).
• A higher apoptotic cell kill in the tumor, may be
reducing the inflammatory response in normal tissues.
• A higher induction of senescence (permanent cell
cycle blockage) may be an even milder way to
235
In this way a more uniform LET distribution with a smaller
variation in the microscopic standard deviation in the energy
deposition is obtained (cf Figs. 3, 7e and 10a and b). b The key
factors influencing the selection of the optimal radiation quality
range: the OER, RBE, Apoptotic Fraction (cf Fig. 13) and the
Dose causing 50% tumor cure are shown as a function of the
ionization density (LET, upper scale) or densely ionizing neon
ion dose fraction (lower scale). Lithium to carbon ions are the
most interesting and useful light ions for radiation therapy. It is
seen that like the RBE the peak apoptotic fraction occurs at
increasing LET as the atomic number of the ions increases.
Interestingly, with light ions from lithium and above about half
the apoptotic fraction is induced by P53 independent pathways so
P53 mutant tumors may still be effectively eradicated by light ions
(cf Fig. 13) (Brahme 2011)
sterilize tumor growth without need to immediately
kill all tumor cells and avoid acute side effects
when large amounts of dying cells have to be dis-
posed of for example with bone and soft tissue
Sarcoma (cf Fig. 16b).
• Narrow Bragg peak beams can be used to treat
Oligo-Metastasis effectively with minimal side
effects in surrounding normal tissues not least with
the uniquely apoptotic Bragg peaks of lithium and
beryllium ions (cf Fig. 13).
• With 3-dimensional (3D) pencil beam scanning
there is increased flexibility in shaping the tumor
dose distribution from almost any direction and
thus less need for a rotary gantry (Brahme 2005).
• Accurate verification of the dose delivery is pos-
sible with PET-CT imaging not least using 11C
and 8B ions. (Figs. 24 and 25) (Lazzeroni and
Brahme 2011).
In general the clinical value of different ions
depends on the target size and the location and
236
Fig. 15 Comparison of the radiobiological effectiveness
(effective LET, RBE and OER) and the lateral and longitudinal
dose-distributional properties (penumbra) and tumor to super-
ficial tissue dose ratio for uniform parallel opposed beam pelvic
irradiation using different radiation beam modalities. The
higher the spherical indicator the more effective the beam is
for eradication of hypoxic and generally radiation resistant
sensitivity of surrounding normal tissues. When sen-
sitive structures are located distal to the tumor the
lightest ions are preferred due to their negligible
fragmentation tail whereas lateral organs at risk
require the heavier light ions like carbon due to their
small penumbra as demonstrated in Figs. 3 and 4.
Most of the properties of light ions are advanta-
geous for radiation therapy when compared to clas-
sical photons and electrons. Among the few negative
aspects are the high installation cost and the need for
heavy equipment due to the large magnets needed to
bend and scan the ions beams. This can partly be
compensated for by using a single gantry surrounded
by 3–6 treatment rooms as demonstrated in Figs. 23,
24, 25, 26.
A. Brahme
tumors. The approximate costs per typical installation and per
patient treated are also indicated (M€ and k€, respectively). The
increase in the Tumor to Normal tissue dose ratio using electron
and photon IMRT are indicated. Similar improvements are
expected using biologically optimized intensity-modulated or
radiation quality modulated radiation therapy (IMRT and
QMRT, Brahme 2009)
3 Clinical Indications
3.1 Radiation Resistant and Hypoxic
Tumors
Candidates for light ion therapy are in particular tumors
that are hypoxic or in general radiation resistant to
conventional low-LET radiations. About 95% of the
worlds clinical experience on the use of carbon ions for
radiation therapy comes from the National Institute of
Radiological Sciences (NIRS) in Chiba, Japan with
almost 6,000 patients treated to date (2011). Especially
encouraging clinical results from Japan are seen for
non-small-cell lung cancers, bone and soft tissue
Physical, Biological and Clinical Background
Fig. 16 a Clinical results from Chiba with an advantageous
steep dose-response relation for lung tumors using carbon-12
ions. The primary tumor as well as the dose delivery and post
therapy normal tissue response is shown as detected by CT
scanning. b The DRR of carbon ions compared to photons for
Non-Small-Cell Lung Cancer. The local tumor control as a
function of time and dose escalation in Stage 1 tumors is shown
in the lower right panel. It is clearly seen that these severely
hypoxic tumors are most effectively controlled by as few as
four fractions delivered during 1 week. Today only a single
four field treatment delivering about 46 GyE carbon ion dose is
used for these lung tumors. This is a significant improvement in
efficiency, cost effectiveness and cure compared to conven-
tional radiation therapy. The increased steepness improves the
sarcomas, Fig. 16, and hepatocellular carcinoma,
prostate cancers, Fig. 17, malignant melanomas, H&N
cancers and adenocarcinomas of the pancreas. Other
interesting tumor sites include: locally advanced
tumors with low metastatic potential, pediatric cancers,
cordomas, low grade gliomas, anaplastic cancers of the
thyroid, locally recurrent tumors in previously irradi-
ated areas, low-grade sarcomas and salivary gland
tumors.
237
therapeutic window and is due to a more efficient kill of
hypoxic tumor cells. The change in normalized dose response
slope as a function of hypoxic fraction and ion species is shown
in Fig. 10. Most of the loss in dose response slope for photons
is thus due to hypoxia. However, both the variation in
sensitivity over the cell cycle (cf Fig. 7) and with tumor stage
(Fig. 10) affects the lower dose response slope for photons.
b Bone and soft tissue sarcoma are very effectively treated by
carbon ions similar to neutrons (PB). However, the normal
tissue morbidity is much lower with ions since the LET in
normal tissue is much lower for carbon ions resulting in a
significantly increased complication free cure (&85% for
carbon ions, and about 15% for neutrons)
3.2 Targets Located Close to Organs
at Risk
Skull base, spinal and paraspinal tumors, H&N,
ocular and brain tumors benefit substantially by light
ions due to their outstanding geometrical selectivity
and the risk for significant hypoxic tumor cell
compartments in these tumors. The improvement
going from photon therapy by electron accelerators
238 A. Brahme

Fig. 17 a Illustration of the

advanced 3-dimensional dose
delivery possible by low-LET
photon beams using
biologically based intensity
and angle of incidence
optimized radiation therapy
(BioArt). The red to pink
region is the high dose tumor
volume accurately enclosing a
prostate tumor enlarged by
tumor growth. The estimated
biologically optimized
complication free cure of
about 74% was based on
clinical observed dose
response data at lower doses.
b Improvement in
Biochemical relapse free
control of prostate cancer
going from conformal to
intensity-modulated (IMRT)
and biologically optimized
photon therapy and protons to
carbon ions. For the largest,
more complex, tumors
(PSA [ 20) more than a
doubling is seen with photon
IMRT (and protons) and more
than a four-fold increase with
carbon ions compared to
3-dimensional conformal
treatments used in the early
90s (21 ? 89%).
Interestingly by using
biologically optimized
radiation therapy and the
BIOART procedure almost as
good result should be in reach
with photons (cf Fig. 17a).
Not only is the tumor cure
significantly increased but
also normal tissue
complications are brought
down to only a few percent as
seen in (a) and also observed
clinically with carbon ions
Physical, Biological and Clinical Background
and the c-knife when treating arteriovenous malfor-
mations a substantial improvement in obliteration
probability is seen with the helium ions used at
Berkeley especially at high doses probably due to
the increased induction of apoptosis in these beams
(cf Fig. 13a and Andisheh et al. 2010). The
improvement of the treatment of cordomas going
from photons and protons to helium ions and finally
to carbon ions is quite significant, and there are
indications that it is important how the dose delivery
is performed, preferably so high and low LET local
dose delivery is as close as possible in time to
maximize the synergistic effect (cf Lind et al. 2003;
Brahme 2011).
3.3 Tumors of Complex Local Spread
Tumors of Complex Local spread such as mesothe-
liomas, cervix cancer and brain tumors may benefit
substantially from the improved geometrical and
biological selectivity of the lightest ions. A significant
improvement in treating cordomas with photon
IMRT, protons and most recently with carbon ions is
seen compared to conformal photons. A steeper dose
response is seen for carbon ions as compared to
photons and protons similar to the curves for lung
cancer in Fig. 16a, probably due to a significant
influence of hypoxic tumors cells (cf Fig. 10). Inter-
estingly there is a significant difference between the
results at GSI and NIRS possibly due to the biological
effect difference between fast lateral but rather slow
longitudinal pencil beam scanning and instantaneous
longitudinal range shifting using ridge filters to get
a more uniform synergistic biological effect by
simultaneous low and high-LET radiation interac-
tion (cf Lind et al. 2003; Brahme 2011). The slow
longitudinal scanning may cause a reduced biolog-
ical synergism between the low and high-LET dose
fractions when the time span between the high and
low-LET dose fractions is too long compared to the
fast repair. Part of the low LET sublethal damage
will then be repaired before the high-LET Bragg
peak arrives at the end of the treatment reducing
the efficiency by some 10–20% (cf Lind et al. 2003;
Brahme 2011).
239
Fig. 18 A more global view of how the complications are
reduced and the tumor cure is increased as we go from
conventional conformal photon therapy to IMRT photons and
protons to carbon ions. Interestingly IMRT photons and protons
again almost do equally well whereas carbon ions are having
very few complications and almost total tumor control
(P+ & 95%, cf Figs. 16 and 17). Clearly, even if the data are
mainly nonrandomized they give a similar indication of the
merits of light ions as seen in Figs. 16 and 17. The upper right
corner correspond to complete complication free cure
(P+ & PB(1 - PI) = 100%)
3.4 Potential Number of Patients
Based on figures from the new European centers for
light ion therapy applied to a small country like
Sweden (*9 Million inhabitants) would give between
2,000 and 5,000 patients/year ideally suitable for light
ion therapy out of some 50,000 new cancers per year.
A small proportion of these tumors may be treated by
IMRT photons or protons, not least microscopically
invasive tumors in sensitive normal tissues. When the
tumor cells are expected to be extra radiation resis-
tant, it may also be advantageous to use the next
lightest ions: helium and lithium.
Quite generally one can estimate that in the future
about one-third of all radiation therapy patients with
small size well-oxygenated tumors can be cured well
by conventional conformal radiation therapy. The
simple well-oxygenated medium to medium large
tumors may be about 1/4–1/3 of all the radiation
therapy patients, will need IMRT, with electrons and
photons. The remaining 40% or so large to medium
sized hypoxic tumors will benefit substantially
240 A. Brahme

Fig. 19 Illustration of the

development from classical
forward therapy planning
to inverse therapy planning
using physical dose (upper
right panel) and biological
(tumor and normal tissue
response cf Fig. 16) treatment
objectives. The ultimate step
in therapy development is to
do biologically optimized
light ion therapy where the
optimal weights of different
light ion species are selected
to maximize the complication
free cure (cf lower right panel
and Figs. 14b, and 16)

Fig. 20 More detailed description of how the dose delivery in
the lower panel of Fig. 19 can be calculated by analytical,
matrix or tensor-type equations. From the dose distribution the
probability of tumor cure and normal tissue damage (cf Fig. 16)
can be calculated and an iterative procedure can be applied to
maximize the probability that the patient is cured without
severe normal tissue reactions. The lower right panels, from top
to bottom, illustrate how the process can be made more
accurate by cone beam radio therapeutic computed tomography
(RCT), accurate dose response data, 3-D in vivo predictive
assay of radiation responsiveness, week 0 and after week 1, in
vivo IMRT dose delivery imaging and sub mm resolution 4-D
laser camera patient imaging and auto set up both during
treatment and 4-D tumor diagnostic imaging (Brahme et al.
2008; Brahme 2009)
Physical, Biological and Clinical Background 241

Fig. 21 Illustration of how

the efficiency of radiation
therapy is increasing going
from photons with &100
portals to single-charged
particles such as electrons and
protons with &50 portals and
negligible exit dose (middle
row) and light multiply
charged ions such as lithium
and carbon ions where 5–20
portals often suffice. With
lithium and carbon ions the
advantage of an increased
apoptotic cell kill and
induction of senescence in the
tumor region is illustrated in
red (cf Fig. 13). A more than
10-fold reduction in the
number of beam portals
and consequently the dose-
delivery work load is thus
possible with light ions

from light ion therapy for efficient cure and minimal
normal tissue damage to obtain a high quality of life
after the treatment. This is clearly seen in Fig. 18
where the percentages of the patients with a recurrent
tumor and treatment complications are clearly
reduced going from 3-D conformal to photon IMRT
and protons and even further to light ions. It will
therefore be natural to eventually treat more than the
10% of the tumors, mentioned above, that are ideally
suitable and treat the most advanced third of our
tumors with radiation quality modulated light ion
radiation therapy (QMRT), which in principal cover
all ionization densities from low to high LET
depending on the state of the local disease and the
proximity to organs at risk.
3.5 Improved Diagnostic Imaging
of Tumor Responsiveness and Dose
Delivery by PET-CT
In the early days of the development of inverse radia-
tion therapy planning (IRTP) and IMRT the goal was to
shape arbitrary physical dose distributions by dynamic
scanning of pencil beams or by dynamic multileaf
collimation (Brahme 1979, 1982, 1988; Brahme et al.
242
Fig. 22 Eight steps in the
development of external-
beam radiation therapy. The
bottom row shows a number
of new imaging techniques
some of which, such as
PET-CT imaging, may
significantly improve the
outcome of radiation therapy
particularly when used in
combination with biologically
optimized approaches.
(cf Figs. 19 and 20)
1980, 1982, 1983, 1989; Lind and Brahme 1985, 1987;
Näfstadius et al. 1984). However, it was very soon
realized that true optimization of radiation therapy
required that the right dose delivery should produce the
best possible clinical combination of tumor cure and
minimal adverse normal tissue side effects.
Thus, a radiation biological optimization of the
treatment outcome is really the key goal of radiation
therapy optimization. This could be done in terms of the
effective quality of life for the patient during and after
therapy or more specifically maximizing tumor cure and
minimizing treatment related side effects. For many
years this was effectively achieved by maximizing the
probability of achieving complication free tumor cure
(P+, cf Fig. 19, Ågren et al. 1990 and Källman et al.
1992a and b) but can today be best achieved by first
maximizing P+ and thereafter minimizing the proba-
bility of treatment-related injury requiring P+ to stay
high during this process as seen in Fig. 17a. These
treatment objectives are much more advanced than
what is commonly mentioned as biologically optimized
ion therapy where just a uniform cell kill is aimed at
disregarding normal tissue side effects in and around the
target volume. In fact, most of the time unavoidable
radiation effects in healthy normal tissues surrounding
the tumor limit the treatment outcome. It is important to
take this into account in a truly biologically optimized
treatment approach since we never know the true
A. Brahme
radiation sensitivity of the tumor. The ultimate devel-
opment of radiation therapy is therefore to try to mea-
sure the radiation response during the initial phase of
therapy and then try to biologically adapt the treatment
to the observed response. For this purpose a new
approach called BIOART—‘‘the art of life’’—using
Biologically Optimized 3-D in vivo predictive Assay
based Radiation Therapy is being developed as illus-
trated in Figs. 19 and 20. This is a truly biologically
adaptive approach where the early tumor response is
picked up by repeated 3-D PET-CT imaging, 3-D
patient position imaging and PET-CT dose delivery
imaging and after the first week of therapy the dose and
biological effect delivery is modified to maximize the
final treatment outcome as illustrated by the right inserts
in Fig. 20 (Brahme 2003 and 2009).
With the increased precision in light ions dose
delivery advanced tumor imaging is really needed for
accurate treatment planning and target volume deter-
mination. Based on a PET-CT image of the paraaortal
lymph nodes, Fig. 21 (cf also Figs. 19 and 20) show the
increased effectiveness of light ion therapy, because the
number of beam portals can be about 10 times lower
than with low-LET photons, electrons and protons
(cf also the insert of Fig. 16a). New diagnostic
modalities such as PET-CT and MRSI, will also give a
measure of the tumor cell density and hopefully in
addition the tumor responsiveness by repeated imaging
Physical, Biological and Clinical Background
(Brahme 2003). Another advantage of most light ions is
that positron emitters are created along the ion track and
not least at the end of the range and could be detected by
PET imaging. It has been shown that the delivered dose
from high energy photons and carbon ions can be
estimated using PET-CT imaging at the treatment
facility. This method could be further refined to com-
pare diagnostic and therapeutic information at different
times during the treatment schedule to determine the
radiation resistance of the tumor. The treatments could
therefore be highly individualized, taking the respon-
siveness of the tumor in 3-D into account using
Biologically Optimized in vivo predictive Assay based
Radiation Therapy (BIOART, Brahme 2003). The sci-
entific bases for the BIOART approach is to do repeated
PET-CT imaging during the early phase of radiation
therapy to estimate the tumor radiation responsiveness
and mean dose delivery during the treatment. This
information can then be used for biologically based
inverse treatment planning as shown in Figs. 19 and 20
and derive the optimal final dose delivery with
available radiation modalities. The figures really shows
how different radiation modalities such as photons,
electrons and light ions can be optimally combined to
give a high therapeutic tumor effect at the same time as
normal tissue side effects are kept as low as possible
from physical and biological points of view.
3.6 Accurate Patient Fixation
and Registration of Organ
and Tumor Movements
High-precision dose delivery using pencil beam scan-
ning require accurate patient set up and control of tumor
and organ movements to achieve accurate dose deliv-
ery to the target volume, as seen in Figs. 17 and 20.
A laser scanner has been developed for use with con-
ventional as well as light ion therapy (Fig. 20 and
Brahme et al. 2008). When gated therapy is used to
irradiate a lung tumor during a specific phase of the
breathing cycle the laser camera can be used for gating
the treatment and largely eliminate movement uncer-
tainties. Breath-hold monitoring or real-time imaging
and treatment synchronization of the motion of tumors
and organs at risk is the final goal. This is perfectly
possible with scanned pencil beams where the accel-
erator pulse can be delivered when chest wall or
breathing motions are in same breathing phase interval
243
as used when deriving the biologically optimized
treatment plan. This plan should preferably be derived
by selecting the best possible phase e.g. in terms of P+
from many 4-D biologically optimized treatment plans.
3.7 Physically and Biologically Based
Treatment Optimization
Computer programs for physical and biological opti-
mization of the dose delivery have been developed
(cf Figs. 17, 18, 19, 20 and 21) for photons and light
ions and they are in fairly widespread use today. Such
programs are particularly useful for the assessment of
optimal treatments with light ions. The calculations
should be based on physics and biological data and the
results compared with the present clinical experience
from Chiba and Darmstadt. Most important are the
tumor DRR that characterize the probability to achieve
tumor cure at high doses as seen in Fig. 16 but also
those of the normal tissues reactions. It is therefore
particularly important to integrate methods like the
BIOART approach into clinical light ion therapy proce-
dures since the biological response is strongly varying
in light ions beams (cf Figs. 2, 3, 7, 8, 9 and 10).
4 Development of Comprehensive
Cancer Centers and Biologically
Optimized Radiation Therapy
Besides a strong multi-disciplinary cancer care and
advanced equipment for tumor diagnostics and ther-
apy, a comprehensive cancer center needs advanced
research departments for medical radiation biology,
medical radiation physics, tumor pathology and
molecular oncology, working in close connection
with clinical oncology. A Comprehensive Cancer
Center should also include laboratories for experi-
mental cancer research and basic tumor biology
research. The infrastructure for clinical research
facilitates, the development of translational research
programs which require a well-developed clinical
trial unit, population-based registries for outcome
research, resources for quality of life studies, a well-
functioning program for biobanking and technical
platforms for genomics and proteomics. With strong
research resources in medical radiation physics the
total environment is well optimized for research with
244
Fig. 23 a Building and equipment locations in the proposed
layout for an expansion of the radiation therapy department of
Karolinska University Hospital is shown in the left part of the
figure. The light ion treatment rooms at two levels to the right are
equipped with two excentric gantries allowing treatments from
practically any direction (cf Fig. 24) via a 1208 wide range of
variability in each of the four rooms. PET-CT and MRSI-based
tumor diagnostics as well as compact high energy scanned photon
therapy allowing PET-CT in vivo dose delivery verification
the aim to develop comprehensive radiation therapy.
The addition of facilities for advanced light ion
therapy to more conventional accelerators for 3-D
conformal, IMRT and tomotherapy treatments as well
as advanced brachytherapy techniques, hyperthermia,
photodynamic therapy and BNCT may be useful to
A. Brahme
(cf Fig. 20) is also available. Furthermore, Carbon-11 can be
produced in the range shifter to produce positron emitting ion
beams to allow 50-fold more accurate in vivo Bragg peak density
monitoring (cf Brahme et al. 2001a, b and Fig. 25). b Cross
section through the HIMAC accelerator at NIRS Chiba, Japan
where 95% of the worlds clinical experience on carbon ion
therapy has been collected as shown to the right. Up to 2011
almost 6000 patients have been treated and more than 3000 of
them by Highly Advanced Medical Therapy (HAMAT) protocols
create a complete set of resources for an advanced
cancer treatment. Coordination of imaging facilities
(MRSI, PET-CT and PS (phase contrast stereoscopic
X-ray imaging)) for an advanced tumor diagnostic
centre is also essential. PET-CT is probably the ulti-
mate tool for accurate tumor imaging and 3–4-D in
Physical, Biological and Clinical Background
Fig. 24 Cross-section through a superconducting cyclotron
with the particle and energy selecting excentric ion gantry
(upper right panel) capable of treating patients in four
surrounding rooms as shown in the lower left panel. The four
treatment rooms with protons to carbon ions allow a 10–12 min
set up time, and a 2–3 min treatment time/room. In this way a
total 12–16 pat/hour, 100–120 pat/day and 2,500–3,000 pat/
vivo predictive assay of radiation sensitivity. There is
a need for very sensitive, large axial field of view
(&1 m) advanced PET-CT-based dedicated tumor
cameras preferably allowing accurate sub-mm phase
contrast X-ray imaging in the central region and ultra
high sensitivity PET imaging in the entire volume of
possible tumor infiltration. An integrated Laser
Camera (LC, cf Figs. 20 and 25) makes it possible to
project all the PET data to any phase of the breathing
cycle to maximize tumor sensitivity in dynamic
regions. By imaging the tumor twice during the early
course of therapy it may also be possible to quantify
both the tumor responsiveness to therapy and the rate
of loss of functional tumor cells.
245
year (at 10–12 fractions/pat) can conveniently be treated. The
decelerating graphite range shifter is indicated where carbon 11
can be produced in therapeutic quantities allowing 50-fold
increase in Bragg peak imaging accuracy. The lower right
panel shows a close up of the stereotactic treatment couch to be
used to dock the patient both to the PET-CT camera and the
therapy unit (cf Fig. 23a)
Development of molecular radiobiology and
genomics should be used to establish methods to
predict treatment outcome. A large patient population
and collaboration with other centers makes a large
number of patients available for routine treatment and
outcome research. Within a Comprehensive Cancer
Centre of this type a Centre of Excellence for Clinical
Radiation Therapy will create fruitful environment for
research and development to which a centre of
excellence on Advanced Radiation Therapy Research
should also be an integral part. The rapidly increasing
body of genetic information that is now becoming
available, not least through projects like the Human
Genome Project (HUGO) the proteomic databases
246 A. Brahme

Fig. 25 Patient set up using

both laser cameras with green
scanned fan-shaped laser
beams for auto set up of the
treatment based on the 3-D
shape of the patient’s surface.
A cone beam CT facility for
set up on internal reference
points is included in the
gantry for fast check that the
patient’s internal structures
are accurately positioned. The
stereotactic treatment couch
docking and cone beam CT
devices as well as the four
PET detector arrays are
retracted into the excentric
gantry during gantry rotation
or when not needed

will rapidly increase our knowledge about genes that
affect radiation sensitivity and malignancy and
improve our understanding of the clinical radiation
responsiveness. Different organs of the human body
have often significantly differing responses to partial
or heterogeneous irradiation, depending on the func-
tional organization of the different tissues and the part
of the genome that is actively transcribing. In addi-
tion, different radiation types have widely varying
biological effects depending on their ionization den-
sity as shown in Figs. 2, 7, 8, 9 and 10.
The fast development of high energy treatment
units and IMRT during the last two decades using
photon and electron beams has resulted in a consid-
erable improvement of radiation therapy, particularly
when combined with radiobiologically-based treat-
ment optimization techniques as seen in Figs. 17, 19,
20 and 22. This has made intensity-modulated elec-
tron and photon beams practically as powerful as
conventional uniform beam proton therapy Brahme
(2004). To be able to cure also the most advanced
hypoxic and radiation resistant tumors of complex
local spread, intensity-modulated light ion beams are
really the ultimate tool and in clinical practice and as
much as 2–3 times more cost effective than just
proton therapy. This development and the recent
development of advanced tumor diagnostics based on
PET-CT imaging of the tumor clonogen density opens
the field for new powerful radiobiologically-based
treatment optimization methods. The ultimate step is
to use the unique radiobiological and dose-distribu-
tional advantages of light ion beams for truly opti-
mized bioeffect planning where the integral 3D dose
delivery and tumor cell survival can be monitored by
PET-CT imaging and corrected by biologically-based
adaptive therapy optimization methods (Brahme
2004, 2005, 2009, 2011; Brahme et al. 2008).
5 Equipment and Building Design
5.1 Patient Recruitment and Treatment
Capacity
The light ion facilities being built for Heidelberg and
Pavia have three treatment rooms each and it is esti-
mated that it should be possible to treat 1,000–1,200
patients/year at each center. In these estimates the
new information on the considerable reduction of the
number of treatment fractions needed per patient, as
shown in the Japanese trials, was not taken into
account. At least a 2-fold increase in the treatment
capacity and a cost effectiveness superior to that of
advanced electron and photon therapy may be
Physical, Biological and Clinical Background 247

Fig. 26 Treatment of a
prostate cancer with a three-
field technique. The treatment
takes place in the lower left
treatment room (cf Fig. 24) to
allow the first vertical beam
(1). The rotation of the
treatment couch is done
automatically by supervision
from the treatment room using
an ordinary video camera and
by the 3-dimensional laser
camera with 0.1 mm
resolution

expected. With conventional radiotherapy equipment
in average 1,000 patients are treated per year using
three treatment units and one shift (8 am–4 pm). The
main difference, when only curative intended treat-
ments are considered for conventional radiation and
ion treatments, is that for the former many more
fractions must be delivered as seen in Fig. 21. In the
recent SBU report (Ringborg et al. 2003) it was
shown that the most common schedule was 25 frac-
tions. In Japan the very successful carbon ion treat-
ments of lung tumors was very successful with only 4
fractions during 1 week but today they are only using
one single treatment fraction. Further, for some
patients only a boost will be given with light ions. In
conclusion taken all these facts into consideration it
seems possible to treat 500–800 patients per room/
year with light ions.
5.2 Conventional Radiotherapy
and Biologically Optimized IMRT
Most small tumors are well-treated by conventional
uniform beam dose delivery. More advanced tumor
stages and tumors of complex local spread may require
Biologically Optimized Intensity-Modulated Radiation
Therapy (BIO-IMRT). The most advanced tumors
benefit substantially by Biologically Optimized PET-
CT imaging using 3D in vivo predictive Assay-based
Radiation Therapy (BIOART). The latest biological
optimization algorithms are a prerequisite for these
developments, not least when multiple treatment
modalities are desirable. The important ability to opti-
mize the complication free cure by QMRT (radiation
Quality Modulated Radiation Therapy) using light ion
therapy is illustrated in Figs. 19 and 20 by first scanning
the therapeutic beam so the high-LET component in
normal tissue is least detrimental and finding the optimal
high- and low-LET dose combination (Brahme 2011).
5.3 Connection to Conventional
Radiotherapy
As an example the Light Ion Center at Karolinska
University Hospital (Fig. 23a) is planned to be in
direct connection to the present radiotherapy center
with eight accelerators covering the energy range
from 2 to 50 MeV for photons and electrons. Inter-
estingly the high energy photons allow PET-CT-based
photo nuclear dose delivery verification in vivo,
similar to the possibilities with the nuclear interac-
tions of light ions. It is of key importance to have a
good connection between conventional radiation
248 A. Brahme

therapy infrastructure and light ion therapy for effi-

cient and careful patient selection and workup. For
comparison the very first carbon ion therapy research
center is shown in Fig. 23b.

5.4 Number of Patients

After running a new facility for about 3 years it seems

realistic to treat about 1,500–2,000 patients/year with
four treatment rooms and one excentric gantry
(Figs. 23, 24, 25 and 26). At 5 years more than double
this value may be possible. Further increases in
patient numbers treated are possible by using an ini-
tial Boost therapy where hypoxic tumors are mas-
sively eradicated in the early phase of the treatment
with light ions and gradually low-LET radiations are
used to eliminate remaining microscopic tumor cells
as recently discussed in more detail elsewhere
(Brahme et al. 2001a). With two excentric gantries
with separate energy degraders and a beam splitter
around 5,000-6,000 patients can be treated per year as
illustrated in Figs. 23, 24, 25 and 26. The beam
splitter will allow simultaneous treatment in one room
each of the two excentric gantries.
Fig. 27 a Overview of the cancer situation in Europe 1991
when the cancer cure was 45% and almost 20% of the patients
were lost locally due to insufficient local treatment. b With
5.5 Beam Delivery System, Treatment early detection and improved local treatments using IMRT and
Rooms and Gantries light ions it should be possible to reduce the locally progressing
fraction to about half its present value and increase the cure to
almost 75%
Since both light ions and high-energy photons acti-
vate the tissues in the patient they all benefit from the
possibility to use PET-CT-based dose delivery veri- used at NIRS in Chiba, Japan where presently one
fication. A light ion center may therefore need to be room have two fixed beam directions (Therapy room
equipped with two PET-CT cameras close to the light B in Fig. 23b). Interestingly, a recent study showed
ion and photon scanned pencil beam treatment rooms that very specific beam angles are generally not
so patients can be rapidly scanned for the dose required with 4-D Bragg peak scanning for shaping of
delivery after treatment as proposed in Fig. 23a. Two biologically optimized dose distributions (Brahme
excentric light ion beam gantries each of which is 2005). Once the right angular interval is available the
covering four treatment rooms (cf Figs. 23, 24, 25 and exact angle of incidence is not very critical provided
26) with a wide range of possible beam angular the angle between two different beam portals is more
intervals and beam directions covering angles of than about 308 and full flexibility in intensity and
incidence of ±608 or about 1208 in each room (See location (4-D) of the Bragg peaks are available. In
Fig. 24) because the couch can be rotated more than fact, Figs. 19 and 20 show how the optimal scanning
1808. These figures clearly illustrate the great flexi- pattern can be calculated using Inverse therapy
bility in treatment set up with excentric gantries on a planning with physically or biologically optimized
number of common treatment techniques currently dose delivery.
Physical, Biological and Clinical Background
Fig. 28 The development of cancer care costs without and
with light ion therapy. Through the reduction of the risk of
locally recurrent tumors, the reduction of the expenditure for
expensive palliative care may be reduced by around 100 M€
each year by a large ion installation as in Fig. 23. This means
that the total cost of the installation will be regained each year
after it is in full use about 5 years after installation
Interestingly, the clinically advantageous syner-
gistic effect between the lower LET plateau regions
and the high-LET Bragg peaks should be considered
when designing the 3-D scanning pattern of the beam
from the treatment units. It is highly desirable to
deliver the majority of the local low- and high-LET
dose fractions as closely in time as possible to max-
imize the therapeutic response. This is automatically
done by the ridge filters used in Chiba. The ridge
filter continuously and instantaneously shifts the
Bragg peak over the entire range of Bragg peak
modulation, achieving maximum synergism. With 3-
D Bragg peak scanning this is achieved only by fast
longitudinal scanning whereas lateral scanning start-
ing at the most distal point may deliver the last
anterior Bragg peaks 1–3 min later reducing the
effective therapeutic high-LET dose fraction by as
much as 20–25% (Brahme 2011). This may explain
the somewhat lower therapeutic effect seen in
Darmstadt for cordomas treating tumors by fast lat-
eral and slow longitudinal electromagnetic scanning
compared to the result from Chiba using ridge filters.
The difference of about 20% seen in the clinical data
indicates a higher therapeutic effect as expected for a
treatment where the high- and low-LET dose frac-
tions are delivered almost simultaneously as it is the
249
case with ridge filters. Unfortunately it is slightly
more difficult to rapidly vary the extraction energy
and range using longitudinal scanning with a syn-
chrotron of slow pulse repetition rate. A fast material
range shifter at the end of the dose delivery system
may therefore be desirable or even needed to achieve
fast longitudinal scanning of the Bragg peak for
optimal tumor cure.
6 Economical Aspects
6.1 Capital Expenditure
The most recent figures on the total costs are available
from the German, Italian, French and Austrian facil-
ities; the former, having three treatment rooms (one
gantry), report 105 M€ and the latter, having five
treatment rooms (three gantries), reported 105 M€.
The planned facility at Karolinska University Hospi-
tal with a novel less expensive design of the gantries
is estimated to about 850 MSEK or 95 M€ with four
treatment rooms. The costs of buildings and most of
the infrastructure are included. With two gantries, the
photon beam IMRT units and PET-CT imaging the
total cost will be about 130 M€.
6.2 Cost per Patient for Different Types
of Cancer Treatments
Through the European light ion collaboration
ENLIGHT the cost of different treatment methods
have been studied. In Austria it is estimated that the
cost for a complete ion therapy schedule will be
20,000 € to be compared with in average 44,000 € for
chemotherapy and 18,000 € for surgery. The French
costs are lower but then a large part of the investment
is from grants. In US each session using IMRT with
conventional radiation are 750 USD and in addition
3000 USD for treatment planning that is for example
for 35 sessions for a prostate cancer about 30,000
USD. Proton treatments in US are charged more than
double the amount (75,000 USD) due to the more
expensive equipment and reimbursement regulation.
The Swedish cost calculations for one ion session are
about 850 €. As much fewer sessions are needed with
250
light ions than with IMRT, a complete treatment
would in average cost between 10 and 25,000 €
depending on the total number of patients treated. (All
costs are on the 2005 level).
Due to the fractionation advantage, the light ions
are about 2–3 times more cost effective than protons
and comparable to IMRT photons and electrons at the
same time as they are more effective and curative on
resistant and hypoxic tumors. In a recent EU study the
situation of cancer treatment in Europe 1991 was
presented showing that almost half of all patients
were cured that year as seen in Fig. 27a. Due to
improved therapeutic methods the situation today is
well above 50% and may reach as high as 75% when
IMRT and light ions are fully taken into clinical use
(cf Fig. 27b, estimated).
7 Conclusion
The total yearly cost for cancer care in Sweden
(9 million inhabitants) is rapidly reaching 1 billion €
(cf Fig. 28). Of this cost only about 5% is presently
due to radiation therapy and it may reach about 7%
after introduction of light ion therapy. The total cost
for palliative care of locally-recurrent tumors is as
high as 200–300 M€ since almost 20% of the treat-
ments are today failing locally (cf Fig. 27). However,
with light ions this fraction may be reduced to about
half its present value or even lower leading to a yearly
gain under full operation of the center of about the
same size as the total cost of the equipment. Light ion
therapy is therefore, despite its large initial invest-
ment costs, one of the most cost-efficient advanced
cancer therapy modalities available today as shown in
Fig. 28, this and the extremely promising clinical
results in Figs. 16, 17 and 18 indicate that we urgently
need to bring it into clinical practice.
Even if biologically optimized radiation therapy
has proven difficult to introduce in most conventional
radiation therapy departments it will be urgently
needed with light ions in order to make full clinical
use of the significant biological advantages. There is
no doubt that QMRT and BIOART are very important
developments for light ion therapy and they are pro-
cedures that are very important to introduce already in
the first generation of clinically dedicated light ion
A. Brahme
installations. The largest benefits are expected for
hypoxic and generally radiation resistant tumors for
conventional low-LET beams, where we can expect
the most important treatment improvements as clearly
shown by the clinical results of Prof Tsujii and his
team at NIRS in Chiba, Japan.
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 Three-Dimensional Treatment Planning
and Conformal Therapy
James A. Purdy, Philip Poortmans, and Carlos A. Perez
Contents
1 Introduction.............................................................. 254
2 Volume Specification for CRT ...............................
2.1 Definition of Target Volumes...................................
2.2 Definition of Organs at Risk.....................................
2.3 Dose Reporting and Dose Prescription.....................
3 Dose-Volume Histograms........................................ 258
4 Biological Models for Dose-Volume Response.....
4.1 Tumor Control Probability ........................................
4.2 Normal Tissue Complication Probability .................
4.3 Equivalent Uniform Dose .........................................
5 Conformal Therapy Planning Process ..................
5.1 Patient Treatment Position/Immobilization
and Planning Imaging Study(s).................................
5.2 Volume Delineation...................................................
5.3 Dose Prescription.......................................................
5.4 Conformal Planning...................................................
5.5 Plan Evaluation/Plan Improvement ..........................
5.6 Plan Implementation and Treatment Verification ....
6 Management of CRT Data ..................................... 270
7 Summary and Conclusion....................................... 270
References.......................................................................... 271
J. A. Purdy (&)
Department of Radiation Oncology,
University of California Davis Medical Center,
Sacramento, CA 95817, USA
e-mail: james.purdy@ucdmc.ucdavis.edu
P. Poortmans
Department of Radiation Oncology,
InstituteVerbeeten, Tilburg, The Netherlands
C. A. Perez
Department of Radiation Oncology,
Mallinckrodt Institute of Radiology,
Washington University School of Medicine,
St. Louis, MO 63110, USA
S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_322,  Springer-Verlag Berlin Heidelberg 2012
Abstract
Three-dimensional conformal radiation therapy
(3DCRT) is now well established in routine
255 clinical practice as an effective means of achieving
255 higher tumor doses without increasing doses to
256 critical normal structures. 3DCRT emphasizes a
257
volumetric image-based virtual simulation
approach based on the delineation of image-based
260 tumor volume(s) and the associated microscopic
260 disease volume(s), as well as the critical normal
261 structures, for every individual patient. It should be
261
understood that the 3D planning process puts
262 increased demands on the radiation oncologist to
specify tumor/target volume(s) and organs at risk
262
263 with far greater accuracy than before. Moreover,
266 this technology also places increased demands on
266 the radiation oncology physicist and radiation
267 technologist to insure adequate treatment planning
268
and quality assurance measures are in place to
accommodate the 3DCRT process, e.g., the need
for increased precision in tumor imaging, patient
set-up reproducibility, organ motion assessment,
and treatment delivery verification. Readers will be
able to appreciate the 3D planning approach and
CRT much more fully, if they view it as a process,
rather than viewing it as a particular beam
configuration, or considering it simply as imple-
menting certain technology. In this chapter, we
discuss the physics and clinical aspects of 3D
treatment planning and conformal therapy includ-
ing volume definitions, planning approaches, plan-
ning tools, plan implementation and treatment
verification.
253
254
1 Introduction
Radiation therapy treatment planning and delivery
processes have changed dramatically since the intro-
duction of three-dimensional treatment planning in the
1980s and continue to change in response to the imple-
mentation of new technologies (Purdy 1996, 2007).
CT-simulation and three-dimensional radiation treat-
ment planning systems (3DTPS) provide the tools for
carrying out 3D conformal radiation therapy (3DCRT),
which is now well-established in routine clinical practice
as an effective means of achieving higher tumor doses
without increasing doses to sensitive normal structures.
The transition to 3DCRT did not come easily and
was met with some resistance (Meyer and Purdy
1996), because 3DCRT was not just an add-on to the
two-dimensional (2D) radiation treatment planning
process. Rather, it represented a radical change in
practice particularly for the radiation oncologist, and
also to some degree for the supporting planning/
delivery team members including physicists, dosim-
etrists,1 and radiation therapists.2
The older 2D treatment planning approach empha-
sized the use of a conventional X-ray simulator in which
standardized beam arrangement techniques could be set
up and planar radiographs generated. These radiographs
were used by the radiation oncologist to design shield-
ing blocks based mainly on the visualized bony land-
marks to create custom beam portals. The 2D approach
was much less laborious than the 3DCRT approach;
however, it greatly limited the ability to escalate dose.
In contrast, 3DCRT emphasizes a volumetric
image-based virtual simulation approach based on the
delineation of image-based tumor volume(s) and the
associated suspected microscopic disease volume(s), as
well as the organs at risk (OARs) within the irradiated
volume, for each individual patient. Hence, the 3D
planning process places increased demands on the
radiation oncologist to delineate tumor/target
volume(s) and OAR(s) with far greater accuracy than
before. Moreover, this modality also places increased
1
There is significant variation in the title and function used for
these positions, especially from one country to another: in the
U.S. the name dosimetrist and radiation therapist are used; in
Europe the name radiotherapy technologist (RTT) is more
common.
2
See foot note 1.
J. A. Purdy et al.
demands on the radiation oncology physicist, dosime-
trists, and radiation therapist to ensure that adequate
treatment planning and quality assurance (QA)
measures are in place to accommodate the 3DCRT
process, e.g., the need for increased precision in tumor
imaging, patient set-up reproducibility, organ motion
assessment, and treatment delivery verification.
More recently, manufacturers have employed
advanced computer technology to produce treatment
planning/delivery systems equipped with computer-
controlled multileaf collimators (MLC) systems. These
planning systems are used to determine MLC leaf
positions that will precisely generate the optimized
incident radiation beam fluence that results in a dose
distribution that meets rigorous a priori specified dose-
volume constraints. This mode of therapy is referred to
as Intensity Modulated Radiation Therapy (IMRT), and
is capable of generating dose distributions that provide
extremely conformal target volume coverage for even
the most complex shapes, and conformal avoidance of
specific sensitive OARs (Webb 2000). IMRT has rap-
idly been implemented in clinics throughout the U.S.
and Europe. This more advanced form of conformal
therapy will be introduced in this chapter and reviewed
in more detail in ‘‘Linac Based Image Guided Intensity
Modulated Radiation Therapy’’ and ‘‘Tomotherapy
Image Guided Radiation Therapy’’.
It should also be noted that the highly conformal
doses provided by IMRT have focused attention on
the need to better account for both intrafraction and
interfraction variations in patient positioning and
internal organ shapes and locations, which has led to
the development of treatment machines with inte-
grated planar and volumetric imaging capabilities
(Jaffray et al. 2002). In addition, improved tumor and
normal organ definition are possible thanks to the
recent advances in both anatomical and functional
imaging. Advances in these technologies continue to
occur at a fast pace and has pushed radiation oncology
toward what is now referred to as image-guided
radiation therapy (IGRT) (Bortfeld et al. 2006).
In this introduction section, it is important to further
clarify the use of the terms 2D and 3D as descriptors for
the planning process. Planning the cancer patient’s
treatment is (and always has been) a 3D problem
(at least in regard to the spatial distribution of dose), and
when the authors refer to 2D planning, we are referring
to the process and tools used. Also, 3D treatment
planning does not require the use of ‘‘noncoplanar’’
Three-Dimensional Treatment Planning and Conformal Therapy 255

beams, a common misconception. The reader will be

able to appreciate the 3D planning approach and CRT
much more fully, if they view it as a process, rather than
viewing it as a particular beam configuration, or con-
sidering it simply as implementing certain technology.
In this chapter, we will emphasize this approach and
discuss the physical and clinical aspects of 3D
treatment planning and conformal therapy including
volume definitions, planning approaches, planning
tools, plan implementation, and treatment verification.

2 Volume Specification for CRT

The International Commission on Radiation Units and

Measurements (ICRU) Reports 50, 62, and 83 have
given the radiation oncology community a consistent
nomenclature and a methodology for image-based
volumetric treatment planning for CRT (ICRU 1993,
1999, 2010). These volume definitions are illustrated
in Fig. 1 and are discussed briefly in the following
sections.

2.1 Definition of Target Volumes
For CRT planning, the physician must specify the
volumes of known tumor, i.e., Gross Tumor Volume
(GTV), the volumes of suspected microscopic spread,
i.e., Clinical Target Volume (CTV), and the additional
margin around the CTV/GTV necessary to account for
set-up variations and organ and patient motion, i.e.,
Planning Target Volume (PTV). At the same time,
organs at risk (OAR) in the vicinity of the treated area
have to be delineated to facilitate the design of
appropriate beam arrangements and to calculate the
dose to the OAR, thereby giving an estimate for the
risk for developing side effects and complications.
ICRU Report 62 formulated more accurately the
definitions of these ICRU 50 concepts to take into
account the fact that modern imaging procedures
provide even more information on the location, shape,
and limits of the tumor/target volumes, as well as the
normal tissues. It introduced the definition of an
Internal Margin (IM) to take into account the varia-
tions in size, shape, and position of the CTV, and the
definition of a Set-up Margin (SM) to take into
account all uncertainties in patient-beam positioning.
The IM is referenced to the patient’s coordinate
Fig. 1 International commission on radiation units and measure-
ments (ICRU) reports 50 and 62 volumes used in 3D treatment
planning: gross tumor volume (GTV) representing volume(s) of
known tumor; clinical target volume (CTV) representing the GTV
added with the volume(s) of suspected microscopic tumor
infiltration; planning target volume (PTV) which is the volume
containing the CTV/GTV with enough margin necessary to
account for setup variations and organ and patient motion
system using anatomical reference points and the SM
is referenced to the treatment machine coordinate
system. Report 62 argues that identification of these
two types of margins is needed since they compensate
for different types of uncertainties and refer to
different coordinate systems. IM uncertainties are due
to physiologic variations (e.g., filling of bladder or
rectum, movements due to respiration, etc.) and are
difficult or almost impossible to control from a prac-
tical viewpoint. SM uncertainties are related largely
to technical factors that can be dealt with by more
accurate setup and immobilization of the patient and
improved mechanical stability of the machine.
The volume formed by CTV and IM is defined as
the Internal Target Volume (ITV) and represents the
movements of the CTV referenced to the patient
coordinate system by internal and external reference
256
points. The volume formed by the CTV, and the IM
and SM combined is the PTV as previously defined.
However, the exact way that these margins should be
combined mathematically is not rigorously defined.
Simple linear addition of the two margins will gen-
erally lead to an excessively large PTV that does not
reflect the actual clinical need. This point will be
discussed further, but for now it should be understood
that the selection of an overall margin and subsequent
contour definitions to generate the PTV typically
involve compromises that require the experience and
judgment of the radiation oncologist (with input
sometimes from the physicist).
As previously stated, the GTV is the gross extent
of the malignant growth as determined by palpation or
imaging studies. The terms GTVprimary and GTVnodal
(or GTV-T and GTV-N) are typically used to distin-
guish between primary disease and other areas of
macroscopic tumor involvement, such as involved
lymph nodes that are visible on imaging studies. The
GTV-T together with the surrounding volume of local
subclinical involvement constitutes the primary CTV
and can be denoted as CTV-T. Note that if the GTV
has been removed by radical surgery, and radiation
therapy to the tumor bed is considered necessary for
the tissues close to the site of the removed GTV, a
volume substituting for the GTV can be delineated—
often called the ‘‘primary tumor bed’’, after which the
surrounding volume of local subclinical involvement
can be added to form the CTV-T. In some occasions,
the CTV-T is delineated without preceding delinea-
tion of a primary tumor bed as well. Additional
volumes with presumed subclinical spread may also
be considered for therapy, e.g., regional lymph nodes.
These may be designated CTV-N (and if necessary
CTV-N1, CTV-N2, etc.). Adding the letter T, N, or M
to identify the volumes, may help to better clarify
their clinical significance. In specifying the CTV, the
physician must not only consider microextensions of
the disease near the GTV, but also the natural avenues
of spread for the particular disease and sites including
lymph nodes, perivascular and perineural extensions.
The GTV and CTV are anatomical–clinical concepts
that should be defined before a choice of treatment
modality and technique is made.
The PTV is a static, geometrical concept used for
treatment planning, including dose prescription. Its
size and shape depend primarily on the GTV and
CTV and the margin needed to account for
J. A. Purdy et al.
uncertainties caused by internal motion of organs and
treatment setup. The PTV can be considered a 3D
envelope, fixed in space, in which the tumor and any
microscopic extensions reside. The GTV/CTV can
move within this envelope, but not through it. Also,
the penumbra of the beam(s) is not considered when
delineating the PTV. However, the beam penumbra
must be considered when drawing each beam aper-
ture, and additional margin may be needed (or more
beams added), to achieve adequate dosimetric
coverage of the PTV.
In addition to the GTV, CTV, ITV, and PTV
definitions, the ICRU defines two other volumes;
these are not anatomic as before, but are based on the
dose distribution. The Treated Volume is defined as
the volume enclosed by an isodose surface selected
and specified by the radiation oncologist as being
appropriate to achieve the purpose of treatment
(e.g., 95% isodose surface). The Irradiated Volume
is defined as the volume that receives a dose
considered significant in relation to normal tissue
tolerance (e.g., 50% isodose surface). These two
volumes are used mainly for plan optimization and
plan evaluation.
2.2 Definition of Organs at Risk
ICRU Reports 50, 62, and 83 define Organs at Risk
(OARs) as those normal critical structures (e.g., spinal
cord) whose radiation sensitivity may significantly
influence treatment planning and/or prescribed dose.
Report 62 introduces the concept of the Planning Organ
at Risk Volume (PRV), in which a margin is added
around the OAR to compensate for that organ’s spatial
uncertainties, analogous to the PTV margin around the
CTV. However, in contrast to the CTV, dose criteria for
OARs typically depend on the organ’s biological
architecture, i.e., serial organs (such as the spinal cord)
often have a maximum dose constraint, whereas parallel
organs (such as lung) are frequently planned using more
complex dose-volume constraint(s) (e.g., V20Gy). This
has resulted in some authors concluding that the PRV
concept is of limited value (Stroom and Heijmen 2006).
Nevertheless, the PRV concept is used widely for some
cases utilizing IMRT (e.g., in head and neck cancer, a
safety margin is often added to the spinal cord) because
of the increased sensitivity of this type of treatment to
geometric uncertainties.
Three-Dimensional Treatment Planning and Conformal Therapy
2.3 Dose Reporting and Dose
Prescription
ICRU Reports 50 and 62 define a series of doses,
including the minimum, maximum, mean dose, and
ICRU Reference Dose (defined at the ICRU Reference
Point) for reporting dose. The ICRU Reference Point
for a particular treatment plan should be chosen based
on the following criteria: (1) be clinically relevant and
defined in an unambiguous way; (2) be located where
the dose can be accurately determined; and (3) be
located in a region where there are no steep dose
gradients. In general, this point should be in the
central part of the PTV. In cases where the treatment
beams intersect at a given point, it is recommended
that the intersection point be chosen as the ICRU
Reference Point.
ICRU Report 83 (ICRU 2010) updates the previ-
ous ICRU recommendation on CRT dose reporting
and now recommends moving from single spatial-
point reporting (i.e., the ICRU Reference Point
Dose, minimum and maximum dose) to dose-volume
reporting. This is justified based on the availability
of more accurate model-based dose-calculation algo-
rithms and the advances and ubiquity of modern-day
anatomic/functional imaging.
It also should be understood that in the past
minimum dose and maximum dose referred to point
doses in the dose calculation grid assigned to a single
voxel. It is now acknowledged that the minimum dose
may not be accurately determined because it is often
located in a high gradient region at the edge of the
PTV, making it highly sensitive to the resolution of
the calculation and accuracy of delineating the CTV
and determining the PTV. Moreover, treatment
planning today represents only one single represen-
tation of the calculated dose distribution, while over
the full course of a radiation treatment the minimum
and maximum dose points are likely to shift slightly
from one day to another. For all these reasons, ICRU
Report 83 (ICRU 2010) recommends discontinuing
the use of maximum and minimum doses and instead
recommends the use of the terms near-maximum
(corresponding to D2%) and near-minimum (D98%).
The maximum dose as specified by a single cal-
culation point (Dmax or D0%) has often been reported
for serial-like organs or structures. Previously, such a
reported maximum dose was considered relevant only
if the involved organ had a minimum diameter of at
257
least 15 mm while an even smaller dimension was
considered appropriate for some organs such as eye,
optical nerve, or larynx (ICRU 1993). ICRU
acknowledged that the minimum diameter for the
maximum dose region in a structure is not always
easy to establish and hence recommended that D2% be
reported. However, ICRU pointed out that care should
be taken in a change from maximum dose to the near-
maximum dose D2%. For example, the Radiation
Therapy Oncology Group (RTOG) Protocols 0225 for
nasopharyngeal cancer set the D1% dose at 45 Gy
for the spinal cord. Replacing D1% in this protocol by
D2%, would possibly require the dose constraint to be
less than 45 Gy depending on the gradient of the
spinal cord DVH curve at high doses.
With regard to dose homogeneity, ICRU Report 50
recommends that the dose coverage of the PTV be
kept within specific limits, namely + 7% and - 5% of
the prescribed dose (ICRU 1993). This level of dose
homogeneity may not be achieved in all cases
(particularly for current IMRT techniques), and the
reader is reminded that ICRU Report 50 explicitly
states that if this degree of homogeneity cannot be
achieved, it is the responsibility of the radiation
oncologist to decide whether the dose heterogeneity
can be accepted or not, pointing out that in those
parts of the PTV where the highest malignant cell
concentration may be expected, i.e., GTV, a higher
dose may even be an advantage. Similarly, a slight
underdose to the PTV may be required (particularly if
in close proximity to an OAR) or may result for lung
tumors surrounded by low density lung tissue as a
result of electronic disequilibrium.
It should be noted that ICRU Reports 50/62 do
not make strict recommendations regarding dose
prescription; rather ICRU states that ‘‘…the radiation
oncologist should have the freedom to prescribe the
parameters in his/her own way, mainly using what is
current practice to produce an expected clinical
outcome of the treatment’’ (ICRU 1993). For dose
reporting however, it is required to state also the
prescribed dose according to the ICRU recommen-
dation (e.g., 95% for photons and 85% for electrons)
if actual prescription was not accordingly done.
It is now recognized that there is a large variability
among institutions in IMRT planning and reporting
(Das et al. 2008; Willins and Kachnic 2008). Such
studies strongly support the ICRU Report 83 recom-
mendation to move away from single spatial-point
258
Fig. 2 Example of treatment planning system display
(PinnacleTM, Philips Medical Systems, Highland Heights,
Ohio) showing the cumulative dose-volume histograms for a
typical prostate cancer patient’s plan: the prostate PTV (red)
prescription/reporting (i.e., the ICRU Reference Point
Dose, minimum and maximum doses) to dose-volume
prescription/reporting. In addition, the American
Society of Radiation Oncology (ASTRO) has gone
further and recommended that specific details of the
inverse treatment planning and image-guided treat-
ment processes be recorded using (1) an IMRT
Treatment Planning Directive, (2) a Treatment Goal
Summary, (3) an Image Guidance Summary and (4) a
Motion Management Summary (Holmes et al. 2009).
The authors strongly encourage radiation oncology
electronic medical record manufacturers (e.g., Elekta-
Impac MOSAIQ and Varian ARIA) to quickly
incorporate these templates into their user interfaces,
allowing physicians to enter their IMRT prescriptions
in a more robust and unambiguous manner.
J. A. Purdy et al.
and multiple OARs (penile bulb-magenta, right femur-yellow,
left femur-orange, rectum-brown, bladder-blue); also shown
are associated dose statistics for the various defined volumes
3 Dose-Volume Histograms
The large amount of dosimetric data that must be ana-
lyzed when a CRT plan is evaluated has prompted the
development of methods of condensing and presenting
the data in more easily understandable formats. One such
data reduction tool is the dose-volume histogram (DVH)
(Drzymala et al. 1991). Two types of DVHs, differential
and cumulative, are available in CRT planning, with the
latter now widely used in plan evaluation for assessing
PTV(s) coverage and dose to OARs, as displayed in
Fig. 2. However, it must be clearly understood that the
DVH does not provide any spatial information, and thus,
can only complement, and not replace, spatial dose
distribution display tools, such as isodose displays.
Three-Dimensional Treatment Planning and Conformal Therapy 259

Fig. 3 Illustration showing how a differential dose-volume

histogram (dDVH) and a cumulative DVH (cDVH) are gener-
ated: shown is a dose grid for a hypothetical three field plan. In
this plan, an irradiated organ has been sub-divided into 144 voxels
(each voxel is a cube 0.5 cm per side; volume = 0.125 cm3) each
of which receives a dose ranging from 0 to 7.5 Gy

The differential DVH (dDVH) is essentially a plot

of the frequency distribution of the individual dose
distribution elements (called dose voxels) obtained
from the dose grid. Generation of a dDVH is illus-
trated in Fig. 3 which shows a dose grid for a hypo-
thetical three-field plan. The irradiated organ has been
divided into 100 voxels (each voxel is a cube 0.5 cm
per side), with each voxel receiving between 0 and
7.5 Gy. The grid size is small enough so that the dose
can be assumed to be constant within each voxel. The
volume’s dose distribution is then divided into dose
bins and the voxels are grouped according to their
dose bin value without regard to their spatial location.
A plot, as shown in Fig. 4, of the number of voxels in
each bin (y-axis) versus the bin dose range (x-axis) is
by definition a differential DVH. Note that the size of
the dose bin used determines the height of each bin of
the dDVH. For example, if the bin widths were
increased, the heights of the histogram bins would
increase because more voxels would fall into any
given bin. Thus, it should be clearly understood that
the detailed shape of a differential DVH depends on Fig. 4 Differential dose-volume histogram display of the
the dose bin size used, although the underlying voxels shown in Fig. 3. The x-axis shows 1 Gy bin sizes.
a The y-axis is expressed in number of voxels receiving a given
dose-volume data are the same.
dose range. For example, 22 voxels received [ 5 but \ 6 Gy.
A cumulative DVH (cDVH) is a plot in which each b Alternately, the y-axis could be expressed in terms of percent
bin represents the volume, or percentage of volume volume (equal to the fraction of the total volume in that bin) as
(y-axis), that receives a dose equal to or greater than shown or in absolute volume (equal to the number of voxels 9
0.125 cm3 per voxel). For example, 15.3% (or 2.75 cm3) of the
the indicated dose on the x-axis. This can be under-
organ received 5 Gy or more but less than 6 Gy
stood using the data from Fig. 3 again and the dDVH
plot shown in Fig. 4. The cumulative cDVH is gen-
erated by summing all the voxels of the corresponding the maximum dose. Note that in the literature, the ‘‘c’’
dDVH to the right of each dose bin as shown in in the cDVH is generally dropped, leaving just DVH.
Fig. 5. Note that the volume value for the first bin Explicit values of dose-volume parameters can be
(dose origin) is the full volume of the structure extracted from the DVH data and are called dose-
because the total volume receives at least zero dose, volume statistics or simply dose statistics. Examples
and the volume for the last bin is that which receives for target volumes include maximum dose, minimum
260
Fig. 5 Cumulative DVH plot of the voxels shown in Fig. 3 and
previously plotted as a dDVH in Fig. 4. For example, 96 voxels
(67% of the organ or 12 cm3) received a dose of 6.0 Gy or more
dose, mean dose, percentage volume receiving greater
than or equal to the prescription dose; for OARs, they
typically include maximum point dose, mean dose,
and percentage volume receiving greater than or equal
to an established tolerance dose. As previously stated,
ICRU Report 83 (ICRU 2010) recommends replacing
the minimum dose and maximum dose point doses
with near-maximum (corresponding to D2%) and
near-minimum (D98%) (ICRU 2010).
4 Biological Models for Dose-Volume
Response
The evaluation of a treatment plan quality (i.e., is Plan
A better than Plan B) is difficult and at best a quali-
tative procedure. For example, it is not clear what
degree of dose uniformity within the PTV is optimum,
as dose levels can now be significantly escalated
using CRT techniques; nor is it always clear which
plan is best if the two DVHs for a specific OAR cross
each other (i.e., difficulty in weighting importance of
dose versus volume).
Researchers have developed biophysical models
that attempt to translate the dose-volume information
into estimates of biologic response, i.e., tumor control
probability (TCP) and normal tissue complication
probability (NTCP) models (Bentzen et al. 2010;
Marks et al. 2010a, b). Today, it is agreed that the TCP
J. A. Purdy et al.
and NTCP models developed thus far are not accurate
enough such that the absolute values can be used to
predict the clinical outcome; however, they are used to
compare rival plans and thus help rank the plan quality.
In any case, such biologic indices should be used
clinically only when their utility has been firmly
established for well-defined clinical conditions. ICRU
Report 83 is clear in stating that if biologically based
metrics are to be reported, the assumptions used in the
models, their parameters, and the model itself must be
unambiguously specified (ICRU 2010).
4.1 Tumor Control Probability
It is well known that tumor control probability (TCP)
plotted as a function of dose has a classical sigmoid
shape having zero control at some low dose to control
at some high-dose. The authors make no attempt to
review in detail the various models but provide some
discussion on relevant issues. Readers are referred to
the following articles for more details (Bentzen and
Tucker 1997; Brahme 1984; Goitein 1987; Moiseenko
et al. 2005; Schultheiss et al. 1983). Simple phe-
nomenological TCP models can be represented by the
logistic function as shown below:
1
TCP ¼   4c50% 
D50%
1þ D
where D50% is the dose at which the TCP is 50% and
c50% is the slope of the dose response curve at 50%
tumor control, and D is the dose administered
(Schultheiss et al. 1983). It should be noted that the
use of the logistic function assumes an approximate
uniform cell response and a uniform dose distribution.
For a nonuniform dose distribution, the total tumor
volume is reduced to smaller volumes having
‘‘uniform’’ doses within each sub-volume element vi.
The TCP value for each volume element, TCP(v, D),
can be inferred from the TCP for uniform irradiation
of the entire tumor volume, TCP(1, D) using the
following equation:
TCPðv; DÞ ¼ TCPð1; DÞv
Thus, the TCP for the tumor receiving an inho-
mogeneous dose is given by the product of the indi-
vidual volume element TCPs as shown in the
following equation:
Three-Dimensional Treatment Planning and Conformal Therapy
Y
N effect is small. When NTCP is plotted against dose, the
TCP ¼ TCPðvi ; Di Þ
i¼1
where TCP(vi, Di) is the TCP for the ith volume element
receiving dose Di and N is the total number of tumor
volume elements. The reader is reminded that the
validity of the above equation is highly dependent on
the validity of the assumptions that the individual tumor
volume elements are uniformly distributed throughout
the tumor volume and are equally radiosensitive.
4.2 Normal Tissue Complication
Probability
There are mainly two different approaches used in
radiation therapy in modeling NTCP: the empiric
model introduced by Lyman and Wolbarst (1987,
1989), and the functional models which introduced
concepts of serial and parallel tissue organization and
functional subunits (FSUs) (Källman et al. 1992; Olsen
et al. 1994; Schultheiss et al. 1983; Withers et al. 1988).
The Lyman NTCP model can be expressed by an
error function of dose (D) and volume (v) as shown
below:
Z1
1
NTCPðD; vÞ ¼ pffiffiffiffiffiffi expðt2 =2Þ dt
2p
1
where
t ¼ ðD  D50 ðvÞÞ=ðm  D50 ðvÞÞ;
with v equal to the partial volume (V/Vref) and the
tolerance dose-volume dependence given by the fol-
lowing power-law relationship:
D50 ðvÞ ¼ D50 ð1Þ  v n
D50(1) is the tolerance dose for 50% complications
for uniform whole organ irradiation, whereas D50(v) is
the 50% tolerance dose for uniform partial-organ irra-
diation to the fractional volume v. The arbitrary vari-
ables m and n are found by fitting tolerance doses for
uniform whole and uniform partial-organ irradiation,
where m characterizes the gradient (slope) of the dose-
response function at D50 and n characterizes the effect
of volume. When n is near unity, the volume effect is
large; conversely, when n is near zero, the volume
261
NTCP equation demonstrates a sigmoid shape.
Two methods are currently used to extend this model
to nonuniform organ irradiation. The interpolation
method, proposed by Lyman and Wolbarst (1989),
modifies the DVH to one in which the whole organ
receives an effective uniform dose, Deff, which is less
than or equal to the maximum organ dose. The second
method, called the effective volume method, proposed by
Kutcher and Burman (1989), modifies the DVH to one in
which a fraction of the organ, veff, receives the maximum
organ dose. The Lyman model coupled with the
Kutcher–Burman DVH reduction scheme (now called
the Lyman–Kutcher–Burman model) has today become
the most widely used NTCP model (Bentzen et al. 2010).
Other NTCP models include two developed by
Niemierko and Goitein, the critical element model to
be used for serial-like organs (Niemierko and Goitein
1991) and the critical volume model for parallel-like
organs (Niemierko and Goitein 1993) which are
similar in form to that of Lyman and Wolbarst (1987),
but includes additional terms to better account for the
radiosensitivity of the FSUs.
4.3 Equivalent Uniform Dose
Equivalent uniform dose (EUD) is a concept first
introduced by Niemierko (1997a) for evaluating and
reporting inhomogeneous dose distributions and later
re-defined by the following equation (Niemierko 1999):
!1=a
X
EUD ¼ vi Dai
i
where vi is the volume of the dose-volume bin with a
dose Di, and the exponent a is a complication-specific
parameter.
The EUD concept assumes that any two dose dis-
tributions are equivalent if they cause the same
radiobiological effect and appears well suited for use
in evaluating competing conformal plans. However,
McGary et al. pointed out that there are conditions in
which EUD is not adequate as a single parameter to
report or analyze inhomogeneous dose distributions,
e.g., when the minimum dose is significantly lower
than the mean dose (McGary et al. 2000, 1997;
Niemierko 1997b).
262
5 Conformal Therapy Planning
Process
As previously stated, 3D treatment planning for CRT
should be looked at as a process along with the tools
used. This process is summarized in Table 1 and
includes (1) establishing the patient’s treatment
position, constructing a patient repositioning immo-
bilization device when needed, obtaining a volu-
metric image data set of the patient in treatment
position; (2) contouring target volume(s) and organs
at risk using the volumetric planning image data set;
(3) specifying a prescription dose for the PTV
and dose-volume constraints for any OARs; (4.a)
for 3DCRT forward planning—determining beam
orientation and designing beam apertures, and com-
puting a 3D dose distribution according to the dose
prescription; (4.b) for IMRT inverse planning—set
up initial beam orientations and enter optimization
parameters (i.e., dose-volume constraints for PTV(s)
and all regions of interest) and initiate TPS optimi-
zation process which generates beam fluences,
resulting dose distribution, monitor units, and leaf
motion files; (5) evaluating the treatment plan, and if
needed, modifying the plan (e.g., beam orientations,
apertures, beam weights, etc.) until an acceptable
plan is approved by the radiation oncologist; and (6)
the approved plan must then be implemented on the
treatment machine and the patient’s treatment veri-
fied using appropriate QA procedures. All these
tasks make up the CRT process and are discussed in
the ensuing sections.
5.1 Patient Treatment Position/
Immobilization and Planning
Imaging Study(s)
In the initial part of the CRT process (pre-planning),
the proposed treatment position of the patient is
determined, and the immobilization device to be used
during simulation/treatment is selected. It should be
clearly understood that repositioning patients and
accounting for internal organ movement for frac-
tionated radiation therapy, in order to accurately
reproduce the planned dose distribution, remains a
difficult technical aspect of the CRT process. Errors
may occur if patients are inadequately immobilized,
J. A. Purdy et al.
with resultant treatment fields inaccurately aligned
from treatment to treatment (interfraction). In addi-
tion, patients and/or their tumor volume may also
move during treatment (intrafraction) because of
either inadequate immobilization or physiologic
activity. Accounting for all the uncertainties in the
CRT planning and delivery process remains a chal-
lenge for radiation oncology and continued research
and development is ongoing.
Determining the treatment position of the patient
and construction of the immobilization device can be
performed on a conventional radiation therapy sim-
ulator, but more preferably, is now done in a dedi-
cated radiation therapy CT-simulator facility
(Fig. 6). A radiation therapy CT-simulator consists
of a diagnostic quality CT scanner, laser patient
positioning/marking system, virtual simulation 3D
treatment planning software, and various digital
display systems for viewing the digital reconstructed
radiographs (DRRs) (Mutic et al. 2003; Perez et al.
1994). The CT scanner is used to acquire a volu-
metric planning CT scan of a patient in treatment
position. CT topograms should be generated first and
reviewed prior to acquiring the planning scan to
ensure that patient alignment is correct; with
adjustments to be made if needed. Radiopaque
markers can be placed on the patient’s skin and the
immobilization device to serve as fiducial marks to
assist in any coordinate transformation needed as a
result of 3D planning and eventual plan implemen-
tation. An example of a typical immobilization
repositioning system used for patients undergoing
radiation therapy for head and neck (H&N) cancer is
shown in Fig. 7 and for prostate cancer in Fig. 8.
The use of intravenous or other contrast to help
delineate target volumes need to be considered dur-
ing simulation in some cases.
Planning CT scan protocols are tumor-site depen-
dent and typically range from 2 to 5 mm slice
thicknesses and 50–200 slices. In general, a 3 mm
slice thickness provides adequate quality DRR.
In some sites, such as H&N, slice thicknesses of
1 mm are often needed for delineation of very small
volumes such as the optic chiasm and the optic
nerves. The same holds true for optimal reconstruc-
tion of the position of any implanted markers used
such as in prostate cancer radiation therapy.
The planning CT data set is typically transferred to
a 3DTPS via a computer network. Data transfer issues
Three-Dimensional Treatment Planning and Conformal Therapy 263

Table 1 3D Treatment planning and conformal radiation therapy delivery process

1. Patient treatment position,
immobilization, and planning imaging:
2. Delineation of tumor/target volumes and
organs at risk
3. Dose prescription
4.a Forward planning (3DCRT)
4.b Inverse planning (IMRT)
5. Plan evaluation/plan improvement
6. Plan Implementation and treatment
verification
• Position patient in proposed treatment position
• Fabricate immobilization devices
• Place radiopaque markers and mark repositioning lines on patient and
immobilization devices
• Obtain topograms to check patient alignment
• Perform volumetric CT scan of patient in treatment position
• Make illustrative photographs to assist in repositioning the patient at the
treatment couch
• Transfer CT images to 3DTPS
• Perform imaging studies (e.g., MRI, PET/CT,…) as requested by treating
physician and transfer image data to 3DTPS
• Physician contours target volume(s)
• Physician or dosimetrist contours organs at risk
• Physician provides prescription dose for PTV and dose-volume constraints for
organs at risk
• Setup initial beam configuration and design field shapes; wedges/bolus/no beam
modifiers; beam weights
• Compute 3D dose matrix
• Compute treatment machine monitor units
• Setup initial beam configuration
• Enter desired dose-volume constraints for PTV(s) and all regions of interest
• Initiate TPS optimization process which generates beam fluences, resulting dose
distribution, monitor units, and leaf motion files
• Evaluate plan (DVHs, planar isodose display, 3D isodose display) and modify
until plan found to be acceptable by treating physician
• Transfer patient’s plan to patient’s chart (Electronic Medical Record) and
treatment machine verify & record (V&R) system
• Physicist performs 2nd check of treatment plan and transfer of data to V&R
system
• For IMRT plans, phantom dosimetric verification performed
• Verify patient position and isocenter placement on treatment machine using
orthogonal portal EPIs versus DRRs or using on-board CT vs. planning CT
• For 3DCRT, check field shapes by comparing treatment field DRR’s with
treatment beam EPIs
• Capture treatment machine settings in V&R system
• Check first day treatment with diode measurements
• Perform periodic imaging verification checks during treatment (e.g., orthogonal
EPIs/DRRs or beam EPIs/DRR’s, cone beam CT/planning CT)

are still somewhat problematic and will be discussed
in more detail in a later section. The planning CT data
set provides an accurate geometric model of the
patient as well as the electron density information
needed for the calculation of the 3D dose distribution
that takes into account tissue heterogeneities.
5.2 Volume Delineation
Delineation of tumor/target volume and organs at risk
contours using the volumetric CT data set is typically
performed by the radiation oncologist and the medical
dosimetrist, working as a team. The CT data are
264
Fig. 6 Typical radiation
therapy CT-simulation suite
design showing the CT
scanner, flat tabletop,
orthogonal laser system,
virtual simulation workstation
and hardcopy output device.
(Philips Medical Systems,
Andovar, MA)
Fig. 7 Example of immobilization repositioning system used
for patients undergoing radiation therapy for head and neck
cancer. Shown are the Type-S patient positioning system with
head extension for table and patient fitted in perforated
thermoplastic mask (CIVCO Medical Solutions, Kalona, Iowa)
displayed at the 3DTPS workstation and contours are
drawn manually by the radiation oncologist/dosimetrist
most often using a computer mouse or stylus on a slice-
by-slice basis. Some OARs with distinct boundaries
(e.g., skin, lung) can be contoured automatically, with
only minor editing required; others (e.g., brachial
plexus) require the ‘‘hands-on’’ effort of the radiation
oncologist (Hall et al. 2008). With modern 3DTPS
image segmentation software, contouring generally
takes 0.5–1 h depending on the disease site. However,
for some complex sites, such as H&N cancer where
J. A. Purdy et al.
Fig. 8 Example of immobilization repositioning system used
for patients undergoing radiation therapy for prostate cancer.
Vac-LokTM cushion (CIVCO Medical Solutions, Kalona, Iowa)
used for legs and feet to form a custom mold of patient’s
anatomical contours and can easily be re-inflated and remolded
many OARs and complex tumor/target volumes are the
norm, this task can take several hours.
CT is still the principal source of imaging data
used for defining the GTV for most sites, but this
imaging modality presents several potential pitfalls.
First, when contouring the GTV, it is essential that the
appropriate CT window and level settings be used in
order to determine the maximum dimension of what is
considered potential gross disease. Second, for those
treatment sites where there is considerable organ
motion, such as for tumors in the thorax, CT images
Three-Dimensional Treatment Planning and Conformal Therapy
do not correctly represent either the time-averaged
position of the tumor or its shape and hence newer 4D
CT technology must be used (Caldwell et al. 2003;
Chen et al. 2004; Rietzel et al. 2005a). This can be
understood by appreciating the fact that single or few
slice CT-simulators rely almost exclusively on the use
of fast spiral CT technology, and thus acquire data
essentially in 2D and combine them to construct a 3D
matrix. This has the effect of capturing the tumor
cross-section images at particular positions in the
breathing cycle. If the tumor motion is significant,
different, and possibly noncontiguous, transverse
sections of the tumor could be imaged at different
points of the breathing cycle, leading to volume
uncertainties. The interpolation process in spiral CT
technology further adds to the uncertainty. As a result,
the 3D reconstruction of the GTV from temporally
variant 2D images often results in a poor representa-
tion of the tumor and its motion. Today 4D-CT
technology has become the standard for CT-simula-
tors making it possible to capture images in each
phase of the respiratory cycle (Qi et al. 2010; Rietzel
et al. 2005b). In addition, other technologies and
methodologies to explicitly help manage the move-
ments induced by the respiratory motion (to the order
of less than 5 mm during treatment preparation and
delivery) continue to be developed, including respi-
ratory gated techniques, respiration-synchronized
techniques, breath-hold techniques, and forced shal-
low-breathing methods (Bortfeld et al. 2004).
Delineating the CTV is even more difficult and
must be done by the radiation oncologist based on
clinical experience (and/or the use of published CTV
atlases for certain clinical sites) because current
imaging techniques cannot be used to directly detect
subclinical tumor involvement. This field has seen a
virtual explosion in the use of multi-modality imaging
over the last decade and radiation oncologists have
developed considerable imaging expertise in order to
accurately define GTVs, and to be able to define non-
imaged CTVs. However, the need for a higher level of
image-based cross-sectional anatomy training in this
field is well recognized (Chino et al. 2011).
The PTV margin is specified by the radiation
oncologist, often in consultation with the radiation
oncology physicist and/or therapist. On most occa-
sions, it is based on published clinical experience, i.e.,
not calculated based on measurements performed by
the department for a particular treatment machine/
265
technique and team. Van Herk and colleagues have
reported extensively on the influence of systematic
and random errors/variations on the required margins
to account for set-up error and organ motion and have
developed margin recipes for calculating individual-
ized (for a department, machine and team) margins
(van Herk 2004; van Herk et al. 2002). Uncertainty
studies addressing these issues for several sites
(e.g., prostate and lung) are increasingly being
reported (Langen and Jones 2001; Senan et al. 2004).
When defining the PTV, the radiation oncologist
should account for the asymmetric nature of posi-
tional uncertainties. For example, it is recognized that
prostate organ motion and daily set-up errors may be
anisotropic (side-to-side or rotational shifts of the
position of the patients are likely to have a different
result compared to movement in the anteroposterior
direction). Thus, the PTV margin around a CTV
generally should not be uniform.
As stated earlier, when the beam portal is defined,
additional margin beyond the PTV is typically
required to obtain dose coverage because of beam
penumbra and treatment technique. This emphasizes
that treatment portal margins in relation to the PTV
must be set according to the dosimetric characteristics
of the beams being used. Typically, a 5 mm margin
(portal edge to PTV) is a good starting point which
can be increased if needed, but one must be knowl-
edgeable of the characteristics of the actual beams
used to make this starting point determination. An
additional point to understand is that in the case of
coplanar treatment techniques, the margins required
across the plane of treatment and the margins
orthogonal (say superior-inferior) to this plane will be
different. To clarify this point, consider a pelvic four-
field axial technique as an example. Portions of the
lateral aspects of the PTV which are in the low-dose
regions (near the penumbra) of the AP and PA fields
will be in the high-dose regions (well away from the
beam penumbra) of the lateral fields. However, the
superior and inferior aspects of the PTV will always
be in the same low-dose regions of all four fields so
there will be no dose filling from any of the fields.
Thus, a larger portal margin in the inferior–superior
dimension is needed to ensure that the 95% isodose
from all beams contains the PTV, while the lateral
and anterior–posterior portal margins for each field
may be reduced thanks to the other beams filling in
the dose. The same holds true for the portals of the
266
boost fields used in the so-called ‘‘integrated boost
technique’’, where the beams used for treating the
large volume fill up the dose in the build-up region
of the boost volume. This has especially been
demonstrated in the case of breast cancer, where the
boost portal’s margins can be reduced, leading to a
significant reduction of the volume of the whole breast
receiving 95% of the prescribed boost dose (Hurkmans
et al. 2006; van der Laan et al. 2007). Lastly, the size of
the margins will also be affected by the relative beam
weighting. Hence, making hard rules about margin
sizes is impossible and requires some planning iteration
to find the right mix of beam margins.
Two final reasons for using different margins in
cranio-caudal direction are the influence of the slice
thickness of the CT scanner in combination with the
interpolation algorithm of the TPS, and the often
smaller size of the PTV at the cranial and caudal
borders which lowers the actual dose delivered due to
a lower electronic equilibrium.
When a PTV overlaps with a contoured normal
structure, it is important to be explicit as to which
volume the overlapping voxels are assigned for
optimization purposes and for DVH calculations.
Planning systems should allow the overlapping voxels
to be included in both volumes for plan evaluation
and reporting purposes. This ensures that the clinician
is aware of the potential of the high-dose region to
include part of the normal structure as well as the
PTV when reviewing the DVHs.
In addition, most 3DTPS cannot accurately
account for a PTV contour that extends outside the
skin surface, resulting in a DVH that does not reflect
clinical reality due to the lack of dose generated in air
and in the build-up region just below the skin. In
those cases, the best solution is to delineate the
PTV 5 mm below the skin surface. This will also
help reduce acute skin reactions by preventing the
optimization process to increase the skin dose to
excessive levels. In all cases however, the treating
physician should be aware of this approximation
when setting or approving actual field margins.
Most specialists involved in the process of radia-
tion therapy consider target volume delineation as
being currently the weakest link in the entire chain
from treatment prescription to follow-up of the patient
after treatment. Numerous studies report a high vari-
ation in the consistency of delineation of target vol-
umes and organs at risk among physicians, making
J. A. Purdy et al.
this still an important area for improvement (Gregoire
et al. 2000, 2003; Matzinger et al. 2009; Poortmans
et al. 2007; Symon et al. 2011; van Mourik et al.
2010). This can be explained by a lack of generally
accepted guidelines for volume delineation and
insufficient training of residents and even senior staff
members. This issue is now being addressed by sev-
eral investigators and research groups but even after
publication of the proposed guidelines, discussion on
how to correctly implement them remains (Girinsky
et al. 2008, 2006; Gregoire et al. 2003; Matzinger
et al. 2009; Poortmans et al. 2007). Another approach
towards solving the difficult issue of reference vol-
umes is done by generating a consensus volume based
on a number of agreed reference points or based on
the delineation performed by a number of specialists
in the field (Miralbell et al. 2007; Symon et al. 2011).
5.3 Dose Prescription
Dose prescription is done by the radiation oncologist,
generally using institutional protocols based on evi-
dence published in the literature combined with the
institutional experience.
5.4 Conformal Planning
For 3DCRT planning, beam apertures can be opti-
mally shaped with MLC leafs or shielding blocks to
help conform the prescribed dose to the PTV and
avoid OARs using beam’s-eye view (BEV) displays.
This ‘‘forward planning’’ approach to conformal
therapy has now been supplemented—but not
replaced—with an ‘‘inverse planning’’ approach as
used for IMRT, which can achieve even greater
conformity and OAR dose avoidance.
5.4.1 Forward Planning: 3DCRT
Design of the beam arrangement is the next step in the
planning process for 3DCRT. The ability to orient
beams in 3D allows one to develop treatment plans
that use noncoplanar beams. However, when nonco-
planar beam arrangements are used, care must be
taken to avoid the selection of gantry and couch
angles that results in table/gantry collisions or a
conflict with other treatment room restrictions. The
BEV display (Goitein et al. 1983; Reinstein et al.
Three-Dimensional Treatment Planning and Conformal Therapy
Fig. 9 a Seven-field 3DCRT technique depicted on axial CT
slice for a prostate cancer patient in a supine position. Planning
target volume contour is shown in red, bladder in blue, rectum
in light red, and femoral heads in yellow/orange. b 3DTPS
1978) and the digitally reconstructed radiograph
(DRR) (Sherouse et al. 1990) as shown in Fig. 9
allows the planner to easily view the target volume
and the organs at risk so that shielding blocks or MLC
apertures can be drawn using a computer mouse or, as
available with most current 3DTPS software versions,
automatically generated with a chosen margin around
the selected volume. DRRs also provide planar ref-
erence images that can be used in facilitating the
plan implementation and treatment verification phases
of CRT.
5.4.2 Inverse Planning: IMRT
The major differences between 3DCRT forward
planning and IMRT inverse planning is the use of a
computer optimization program that requires a formal
description of the requirements using a mathematical
objective function and constraints that are used by the
program to find the solution. For example, after the
design of the initial beam geometry, the physician/
treatment planner puts into the TPS the desired dose-
volume constraints for the PTVs and all OARs. The
TPS optimization algorithm then divides each beam
into many small beamlets (i.e., pencil beams that
together make up the IMRT beam) and then itera-
tively alters the beamlet intensities until the 3D dose
distribution best conforms to the a priori specified
267
Beam’s-eye-view (BEV) and digitally reconstructed radiograph
(DRR) display of left-anterior oblique beam with beam shape
defined by multileaf collimator (MLC)
dose-volume objectives. After the optimal beam
intensities and resulting dose distribution have been
determined, the TPS then calculates the MLC leaf
sequence motions that will achieve this dose distri-
bution and the dose recalculated. Typically, there may
be some differences in the optimized dose distribution
and the final dose distribution that can be delivered
with the computer-controlled MLC system, but this
difference is usually acceptable.
5.5 Plan Evaluation/Plan Improvement
The 3DCRT plan evaluation/improvement process
involves an iterative, interactive approach. Typically,
the initial beam arrangement had been selected based
primarily on clinical experience using BEV displays.
The generated dose distribution is reviewed by the
planner/physician and the beam arrangement is then
modified based on the review of DVHs and multi-
level 2D displays showing isodose lines superimposed
on CT images (Fig. 10); or sometimes the display is
in the form of a color wash, i.e., a spectrum of colors
superimposed on the anatomic information.
Another powerful display feature in a 3DTPS is
the 3D View, which is sometimes referred to as the
Room’s-Eye-View (REV), in which the planner can
268
Fig. 10 Dose distribution displays for prostate cancer patient
treated with seven-field 3DCRT technique. Shown are coronal,
sagittal, axial CT sections with superimposed color-coded
simulate any arbitrary viewing location within the
treatment room (Purdy et al. 1993, 1987). The REV
display is used to display ‘‘dose clouds’’ along with
rendered PTV and OARs. Hot or cold spots that occur
in the volumes of interest are clearly seen, as shown
in Fig. 11. Another valuable REV display is the
so-called ‘‘skin view’’ in which the beam aperture
projection can be clearly seen on the skin of the
(virtual) patient (Fig. 12).
The planned dose distribution approved by the
radiation oncologist is most often one in which a
uniform dose is delivered to the target volume
(e.g., ? 7% and - 5% of the prescribed dose) with
doses to critical structures held below tolerance levels
(Emami et al. 1991; Marks et al. 2010a, b; Milano
et al. 2007) as well within the constraints for the
absolute maximum dose, a median dose or a volume
(e.g., V20Gy) that has been specified by the radiation
oncologist.
J. A. Purdy et al.
isodose lines and cumulative DVH for PTV (red), penile bulb-
magenta, right femur-yellow, left femur-orange, rectum-brown,
bladder-blue
5.6 Plan Implementation and Treatment
Verification
Once the treatment plan has been designed, evaluated,
and approved, documentation for plan implementa-
tion must be generated. Documentation includes
beam parameter settings transferred to the treatment
machine to verify and record systems including
multileaf collimator parameters communicated over a
network to the computer system that controls the
MLC system of the treatment machine, DRR gener-
ation and transfer to an image database.
QA checks used to confirm the validity and accu-
racy of the 3DCRT plan include an independent check
of the plan and monitor unit calculation by a physicist
and radiation therapist, isocenter placement check on
the treatment machine using orthogonal radiographs
or, in some occasions, with an individualized beam
angle combination. Depending on the irradiated site
Three-Dimensional Treatment Planning and Conformal Therapy 269

Fig. 11 Planning system’s

3D-view or room’s-eye-view
(REV). Shown is a four-panel
REV meant to simulate
real-time interactive viewing
of the prostate PTV, bladder,
rectum, and the 73.8 Gy
‘‘dose cloud’’ of a prostate
cancer patient treated with a
seven-field technique. The
REV display with real-time
interactivity is a valuable tool
for evaluation of 3D dose
distributions in terms of ‘‘hot
and cold spots’’ locations
relative to target volumes and
organs at risk

Fig. 12 Room’s-eye-view
(REV) display showing
simulated skin surface for
breast cancer patient
undergoing radiation therapy
using tangential,
supraclavicular, and internal
mammary fields. Beam
aperture projection can be
clearly seen on the skin of the
(virtual) patient

and the departmental protocol, field apertures check is now considered essential to help manage 3DCRT
using portal films or electronic portal images, and treatments. However, careful scrutiny must be given
diode or MOSFET in vivo dosimetry check can be to ensure that the input of data into the R&V system is
performed as well. A record and verify (R&V) system correct.
270
In the initial period of implementing 3DCRT
techniques (or of implementing non-conventional
beam arrangements) in the clinic, it was commonly
accepted to recommend a verification simulation
procedure to confirm the geometric validity and
accuracy of the 3D treatment plan. DRRs generated
by the 3DTPS are used for comparison with the ver-
ification simulation radiographs to confirm the cor-
rectness of the beam orientations in the physical
implementation. When a beam orientation cannot be
simulated, orthogonal radiographs may be taken and
compared with similar DRRs to ensure correct iso-
center positioning. The optical distance indicator is
also useful in assessing the correctness of the setup of
a particular beam. Documentation provides a depth
of isocenter below the skin surface on the central ray
of the beam, which can then be compared with the
isocenter depth measured on the simulator or treat-
ment machine after the beam is set-up using the couch
and gantry positions specified by the treatment plan.
Nowadays however, many modern radiotherapy
departments do not have a functional conventional
simulator in clinical use any more. Although this is a
logical consequence of progress in treatment prepa-
ration, it carries the pitfall that young radiation on-
cologists, technologists and physicists do not develop
anymore the insight and skills that were so useful
while going through the conventional simulation
procedure.
6 Management of CRT Data
To accurately perform the steps involved in CRT,
several forms of patient imaging and other data must
be acquired, displayed, manipulated, and stored.
Typically, patient image data acquired from several
imaging subsystems must be communicated to a TPS
to permit these images to be used for treatment
planning. Several software components also must be
integrated so that the output of one processing step
can be made available for use as input to the next
step. Daily IGRT imaging is also placing large
demands on data storage and the need for more
robust image processing tools is evident. These
issues in data management in CRT are complex and
continue to be somewhat problematic, although
some progress is being made through the ‘‘Integrat-
ing the Healthcare Enterprise in Radiation Oncology
J. A. Purdy et al.
(IHE-RO)’’ effort initiated by ASTRO (Abdel-Wahab
et al. 2009).
This issue is just part of larger informatics issues
facing radiation oncology. There is an explosion in the
types and volume of data objects that must be made
available for scientific query. Difficulty in accessing the
available data in practical ways has become a critical
limitation to investigators in this field and to its
advancement. Unfortunately, the commercially avail-
able radiation oncology information systems are not yet
adequate to meet this challenge. The great volume and
diversity of the data have rendered their storage, man-
agement, and processing extremely problematic,
resulting in real-world situations in which important
data and information are inefficiently disseminated and
sometimes lost. In the busy clinic, failure to manage
critical information may compromise patient safety.
Here, a major issue is the lack of integration of the
radiation oncology electronic medical record (EMR),
based in systems such as Elekta-Impac MOSAIQ or
Varian ARIA, with the electronic hospital record
(EHR), based in systems such as EPIC. In most cases,
we must resort to hybrid charting systems (ad hoc
combinations of EMR, EHR, and paper charting),
which entail risks that makes it a dangerous situation.
Immediate and focused efforts in achieving these
integrations and improving the radiation oncology
informatics infrastructure are urgently needed.
7 Summary and Conclusion
The practice of radiation therapy continues to expe-
rience rapid advancements in treatment planning and
delivery technologies. There is ample evidence that
image-based CRT treatment planning and treatment
delivery has had a major impact on the practice of
radiation therapy. There are very few tumor types
whose treatment has not been radically impacted by
its use. But as with any major technical advance, the
requirements for its use have had a major impact on
the requirement for enhanced quality assurance from
all members of the treatment team and we must all
stay vigilant (Levitt et al. 2008).
Imaging will continue to impact the field as we
will see in a not too distant future imaging systems
other than CT (e.g., US, MR, PET) fully integrated
into radiation treatment delivery systems. Likewise,
advances in planning and delivery technologies will
Three-Dimensional Treatment Planning and Conformal Therapy
continue to occur at record paces and push the field
toward even higher expectations for radiotherapy
accuracy and reliability. However, this optimism must
be tempered with the realization that, for this to
happen, progress is urgently needed mainly in three
areas, namely improved accuracy in specification of
GTV/CTV, radiation oncology informatics and qual-
ity assurance, if we are to keep pace with these rapid
planning and delivery developments.
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 Linac-Based Image Guided Intensity
Modulated Radiation Therapy
Ruijiang Li, Paul Keall, and Lei Xing

Contents 4.3 Real-Time Imaging Techniques for Radiation

Therapy ...................................................................... 295
4.4 Future 4D Radiation Therapy and Real-Time Image
1 Introduction.............................................................. 276 Guided IMRT/VMAT................................................ 297
1.1 Currently Available Image Guidance Tools and Role
of Imaging in Motion Management.......................... 276 5 Image Guided LINAC-Based SBRT ..................... 298
5.1 Specific Requirements of LINAC-Based SBRT
2 CT Simulation for IGRT ........................................ 277 (Patient Setup, Motion Management, Imaging
2.1 3D and 4D CT Simulation ........................................ 277 Strategy for SBRT).................................................... 298
2.2 MRI and PET for Treatment Planning ..................... 278 5.2 Recent Progress in SBRT Delivery Techniques ...... 299
2.3 Image Segmentation and Registration ...................... 280 5.3 Imaging in SBRT ...................................................... 301
2.4 Recent Progress in IMRT and VMAT Treatment
Planning ..................................................................... 283 6 Closing the Loop of Radiation Therapy: Dose
Delivery and Reconstruction .................................. 302
3 Role of In-Room and Onboard Imaging 6.1 Pitfalls of Current IMRT/VMAT and QA................ 302
in LINAC-Based Radiation Therapy .................... 286 6.2 Dose Reconstruction for IMRT and VMAT
3.1 Use of 2D Projection Images for Patient Setup....... 286 and Respiration-Gated VMAT .................................. 302
3.2 Volumetric (3D) CBCT for Patient Setup 6.3 Adaptive Therapy with Consideration of Dose
and Adaptive Radiation Therapy .............................. 287 Delivery History ........................................................ 303
3.3 4D CBCT and its Role in 4D Radiation Therapy ... 290
3.4 Imaging Dose and QA of Onboard Imaging Devices 291 7 Summary................................................................... 304

4 Real-Time Guidance in IG-IMRT and VMAT.... 293 References.......................................................................... 304

4.1 Current Techniques for Respiratory Gating ............. 293
4.2 The Unmet Clinical Needs for Real-Time Imaging 294
Abstract
Intensity modulated radiation therapy (IMRT) has
become the mainstay of modern radiation therapy
and it is now possible to produce highly conformal
R. Li (&) radiation dose distribution. The ubiquitous organ
Department of Radiation Oncology, Stanford University, motion either between fractions or within a
875 Blake Wilbur Drive Room G204,
fraction has been one of the major uncertainties
Stanford, CA 94305-5847, USA
e-mail: rli2@stanford.edu in radiation therapy. This fact coupled with the
improved dose conformity and steep dose gradi-
P. Keall
Radiation Physics Laboratory, University of Sydney, ents in IMRT has made accurate target localization
Sydney Medical School—Central Room 475, and beam targeting all the more important for
Blackburn Building D06, Camperdown 2006, radiotherapy treatments. Image-guided radiation
NSW 3590, Australia
therapy (IGRT) utilizes advanced imaging tech-
L. Xing nology to better define and localize the tumor
Department of Radiation Oncology, Stanford University,
target and is the key to reducing and ultimately
875 Blake Wilbur Drive Room G233,
Stanford, CA 94305-5847, USA eliminating the uncertainties in radiation therapy.

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 275
DOI: 10.1007/174_2011_325, Ó Springer-Verlag Berlin Heidelberg 2012
276 R. Li et al.

This chapter reviews the basics and some of the

recent advancements in LINAC-based IGRT. Var-
ious image guidance techniques will be discussed,
covering the full range of the radiation therapy
process, including patient simulation, treatment
planning, patient setup, and treatment delivery. In
addition to the techniques currently used in clinical
practice, some important research topics will also
be discussed. We hope to provide the reader with a
comprehensive understanding of the concepts and
components of the new developments in IGRT,
and offer useful hints on how to apply the new
modalities in clinical practice.

Fig. 1 The cumulative adoption of IGRT technologies based

on a large radiation oncology survey. Source Simpson et al.
1 Introduction 2010, with permission

The last decade has witnessed major advancements in

radiation therapy, largely due to the introduction of
dynamic dose delivery with computer controlled
multileaf collimators and onboard image guidance.
After the successful implementation of intensity
modulated radiation therapy (IMRT) in the 1990s,
slice-by-slice Tomotherapy and cone beam volumetric
modulated radiation therapy (VMAT) with various
image guidance tools have entered into the clinical
place. This trend is continuing—the digital linear
accelerator with unprecedented real-time controls over
dose rate, gantry rotation, and imaging has emerged
recently as the next generation therapy machine for
advanced applications such as stereotactic body radi-
osurgery, and respiration-gated volumetric modulated
arc therapy. The purpose of this chapter is to highlight
some of the recent progresses in linac-based image
guided radiation therapy (IGRT), help the reader
understand the concepts and components of the new
developments, and provide useful hints on how to
master the new modalities in clinical practice.
1.1 Currently Available Image Guidance
Tools and Role of Imaging in Motion
Management
There are many tools available—and under develop-
ment—for use in image guidance during a course of
radiation therapy. The widespread and growing
implementation of these technologies is highlighted in
Fig. 1, showing a 90% increase in the adoption of
IGRT techniques over a 15-year period (Simpson
et al. 2010). The trends in most of these technologies
are continuing to increase.
Before discussing the image guidance methods
available, it is useful to describe the characteristics of
an ideal system. The requirements of an ideal system
allow us to compare what is currently available and
their limitations, as well as determine new methods,
or improve currently existing methods to be closer to
the ideal system. These include:
1. Volumetric
2. High spatial resolution
3. High temporal resolution
4. High fidelity
5. Can transfer planning contour and dose infor-
mation to and from images acquired during
planning and delivery
6. Low latency
7. No interference with delivery system
8. Noninvasive
9. No imaging dose
10. Can be used for adaptive replanning and real-time
optimization
11. Reduces treatment time
12. Cheap with low operational costs
The available systems and those under develop-
ment span multiple parts of the electromagnetic (EM)
spectrum and non-EM based methods. Some existing
systems are summarized in Table 1.
Linac-Based Image Guided Intensity Modulated Radiation Therapy 277

Table 1 A selection of image guidance methods currently available and under development
Method Examples Advantages Disadvantages
Megavoltage Electronic portal imaging Available on most linacs Poorer contrast than kV
imaging device Imaging coordinate system same as For modulated IMRT fields can
treatment coordinate system only see part of anatomy
Can perform fluoroscopy and CBCT
kV imager Dual imagers on Novalis, Higher contrast than MV Requires additional imaging dose
Cyberknife, Vero; single Can image independently of treatment
imagers on Elekta, beam
Siemens, Varian
linacs Can perform fluoroscopy and CBCT
Optical imaging Brainlab, Varian RPM, Surface information without radiation As sole modality cannot determine
VisionRT dose internal target positions
Can be combined with other internal
positioning methods
Radio-frequency Calypso, Micropos, High accuracy Only information about individual
Radpos points
High frequency Requires implantation. Severe MRI
artifacts.
c-ray Navotek High accuracy Additional radiation dose
High frequency Requires implantation
Ultrasound Nomos, Resonant Volumetric images Poorer image quality
No implanted markers Limited to some anatomic sites
Magnetic IMRIS, U Alberta, U Volumetric imaging Mutual compatibility with linac
resonance Utrecht, Viewray No implanted markers Cost
imaging

If the output from the imaging method is
pretreatment, then the information can be used to shift
the treatment beam or patient prior to beam delivery. If
the target position output is available in real-time, then
the method can be used for verifying motion inclusive
delivery, respiratory gating, or tumor-tracking.
It is likely that the current paradigm of imaging
before treatment will be extended to image continu-
ously or occasionally during treatment to facilitate
improved beam-target alignment and adaptation of
the radiation beam to the temporally changing tumor
and normal anatomy.
2 CT Simulation for IGRT
2.1 3D and 4D CT Simulation
More imaging modalities are being used more fre-
quently before, during, and after a course of radiation
therapy (Simpson et al. 2009). However, the central
imaging modality in radiation therapy remains
computed tomography (CT). CT has high geometric
fidelity, allows accurate dose calculation through the
transfer of Hounsfield units to density values, and has
reasonable soft tissue and excellent bony structure
contrast. Other anatomic or functional imaging
modalities such as magnetic resonance imaging
(MRI), positron emission tomography (PET), and
single photon emission computed tomography
(SPECT) can be registered (rigid or deformable) to
the CT image.
The use of CT for simulation in radiation therapy
has additional requirements to that over CT for radi-
ology. The CT-simulator is a CT scanner equipped
with a flat tabletop and external patient positioning
lasers. The scanner is accompanied with specialized
software and integrated to a treatment planning sys-
tem to allow the development and calculation of
treatment plans on volumetric patient CT scans. A flat
tabletop is needed to maintain the same position for
imaging and treatment. External lasers allow for the
creation of a reference frame external to the patient
that relates to the patient’s internal anatomy at the
278
Fig. 2 The 4D CT phase-sorting process: the CT images,
breathing tracking signal and ‘X-Ray ON’ signal form the input
data stream. The breathing cycle is divided into distinct bins
(for example, peak-exhale, mid-inhale, peak-inhale, mid-
time of the imaging procedure. Typically, small point
tattoos are marked on the patient along with the
information about the position of the tattoos with the
internal anatomy.
Because the CT information is used for the plan-
ning and delivery of treatment beams based on this
information, there are many steps and tests needed to
ensure the fidelity of the information. AAPM Task
Group 66 (Mutic et al. 2003) describes the role and
quality assurance aspects of CT simulators for radia-
tion therapy.
In the presence of respiratory motion, large arti-
facts in 3D CT images can often be observed as the
anatomy moving during the image procedures,
resulting in parts of the anatomy being imaged more
than once and other parts not being imaged at all.
These artifacts are most clearly seen on the
diaphragm/lung boundary, with the diaphragm either
being cut off or the dome of the diaphragm duplicated
within the image. In a normal anatomy where we
know the structure a priori is not faithfully reproduced
then the tumor shape of which we have no prior
knowledge will not be faithfully reproduced. The
artifacts in the tumor and normal tissue will lead to
errors in target delineation and ultimately affect the
quality of care given to the patient.
R. Li et al.
exhale). Images are sorted into these image bins depending
on the phase of the breathing cycle in which they were
acquired, yielding a 4D CT data set. Source Vedam et al.
2003a, with permission
To address the artifacts present in 3D CT images,
techniques to oversample CT acquisition synchro-
nously with the respiratory signal were developed,
leading to respiratory correlated or 4D CT imaging
(Vedam et al. 2003a). An example of the data flow
and image reconstruction is shown in Fig. 2. Four-
dimension CT has grown in use from a few percents
in 2003 to 44 percent in 2009 (Simpson et al. 2009),
with a continuous upward trend.
Despite the significant reduction in artifacts of 4D
CT over 3D CT, residual artifacts remain: Yamamoto
et al. (2008) found artifacts of more than 4 mm in 45
or 50 consecutively acquired 4D CT scans. Ongoing
methods to reduce the magnitude and frequency of
artifacts include improved sorting, audiovisual bio-
feedback, respiratory-controlled image acquisition,
and post-processing algorithms.
2.2 MRI and PET for Treatment Planning
Since the introduction of 3D conformal radiotherapy,
CT has been the preferred choice of imaging modality
for treatment planning, mainly because of its high
geometrical accuracy and direct relation to electron
density used for dose calculations. However, it has
Linac-Based Image Guided Intensity Modulated Radiation Therapy
become evident that CT alone does not always pro-
vide sufficient information for accurate delineations
of the target volume. Relying on CT alone for GTV
definition can lead to large inter-observer variations
and greatly reduce the effectiveness of radiation
therapy. For instance, based on a study of eight lung
cancer patients whose GTV was defined on planning
CT by five clinicians, van de Steene et al. (2002)
reported an inter-observer variation of a ratio up to
more than 7 mm between the maximum and minimum
geometric content.
2.2.1 MRI
Compared with CT, MRI offers superior soft tissue
contrast, especially for tumors in the central nervous
system (CNS) and within the abdomen and pelvis.
MRI is a very versatile imaging modality: its contrast
can be varied by manipulating imaging parameters
(T1 and T2) and imaging sequences. There is a host of
specialized MRI scans that can provide physiological
and biochemical information, such as diffusion and
perfusion MRI, dynamic contrast MRI, MR angiog-
raphy, MR spectroscopic imaging (MRSI), and
functional MRI (fMRI). All these unique features of
MRI contribute to its success in the diagnosis and
tumor delineation in certain disease sites, either as a
complement to CT or as the sole modality. MRI is the
imaging modality of choice for brain, spinal cord, and
certain head and neck tumors (Datta et al. 2008;
Lemort et al. 2006; Prabhakar et al. 2007). It has also
been shown to be superior to CT in the staging and
definition of certain pelvic tumors (Hricak 1991;
Rasch et al. 1999). On the other hand, MRI is
insensitive to calcification and bony structures, which
are best imaged with CT. Although the spatial reso-
lution of the two modalities is similar (*1 mm), MRI
usually takes a longer time to acquire than CT, and
thus is more susceptible to image artifacts from
patient motion. On the upside, MRI can be used to
directly acquire images in any oblique planes, in
addition to the conventional axial, sagittal, and
coronal planes.
The main obstacles of using MR images for
radiotherapy treatment planning are the associated
geometric distortions and lack of electron density
information. Geometric distortions in MRI are mainly
caused by inhomogeneities in the static magnetic
field, nonlinearities in the magnetic gradients, and
magnetic susceptibility. In modern MRI scanners, the
279
technology has become sophisticated enough so that
the problems associated with field inhomogeneities
are becoming less important. Gradient nonlinearities
may be characterized and corrected using spherical
harmonic expansions of the fields generated by the
gradient coils (Janke et al. 2004). Also, modern
imaging sequences such as 3D turbo spin echo
sequences are able to reduce the geometric distortions
caused by susceptibility differences in tissue/bone and
air/tissue interfaces. The other issue associated with
MRI for treatment planning, i.e., the lack of electron
density information, may be overcome by simply
ignoring the variations in electron density inside the
patient. By switching off the inhomogeneity correc-
tion in dose calculations, the resultant dose differ-
ences in calculated dose with and without
inhomogeneity correction range from 0.9 to 2.5% for
prostate cancer patients (Eilertsen et al. 2008;
Pasquier et al. 2006; Chen et al. 2004) and 1–1.5% for
brain tumors (Kristensen et al. 2008). A more accu-
rate approach is to perform segmentation and bulk
density assignment of the relevant organs on MR
images. It has been shown that for brain and prostate
cancer patients, the difference in target dose calcu-
lated with MRI compared with CT is below 0.5% with
this approach (Eilertsen et al. 2008; Kristensen et al.
2008). In addition, a more recent study (Jonsson et al.
2010) reported an agreement within1% between CT
and MRI for thorax and head and head cases. Wang
et al. (2008) performed a feasibility study to investi-
gate and evaluate an MRI-based radiation dose cal-
culation process by providing MR images with the
necessary electron density information from a
patient’s readily available diagnostic or staging CT
images using an image registration model. The MRI-
based dose calculations with mapped electron density
yielded dose values within 2% to that of the CT-based
calculations based on three brain and three intracra-
nial cases. Overall, it is anticipated that future
research and development in MRI technology could
provide sufficient geometric accuracy and dose
calculation for treatment planning purposes in
radiotherapy.
2.2.1.1 Positron Emitted Tomography
In contrast to CT and traditional MRI which provide
only anatomical and physiological information about
the patient, PET is a type of functional imaging
modality that provides unique information about
280
metabolism. It has been widely used for cancer
diagnosis, staging, and more recently for target
delineation in the treatment planning process. In
general, PET has a lower image resolution than CT
images and contains no anatomic information about
normal structures. Thus, PET images have to be fused
with the corresponding CT images for treatment
planning purposes.
There are multiple tracers that have been used for
PET imaging, among which fluorine-18-labeled
deoxyglucose (FDG) is the most commonly used. The
high sensitivity of FDG-PET imaging is related to the
uptake of glucose in tumor cells which provides a
means to study the metabolic activity of tumors in
vivo. Initial studies incorporating FDG-PET into the
treatment planning process have been reported (Hicks
et al. 2001; Mac Manus et al. 2001; Bradley et al.
2004). Bradley et al. (2004) studied the impact of
FDG-PET imaging on target volume definitions in
non-small cell lung cancer (NSCLC) patients being
considered for definitive radiation therapy. They
found that radiation targeting with fused FDG-PET
and CT images resulted in alterations in treatment
planning in over 50% of patients compared with CT
targeting alone. In another study, Mac Manus et al.
(2001) reported that 30% of patients with locally
advanced NSCLC became ineligible for curative
radiotherapy because of detection of either distant
metastatic disease or intrathoracic disease, too
extensive for radical radiation therapy. Similar find-
ings were also reported in head and neck cancer
patients. Rahn et al. (1998) studied 34 patients with
histologically confirmed carcinoma of the head and
neck by performing FDG-PET prior to treatment
planning in addition to conventional staging proce-
dures, including CT, MRI, and ultrasound. The inte-
gration of FDG-PET in radiation treatment planning
led to significant changes in 9/22 patients (44%) with
a primary tumor and in 7/12 patients (58%) with
tumor recurrence. This was mainly due to the lymph
node metastases detected by FDG-PET.
While FDG-PET has been shown to be effective to
detect certain malignancies, imaging of many others,
such as breast and prostate cancer, has been less
successful with FDG-PET (Hofer et al. 1999; Liu
et al. 2001). There are several limitations associated
with FDG-PET imaging for detection of tumor cells.
First, FDG uptake is not tumor-specific; several
benign conditions such as inflammatory processes and
R. Li et al.
pneumonia can lead to an increased glucose uptake.
Second, slow-growing indolent tumors exhibit only a
mild increase in glucose metabolism and may be
missed by FDG-PET (Hoh et al. 1997; Quon and
Gambhir 2005; Schoder and Larson 2004; Delgado
Bolton et al. 2009). Therefore, FDG-PET is only
minimally useful for the detection of indolent tumors
such as prostate cancer.
In addition to FDG, there are many other types of
nuclide imaging tracers under clinical or laboratory
investigations. The development of fluorothymidine
(FLT) (Buck et al. 2003; Shields et al. 1998) opened
up a new venue to improve PET imaging for cancer
detection and target definition. Compared with the
commonly used FDG tracer, the accumulation of FLT
has been shown to correlate better with proliferation
of tumor cells (Shields et al. 1998). FLT-PET is
suitable for the diagnosis of primary breast cancer and
locoregional metastases (Smyczek-Gargya et al. 2004).
It has a high image contrast which may facilitate the
detection of small lesions. Another example is cho-
line, whose elevated level has been associated with
enhanced cell proliferation and transformation (Hara
et al. 1998). Its potential applications in prostate
cancer and other malignancies have been documented
in several preliminary studies (Hara et al. 1998;
Kotzerke et al. 2003; Chao et al. 2001). With different
agents, such as antisense molecules, aptamers, anti-
bodies, and antibody fragments, many physiologic
activities, including metabolism, hypoxia, prolifera-
tion, apoptosis, angiogenesis may be targeted for PET
imaging.
2.3 Image Segmentation
and Registration
2.3.1 Segmentation
After the simulation images are acquired for treatment
planning purposes, different anatomical regions of
interest, such as targets, critical organs, normal
structures, external body contours, and anatomical
landmarks, have to be delineated on the volumetric
image sets. Image segmentation is essential for visu-
alization and optimization of a treatment plan. In
addition, it allows important dose statistics such as
dose-volume histogram (DVH) for different organs of
interest to be calculated, which is useful for evalua-
tion of a treatment plan.
Linac-Based Image Guided Intensity Modulated Radiation Therapy
In order for an image segmentation algorithm to be
clinically practical, it has to be accurate, efficient, and
automatic. Despite intense research efforts in the past,
image segmentation remains a time-consuming and
laborious task in treatment planning. In most cases, the
segmentation is performed manually in a slice-by-slice
fashion, creating a strong need for automated seg-
mentation tools in the clinics.
Much work has been devoted to the development
of clinically practical segmentation tools in the past
few decades. The reported methods include intensity-
based segmentation, model-based segmentation,
multiscale segmentation, knowledge-based segmen-
tation, and so on. Segmentation using image intensity
information such as threshold is a good example of
the intensity-based model. A drawback of this type of
approach is that it is local in nature, and the global
properties of an organ’s surface are not taken into
account. One of the most popular model-based seg-
mentation is the snake model, in which a physical
model is used to represent the contours through a set
of elastically deformable curves or surface. The initial
contours iteratively evolve to the desired organ
boundary by an internal elastic force and an external
force generated by the image data. Elastically
deformable parametric models offer a mechanism for
the incorporation of prior knowledge into the image
segmentation process. However, the determination of
model parameters and the initialization of the calcu-
lation could be problematic in practice. A combina-
tion of the snake model and a statistical model seems
to be helpful for medical image segmentation. For
instance, the active shape models restrict the possible
deformations using the statistics of training samples
(Cootes et al. 1994). In multiscale segmentation, the
computation is done at multiple scales and the
contours are propagated from coarse to fine scales.
The need for automated image segmentation tools
is further amplified by the introduction of 4D CT in
radiation therapy as the number of images to be
segmented is increased dramatically (Xing et al. 2006;
Keall 2004; Li et al. 2005). It is not practical to
perform manual segmentation because of the
immense workload associated with this process. In
order to deal with this issue, a natural approach is to
start with a given set of contours for a selected static
image set (or phase) and map these contours onto all
the other phases. The mapping can be accomplished
either with a deformable model or surface mapping
281
techniques. Deformable model-based contour map-
ping (Ragan et al. 2005) has limited accuracy,
especially in regions close to organ boundaries, and
is brute force in nature. Surface mapping iteratively
deforms the contour-extended surface until the
optimal match with the reference is reached (Cootes
et al. 1994; McInerney and Terzopoulos 1996;
Montagnat et al. 2005). Many surface mapping
techniques have been used, such as spatial parti-
tioning, principal component analysis, conformal
mapping, rigid affine transformation, deformable
contours, and warping based on the thin-plate spline.
Although the computation involved with surface
mapping is more efficient than deformable models, it
suffers from the fact that the resultant mapping
heavily depends on the model used and the fact that
the model parameters do not always have easily
interpretable physical meanings. Chao et al. (2008a)
developed a hybrid approach to contour mapping
that combines the useful features of both techniques.
In this approach, the image feature surrounding a
contour point is used as a signature of the point to
aid the search for its corresponding position on the
target phase. The final segmented organ surface is
determined by balancing the need for the control
volumes to move to their corresponding locations
with the desire to maintain image features and shape
integrity of the contour. Application to four clinical
lung cases suggests that the technique is accurate and
quite robust. This study showed that the information
contained in the boundary region is sufficient to
guide the contour mapping process without regis-
tering the entire image or relying on the use of an ad
hoc surface deformable model. This technique
significantly decreases the workload involved in
the segmentation of 4D image sets and has been
applied to head and neck as well as prostate cases
(Chao et al. 2008a; Chao et al. 2008b).
It is worth mentioning that the definition of GTV
and CTV does not lend itself easily to automated
segmentation methods. The GTV is defined as the
palpable or visible extent of the malignant tumor. It is
not always easy to see on treatment planning images
(e.g., CT images), and the boundary may not corre-
spond to a high-contrast region in the images. The
CTV includes the GTV and a local margin for sub-
clinical diseases. This can only be defined from the
knowledge of how tumor cells spread and from the
knowledge of the anatomy of potentially involved
282
lymph nodes. Since these definitions incorporate
factors that are rarely related to the image data, the
automated and semi-automated segmentation meth-
ods mentioned above cannot be used. The tumor
volume is usually drawn manually by a radiation
oncologist, slice by slice.
2.3.2 Registration
One of the most important requirements in treatment
planning is the geometric accuracy. When images
from multiple studies are acquired for treatment
planning purposes, they must be correlated to each
other in order to establish the correspondence
between different anatomic structures or regions.
Image registration facilitates comparison of images
from different studies and fuses them into one image
set which can be used for treatment planning. Reg-
istration can be performed either for images of the
same modality, e.g., CT to CT, or for images of dif-
ferent modalities, e.g., MRI to CT. Due to the
extensive use of multi-modality imaging and the
emergence of new imaging techniques and methods,
the clinical need for a robust image registration
algorithm is ever increasing in order to compare and
fuse images acquired under different conditions.
Various image registration techniques have been
developed in the past (Maintz and Viergever 1998;
Zitov and Flusser 2003). Depending on the nature of
the underlying geometric transformations, image reg-
istration can be broadly classified into two categories:
rigid registration and deformable registration. In rigid
registration, the relative geometry of different objects
is assumed to be fixed in the entire image and no dis-
tortion occurs between the image acquisitions. A rigid
transformation consists of six degrees of freedom:
three translational parameters and three rotational
parameters. Rigid image registration has been under
active development for a long time and is becoming a
mature technology nowadays. It has reached the point
of being fully automated and is currently used in rou-
tine clinical practice (Court and Dong 2003).
Deformable registration, on the other hand, is
much more flexible than rigid registration and
requires the modeling of voxel-dependent transfor-
mations. A variety of transformation models may be
used, such as B-splines (Schreibmann et al. 2006),
thin-plate splines (Lian et al. 2004), optical flow
algorithms (Guerrero et al. 2004), and fluid flow
R. Li et al.
algorithms (Mageras et al. 2004). An improvement to
this method can be achieved by imposing some
physical constraints on the geometric transformations,
e.g., smoothness of the deformation field (Lian et al.
2004; Fei et al. 2002; Coselmon et al. 2004) or con-
sistency of the inverse deformation field (Yang et al.
2008). A deformable registration technique based on
the finite element model (FEM) was proposed by
Bharath et al. (2001) and Brock et al. (2002), in which
images are modeled as blocks of elastic materials on
which forces can apply. The Young’s elastic modulus
and Poisson’s ratio are used for the conversion of
forces into local deformations of the elastic material.
Schreibmann and Xing (2005) proposed a general
narrow-band approach for deformable registration.
Initial validation of the deformable registration
algorithms suggests that they seem to provide ade-
quate accuracy for some IGRT applications, e.g., in
head and neck (Schwartz et al. 2005), in prostate
(Wang et al. 2005), and in lung (Gu et al. 2010).
However, due to its complexity, the accuracy, and
robustness of deformable registration is still quite
limited and therefore it has not been widely accepted
in clinical practice. Much research remains to be
done, for instance, to enhance the robustness and
apply to multi-modality settings.
An interesting alternative to retrospective software-
based fusion has become available. The so-called
hardware fusion, automatically combines and fuses
two imaging modalities within a single device
(Townsend 2008). For instance, the fusion of PET and
CT images are simplified with the use of the hybrid
PET/CT scanner. Hybrid PET/CT systems have
several advantageous features that are absent in stand-
alone PET and CT units. PET/CT is a hardware-based
image-fusion technology that virtually eliminates the
uncertainty and inconvenience of currently available
software fusion of separate PET and CT images, which
are often acquired with patients in different positions.
As a result, combined PET/CT and SPECT/CT scan-
ners are now playing an increasingly important role in
radiation therapy since their introduction into the
clinic. Recently, a technically challenging design, a
clinical MR/PET scanner (Marsden et al. 2002;
Schlemmer et al. 2008), has been undergoing clinical
evaluation, although limited to brain.
Linac-Based Image Guided Intensity Modulated Radiation Therapy
2.4 Recent Progress in IMRT and VMAT
Treatment Planning
2.4.1 IMRT
There have been numerous technical advances and
developments in IMRT treatment planning, including,
but not limited to, multiobjective treatment planning,
biologically conformal treatment planning, treatment
planning incorporating patient (e.g., organ motion) or
machine (e.g., beam) factors, etc. Conventionally, the
objectives of each treatment plan are reduced to a
single numerical value by the objective function,
mainly for the sake of simplicity. The objectives of
the treatment are usually expressed as the desired
dose distributions to target and normal tissues.
However, the treatment planning process is inherently
a multi-dimensional problem: there are multiple nor-
mal structures surrounding the target and sometimes
there are multiple targets to be treated. Therefore,
multiple objective functions need to be used to fully
describe the quality of a treatment plan, which leads
to multiobjective treatment planning. The difficulty
with this is that the objectives specified for these
structures are often in conflict. There have been sev-
eral approaches proposed by different researchers for
dealing with such conflicting objectives. One of the
approaches is to specify the treatment objective as a
probability density function rather than as a single
value (Xing et al. 1999; Lian et al. 2003). In this
approach, the prescription dose is allowed to deviate
from the most desired dose, with a certain preference
level. Another approach is to build a database of plans
by varying the relative weights of different objectives.
Using an interactive plan navigation tool, the trade-
offs between different objectives can be made
explicitly based on the user’s clinical goals (Craft
et al. 2007). The resultant plans from this approach
are also called Pareto optimal plans. Along this line,
Holdsworth et al. (2010) developed a hierarchical
evolutionary multiobjective algorithm designed to
quickly generate a small diverse Pareto optimal set of
IMRT plans that meet all clinical constraints and
reflect the optimal trade-offs.
Conventional IMRT inverse planning methodol-
ogy is typically based on the assumption of uniform
biology within the target volume. However, it is well
known that in reality, the spatial biology distribution
(e.g., clonogen density, radiosensitivity, tumor pro-
liferation rate, functional importance) in most tumors
283
and critical structures is heterogeneous. Recent pro-
gress in biological imaging has made the mapping of
this distribution possible and opened up a new avenue
for research, termed biologically conformal radiation
therapy (BCRT). The goal of BCRT is to take into
account the inhomogeneous biological information
derived from biological imaging and to produce
customized nonuniform dose distributions on a
patient-specific basis (Ling et al. 2000; Brahme 2001;
Xing et al. 2002; Alber et al. 2003; Yang and Xing
2005; Stewart and Li 2007). The simultaneous inte-
grated boost to deliver different amounts of doses to
elective target volumes represents a simple example
of BCRT. To accomplish BCRT in general, three
major aspects must be achieved: (1) determination of
the distribution of biological properties of the tumor
and critical structures; (2) prescription of the desired
dose distribution for inverse planning; and (3) inverse
planning to generate most faithfully the prescribed
nonuniform dose distribution. Yang and Xing (2005)
established a theoretical framework to quantitatively
incorporate the spatial biology data into IMRT
inverse planning. By maximizing the TCP based on a
linear-quadratic (LQ) model, they derived a general
formula for determining the desired dose distribution
to each tumor voxel for a known biology distribution,
in particular, tumor cell density, radiosensitivity, and
proliferation rate. Das (2009) proposed a method to
incorporate biological optimization after dose-volume
constrained optimization so as to improve the dose
distribution without detrimentally affecting the
important reductions achieved by dose-volume opti-
mization. This reduces biological metrics while
preserving the important dose reductions achieved by
dose-volume constrained optimization.
There are two types of treatment planning algo-
rithms for IMRT: beamlet-based and segment-based.
The beamlet-based algorithm generates beamlet
intensity maps with high complexity, resulting in large
numbers of segments in delivery. The segment-based
direct-aperture optimization (DAO) algorithm incor-
porates the physical constraints of the deliverable
apertures and achieves a conformal dose distribution
using a small number of segments. However, the
number of segments is pre-fixed in most of the DAO
approaches, and the typical random search scheme in
the optimization is computationally intensive. Zhu
et al. (2008a) and Zhu et al. (2010) proposed a total-
variation (TV) based technique to better balance the
284
Fig. 3 Fluence maps for the
HN case obtained using TVR
method. Source Zhu et al.
2008a, with permission
trade-off between fluence modulation complexity and
plan deliverability. The central idea of the approach is
to introduce an L-1 norm to encourage piecewise
constant fluence maps, such that the number of beam
segments is minimized, while the desirable dose dis-
tribution is ensured using a quadratic term. Instead of
directly including the nonconvex physical constraints
in the optimization, the CS method obtains a global
R. Li et al.
optimal solution, only in a sparse space of fluence
maps where piecewise constant fluence maps are
encouraged, and allows us to balance the dose opti-
mally and deliver efficiency in a controlled manner.
Figure 3 contains piecewise constant fluence maps
resulted from CS-based inverse planning for a seven-
field head and neck IMRT. (Zhu et al. 2008b) The
corresponding dose distribution is almost identical to
Linac-Based Image Guided Intensity Modulated Radiation Therapy
that of the unregularized beamlet-based IMRT plan.
The study indicated that, with the intelligent fluence
map regularization using the CS technique, the total
monitor units for delivery are reduced by more than 20
percent for even a simple prostate case. Radiation
therapy with flattening filter-free (FFF) beams has the
potential to greatly reduce treatment time and out-
of-field dose. However, current inverse planning
algorithms are not customized for beams with non-
uniform incident profiles and the resultant IMRT plans
are often inefficient to deliver. Kim et al. (2011) pro-
posed a TV regularization formalism by taking the
inherent shapes of incident beam profiles into account.
The TV regularization encourages piecewise constant
fluence in the nonuniform FFF fluence domain. The
proposed method significantly reduced the number of
segments, while achieving similar coverage of target
volume and sparing of the organs-at-risk compared
with conventional algorithms for lung, prostate, and
head and neck cases. Finally, in order to enhance the
visibility of the implanted fiducials in cine MV ima-
ges, Ma et al. (2009) developed an inverse planning
strategy to control the appearance of the implanted
fiducials in segmented IMRT fields. The system is
modeled by a quadratic objective function with
inclusion of a hard/soft constraint characterizing
preference for the fiducials to be included in the seg-
mented fields. It was shown with two clinical cases
that the MLC blockage of the implanted fiducials
during the segmented delivery can be avoided without
severely compromising the final dose distribution and
the visibility of implanted fiducials can be improved
without significantly deteriorating the final dose
distribution.
2.4.2 VMAT
Another form of treatment delivery technique, namely
VMAT is becoming increasingly popular in radiation
therapy (Yu 1995; Crooks et al. 2003; Otto 2008).
Standard fixed-gantry IMRT has increased treatment
time by requiring a larger number of beam directions
and increased MU. The goal of VMAT is to reduce
treatment time without sacrificing the treatment plan
quality. This is realized by delivering the dose during a
single 360° gantry rotation. In VMAT optimization
(Otto 2008), the continuous gantry motion is modeled
as a coarse sampling of static gantry positions and
fluence maps or MLC aperture shapes. Then gantry and
MLC position sampling are progressively increased
285
throughout the optimization. During planning, MLC
leaf motion and number of MU per degree of gantry
rotation are restricted during the optimization so that
gantry rotation speed, leaf translation speed, and dose
rate maxima do not excessively limit the delivery
efficiency. Using the full gantry rotation for beam
delivery will theoretically provide more flexibility in
generating highly conformal treatment plans. In prac-
tice, however, the additional flexibility is somewhat
negated by the additional constraints placed on the
amount of MLC leaf motion between successive gantry
angles. Preliminary results show that plans generated
with VMAT optimization exhibit dose distributions
equivalent or superior to static gantry IMRT. Timing
studies have shown that the VMAT technique is well
suited for online verification and adaptation with
delivery times that are reduced to *1.5–3 min for a
200 cGy fraction.
A few recent studies on VMAT are worth of
mention. Bedford (2009) created uniform arc control
points throughout one or more arcs and used iterative
least-squares algorithm to generate a fluence profile at
every control point. The control points are then
grouped and all the control points in a given group are
used to approximate the fluence profiles. A direct-
aperture optimization was then used to improve the
solution, taking into account the allowed range of leaf
motion of the MLC. The method was applied to five
clinical cases, including lung, prostate and seminal
vesicles, prostate and pelvic nodes, head and neck,
and rectum cases. VMAT either provides a plan of
similar quality to standard IMRT or with faster
delivery by up to a factor of four. Bzdusek et al.
(2009) derived the MLC segments from fluence maps
at relatively coarsely sampled angular positions. The
beam segments, dose rate, and gantry speed are then
optimized based on dose-volume objectives and leaf
motion constraints. The method can vary both dose
rate and gantry speed or alternatively determine the
optimal plan at constant dose rate and gantry speed.
The method was used to retrospectively generate
VMAT plans to 10 patients with head and neck,
prostate, brain, lung, and tonsil cancers. In compari-
son to standard IMRT, the VMAT plan quality was
comparable or improved. Optimization and final dose
calculation took 5–35 min depending on plan com-
plexity. Men et al. (2010) developed a GPU-based
aperture-based algorithm for VMAT. Most recently,
Li and Xing (2011) investigated the inherent relation
286
between VMAT and IMRT and provided a hybrid
scheme to complete the map of intensity and aperture
modulated radiation therapy. On the research front,
4D VMAT inverse planning aiming to derive an
aperture and weight modulated arc therapy treatment
plan that optimizes the accumulated dose distribution
from all gantry angles and breathing phases has also
been proposed (Ma et al. 2010). This study provides
insight into how the time dimension can be exploited
in rotational arc therapy to maximally compensate for
the intrafraction organ motion.
3 Role of In-Room and Onboard
Imaging in LINAC-Based Radiation
Therapy
In radiation therapy, it is essential that CTV be
accurately positioned before every treatment fraction
in order to avoid the adverse effects of a geographic
miss. Historically, a patient is set up based on skin
marks and MV portal imaging. The main limitations
of this approach are the low subject contrast at MV
energies and the use of 2D projections of bony
landmarks to infer the 3D target location. Therefore, a
substantial PTV margin has to be added to the CTV in
order to compensate for the uncertainty in patient
setup. This large margin dictated by conventional
setup techniques limits the potential for highly con-
formal dose delivery and normal tissue sparing
offered by IMRT. Over the last decade, a wide variety
of in-room and onboard imaging methods have been
developed to ensure more accurate patient setup and
target localization and to facilitate margin reduction.
3.1 Use of 2D Projection Images
for Patient Setup
The use of MV portal imaging for patient setup has
evolved over the past decade. Advances in detector
technologies have greatly enhanced the visualization
of implanted opaque markers in MV projection
images to assist patient setup and target localization.
The major challenge with MV portal imaging is the
low subject contrast at MV energies. Improvements
in the quality of these images have been achieved
through the development of low-noise digital imag-
ing devices. These developments have led to the
R. Li et al.
commercially available large-area amorphous silicon
(a-Si) detectors that offer portal image quality lim-
ited only by the inherent physics of image formation
at MV energies (Munro and Bouius 1998; El-Mohri
et al. 2001).
If one would like to achieve similar levels of
subject contrast in the treatment verification images as
those used for treatment simulation and planning,
X-ray sources at kV energy ranges have to be used for
in-room imaging systems. There are two major modes
of 2D projection imaging: radiographic imaging and
fluoroscopic imaging. Radiographic imaging is the
acquisition of 2D projection or planar X-ray images.
It is the most basic imaging technique. Fluoroscopic
imaging is a continuous stream of planar X-ray ima-
ges acquired in real-time during patient setup or
treatment delivery. It allows real-time monitoring and
verification of treatment structures, based on visible
anatomical landmarks or implanted fiducial markers.
The information can be used for patient setup as well
as for the management of intrafractional patient
motion and organ motion and the adjustment of
treatment in some cases.
Several distinct in-room and onboard kV imaging
systems have been made commercially available, each
with unique capabilities. They can be broadly divided
into two classes: room-mounted and gantry-mounted
(or onboard) imaging systems. Room-mounted system
is commonly referred to as a stereoscopic imaging
system. In these systems, the kV X-ray tubes are
mounted permanently either to the ceiling or to the floor
such that the tube and detector locations are fixed
relative to the coordinates of the treatment room. Thus
room-mounted imaging systems can provide a high
mechanical precision once they are calibrated. Both
radiographic and fluoroscopic imaging modalities are
offered. The stereoscopic images can be used to provide
3D information about the patient geometry. The
downside is a smaller field of view due to a large
source-to-detector distance and a lower imaging
efficiency, which leads to higher imaging dose. One
distinctive feature of room-mounted systems is the
unconventional imaging angle, which makes human
interpretation of the images difficult. Gantry-mounted
system is mounted on the LINAC gantry, usually
orthogonal to the central axis of the treatment
beam. One or two imaging systems may be mounted.
The kV imaging system moves as the gantry rotates
and shares the same isocenter as the MV treatment
Linac-Based Image Guided Intensity Modulated Radiation Therapy
beam. Gantry-mounted systems can be used to acquire
radiographs with a large field of view at conventional
beam angles (anteroposterior and lateral). The major
weakness of gantry-mounted systems is the suboptimal
mechanical precision due to gantry sagging.
LINAC-based room-mounted imaging systems
include the Mitsubishi/Hokkaido real-time tumor-
tracking radiation therapy (RTRT) system and
Novalis ExacTrac 6D system from BrainLAB. The
RTRT system was developed jointly by Hokkaido
University Hospital and Mitsubishi Electronics
(Tokyo, Japan) (Shirato et al. 2000a). The RTRT
imaging system consists of four sets of diagnostic
X-ray camera systems, each consisting of an X-ray
tube mounted under the floor, a nine-inch image
intensifier mounted on the ceiling, and a high-voltage
X-ray generator. The four X-ray tubes are placed at
right caudal, right cranial, left caudal, and left cranial
position with respect to the patient couch at a distance
of 280 cm from the isocenter. The image intensifiers
are mounted on the ceiling, opposite to the X-ray
tubes, at a distance of 180 cm from the isocenter, with
beam central axes intersecting at the isocenter. The
ExacTrac 6D X-ray imaging system consists of two
floor-mounted kV X-ray tubes, projecting obliquely
into two corresponding a-Si flat panel detectors
mounted on the ceiling. The X-rays project in oblique
directions relative to the patients, and the source
isocenter and source detector distance is relatively
large (224 and 362 cm, respectively).
Gantry-mounted kV imaging systems include
Elekta Synergy, Varian onboard imager (OBI), and
the integrated radiotherapy imaging system (IRIS)
developed jointly by Massachusetts General Hospital
and Varian Medical Systems. The Synergy system
was developed by Elekta Inc. (Stockholm, Sweden) in
collaboration with William Beaumont Hospital. The
system consists of an X-ray tube and an a-Si flat panel
imager mounted on the LINAC gantry and orthogonal
to the therapy beam. A similar system called onboard
imager, or OBI system was also developed by Varian
Medical Systems, Inc. (Palo Alto, CA, USA). Both
Elekta Synergy and Varian OBI systems have only
one imager. The IRIS system (Berbeco et al. 2004)
consists of two gantry-mounted kV X-ray tubes and
two flat panel a-Si detectors. The central axes of the
two kV X-ray beams are orthogonal to each other, 45°
from the MV beam central axis, and intersecting each
other at the LINAC isocenter. Both X-ray sources are
287
100 cm away from the isocenter, while the imagers
are at 162 cm distance from the isocenter.
3.2 Volumetric (3D) CBCT for Patient
Setup and Adaptive Radiation
Therapy
It has been demonstrated that, for many tumor sites,
the bony structures are unreliable and inadequate for
accurate target localization and the visualization of
soft tissues is essential to achieve further reductions
in geometric uncertainty during patient setup
(Roeske et al. 1995; Stroom et al. 1999; Kubo and
Hill 1996; Kupelian et al. 2007). The use of 2D
projections is generally inadequate to achieve this
goal. This has spurred the development of volu-
metric imaging systems for accurate patient setup
and target localization in the last decade or so.
Furthermore, the availability of patient’s volumetric
images at the treatment is an essential component to
achieve adaptive radiation therapy (ART).
3.2.1 CBCT for Patient Setup
Jaffray et al. (1999) developed a kV X-ray imaging
system integrated with the LINAC. This system
featured MV and kV X-ray sources mounted 90° apart
and dedicated charge-coupled device (CCD) imaging
devices for each source. Due to the poor detector
quantum efficiency of CCD imagers, the system
quickly evolved into one based on large-area flat
panel detectors (Drake et al. 2000; Jaffray et al. 2002).
The system is capable of radiographic and fluoro-
scopic imaging as well as tomographic imaging using
CBCT methods. CBCT imaging involves acquiring
multiple kV radiographs as the gantry rotates through
a full 360° of rotation. A filtered back-projection
algorithm was employed to reconstruct the volumetric
images. The system was demonstrated to produce
images of soft tissue with excellent spatial resolution
at acceptable imaging doses (Jaffray et al. 2002).
Factors that affect the overall performance of
CBCT imaging have since been thoroughly discussed
and addressed and the CBCT technology has been
refined. Accurate characterization of the imaging
geometry is imperative for accurate volumetric
image reconstructions. The stability of the imaging
system’s geometry has been well characterized and its
capacity for accurate back-projection demonstrated
288 R. Li et al.

Fig. 4 Images showing the

superior performance of MV
CBCT (right) over CT (left) in
the presence of dense metal
objects. All metal pieces used
for this hip reconstruction are
clearly visible on the MV
CBCT 3D rendering (bottom).
Source Morin et al. 2006, with
permission

(Sharpe et al. 2006). Issues related to detector effi-
ciency, signal lag, X-ray scatter, and overall perfor-
mance have also been discussed and addressed in the
literature (Drake et al. 2000; Jaffray et al. 2002;
Siewerdsen and Jaffray 2000; Siewerdsen and Jaffray
1999; Siewerdsen and Jaffray 2001; Yin et al. 2005).
The field of view (FOV) of onboard CBCT is typi-
cally limited due to the detector size if the detector is
centered at the beam axis (called full-fan CBCT
reconstruction). In order to increase the FOV of
CBCT, a half-fan scan geometry can be adopted
where the detector center is shifted laterally from the
beam axis so that one side of the anatomy can be
fully sampled by the projections with the initial 180°
gantry rotation and the other side of the anatomy by
the projections with the second 180° gantry rotation.
Linac-Based Image Guided Intensity Modulated Radiation Therapy
Numerous studies have examined the accuracy of
CBCT for patient setup and demonstrated its potential
for high resolution, soft tissue imaging (Kriminski
et al. 2008; Li et al. 2008; Nelson et al. 2009; Oldham
et al. 2005; Yin et al. 2006; Wang et al. 2009a; Chang
et al. 2008). Currently, the most significant factors
affecting CBCT performance are (1) the limited
dynamic range of the X-ray detector, (2) the presence
of elevated X-ray scatter at large cone-angles and
object diameters, and (3) patient motion during the
scan. Despite these challenges, the image quality
being generated in the clinical environment is suffi-
cient to consider the use of CBCT images for image
guidance of many anatomic sites (Yin et al. 2008).
MV CBCT technologies have also been developed
utilizing the MV treatment beam. The MV CBCT
system consists of an amorphous silicon flat panel
adapted for MV imaging attached to a Siemens linear
accelerator (Pouliot et al. 2005; Pouliot 2007). The
MV CBCT system demonstrated sufficient localiza-
tion accuracy and soft tissue contrast to visualize
structures such as the prostate. However, the subject
contrast of these MV CBCT images is generally
believed to be lower than those acquired at the kV
energies. On the other hand, it is evident that MV
CBCT images contain fewer metal artifacts than their
kV counterpart (Morin et al. 2006), as shown in
Fig. 4. However, competing metal artifacts removal
techniques for kV CBCT are being developed (Meng
et al. 2010; Wang and Xing 2010) and it is foresee-
able that this will become less of a problem in clinical
kV CBCT applications in the near future.
3.2.2 CBCT for Adaptive Radiation Therapy
CBCT provides a valuable 3D geometric model of the
patient at the treatment. This not only allows the
correction of patient setup error and interfractional
organ motion, but also opens the door to ART (Yang
et al. 2007; Yan et al. 1997; Langen et al. 2005). ART
utilizes the volumetric information acquired at each
fraction to adjust the treatment plan according to the
new patient geometry and anatomy. A significant
advantage of ART over conventional radiation ther-
apy is the optimal compensation of geometric
uncertainties and dosimetric errors incurred by setup
errors and organ motion and deformation (Mohan
et al. 2005; Thongphiew et al. 2009; Trofimov et al.
2005; Wu et al. 2006; de la Zerda et al. 2007;
Wu et al. 2008; Nijkamp et al. 2008).
289
An integral part and critical component of ART is
the calculation of dose at every treatment fraction.
CBCT acquired at the treatment makes this possible by
providing 3D geometric model of the patient. Although
imaging system-specific conversions between Houns-
field units (HUs) and electron density would allow dose
to be calculated based on CBCT, various factors, such
as X-ray scatter and image artifacts can severely affect
the accuracy of the calculated dose. Careful consider-
ation of these issues is required when using CBCT for
dose calculation purposes.
One of the most significant factors affecting CBCT
performance is the presence of elevated X-ray scatter
at large cone-angles and object diameters. Increasing
the amount of scattered radiation introduces a shift in
the CT calibration curve. Methods to reduce the
contribution of scattered photons in the projection
images can be broadly divided into two main types.
The first type of methods perform scatter reduction
based on the different incidence angles of primary and
scattered photons during the acquisition process. A
typical example is the anti-scatter grid method
(Siewerdsen et al. 2004). These methods achieve
instant scatter suppression, but their efficacy is usually
limited. Siewerdsen et al. (2004) showed that an anti-
scatter grid was effective only in improving the con-
trast-to-noise ratio of low resolution objects. An anti-
scatter grid attenuates primary photons as well, and
the imaging dose needs to be increased to maintain
the same image quality. The second type of methods
correct for scatter using post-processing techniques on
the projection images (Zhu et al. 2006; Ning et al.
2004; Kyriakou et al. 2006; Lo et al. 1994; Seibert
and Boone 1988; Honda et al. 1991; Zhu et al. 2009).
These methods typically involve an estimation of the
scatter distribution and subsequent subtraction or a
deconvolution technique to remove the scatter. A
clinically practical scatter reduction technique needs
to take several factors into consideration, such as
correction efficacy, computational complexity, imag-
ing dose, scan time increase, and hardware
compatibility.
For LINAC-mounted CBCT systems, cupping
artifacts, ring artifacts, streaking artifacts, and motion
artifacts continue to be challenging problems for
accurate dose calculations. To alleviate these prob-
lems, a deformable electron density mapping
approach (Yang et al. 2007) has been proposed, where
deformable image registration algorithms are applied
290
Fig. 5 Dose distributions in a transverse-slice calculated based
on: a pCT, b CBCT, and c mCBCT for a prostate case. DVHs
of the prostate, PTV, rectum, and bladder obtained based on the
to map electron density information from the initial
planning fan-beam CT (FBCT) to the CBCT images
at the treatment. The dose calculation occurs on a
deformed FBCT image set (mCBCT), thus circum-
venting the image artifact problems inherent in
CBCT. Figure 5 shows the reconstructed dose based
on CBCT and mCBCT together with the original
treatment plan for a prostate case. A comparison of
dose-volume histograms of PTV, prostate, seminal
vesicles, bladder, and rectum is also presented. Note
that the results obtained using the CBCT or mCBCT
are similar, indicating that CBCT may be used for
dose calculation when there is minimal image artifact.
However, the dosimetric error caused by the inter-
fractional organ motion/deformation is not negligible,
as suggested by the large discrepancies between the
original plan and the dose calculated based on CBCT
or mCBCT. The discrepancy reaffirms the need for
adaptive therapy. Although the deformable electron
density mapping approach seems adequate in certain
R. Li et al.
pCT, CBCT, and mCBCT images for the case are plotted in (d).
Source Yang et al. 2007, with permission
cases, the ultimate solution lies in the improvement in
image quality for CBCT.
3.3 4D CBCT and its Role in 4D
Radiation Therapy
As with 3D CT, respiratory motion induces artifacts in
CBCT. To address this, respiratory correlated or 4D
CBCT has been developed (Sonke et al. 2005; Li et al.
2007; Li et al. 2006; Li and Xing 2007). An example 4D
CBCT is shown in Fig. 6. The blurring artifacts present
in the 3D CBCT are not seen in the 4D CBCT phases,
and the superior–inferior motion of the tumor is cap-
tured. The first commercial version of 4D CBCT was
released by Elekta in 2010; with the growth of 4D CT
being so rapid, 4D CBCT is likely to be a mainstay of
in-room imaging in the future of radiation therapy.
4D CBCT is currently being used for a 4D-4D
match procedure prior to treatment, by shifting the
Linac-Based Image Guided Intensity Modulated Radiation Therapy 291

Fig. 6 Sagittal, coronal, and transverse slices of a patient depicting the 3D CBCT scan and the peak-exhale, mid-inhale,
peak-inhale, and mid-exhale phases of the 4D CBCT scan. Source Sonke et al. 2005, with permission

moving tumor position measured during the 4D CBCT
to that of the planned 4D CT. Future applications of 4D
CBCT could be for adaptive radiotherapy and estab-
lishing external/internal correlation models to guide
respiratory-gated or tumor-tracking radiotherapy.
3.4 Imaging Dose and QA of Onboard
Imaging Devices
3.4.1 Imaging Dose
IGRT makes use of many different imaging tech-
niques, ranging from portal imaging to fluoroscopy to
kV and MV CBCT. The total imaging radiation dose
experienced by a patient can include multiple CT
scans for planning, pretreatment fluoroscopic studies
to analyze tumor motion, and a series of interfrac-
tional and intrafractional images for target localiza-
tion. Imaging dose can be concentrated at the skin or
distributed throughout the anatomical volume of
interest. Given these circumstances, the cumulative
imaging dose is no longer negligible compared to the
therapeutic dose. Therefore, the concomitant imaging
dose should be carefully considered and documented.
AAPM Task Group 75 (Murphy et al. 2007) provides
a comprehensive report on the radiation dose deliv-
ered during IGRT.
292
The imaging dose to the patient is mainly deter-
mined by the required image quality, the attenuation
characteristics of the anatomy, the imaging duty cycle
(duration and frequency), and the imaging geometry
(source/patient/detector distance, field of exposure),
although there can be considerable variations among
equipment geometries and dose details for different
imaging modalities during IGRT.
For portal imaging (Wang et al. 2009b), the cumu-
lative dose to acquire a single image using amorphous
silicon panels ranges from 1 to 5 MU. For those
LINAC systems that permit the setting of an arbitrary
portal image exposure level, it is possible to acquire
images with less than 1 MU. There are instances where
this can provide an adequate image. This capability is
an important means to reduce the total portal imaging
dose, especially when daily portal imaging is used.
Both Elekta Synergy XVI and Varian OBI systems
have radiographic, fluoroscopic, and CBCT capabilities.
When used in radiographic mode to acquire AP and
lateral radiographs, the dose to the patient is approxi-
mately 1–3 mGy per image depending on technique
(Perkins et al. 2006). The dose delivered by Elekta XVI
kV CBCT has been measured by Islam et al. (2006). The
tube was operated at 120 kVp and the complete scan
technique was 660 mAs. Torso and head doses were
simulated using 32-cm diameter and 16-cm diameter
cylindrical water phantoms. The typical doses at the
center and surface of the body phantom were 16 and
23 mGy, while for the head phantom the center and
surface doses were 30 and 29 mGy, respectively.
Cossmann et al. (2005) and Wen et al. (2007) reported
doses of 30–80 mGy from the Varian OBI system for
900 projections, an FOV of 48 cm, and a scan length of
17 cm. Endo et al. (1999) have measured both local and
effective doses for kV CBCT. All these measurements
are consistent with each other when adjusted for tech-
nique, geometry, and scan protocol, i.e., number of
projections. Another methodology for kV-CBCT
imaging dose was discussed by Ding et al. (Ding et al.
2008), who found that the dose to the bone due to the
photoelectric effect can be as much as 25 cGy, about
three times the dose to soft tissues.
MV CBCT has been implemented clinically at the
University of California, San Francisco (UCSF), in
partnership with Siemens Medical (Chen et al. 2006),
and at the Memorial Sloan-Kettering Cancer Center
(MSKCC), in collaboration with Varian Medical Sys-
tems. Both these systems are based on conventional
R. Li et al.
LINACs. The dose for the UCSF system typically
ranges from 2 to 10 MU depending on the clinical
application (Pouliot et al. 2005). The MSKCC system
can obtain an MV CBCT of the thorax suitable for
tumor delineation from 100 projections using a total of
20 MU of radiation (Sillanpaa et al. 2005). Low-dose
MV CBCT is complicated by variations in beam flat-
ness, symmetry, and other characteristics.
The general rule for managing dose in diagnostic
imaging is represented as low as is reasonably
achievable. For imaging associated with radiotherapy,
there are several ways to reduce the effective dose
without reducing the image information. These
methods include, but are not limited to, narrowing the
field of view, more efficient imaging modes and
protocols, nonradiographic imaging (e.g., electro-
magnetic transponders or MRI), and hybrid imaging.
3.4.2 QA
QA procedures are designed to ensure that the
imaging systems, including hardware and software,
function safely and reproducibly and perform as
accepted and commissioned. QA procedures involve
periodic measurements of specified parameters using
dedicated tools and phantoms that are validated with
specific acceptability criteria and tolerance levels. In
general, each clinic should define daily, monthly, and
annual QA procedures. The daily QA should include
safety checks, positioning and repositioning accuracy
tests, and basic tests to verify the coincidence of
imaging and treatment coordinates. The monthly QA
should include thorough tests of the coincidence of
imaging and treatment coordinates, image quality
including noise, resolution and contrast, HU consis-
tency, and the scaling factor. The annual QA should
include a full range of tests on mechanical accuracy,
imaging dose, kV beam energies, tube current.
Typically, the imaging coordinate system is cor-
related with the delivery coordinate system through a
calibration process. It is critical to ensure the coinci-
dence of these two coordinate systems for different
clinical needs of IGRT procedures. Each system
performing patient positioning/repositioning, either
2D or 3D, relies upon vendor software that compares
and registers onboard images and reference images.
Quality assurance of this process could be easily done
by a phantom study with known shifts and is rec-
ommended for each system used clinically (Yin FF
Wong J (2009) The role of in-room kV X-ray imaging
Linac-Based Image Guided Intensity Modulated Radiation Therapy
Fig. 7 A treatment sequence
for respiratory-gated DMLC
IMRT. Source Keall et al.
2006, with permission
for patient setup and target localization. American
Association of Physicists in Medicine Task Group
Report 104, unpublished).
AAPM Task Group 142 (Klein et al. 2009) set
basic recommendations for the use of various onboard
imaging systems. For MV portal imaging, the imag-
ing quality, dose rate, energy, and calibration dis-
tances should be checked and determined specifically
for each type of electronic portal imaging device
(EPID). The basic QA for planar kV imaging system
mainly handles 2D X-ray imaging, either with
radiographic imaging (single shot of a planar image)
or continuous fluoroscopic imaging. The baseline data
from acceptance testing are recommended as the
criteria for imaging quality QA. For onboard CBCT
imaging systems, the positioning and repositioning
accuracy should include couch movement from the
treatment position to the imaging position. Although
spatial accuracy of image reconstruction is paramount
and most heavily emphasized, image quality param-
eters (e.g., contrast, noise, uniformity, and spatial
resolution) are also important aspects and should be
included in QA procedures. A direct measure of
imaging dose and beam quality/energy is recom-
mended at least annually. The baseline data (includ-
ing both means and ranges or measured values and
their upper and lower limits) established during the
acceptance testing should be used for QA criteria.
4 Real-Time Guidance in IG-IMRT
and VMAT
4.1 Current Techniques for Respiratory
Gating
Respiratory-gated radiotherapy is defined as the syn-
chronization of imaging and radiation delivery with res-
piration, such that image acquisition/radiation delivery
293
only occurs during a certain part of the respiratory cycle.
(Keall et al. 2006a) Respiratory gating is applicable to
thoracic and abdominal tumor sites affected by respira-
tory motion, such as lung, breast, pancreas, liver, kidney,
and esophageal cancer radiotherapy.
One of the big advantages of respiratory gating is
that the images used for treatment planning are gated,
either as a subset of a 4D CT scan (Keall 2004; Keall
et al. 2005) or the CT acquisition is prospectively gated
by acquiring CT data only when the patient’s breathing
is in a certain respiratory phase, typically end exhale or
inhale. Therefore, motion artifacts typically present
during a 3D CT scan are reduced. During treatment,
beam delivery occurs only when the patient’s breathing
is in the same phase as that used for pretreatment
imaging and planning. An example of a gated intensity
modulated radiation therapy (IMRT) delivery is shown
in Fig. 7. During (in this case) exhale, the radiation
beam is delivered. As the patient breathes in, delivery
is paused and resumes when the patient re-enters the
respiratory phase or gating window defined for treat-
ment. Respiratory-gated radiotherapy requires a
respiratory signal integrated with the imaging and
delivery systems. Clinical workflows, patient selec-
tion, training, and quality assurance guidelines for
respiratory-gated radiotherapy can be found in (Keall
et al. 2006a; Keall et al. 2006b).
The trade-off between treatment accuracy and
efficiency for respiratory gating is shown in Fig. 8.
To increase treatment accuracy, the treatment effi-
ciency is reduced and the overall treatment time is
increased (Vedam et al. 2003b).
One of the concerns of some respiratory gating
implementations is the reliance of the external respi-
ratory signal to gate the treatment beam without
internal tumor position verification. However, newer
implementations of respiratory gating are addressing
this issue and allowing imaging to be acquired during
the treatment.
294
Fig. 8 Demonstration of the trade-off between efficiency, or
‘duty cycle’ versus treatment accuracy, the variation of internal
motion during the gating window. The increase in motion with
duty cycle is due to the residual motion within the gating
window. Source Vedam et al. 2003a, with permission
4.2 The Unmet Clinical Needs
for Real-Time Imaging
There is abundant clinical evidence in radiation
therapy that higher dose levels lead to higher local
control and survival rates (McGarry et al. 2005; Perez
et al. 1986; Choi and Doucette 1981; Okunieff et al.
1995; Perez et al. 1980; Machtay et al. 2010; Wulf
et al. 2005; Martel et al. 1999). On the other hand,
higher dose levels also lead to higher normal tissue
complication rates. For instance, lung complications
have shown to correlate with mean lung dose (Kwa
et al. 1998; Hernando et al. 2001; Graham et al. 1999;
Seppenwoolde et al. 2003; Yorke et al. 2002). Due to
the growing use of concomitant chemotherapy, the
need for normal tissue sparing is becoming increas-
ingly important. Therefore, the ability to deliver an
increased dose to the tumor while sparing healthy
tissue will ultimately improve the balance between
complications and cure. The key to realize this goal is
a substantial reduction in the CTV–PTV margin.
However, in practice, the ability to do this has been
limited by the uncertainties in measuring and man-
aging both interfractional and intrafractional organ
motion. Although the issue of interfractional organ
motion may be largely resolved by accurate patient
R. Li et al.
setup at every treatment fraction, e.g., using in-room
and onboard imaging mentioned before, the other half
of the story, i.e., intrafractional organ motion, can still
cause serious errors during treatment delivery and
simply cannot be ignored.
Several sources can cause intrafractional motion,
e.g., the respiratory, skeletal muscular, cardiac, and
gastrointestinal systems. Of these four systems, much
research has been directed towards accounting for
respiratory motion, which is the subject of AAPM
Task Group report 76 (Keall et al. 2006c). Respiratory
motion affects all tumor sites in the thorax and
abdomen. Generally, abdominal organ motion is in
the SI direction, with small displacements (\2 mm) in
the AP and lateral directions (Davies et al. 1994;
Korin et al. 1992). Lung tumor motions generally
show a much greater variation. The amount a lung
tumor moves during breathing can vary widely.
Stevens et al. (2001) found that out of 22 lung tumor
patients, 12 patients showed an average SI displace-
ment anywhere from 3 to 22 mm; while the remaining
10 patients showed no tumor motion in the SI direc-
tion. No correlation was found among the magnitude
of tumor motion and tumor size, location, or pul-
monary function, suggesting that tumor motion
should be assessed individually. Seppenwoolde et al.
(2002) measured the 3D trajectories of lung tumors
for 20 patients via dual real-time fluoroscopic imag-
ing of a fiducial marker implanted in or near the
tumor. They observed hysteresis in the trajectories of
10 patients, with a 1–5 mm separation of the trajec-
tories during inhalation and exhalation. Figure 9
shows the motion trajectories of lung tumors during
radiotherapy, measured using implanted gold markers
(Seppenwoolde et al. 2002). Overall, there are no
general patterns of tumor motion that can be assumed
for a particular patient. The tumor motion variations
associated with tumor location and pathology lead to
distinct individual patterns in displacement, direction,
and phase of tumor motion that can change during the
treatment delivery.
Based on the above observations, the only way to
effectively manage intrafractional motion in general is
through real-time imaging during treatment delivery.
Some desirable properties of real-time imaging
include: (1) it must have sufficient accuracy in cap-
turing the real-time tumor motion and deformation
caused by any physiological processes, e.g., respira-
tion; (2) it should be capable of imaging the tumor as
Linac-Based Image Guided Intensity Modulated Radiation Therapy
Fig. 9 Tumor trajectories (not to scale) in 23 lung tumor patients, measured using implanted markers and real-time stereoscopic
fluoroscopy. Source Seppenwoolde et al. 2002, with permission
well as the surrounding healthy structures, preferably
with volumetric imaging capability; (3) it should be
noninvasive and present only minimal additional risk
to the patient. To date, there has been no such LINAC-
integrated imaging system commercially available yet.
However, considerable amount of efforts have been
devoted to the development of such a system, which
will be the subject of our next section.
4.3 Real-Time Imaging Techniques
for Radiation Therapy
Real-time imaging techniques in RT cover a wide
range of medical imaging modalities, including radi-
ography (kV and MV), MRI, ultrasound, radio-
frequency (RF) electromagnetic, and optical as listed
in Table 1. Some systems are already commercially
available and have been extensively used in the clinic;
some are under active development, while still others
are active research topics.
295
4.3.1 Radiographic Imaging
All the commercially available in-room and onboard
kV imaging systems discussed in Sect. 3.1 are capa-
ble of fluoroscopic imaging. The imaging frequency
of fluoroscopy can be made as high as 30 Hz.
It allows real-time imaging of the tumor as well as
surrounding structures, which can be used for the
management of intrafractional organ motion and the
adjustment of treatment in some cases. Fiducial
markers made of high-density materials may be
implanted inside or near the tumor to aid visualization
and detection of the target (Murphy et al. 2000; Mah
et al. 2000). This technique is commercially available
in the Mitsubishi/Hokkaido RTRT system and has
been extensively used for the treatment of lung, liver,
prostate, and other tumor sites (Shirato et al. 2000a;
Seppenwoolde et al. 2002; Shirato et al. 1999;
Shimizu et al. 2000; Shirato et al. 2000b; Shirato et al.
2003).
MV radiographic imaging using EPID is currently
under study, primarily for real-time tumor localization
296
using implanted markers (Park et al. 2009; Berbeco
et al. 2007). An automatic algorithm based on image
processing techniques has been developed to extract
the markers in EPID images and estimate marker
positions (Park et al. 2009). A potential problem when
using the MV beam for real-time imaging is the small
and highly irregular beam apertures, especially in
IMRT and VMAT. Thus, visualization of the sur-
rounding normal structures is usually not possible with
MV imaging. (Another reason is of course the reduced
contrast in MV images). Research on simultaneous kV
and MV imaging for real-time localization of implan-
ted fiducial markers is also under way (Wiersma et al.
2009; Liu et al. 2008; Mao et al. 2008a; Mao et al.
2008b; Wiersma et al. 2008; Cho et al. 2009). Locali-
zation accuracy below 1 mm in all three spatial
dimensions and frequency up to 10 Hz (limited by
EPID acquisition speed) has been reported (Mao et al.
2008a).
A unique feature of these radiographic imaging
techniques is that they provide 2D projection images
of the patient. Real-time 3D anatomy of the patient is
not available. The volumetric information provided
by CBCT is not in real-time since a considerable
amount of time (*1 min) is required in order to
acquire multiple images at different gantry angles and
reconstruct a volumetric image. Some notable pro-
gress has been made recently by Li et al. (2010),
where volumetric images can be reconstructed from a
single X-ray projection image. The method uses
4DCT from treatment simulation as a priori knowl-
edge. Deformable image registration is performed
between a reference phase and the other phases,
resulting in a set of deformation vector fields (DVFs).
This set of DVFs can be represented efficiently by a
few eigenvectors and coefficients obtained from prin-
cipal component analysis (PCA) (Zhang et al. 2007),
After a parameterized PCA lung motion model is
obtained, the optimal PCA coefficients are obtained
such that the projection of the reconstructed volu-
metric image corresponding to the new DVF matches
with the measured X-ray projection. The accuracy of
image reconstruction from 2D projection images
approaches to that obtained by deformable registra-
tion of 3D volumetric images. Through an imple-
mentation on graphic processing units, real-time
efficiency can be achieved: it takes around 0.2 s to
reconstruct a volumetric image. The initial study (Li
et al. 2010) was validated on a digital phantom and
R. Li et al.
for lung cases only. A more comprehensive clinical
validation and possible extensions to other tumor sites
warrant further investigation.
4.3.2 MRI
MRI is an emerging technology in radiotherapy that
uses non-ionizing electromagnetic fields. Real-time
localization of soft tissue structures with MRI has
been shown to be feasible at a sub-second time scale
(Terashima et al. 2005). The major technical chal-
lenge is to integrate the MRI scanner with the LINAC
and allow simultaneous MR imaging and irradiation
without interfering with each other. Recently, a pro-
totype MRI/LINAC has been constructed at Univer-
sity Medical Center Utrecht in Netherlands, in joint
work with Elekta and Philips Research (Raaymakers
et al. 2009). The prototype is a modified 6 MV Elekta
LINAC, next to a modified 1.5 T Philips Achieva
MRI system. The two systems operate independently
and no degradation of the performance of either sys-
tem was found in initial testing. Another MRI/LINAC
prototype has been built at Cross Cancer Institute in
Canada (Fallone et al. 2009), which consists of a
6 MV LINAC-mounted onto the open end of a
biplanar 0.2 T permanent MR system.
The integration of the MRI and LINAC systems is
a technology still in its infancy. There are numerous
open questions that need to be answered, e.g., geo-
metric accuracy of the MR images, calibration of the
coupling of coordinate systems between MRI and
LINAC, and radiation dosimetry in the presence of a
magnetic field (Lagendijk et al. 2008), etc. Nonethe-
less, because of its superior soft tissue contrast
compared with conventional radiographic imaging,
MRI will find its applications throughout all aspects
of radiotherapy: simulation, setup, delivery, and ver-
ification in the future.
4.3.3 Ultrasound
Ultrasound is another real-time imaging modality that
does not involve ionizing radiation and can be easily
adapted for use in radiation therapy. In addition, it has
the advantages of being noninvasive and inexpensive.
US imaging relies on the reflection of sound waves
from interfaces between different tissues. The reflec-
tion and transmission at interfaces depend on the
difference in acoustic impedance between the tissues.
The larger the mismatch between the acoustic
impedances of two materials, the greater the reflection
Linac-Based Image Guided Intensity Modulated Radiation Therapy
of ultrasound from the interface. Feasibility of real-
time target localization using ultrasound during
radiotherapy treatment has been demonstrated in a
phantom study (Hsu et al. 2005). It was observed that
the periodic noise in ultrasound images due to pulsing
of the LINAC did not significantly degrade the
accuracy of target localization and the presence of the
transducer at the surface of the phantom presented
minimal change to the dose distribution.
The main clinical application of US in radiation
therapy is the target localization for prostate cancer
patients (Tome et al. 2002). However, there are some
concerns about the use of US to improve localization for
prostate treatments. First, due to the relatively low
quality of US images, the accuracy of target localization
is limited. Second, differences in localization performed
by different users may be significant in some clinical
applications. Finally, the US probe itself may move the
prostate significantly, especially if excessive pressure is
used. Despite the above shortcomings, the noninvasive
and inexpensive nature of US makes it worthy of further
investigation, and in future may be useful for real-time
tracking of the prostate motion during treatment.
4.3.4 Electromagnetic Transponder System
RF transponders have also been utilized for real-time
imaging in RT (Kupelian et al. 2007). The Calypso
4D Localization System (Calypso Medical Technol-
ogies, Seattle, WA) uses small EM transponders
implanted at the treatment site and an external
antenna array system positioned over the patient.
Transmitters in the antenna array excite EM oscilla-
tions in the transponders, which re-radiate a charac-
teristic signal detected by receivers in the antenna
array. Multiple receiver antennas allow triangulation
of each transponder’s position. Currently, the prostate
and the prostatic bed are the only implantation sites
cleared by the US Food and Drug Administration.
The overall accuracy of the system has been shown
to be approximately 0.3–0.5 mm per axis at a distance
of 27 cm between the transponders and the array
(Balter et al. 2005). The advantage of the system is
that it does not involve ionizing radiation and can
achieve near real-time (at 10 Hz) tracking.
However, the present size of the transponders,
which requires implantation with a 14 gauge needle,
limits their use in the lung. Compared with conven-
tional imaging modalities such as MRI, which can
provide 3D anatomical information of the patient, EM
297
transponder system only provides point (e.g., the
target) measurements. Furthermore, the transponders
produce severe MRI artifacts, which may be prob-
lematic for future MR-based follow-up and retreat-
ment of the patient.
4.3.5 Optical Tracking
Optical tracking is another noninvasive and non-
radiation method that provides real-time information
about patient motion. One prominent example is the
Varian realRPM system. This system monitors
infrared reflective markers attached to the patient
surface. More recently, 3D surface imaging systems
using video cameras are able to obtain surface images
and track and monitor the patient’s surface in real-
time. Such a surface imaging system is commercially
available from VisionRT Ltd., London, UK (Bert
et al. 2005). Similar to the EM transponder system,
optical tracking systems typically provide point (and
surface at best) measurements. In addition, these
systems assume a constant relation between the
external surrogates and internal target. Therefore, a
strong and stable correlation between the treatment
site and the observed external motion is required.
Treatments using such methods to determine the
tumor location must verify (and reestablish if neces-
sary) the relation between the external surrogates and
internal target during the treatment course.
4.4 Future 4D Radiation Therapy
and Real-Time Image Guided
IMRT/VMAT
4D radiation therapy (4DRT) aims to track and
compensate for target motion in real-time during
radiation treatment. The major advantage of 4DRT
over radiation therapy at the current stage is its
promise of normal tissue sparing and target dose
escalation, which leads to reduced normal tissue
complications and improved local control and sur-
vival. This is achieved through a substantial reduc-
tion in CTV–PTV margin (essentially down to zero)
by synchronizing the radiation beam with the mov-
ing target in real-time during treatment delivery.
In order to realize 4D radiation therapy, three critical
components have to be in place: 4D treatment sim-
ulation, 4D treatment planning, and 4D treatment
delivery.
298
Treatment simulation with 4D CT has been dis-
cussed in Sect. 2.1. A methodology for 4D treatment
planning using 4D CT was proposed by Keall et al.
(2005), where deformable image registration was
performed to map each CT image from the peak-inhale
respiration phase to the CT images corresponding to
subsequent respiration phases. This allows the con-
tours defined on the peak-inhale CT to be automatically
transferred to the other respiratory phases. Treatment
planning was simultaneously performed on each of the
CT image sets in which the beam aperture conforms to
the PTV at each respiratory phase. The dose distribu-
tion from each respiratory phase CT image set was
mapped back to the peak-inhale CT image set for
analysis.
The delivery of a 4DRT plan can be achieved
through real-time image guidance. A prerequisite for
real-time image guidance strategies is the knowledge
of target position in real-time during the treatment
course. For this purpose, the real-time imaging
methods discussed in the previous section can be
used. Besides real-time target tracking, a complete
4DRT treatment delivery system also includes real-
time beam tracking and a feedback control system.
4.4.1 Beam Tracking
In real-time image guidance, the beam tracking
system monitors the target and/or normal anatomy
and continuously adapts the alignment of the radiation
field to follow the moving target. There are several
ways to align the radiation beam with a moving target
during LINAC-based radiotherapy: block motion
(Uematsu 2004), couch motion (Souza et al. 2005),
and DMLC target tracking (Cho et al. 2009; Keall
et al. 2001; Suh et al. 2004; Neicu et al. 2003; Langer
et al. 2001; Keall et al. 2006d). Cho et al. (2009)
recently demonstrated a real-time tracking system
by combining fiducial marker-based tracking via
simultaneous kV and MV imaging and a DMLC
beam-tracking system. The integrated tracking system
employed a Varian Trilogy system equipped with kV/
MV imaging systems and a Millennium 120-leaf
MLC. Phantom studies indicated a sub-mm tracking
error and negligible dosimetric error.
4.4.2 Control System
No adaptive response to a signal can occur instanta-
neously. System latency can range from 50 ms
to several hundred ms. In the case of lung cancer
R. Li et al.
radiotherapy, this can represent up to a quarter of an
entire breathing cycle, during which the tumor can
move by more than one cm. Therefore, the control
loop that couples the tumor-tracking component with
the beam delivery component must be able to predict
the tumor’s future position to compensate for the
system latency. Many algorithms have been proposed
to predict tumor motion, primarily in the context of
respiratory motion (Ruan and Keall 2010; Sharp et al.
2004; Wu et al. 2005; Ruan et al. 2007; Ren et al.
2007; Kakar et al. 2005; Murphy and Dieterich 2006;
Ruan 2010). Dynamic motion-compensation systems
also need beam-hold functions, in case the detected
target position change is faster than the mechanical
ability of the motion-compensation device or the
target motion becomes highly irregular, e.g., during
coughing, swallowing, and gas movement.
5 Image Guided LINAC-Based SBRT
5.1 Specific Requirements of LINAC-
Based SBRT (Patient Setup, Motion
Management, Imaging Strategy
for SBRT)
Stereotactic body radiation therapy, SBRT, refers to
an emerging radiotherapy procedure that is highly
effective in controlling early stage primary and oli-
gometastatic cancers at locations throughout the
abdominopelvic and thoracic cavities, and at spinal
and paraspinal sites (Benedict et al. 2010). In SBRT
large radiation doses are given in a few fractions
(typically 1–10) which results in a very high biolo-
gically effective dose to the tumor. Because large
doses are used, correct tumor targeting is an even
higher requirement for SBRT to facilitate local tumor
control and reduce normal tissue toxicities.
SBRT is used for both primary and metastatic
diseases with results comparing favorably with sur-
gery (Grills et al. 2009; Timmerman et al. 2009).
Fewer fractions make the treatment more convenient
for the patient and potentially more cost effective than
conventional radiation therapy. In addition to the dose
and number of fractions, other differentiating features
of SBRT include higher technological requirements,
more treatment beams often including non-coplanar
beams, smaller margins (facilitated by improved
targeting), increased geometric verification, higher
Linac-Based Image Guided Intensity Modulated Radiation Therapy
spatial accuracy, respiratory motion management,
staff training, and higher technological requirements.
The pathway for SBRT mirrors that of conven-
tional treatments in several ways. A CT (or 4D CT) of
the patient is acquired though the resolution may be
finer and the scan region longer if non-coplanar
beams are to be used. Additional immobilization
devices may be used for SBRT imaging and treat-
ment. Often additional functional images will be
acquired for SBRT. Treatment planning proceeds
with careful delineation and determination of the
GTV, CTV, and PTV and also the identification of
organs at risk. The number and dose constraints for
the organs at risk can differ for SBRT. For example,
erythema, rib fracture, and mainstem bronchus ste-
nosis/fistula are more common toxicities observed in
SBRT and therefore require additional planning
consideration.
During planning, the use of multiple non-overlap\ping
beam angles facilitates the requirement to deliver a very
high dose per fraction to a limited volume of tissue
containing the gross tumor and its close vicinity. Whilst
the volume of normal tissue receiving high doses outside
the target should be minimized to limit the risk of treat-
ment toxicity. Thus, the gradient describing the dose fall-
off outside the target should be sharp. Hotspots within the
target are often deemed to be acceptable. Dose calcula-
tion needs to proceed carefully—often small fields are
used. Heterogeneities in the beam path and near the target
can also cause uncertainties.
For some spinal tumors and sites in which implanted
markers are used for guidance, planar X-ray imaging
from multiple angles may be used, with special
emphasis being placed on accounting from motion due
to respiration or other sources. For the treatment of soft
tissue targets, prior to treatment delivery, volumetric
imaging is recommended. Careful correction of the
target to the treatment plan should be made prior to
treatment and potentially evaluated and corrected as
necessary throughout the treatment.
The crucial steps for clinically implementing
SBRT, as identified by AAPM TG 101(Benedict et al.
2010) are:
1. Establish the scope of the SBRT program includ-
ing a selection of treatment sites and the clinical
goals for each site.
2. Determine a treatment modality, dose-fractionation
scheme and treatment planning goals including
target definition, target coverage, conformity index,
299
etc. that support the clinical goals for each treatment
site.
3. For each treatment modality and treatment scheme,
determine the equipment requirements for patient
positioning, treatment delivery, and verification.
4. Determine personnel needs for SBRT implemen-
tation and maintenance.
5. Establish and perform acceptance and commis-
sioning test procedures for the SBRT equipment.
6. Establish SBRT simulation, treatment planning,
delivery and verification guidelines, reporting
methodology, routine QA procedures and action
levels.
7. Conduct personnel training.
SBRT is currently expanding from the domain of
selected academic institutions to widespread com-
munity use. Careful implementation at all centers is
required to avoid SBRT toxicities and fatalities
caused by misuse that may set this promising field
back.
5.2 Recent Progress in SBRT Delivery
Techniques
5.2.1 TrueBeamTM
There has been significant progress in SBRT delivery
techniques, notably, the TrueBeamTM system intro-
duced by Varian Medical Systems. TrueBeamTM is a
new generation of digital LINAC recently developed
and manufactured by Varian. It is designed to be a ver-
satile platform, which can be used for all forms of
advanced external-beam radiotherapy including image
guided radiotherapy, radiosurgery, and SBRT. The
TrueBeamTM system features a high dose rate FFF mode
and a high-definition MLC (HDMLC) and can deliver
both regular and gated IMAT treatments. Figure 10
shows the picture of one of the first three TrueBeamTM
linacs installed at Stanford University Hospital.
Precision and speed of a treatment delivery are
particularly important for SBRT, where a large frac-
tional dose is delivered to the patient in one or a few
fractions. The precision of a TrueBeamTM system is
measured in less than a mm through the synchroni-
zation among imaging, patient positioning, motion
management, beam shaping, and dose delivery. In
addition, the treatment couch can be positioned with
sub-mm accuracy in relation to imaging and delivery
processes. The TrueBeamTM system can deliver
300
Fig. 10 One of the first three TrueBeamTM Linacs installed at
Stanford University Hospital
treatments up to 50% faster with a dose rate of up to
2400 MU/min, more than doubling the maximum
output of most LINAC systems. This makes it pos-
sible to offer greater patient comfort by shortening
treatments, and to improve precision by leaving less
time for tumor motion during dose delivery. Treat-
ment workflows of the TrueBeamTM system are
simplified by a streamlined treatment console with a
graphical interface that consolidates all controls for
imaging, treatment, and motion management. This
enhances safety by guiding therapists through the
steps of complex treatments and allowing them to
spend more time attending to the patient, and less
time operating the machine.
5.2.2 FFF Mode
FFF mode allows faster treatment because the removal
of the flattening filter leads to an increase in dose rate.
TrueBeamTM is capable of delivering FFF photon
beams at a dose rate up to 1400 MU/min at 6 MV and
2400 MU/min at 10 MV. This is particularly attractive
for SBRT where a high dose is prescribed per fraction
and the treatment time is an important factor. The high
dose rate offered by FFF mode can also prove to be
beneficial for respiratory-gated or breath-hold treat-
ments where delivery time is limited. Another potential
R. Li et al.
advantage of FFF mode is a reduced out-of-field dose
and a reduction in head scatter and leakage (Vassiliev
et al. 2006). Figure 11 show examples of diagonal
profiles for different beams from TrueBeamTM at
Stanford (Mok et al. 2010).
Hrbacek et al. (2011) recently investigated the
dosimetric characteristics of photon beams in FFF
mode during the commissioning of a Varian True-
BeamTM LINAC, including depth-dose curves, pro-
files, surface dose, penumbra, out-of-field dose, output,
total, and scatter factors. Compared with photon beams
with flattening filters, they found that the FFF beams
have lower mean energy due to the removal of the
flattening filter. Maximum dose is located closer to the
surface; and surface dose increases by 10%. The dose
profiles of FFF beams have sharper but faster diverging
penumbra. For small fields and shallow depths, dose
outside the field is lower for FFF beams; however, the
advantage fades with increasing phantom scatter. The
output for FFF beams is about twice that of flattened
beams at 6 MV and four times of that of flattened beam
at 10 MV. They evaluated the accuracy of beam
modeling under physical conditions using an aniso-
tropic analytical algorithm and found a good agreement
between modeled and measured data with criteria of
2% depth-dose and 2-mm distance-to-agreement.
Similar results were also reported by Mok et al. (2010).
5.2.3 HDMLC
Compared with regular MLC, HDMLC has a smaller
leaf width. For instance, TrueBeamTM STx is equip-
ped with a 120-leaf collimator which has 32 leaf pairs
with 2.5-mm leaf projection width at the isocenter,
surrounded by 28 leaf pairs of 5-mm leaf projection
width. The same HDMLC configuration is also
available on the Novalis Tx system. The main
advantage of HDMLC is that the smaller leaf width
helps shape finer dose distribution around the target,
especially the small tumors in SBRT.
5.2.4 Gated RapidArc
Varian Medical Systems has recently implemented a
motion management technique called gated RapidArc
as a standard feature on the TrueBeamTM system and
as an option or upgrade on the Trilogy and Clinac iX
accelerators. Gated RapidArc is an IMAT delivery
technique which makes it possible to monitor patient
breathing and gate the beam in response to tumor
motion while quickly delivering dose during a
Linac-Based Image Guided Intensity Modulated Radiation Therapy
Fig. 11 Diagonal profiles of
the photons beams WFF and
FFF, at 6 MV and 10 MV for
TrueBeamTM at Stanford
continuous rotation around the patient. The technique
is frequently used at Stanford for SBRT treatments of
lung and other thoracic and abdominal tumors. As a
result of being able to deliver radiation therapy
treatments much more quickly than conventional
fixed-gantry IMRT, gated RapidArc has the potential
to enhance the SBRT treatment precision and patient
comfort while significantly lowering the cost per
treatment.
5.3 Imaging in SBRT
5.3.1 Simulation Imaging
SBRT requires precise delineation of the targets for
planning and clear visualization for localization dur-
ing treatment delivery. For SBRT applications, the
tomographic slice thickness of 1–3 mm through the
tumor site is recommended for most clinical cases
(Winer-Muram et al. 2003). The most appropriate
imaging modality for a given clinical situation is
determined by the characteristics of the target and
surrounding tissues being imaged. In general, CT is
the primary imaging modality for SBRT and forms
the basis for dose calculations and treatment planning.
CT is helpful in identifying pulmonary nodules,
parenchymal diseases, and chest-wall involvement for
superior sulcus tumors and lung disease (Komaki
et al. 2000; Kauczor et al. 2000). MRI is the gold
standard for brain neoplasms and is increasingly
being used in SBRT applications including prostate,
spinal tumors, chest, and solid abdominal tumors
(Debois et al. 1999; Husband et al. 2001; Webb et al.
1991; Gunther et al. 2004). FDG-PET greatly
enhances the specificity and sensitivity in diagnosis
and staging compared to CT (Gambhir et al. 2001).
Combined PET/CT systems can reduce image regis-
tration/fusion uncertainties to less than 2 mm due to
inherent co-registration. Currently, PET/CT is widely
301
used for lung cancer, head and neck tumors, colon
cancer, liver cancer, melanoma, lymphoma, and
ovarian cancer (Gharib et al. 2004; Lin et al. 2005).
5.3.2 Imaging for Setup
AAPM Task Group report 101 (Benedict et al. 2010)
recommends that for SBRT, image guided localiza-
tion techniques can be used to guarantee the spatial
accuracy of the delivered dose distribution with a high
confidence level. The setup error of a stationary target
can now be corrected to within the imaging and
positioning accuracy of the system. Residual transla-
tions of less than 2 mm are achievable for bony
targets (Yin et al. 2002). Small rotational errors (up to
3–4° for roll and pitch and 10° for yaw) can be cor-
rected by robotic couches combined with stereotactic
X-ray or volumetric imaging (Soete et al. 2006).
However, soft tissue targets require volumetric
imaging such as CBCT to achieve the necessary setup
precision (Ryu et al. 2001).
5.3.3 Imaging During Treatment Delivery
For SBRT, it is crucial to maintain the spatial accu-
racy throughout the treatment delivery through inte-
grated real-time image-based monitoring systems. For
this purpose, the same real-time imaging techniques
discussed in Sect. 4.3 may be used. For instance, 2D
MV EPID in conjunction with implanted fiducial
markers has been used to deliver SBRT treatments to
spinal sites while keeping the target within 2 mm of
its planned position (Lovelock et al. 2005). Volu-
metric image guidance via MV or kV CBCT allows
for the precise localization of bone and soft tissue
targets (Shiu et al. 2003; Yenice et al. 2003). Dual or
multiple room-mounted kV imaging systems are used
to provide real-time 3D localization of targets or
implanted markers using pairs of 2D radiographs.
Treatment machines with gantry-mounted kV units
capable of fluoroscopy, radiographic localization, and
302
cone beam imaging (especially for soft tissue targets)
are being widely adopted in SBRT. Onboard imaging
integrated with image registration software, makes
accurate target positioning and verification for SBRT
readily available. Ultrasound is effective for imaging
soft tissue structures and tumors in the pelvis and
abdomen. The use of ultrasound in SBRT for a variety
of sites has been described by Meeks et al. (2003),
Fuss et al. (2007), and Kuban et al. (2005).
6 Closing the Loop of Radiation
Therapy: Dose Delivery
and Reconstruction
6.1 Pitfalls of Current IMRT/VMAT
and QA
Radiation therapy typically involves four sequential
steps: treatment simulation, treatment planning,
patient setup, and treatment delivery. From a control
system perspective, Current IMRT/VMAT is an
open-loop system, where treatment planning and
treatment delivery are decoupled. It is essentially a
‘one-plan-fits-all’ approach where the same treat-
ment plan is usually delivered for the entire treat-
ment course. Clinically, the goal of patient setup at
each fraction is to reproduce the patient’s geometry
at the time of simulation, through a set of rigid
transformations of the patient, i.e., translation and
occasionally rotation. However, it has been well
documented in the literature that a patient’s anatomy
is subject to change both on an interfractional and
intrafractional basis (Xing et al. 2006; Langen and
Jones 2001). These changes can be highly complex:
the geometric sizes, shapes, and locations of the
targets and normal tissues as well as the geometric
topography of the patient’s anatomy can change
from fraction to fraction. For instance, head and
neck cancer patients who undergo fractionated
radiation therapy can have significant anatomic
changes due to organ deformation, tumor shrinkage,
weight loss, or a combination of these during the
treatment (Barker et al. 2004). Although inter frac-
tional target motion may be accounted for by adding
population-based margins around the target, these
generic margins are often either too large for some
patients or too small for others and can significantly
compromise the treatment outcome. This issue poses
R. Li et al.
a particular concern in IMRT because of the steep
dose gradient near the boundary of the target.
Therefore, the current IMRT procedure is funda-
mentally deficient wherein it attempts to address the
multi-dimensional and highly complex changes in
patient anatomy by only a few degrees of freedom
(i.e. translation and possibly rotation) and an over-
simplified margin approach. This is perhaps one of
the weakest links in the quality chain of current
radiation therapy.
Another issue, related to QA, is that the delivered
fluence maps are not necessarily the same as the plan-
ned ones. For instance, in an MLC-based IMRT treat-
ment delivery, there may be errors associated with the
control of leaf motion and fractional MU delivery such
as overshoot, undershoot segmental MU, dropped
segments, and beam delivery during leaf motion
(Ezzell and Chungbin 2001; Xia et al. 2002; Wiersma
and Xing 2007; Litzenberg et al. 2007). These factors
can lead to a discrepancy between the delivered dose
and planned dose, even if there is no anatomic change
and patient setup is perfect. These and other practical
issues must be taken into consideration in order for
IMRT/VMAT to be effective.
6.2 Dose Reconstruction for IMRT
and VMAT and Respiration-Gated
VMAT
Because there can be clinically significant and highly
complex changes in a patient’s anatomy from fraction
to fraction, the actual delivered dose distribution in
the patient will differ from the planned one, which
leads to insufficient dose coverage of the tumor vol-
ume and over-dosage of normal tissues. It is therefore
attractive to adopt an adaptive approach in which the
volumetric information acquired at each fraction (e.g.,
CBCT) is utilized to adjust the treatment plan
according to the new patient anatomy. In order to
create and effectively evaluate the new treatment
plan, the cumulative dose delivered to the patient up
to the day of treatment must be known. This neces-
sitates the reconstruction of dose in the patient at
every treatment fraction. The reconstructed dose
distribution is also a useful QA tool, e.g., for dose
verification purposes.
The onboard CBCT technology provides a 3D
geometric model of the patient during the treatment.
Linac-Based Image Guided Intensity Modulated Radiation Therapy
This not only allows the online correction of patient
setup error, but also makes it possible to calculate the
dose distribution directly on the updated patient
anatomy. Feasibility studies have been carried out by
several research groups to reconstruct the dose dis-
tribution using CBCT and the planned fluence maps
from the treatment planning system (TPS) for IMRT
(Yang et al. 2007; Langen et al. 2005; Yoo and Yin
2006). The reconstructed dose provides an objective
evaluation of what is to be delivered to the patient, if
the delivery is done correctly. Such an evaluation is
useful for the assessment of dosimetric impacts of the
anatomical variation of the patient as well as the
clinical decision making of whether a replanning or
reoptimization is necessary for that particular treat-
ment fraction.
The assumption of the above studies is that the
planned fluence maps can be perfectly and faithfully
delivered by the LINAC. As mentioned in Sect. 6.1,
several practical issues related to the MLC leaf
motion and LINAC radiation output render this
assumption invalid. A more practical approach is to
utilize the record and verify system associated with
the LINAC. In contrast to previous methods that use
the planned beam arrangements prior to treatment
delivery (so-called prospective dose reconstruction),
these methods use the actual MLC leaf motion and
LINAC output, which are available in the MLC log
files after treatment delivery. For this reason, they
are called retrospective dose reconstruction methods.
These methods provide the dose distribution that has
actually been delivered to the patient after a treat-
ment fraction. Related work has been done for
IMRT treatment delivery by Lee et al. (2008a) in kV
CBCT setting and Pouliot et al. (2007) in MV CBCT
setting. These works provide a valuable and practical
tool for dose reconstruction in IMRT delivery and
the necessary dosimetric information for treatment
plan adaption. The dosimetric impact of retrospec-
tive dose reconstruction has been clinically assessed
for head and neck cancer patients who have under-
gone IMRT (Lee et al. 2008a). For most treatment
sessions, the CBCT-based dose reconstructions
yielded DVHs of the targets very close (within 3%)
to that of the original plans. However, dosimetric
changes (within 10%) were observed for the critical
organs due to the anatomic variations caused by
setup errors, organ deformation, tumor shrinkage, or
weight loss.
303
The above dose reconstruction technique using
MLC log files is dependent on the accuracy of leaf
calibration. In addition, these log files are available
for only one LINAC manufacturer (Varian). This may
limit its scope of applications and a more general
technique is required in order to obtain the fluence
maps necessary for accurate dose reconstruction. Lee
et al. extended the above approach and used EPID to
capture the MLC segments during an IMRT treatment
delivery and reconstitute a leaf sequence file as well
as the delivered fluence maps for dose reconstruction
(Lee et al. 2008b). This approach allows users who do
not have access to MLC log files to perform dose
reconstruction and dosimetric assessment of an actual
IMRT treatment delivery.
Recently, the retrospective dose reconstruction
method has been extended to VMAT treatment
delivery (Qian et al. 2010). In this work, the actual
MLC leaf positions, gantry angles, and cumulative
MUs at each control point were extracted from the
dynamic log files after VMAT delivery and the
information was then embedded into the original
treatment DICOM radiation therapy (RT) file to
replace the original control point parameters. This
reconstituted DICOM-RT file was imported into the
Eclipse TPS and dose was computed on the corre-
sponding CBCT. In principle, the same methodology
can be applied to more sophisticated treatment tech-
niques, e.g., respiration-gated IMRT and VMAT.
6.3 Adaptive Therapy
with Consideration
of Dose Delivery History
A major attraction of ART is the optimal compensa-
tion of uncertainties including organ deformation and
interfraction organ motion as well as dosimetric errors
incurred in previous fractions. To realize its promises,
an effective treatment planning strategy capable of
taking into account the dose delivery history and the
patient’s on-treatment geometric model must be
developed. Several groups have studied volumetric
image guided adaptive replanning for different dis-
ease sites (Wu et al. 2006; de la Zerda et al. 2007;
Wu et al. 2008; Wu et al. 2002). McQuaid and Webb
(2008) presented an adaptive optimization scheme for
coping with intrafractional organ motion in IMRT,
although the much smaller timescale of intrafractional
304
motion makes dose reconstruction and plan optimi-
zation an extremely challenging task. A general
theoretical framework of dynamic closed-loop control
for ART was established by de la Zerda et al. (2007).
Closed-loop control algorithms are a general tool for
dealing with time-dependent systems and share the
same basic features of repeated reevaluation and
replanning. The formalism is valuable because it
attempts to answer fundamental questions in ART
such as how to effectively use information about the
current state and past delivery errors and how to
benefit from including the patient’s future treatments
into today’s adaptation strategy. Clearly, much
research remains to be done in developing more
sophisticated closed-loop algorithms and searching
for the best ART strategy to maximally utilize the
geometric and dosimetric information that become or
will soon become available. Given the complex
interaction among errors, motion, and the doses
delivered to the patient, sophisticated disease-site
specific adaptation schemes may be necessary and
prove useful. It is hoped that future developments of
more sophisticated closed-loop control algorithms
will ultimately approach this goal.
7 Summary
Intensity and aperture modulated therapies have
become the mainstay of modern radiation therapy. The
techniques are becoming increasingly complicated
because of the increased use of computer control. Safe,
accurate, and efficient use of these techniques have
posed daunting challenges to the field of radiation
oncology. The ultimate success of radiation therapy
depends not only on technical and clinical innovations,
education and training, but also systematic evaluation
of the workflow and quality assurance. Careful com-
pletion and review of the acceptance test procedure,
followed by detailed commissioning of the individual
components and integrated or ‘end-to-end’ tests are
important QA steps toward our goal of providing the
best possible patient care.
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 Tomotherapy Image Guided Radiation
Therapy
Walter H. Grant III, E. Brian Butler, and Dirk Verellen

Contents
1 Introduction.............................................................. 314
2 Tomotherapy’s Helical Megavoltage Computed
Tomography .............................................................
2.1 Helical Imaging Terminology ...................................
2.2 Tomotherapy Imaging Schema .................................
2.3 Megavoltage Imaging Versus Kilovoltage Imaging
2.4 Tomotherapy Co-registration ....................................
2.5 Strategies for Imaging ...............................................
2.6 Use of Tomotherapy MVCT Images in Treatment
Planning .....................................................................
2.7 Tomotherapy Images and Adaptive Radiotherapy ...
3 Clinical Examples of the Use of Megavoltage CT
Images ....................................................................... 317
4 Summary................................................................... 323
References.......................................................................... 324
Abstract
There are a growing number of imaging modalities
being implemented to maximize the precision of
delivery of radiation therapy. The latest techniques
314 involve volumetric imaging of the patient in the
314 treatment room and automated adjustment of that
314
current position to best match the position of the
315
315 patient, the tumor and the critical structures
316 obtained in the planning simulation. This chapter
discusses the system implemented in the Tomo-
316
therapy Hi-Art machine which is basically a
316
helical computed tomography scanner with a
megavoltage X-ray source rather than a kilovoltage
source. This means that all imaging components
are rigidly affixed to a rotating gantry and the same
point source is used for imaging and treatment.
The system has advantages and disadvantages and
processes to maximize the effectiveness of this
system are discussed.

Abbreviations

OAR Organs at Risk

W. H. Grant III (&) FOV Field of View
Department of Radiology, BCM 360,
Baylor College of Medicine, MV Megavoltage
Houston, TX 77030, USA kV Kilovoltage
e-mail: wgrant@bcm.edu CT Computed Tomography
E. B. Butler IGRT Image Guided Radiation Therapy
Radiation Oncology, The Methodist Hospital, ROI Regions of Interest
Houston, TX 77030, USA IVDT Image Value to Density Table
D. Verellen ART Adaptive Radiotherapy
Department of Radiation Oncology and Biomedical DVH Dose–Volume Histograms
Physics, UZ Brussel, Vrije Universiteit Brussel,
Brussel, Belgium

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 313
DOI: 10.1007/174_2011_352, Ó Springer-Verlag Berlin Heidelberg 2012
314
1 Introduction
The use of images as a verification tool has played a
role in radiation therapy treatments for many decades.
However, the last decade has seen the introduction of
imaging techniques that integrate the imaging and
decision-making processes. This latest technology
implementation is referred to as image guided radiation
therapy or IGRT. Today’s technology offers automated
patient positioning and abilities to visualize targets as
well as organs-at-risk (OAR) on a daily basis, thereby
enabling even more precise radiation deposition.
The Tomotherapy Hi-ArtÒ machine not only intro-
duced a new radiation therapy delivery mechanism, but
also introduced the first practical clinical implemen-
tation of a system that combined a volumetric imaging
system with an IMRT delivery system. In fact, the
name is an acronym for Highly Integrated Adaptive
Radiation Therapy. All components are rigidly
mounted and one is able to perform a scan on the
treatment machine immediately prior to treatment,
perform a rigid-body co-registration of the resulting
volume to the treatment planning image volume, and
have the machine make translational and rotational
adjustments automatically prior to commencement of
treatment.
This ability to determine as well as correct for
target location is invaluable as one attempts to
determine the adequacy of margins for targets as well
as the potential overdosing of nearby normal
structures. However, volumetric image collection
takes time and delivers extra dose to the body, so one
is required to devise strategies that optimize the
minimum data collection time and dose with adequate
positional accuracy.
In this chapter we will discuss the basic physical
parameters of Tomotherapy volumetric image
creation, the options available for creating the
images and the options to co-register the daily
treatment and planning image volumes.
Then we will discuss strategies for optimizing the
use of Tomotherapy image guidance for tumors in the
brain, head and neck, lung and abdomen.
Finally, the created volumes are suitable for
treatment planning, so we will discuss the current
value of Tomotherapy images in the general concept
of Adaptive Radiotherapy (Martinez et al. 2001;
Welsh et al. 2006).
W. H. Grant III et al.
2 Tomotherapy’s Helical
Megavoltage Computed
Tomography
2.1 Helical Imaging Terminology
The Tomotherapy machine has been described in detail
by numerous authors (Mackie et al. 1993; Mackie et al.
1999; Welsh et al. 2002; Jeraj et al. 2004), so only the
salient imaging features will be identified here. Basi-
cally, the Tomotherapy unit is a helical computed
tomography (CT) machine that has a megavoltage
(MV) linear accelerator instead of a kilovoltage (kV)
X-ray tube mounted as the radiation source. We have
found it convenient to discuss it as such rather than a
conventional linear accelerator. The meaningful
parameters in helical scanning are energy, field of view
(FOV), slice width (the field size dimension in the
length axis), rotation period (the number of 3600 gantry
rotations/min), and Pitch (the ratio of the distance the
couch moves longitudinally in one gantry rotation to
the slice width). The following section will address the
choices of parameters for imaging only.
2.2 Tomotherapy Imaging Schema
The machine is magnetron powered and operates at
6 MeV for treatments and 3.5 MeV for imaging
purposes (Welsh et al. 2002; Meeks et al. 2005). In
the imaging mode, the slice width is fixed at 4 mm,
the FOV is 40 cm (the maximum width of the MLC),
and the gantry rotation speed is 6 revolutions/min.
The operator has the option of operating the unit with
a Pitch of 1, 2, or 3. (These are named Fine, Normal,
and Coarse at the console Scan Window). For a Pitch
of 1, the scan length is 6 9 1 9 4 mm or 24 mm/min
while for a Pitch of 3 the scan length is 6 9 3 9 4
mm or 72 mm/min.
While preparing to perform a scan, the operator can
measure the length of the region to be scanned. In order
to estimate the time for a scan prior to its initiation, it is
helpful to consider the time to scan a fixed length.
For example, to scan a 10 cm length takes approxi-
mately 250 s (*4 min), 125 s (*2 min), and 83 s
(*1 min) for Pitch values of 1, 2, or 3, respectively.
Regardless of the chosen parameters, the MVCT image
will be an average of organ motion and organs may
Tomotherapy Image Guided Radiation Therapy
appear larger or displaced as compared to a CT-Sim-
ulator data set that is captured quickly.
The dose delivered by an MVCT has been reported
to decrease from a maximum of about 3 cGy to a
minimum of about 1 cGy as one varies the pitch from
1 to 3 (Shah et al. 2008; Xu et al. 2009). The dose is
uniform from the center to the surface of the phan-
toms that have been scanned. One should recognize
that as the dose increases, so does the signal to noise
ratio thus resulting in better image quality. The choice
of pitch and scan length is determined by the treat-
ment intention as well as the expansion margins
(International commission on radiation units and
measurements 1999) created in treatment planning.
There are a number of strategies that can be employed
to optimize the parameter selections and there is no
single ‘‘best choice’’ because one does IGRT so as to
reduce margins by a few millimeters. To measure
small adjustments is difficult and development of a
‘‘Class Solution’’ may not be a practical goal.
2.3 Megavoltage Imaging Versus
Kilovoltage Imaging
At a maximum photon spectrum energy of 3.5 MeV,
the megavoltage (MV) X-rays that create the image
interact with matter predominantly by the Compton
scatter mechanism that depends on the mass density of
the matter and not on its Atomic Number, Z. This
differs from the interaction of a diagnostic X-ray
spectrum (kV) where the Photoelectric Effect is the
predominant mechanism and the probability of an
interaction depends strongly on the Atomic Number of
the matter, i.e., Z3. This results in Megavoltage images
having less ability to differentiate small changes in Z as
compared to kV generated images (a loss of contrast),
but it also means that MV generated images are not
susceptible to the high-Z streaking artifacts, i.e., tooth
fillings, hip prostheses, etc., seen in kV images.
2.4 Tomotherapy Co-registration
The algorithm used in Tomotherapy at this time is a
rigid-body adjustment that will only provide
translational, rotational, pitch and yaw calculations.
Deformable co-registration remains in a developmental
stage and is not yet available (Lu et al. 2006). The
315
Registration process allows the user to define structures
for co-registration including the Whole Image (Mutual
information with no thresholding), Bone and Tissue
Technique (pixel threshold [ 0.3 g/cm3), or a Bone
Technique (pixel threshold [ 1.1 g/cm3) as the focus
for registration. In addition, if the entire body is not
covered in the MVCT, there is an opportunity to use
a tool for improvement of the registration (Ruchala
et al. 2002).
One major limitation in the current version is the
absence of user-defined regions of interest (ROI) in
guiding the registration process. As the registration
process is rigid, non-rigid changes in the patient’s
anatomy (e.g. differences in flex between two con-
secutive scans in case of head and neck patients) can
pose problems in the registration process that cannot
be solved by translating and/or rotating the entire
patient. In some cases it would be useful to be able to
define a ROI around the target and/or critical organs
to register the patient’s anatomy. Another useful tool
could determine regions to either emphasize (target
region) or ignore (e.g. the mandible or a shoulder)
during the registration process. Currently, this can be
resolved by manually re-adjusting the results of the
auto-registration based on clinical considerations, but
for safety reasons one needs to establish limits to the
amount of adjustment that can be made without
intervention by a physician or physicist.
One can use an additional feature of the system
that allows the dose distribution as calculated on the
original kV CT planning data set, to be superimposed
on the MVCT data set ‘‘of-the-day’’. As such the user
can align the patient’s anatomy to the dose distribu-
tion for assuring adequate coverage of the target
volume and/or avoiding excess dose to critical
structures (Verellen et al. 2007).
Since the co-registration is a statistical process,
one seeks to minimize the amount of information to
utilize, i.e., the time for calculation versus the accu-
racy of the alignment. At the time of registration, in
addition to selecting the threshold to scan, the oper-
ator can select a Superfine Resolution in which there
is no down-sampling of image sizes, a Fine Resolu-
tion which has a 2x down-sampling, or Standard
Resolution which has a 4x down-sampling.
Experiments with a Head Phantom have shown
that setup accuracy in the Right/Left and Anterior/
Posterior axes is within ‘ of a voxel, or about 2 mm
for the coarsest selections (Boswell et al. 2006).
316
The Superior/Inferior co-registration accuracy is
harder to define. For a Pitch = 1, it has been stated
that the voxel size is 2 mm (Jaffray 2007; Langen
et al. 2010). This is based on a 1800 reconstruction
and there is no documentation that this is what is
employed by the software. To maximize accuracy,
one should scan ample lengths of bone, especially in
regions where there are very distinct shapes.
2.5 Strategies for Imaging
As mentioned, the two parameters that one has to
balance are dose to the patient and time for the scan.
While it is possible for the software to determine all
the six degrees of freedom, the machine can only
correct for four of them automatically, specifically the
translational axes and roll. However, the pitch and
yaw adjustments provide valuable clues on the
accuracy of the patient positioning reproducibility for
all but the smallest targets. This occurs because, while
bones are rigid, the human body is designed to
articulate and the relationship with boney landmarks
and organs can shift daily.
The first suggestion is to scan an adequate patient
length so that one can determine whether the values of
pitch and yaw are significant. If so, then one needs to
have the patient sit up and then return to the treatment
position. We have found that this minimizes the dis-
crepancies seen on volumetric imaging. As stated
earlier, a 10 cm scan in the Coarse mode takes
slightly over a min and if the region contains adequate
boney landmark changes, this scan can provide suf-
ficient registration for targets with 3–5 mm margins.
The total time for scanning and registration can be
3–4 min in such a case.
Scanning of targets that have smaller margins
becomes more challenging, especially if one is in a
region that may not have enough landmarks to ensure
that a major registration error did not occur.
An example of such a problem is a target in the lung
where the vertebral bodies are not easily distinguish-
able. In such a case, we do a coarse scan over a 7 cm
length to ensure that we have a minimum of two ver-
tebral bodies. After that, a short scan in the Fine mode
will allow for the final one or two mm adjustment.
Others have published recommendations for cra-
nial (Woodford et al. 2007) and thoracic targets
(Woodford et al. 2007) that suggest other
W. H. Grant III et al.
possibilities. One should feel free to evolve into any
schema based on the positioning and immobilization
skills of the department.
2.6 Use of Tomotherapy MVCT Images
in Treatment Planning
There are two uses for using MVCT images in
treatment planning. First, as mentioned above, the
MVCT does not contain artifacts from high-Z mate-
rials such as hip prostheses, dental fillings, etc. The
MVCT image can be exported to a registration-
enabled workstation where it can be co-registered to
the kVCT planning data set. One draws anatomy on
the MVCT but uses the kVCT data set for calcula-
tions. One should determine the magnitude of the
dose error caused by the artifacts in any heteroge-
neous calculation, but the effect may be small enough
to ignore or one can apply density overrides.
A second use is for actual dose calculation.
An advantage of the slit-beam generated image is that
the scatter tends to be uniform throughout the image
and one can use the MVCT images generated by
Tomotherapy for treatment planning. It has been
demonstrated that the MVCT created by the Tomo-
therapy machine can be used for treatment planning
(Willoughby 2005). In order to do so, one must create
an accurate image value to density table (IVDT) just
as one creates a Hounsfield unit to density table for a
kVCT machine. There are considerations of dose rate
and target thinning which can affect the accuracy of
the IVDT (Duchateau et al. 2010; Yadav et al. 2010)
and The American Association of Physicists in
Medicine’s Task Group 148 recommends that IVDT
calibration be obtained at the same time that an
MVCT planning data set is performed (Langen et al.
2010).
2.7 Tomotherapy Images and Adaptive
Radiotherapy
There are two approaches to the concept of adaptive
radiotherapy (ART). The first is to scan a patient daily
and recalculate the plan to attain accurate dose
delivery. This would be an online process. The second
approach is to calculate the delivered daily dose from
the MVCT image and adjust subsequent deliveries to
Tomotherapy Image Guided Radiation Therapy
compensate for setup error and/or tumor shrinkage.
This would be performed as an offline process.
In its current configuration, the planned adaptive
software module is used as an offline process. One
recalculates the dose distribution delivered for each
fraction using an MVCT taken immediately prior to
treatment or immediately after treatment. One then
adds the dose to the various organs to compare the
cumulative dose to the intended dose–volume histo-
grams (DVH). If there are areas with too high or too
low a dose, one then creates contours of these regions
to use to modify the dose in a new treatment plan so
that the ‘‘adapted’’ plan will result in the cumulative
DVH for each organ being identical to the originally
planned DVH for each organ.
As with any new imaging modality, one must also
evaluate anatomy-drawing skills using the MVCT
images. These are not diagnostic quality images and it
is important to evaluate the accuracy of organ
visualization. For example, comparisons of prostate
volumes drawn on MVCT to that drawn on diagnostic
kVCT images were measured to be 10–20% larger.
(Song et al. 2006) While this represents only a
2–3 mm difference, it does indicate the physical
magnitude of that which could be compensated
erroneously.
One also has to evolve strategies for the frequency
of plan adaption. For non-small-cell lung cancer,
Woodford et al. recommend no adaption of the plan
unless the gross tumor volume changes by more than
30% in the first 20 fractions while Siker et al. do not
believe that ART has a role in this disease (Woodford
et al. 2007; Siker et al. 2006).
While ART is discussed widely, it is still very
much in its infancy in the radiotherapy community.
For example, the current release of the Planned
Adaptive module lacks deformable image registration
that makes this process somewhat tedious. In addi-
tion, the MVCT images are not of diagnostic quality,
so one should approach drawing of reduced contours
with trepidation. Finally, the images are not taken
during treatment hence there is no guarantee that the
patient position in the image set is identical to when
the treatment was delivered. On the other hand, this is
the only system to date that allows planning on the
volumetric image data set taken on the machine as
well as using the treatment beam and fixed image
receptors so that one can investigate the value of
adaptive radiation therapy.
317
3 Clinical Examples of the Use
of Megavoltage CT Images
Image guided radiation therapy via the use of a
MVCT images offers the radiation oncologist an
opportunity to visualize the target with confidence.
Just as a diagnostic radiologist develops a systematic
way of reviewing an image for diagnostic purposes,
the radiation oncologist needs to develop a systematic
way of viewing a megavoltage CT scan. This requires
that the radiation oncologist use all available data that
are present in the MVCT image.
As discussed in Sect. 2.3, a unique opportunity
exists to use MVCT scans in treatment planning. This
opportunity presents itself when a patient has internal
metallic hardware that causes significant artifacts
preventing adequate target delineation. In the case of a
patient with bilateral hip prosthesis or extensive fillings
or titanium plates in the head and neck area, the MVCT
scan can be transferred to the treatment planning sys-
tem and co-registered with the treatment planning
kVCT scan for delineation of the prostate cancer or a
head and neck malignancy. Here are some examples:
Figure 1 shows the kVCT and MVCT of a 74-year-
old man with a localized adenocarcinoma of the pros-
tate. One cannot delineate the target in the kVCT image
because of artifacts related to bilateral hip prosthesis.
In this case the patient’s MVCT scan was co-registered
with the kVCT scan and utilized for treatment planning
purposes. Daily imaging with the MVCT scan verified
reproducibility of setup and target.
Figure 2 is a 54-year-old male with oral cavity/
oropharynx cancer with dental fillings that do not
allow delineation of the target in the head and neck
area with any confidence. Again, the kVCT and
MVCT data sets were co-registered for treatment
planning purposes. The target was identified with
daily megavoltage scanning.
Effective use of Tomo Images requires development
of systematic approaches that include all known ana-
tomical landmarks, i.e., kidneys, aorta, inferior vena
cava, vertebral bodies, pubic bone, spinal cord, as often
a soft tissue mass may not be easily visualized.
There also may be visible anatomic references (surgi-
cal cavity in the brain, cystic lesion in the liver, cal-
cifications within a blood vessel, fiducial markers, or a
drain) that can be recognized and help orient the phy-
sician. These references are patient specific and
318 W. H. Grant III et al.

Fig. 1 The kVCT (left) and MVCT (right) of a patient with Titanium hip prostheses and prostate cancer

Fig. 2 The kVCT (left) and MVCT (right) demonstrating the lack of streaking artifacts from dental fillings

provide confidence that the radiation plan is being
delivered correctly. One must be able to use all the
tools that are available before accepting the co-
registration of the treatment planning CT and the
MVCT scan. These tools include the use of windowing
and leveling. There are four preset settings for viewing
images when evaluating Tomo Images. They are
General, which is the default, Soft Tissue, Lung, and
Bone. Some work well for both the kVCT and MVCT
while some work well for only one data set. There is the
ability to manually adjust the settings but these are
difficult to reproduce precisely on a daily basis.
Here are some examples:
Figure 3 shows images of a 48-year-old female
with metastatic breast cancer with a liver metastasis
who is undergoing SBRT. The commercial fiducial
markers (Core Oncology, Santa Barbara, CA) are
easily identified on both the treatment planning kVCT
scan and the MVCT scan and somewhat more pre-
cisely on the latter.
Tomotherapy Image Guided Radiation Therapy 319

Fig. 3 The kVCT (left) and MVCT (right) of commercial fiducial markers in the liver

Fig. 4 The vertebral body is used as a reference for localization of the target and dose is superimposed daily to visualize dose to
the spinal cord

Figure 4 shows images a 61-year-old female
with a paraspinal mass recurrence in a previously
treated area. The vertebral body is used as a
reference for localization of the target and dose is
superimposed daily to visualize dose to the spinal
cord.
Figures 5 and 6 demonstrate the alignment of the
patient in the immobilization device by evaluating the
spinal cord in the sagittal and coronal views. Critical
to reproducibility of delivery is the alignment of the
patient. This is one of the tools routinely used in the
use of MVCT image guidance.
320 W. H. Grant III et al.

Fig. 5 The coronal view of a long, Coarse MVCT scan to align a patient

Fig. 6 The sagittal view of a long, Coarse MVCT scan to align a patient. Note that the curvature of the spine is used to enhance
the statistical nature of the co-registration algorithm

Figure 7 shows a 47-year-old male with metastatic
disease to the liver. A cystic lesion in the liver is used
as a reference in the localization process in this
patient who could not undergo fiducial marker
placement in the target.
Figure 8 shows a 36-year-old female with a pri-
mary brain tumor status postsurgical resection. The
cavity is recognized on both treatment planning and
MVCT scans. This allows verification of patient
position on a daily basis.
Tomotherapy Image Guided Radiation Therapy 321

Fig. 7 The presence of a cystic region in the liver helping to verify the location of outlined target

Fig. 8 An example of the visibility of soft tissue abnormalities in the brain on kVCT (left) and MVCT (right) images

Figure 9 shows a 64-year-old male with meta-
static prostate cancer to the retroperitoneal lymph
nodes. Lymph nodes are not easily visualized but
calcifications in the aorta, the vertebral body, and
paraspinous muscles are visible. Often a soft tis-
sue target cannot be visualized but reference
anatomical structures that do not change with
respiration can be identified and used for
verification
Figures 10 and 11 show a 63-year-old female with
a solitary lung metastasis from endometrial cancer.
The images in the sagittal plane demonstrate a
322 W. H. Grant III et al.

Fig. 9 The kVCT image (left) and MVCT image (right) demonstrating the presence of calcifications and bones to assist in setup

Fig. 10 The axial view of a solitary lung metastases using manual window and leveling settings

difference in size and shape of the lesion.
The physician must be aware that the image acqui-
sition algorithm may distort the viewing of the target
and that window and level settings make determina-
tion of the target edges difficult.
Figure 12 shows the co-registered Tomo Images
with and without the dose overlaid. One can see that
the dose avoids the spinal cord and kidney. If not,
manual adjustments can be performed to ensure that
conformal avoidance is achieved.
Tomotherapy Image Guided Radiation Therapy 323

Fig. 11 The sagittal view of the patient in Fig. 10 illustrating the difficulty of determining tumor extent in all directions

Fig. 12 The dose overlay feature of a Tomo Image is shown. One can use the overlay to make manual adjustments if necessar

for a patient and, because the additional dose is low,

4 Summary
Image guided radiation therapy using Megavoltage
CT scans has proven to be an effective addition to
improve the precision of radiation delivery. The scans
add only a few minutes to the overall treatment slot
they can be applied daily. The co-registration and
automated adjustment of the translational positions of
the couch as well as roll minimize the human inter-
action. However, one must develop strategies to
ensure that these corrections are made as accurately as
possible by the Therapy Staff.
324
Acknowledgments The authors express their appreciation to
Yessenia Reyes and Shirley Clark for their assistance in the
preparation of this chapter.
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 Robotic Image Guided Radiation Therapy
Rodney E. Wegner, Dwight E. Heron, Arlan H. Mintz,
and M. Saiful Huq

Contents Abstract
Stereotactic radiosurgery (SRS) is a highly spe-
1 Introduction.............................................................. 325 cialized type of external beam radiation treatment
2 Origins of Radiosurgery ......................................... 326 in which a precise and conformal, image-guided
focus of ionizing radiation is delivered to a well-
3 CyberKnifeÒ Robotic Radiosurgery: Treatment
Planning and Delivery System ............................... 327 defined target volume in a single procedure. The
3.1 Adaptive and Active Target Localization origins of radiosurgery date back to the 1960s and
and Tracking .............................................................. 327 the use of cobalt based techniques. Over the past
3.2 CyberKnifeÒ Treatment Planning............................. 328 10–15 years, linear accelerators have been
3.3 Treatment Delivery.................................................... 329
3.4 Quality Management ................................................. 329 designed to allow for the delivery of radiosurgery
as well. Robotic radiosurgery couples a linear
4 Clinical Applications ............................................... 330
accelerator to a robotic articulated manipulator
4.1 Spinal and Paraspinal Tumors .................................. 330
4.2 Lung Cancers............................................................. 330 which allows for the delivery of both SRS and
4.3 Prostate Cancers ........................................................ 331 fractionated SRS (also referred to as stereotactic
4.4 Pancreatic Cancers..................................................... 331 body radiation therapy (SBRT)). In addition, since
4.5 Head and Neck Cancers ............................................ 331
frameless techniques are most often employed with
4.6 Liver Lesions ............................................................. 332
4.7 Adrenal Metastases.................................................... 333 robotic radiosurgery, areas outside the cranium can
now be treated with similar accuracy. Robotic
5 Summary................................................................... 333
radiosurgery is currently being used to treat
References.......................................................................... 333 targets located in the brain, spine, head and neck,
lung, liver, pancreas, prostate amongst others.
This chapter provides the background and techni-
cal details of robotic radiosurgery, as well as
R. E. Wegner
D. E. Heron (&)
M. S. Huq the current evidence for treatment of various
Department of Radiation Oncology,
University of Pittsburgh Cancer Institute, body sites.
5150 Centre Avenue, #545, Pittsburgh,
PA 15232, USA
e-mail: herond2@upmc.edu
D. E. Heron 1 Introduction
Department of Otolaryngology,
University of Pittsburgh Cancer Institute,
Stereotactic radiosurgery (SRS) is a specialized type
Pittsburgh, PA, USA
of external beam radiation treatment in which a pre-
A. H. Mintz
cise and conformal, image-guided focus of ionizing
Department of Neurological Surgery,
University of Pittsburgh Cancer Institute, radiation is delivered to a well-defined target volume
Pittsburgh, PA, USA in a single procedure. Radiosurgery can halt tumor

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 325
DOI: 10.1007/174_2011_319, Ó Springer-Verlag Berlin Heidelberg 2012
326 R. E. Wegner et al.

cell division, cause neoplastic blood vessels to

occlude, induce apoptosis or necrosis, and when used
intracranially, modify the blood–brain barrier around
the tumor (Kondziolka et al. 1992a, 1992b, 1999,
2000; Niranjan et al. 2004; Witham et al. 2005). In
contrast, external beam radiation therapy (EBRT)
delivers a therapeutic course over a time frame of
several weeks. The effectiveness of EBRT relies
upon the fundamental concepts of radiobiology by
optimizing normal tissue repair, promoting reoxygen-
ation and cell-cycle redistribution, as well as allowing
for tumor cell repopulation (Hall and Giaccia 2006). In
recent years, fractionated stereotactic radiosurgery
(FSR), also called stereotactic body radiation therapy
(SBRT) has emerged as a bridging technique that
employs the advantages of stereotactic guidance to
deliver a highly conformal high dose of radiation in two
to five sessions. Robotic radiosurgery, of which the
CyberKnifeÒ is the quintessential example, couples an
X-band 6-MV linear accelerator to a robotic articulated
manipulator (Fig. 1), and allows for the delivery of
both SRS and SBRT.

Fig. 1 a The CyberKnifeÒ robotic radiosurgery system

2 Origins of Radiosurgery
Lars Leksell, a Swedish neurosurgeon developed the
term stereotactic radiosurgery in 1951 as a novel
concept of a non-invasive method to treat lesions that
were not accessible by open surgery techniques.
Trigeminal neuralgia patients were the first to be
treated using an orthovoltage X-ray machine mounted
to a stereotactic frame. Lars Leksell later developed
the first commercially available dedicated radiosur-
gical device called the ‘‘Gamma Knife’’ in 1968.
Treatments initially were limited to patients with
arteriovenous malformation (AVM) and acoustic
neuroma in an era before the emergence of computed
tomography (Chin and Regine 2008; Leksell 1951).
This machine made it possible to precisely deliver a
single, large dose of highly conformal radiation to any
number of intracranial sites using 201 fixed cobalt
sources aimed at a center point. This provided an
alternative treatment to certain neurosurgical proce-
dures, which were then associated with significant
morbidity (Leksell 1951, 1983). Conditions thought to
be appropriate for radiosurgery included acoustic
schwannomas, intracranial arteriovenous malforma-
tions, pituitary adenomas, metastatic tumors, skull
(generation 3) in action. b The latest version of the Cyber-
KnifeÒ robotic radiosurgery system (the CyberKnife VSI
system) displaying the robotic manipulator, updated couch,
and diagnostic X-ray sources/detectors
base meningiomas, as well as functional disorders
such as trigeminal neuralgia and essential tremor.
While the vast majority of clinical experience and
biological understanding of radiosurgery is the result
of the body of work generated by the Gamma
KnifeÒ (Elekta Medical Systems, Stockholm, Sweden)
delivery radiosurgery system, more recently, linear
accelerators (linacs) have been extensively used for the
treatment of both intra-cranial and extracranial targets.
Using both frame-based and frameless approaches, the
linear accelerator allows for accurate, efficient, precise,
and reliable delivery of single fraction regimens of
ionizing radiation to the brain and other extracranial
targets, while also facilitating fractionation when
necessary. An alternative to frame-based approach to
radiosurgery, the CyberKnifeÒ system, was developed
by Dr. John Adler, Jr., a neurosurgical trainee of
Dr. Lars Leksell. Since this system does not rely on a
surgically placed frame, it allows for treatment to other
areas outside the skull.
Robotic Image Guided Radiation Therapy
In the original CyberKnifeÒ configuration, a 6-MV
linear accelerator was mounted to a robotic manipu-
lator which could direct the radiation beam anywhere
in space with six degrees of positioning freedom under
continual X-ray image guidance, without being
constrained to a conventional isocenter. During the last
20 years, this system has undergone significant tech-
nical developments leading to the introduction of its
most recent version, the CyberKnife VSITM system.
3 CyberKnifeÒ Robotic Radiosurgery:
Treatment Planning and Delivery
System
The CyberKnifeÒ robotic radiosurgery system com-
bines a number of advanced technologies. The
LINAC used for robotic radiosurgery employs an
X-band cavity magnetron and a standing wave, side-
coupled accelerating waveguide to produce a 6-MV
X-ray treatment beam with a dose rate of 1,000 cGy/
min. The machine does not have a bending magnet or
a beam-flattening filter and secondary collimation
is accomplished via the use of 12 fixed circular
collimators with diameters ranging from 0.5 to 6.0 cm
or a variable aperture collimator called ‘‘IrisTM.’’ The
aperture size of the IrisTM collimator can be contin-
uously varied up to a maximum size of 6.8 cm.
However, its current use is restricted to 12 circulator
collimator openings corresponding to the sizes of the
12 fixed collimators mentioned above. During treat-
ment the fixed collimators can be manually attached
to the linac or fitted automatically using the
XchangeÒ robotic collimator changer. On the other
hand, if the IrisTM collimator is used for treatment,
then any of the 12 field sizes can be used at any beam
position without the need to swap collimators.
The LINAC is mounted on a KR240-2 (Series
2000) robotic manipulator (Kuka Roboter GmbH,
Augsburg, Germany) that has a specification for
position reproducibility better than 0.12 mm. It has
six degrees of-freedom capabilities and can position
the LINAC in a large 3D workspace around the
patient with high precision. This allows each radiation
beam to be directed at any unique point in space
(i.e., there is no isocenter or restriction on constrain-
ing the beams to a coplanar beam geometry). The
robotic manipulator also enables the CyberKnifeÒ
to compensate for changes in target position and
327
orientation during treatment by adjusting the beam
position and orientation rather than by moving the
patient, in contradistinction to other radiosurgical
systems which require the physical movement of the
patient or couch during treatment (Kilby et al. 2010).
The CyberKnifeÒ radiosurgery system also incor-
porates two diagnostic X-ray sources that are mounted
to the ceiling and two amorphous silicon flat-panel
X-ray detectors with pixel size of 0.4 9 0.4 mm that
are mounted flush to the floor. The kilovoltage sources
and the detectors panels are mounted such that the
kilovolt radiation beams project square X-ray fields at
the detector panels at 458 from vertical. This source–
detector combination is used for image guidance during
treatment. For patients with tumors that are subject
to motion during treatment such as lung cancers, a
stereoscopic camera system is also used to monitor the
position of optical markers attached external to the
patient during treatment. The different forms of target
tracking and how image guidance plays a role are
discussed in greater detail below.
3.1 Adaptive and Active Target
Localization and Tracking
For patients with intracranial or head and neck targets,
6D skull tracking is used for target localization. With
this method, high-contrast bone information from the
skull contained within the entire field of view is used to
perform 2D registrations. The resulting 2D transfor-
mations for each orthogonal projection are then
combined to determine the 3D rigid transformation that
aligns the position and orientation of the skull in the
treatment planning CT image with the treatment
delivery coordinate system. A similar method is used to
track lesions located in or near the spine that are con-
sidered to be fixed relative to it. However, for spine
tracking, additional image processing filters are used to
enhance the bony anatomy in both the planning and
treatment X-ray images. When treating tumors in the
lung, two modes of tracking may be used: XsightTM
Lung and/or Synchrony. XsightTM lung tracking is
used for tracking lung tumors that do not have any
implanted fiducial markers and therefore poses less
risk of pneumothoraces in patients with already com-
promised pulmonary function. This tracking involves a
two-step process. In the first step the patient is globally
aligned in both position and orientation by using the
328
Fig. 2 Gold fiducial markers
used for target localization
and tracking during
CyberKnifeÒ robotic
radiosurgery
region of the spine nearest to the tumor. This is done
only once at the beginning of the treatment. After the
patient is globally aligned, the patient is moved from
the spine alignment center to the tumor treatment
center by a movement of the couch. At this position
orthogonal X-ray images are taken. Tumor tracking is
performed by comparing image intensity pattern of the
tumor region in the DRRs with the corresponding
regions in the orthogonal X-ray images. This regis-
tration process provides 2D translations for each pro-
jection from which 3D translations for the tumor is
determined by backprojection of the 2D translations.
This tracking system works well for tumors that are
larger than 15 mm in diameter and are located
peripherally and at the apex of the lung. The other
tracking mode for lung tumors is SynchronyTM which
provides real-time tracking for tumors that move with
respiration. This is accomplished by establishing a
mathematical correlation model between tumor posi-
tions at various phases of breathing cycle and an
external marker position placed on the patient during
treatment. Using the correlation model, the position of
the tumor is predicted from the position of the external
marker. This information is then used to move the
accelerator dynamically with the target.
The fiducial markers are typically cylindrical gold
seeds, 0.8–1.2 mm in diameter and 3–6 mm in length
(Fig. 2). Fiducial markers are also used for other soft
tissue targets that are not fixed relative to bony
anatomy. The fiducial markers are radiopaque and
implanted under image guidance within or near the
tumor as a frame of reference. Typically three to five
markers are implanted approximately 2 cm apart in or
near the target. Approximately 1 week after place-
ment the planning CT is done to allow time for
stabilization, as migration of seeds has been known to
occur. Since the fiducial markers are radiopaque they
are easily visible on the digitally reconstructed
radiographs (DRR) from the planning CT scan and
can be visualized on the X-ray images taken at the
R. E. Wegner et al.
time of treatment. For fiducial tracking the image
registration is based on the alignment of known
positions of fiducials on the DRR images with the
marker location extracted from the treatment X-ray
images. (Kilby et al. 2010).
3.2 CyberKnifeÒ Treatment Planning
The process of treatment planning requires, at a mini-
mum, a CT scan to delineate the target and surrounding
critical structures. Frequently, an MRI or PET-CT is
also used to assist in the planning process. Once the
necessary images are acquired they are transferred to
the MultiplanÒ treatment planning system (TPS) via a
dedicated database server. The TPS uses the images to
create a 3D patient model in which treatment beams are
positioned. Each beam has a source point (the LINAC
focal spot) and a direction point (typically within the
target being treated). In theory, there can be an
infinite number of source and direction points within
the delivery system, although they are typically
constrained to a practical size during treatment
planning using a finite set of beams. The source point is
often referred to as the node and a complete set of
nodes is called a path set. Path sets are constructed to
provide a range of non-coplanar beam directions for
various intra- and extra-cranial sites. Unlike other
linac platforms, all non-coplanar beams are achieved
without moving the patient, which is the hallmark of
CyberKnifeÒ radiosurgery.
Treatment plans can be generated in either an
isocentric or non-isocentric manner. In the isocentric
mode, the user manually places one or more isocen-
ters within the patient model, resulting in one beam
from each node to each isocenter. This mode is
typically used for spherical lesions such as brain
metastases. The non-isocentric mode allows the
robotic manipulator to direct each beam at a unique
point within the patient model, without any need for
repositioning the patient between beams. The TPS
accomplishes this by generating a large number of
direction points semi-randomly within the target
volume. These direction points are then uniformly
distributed among the nodes to form a beam set.
The TPS also allows the user to choose beams such
that they do not pass through the surrounding critical
structures that have been contoured, thereby reducing
dose and potential toxicity.
Robotic Image Guided Radiation Therapy
The CyberKnifeÒ system has only circular cones.
Depending on the tumor volume, one to three cone
sizes can be chosen for treatment planning. Typically,
only one cone size is sufficient to produce an
acceptable plan. Larger cones are typically used for
extracranial lesions. The treatment planning system is
capable of producing single-, multiple-, or non-iso-
centric plans. Especially for extracranial lesions
which are typically much larger than intracranial
tumors, single or multiple-isocentric plans produce
very poor dose coverage. Since the CyberKnifeÒ
robot has six-degree-of-freedom maneuverability, it
can deliver an array of overlapping beams to be
superimposed without an isocenter. Non-isocentric
plans which can be generated using the CyberKnifeÒ
inverse planning optimization algorithm typically
produce homogeneous dose distributions that closely
conform to highly irregular volumes. This unique
feature of CyberKnifeÒ makes it highly suitable for
body radiosurgery applications.
An optimization algorithm chooses the optimal
beam directions automatically; the treatment planning
system does not allow manual selection of beam
directions. Inverse planning is used for the creation of
all plans. Because of the robot’s great maneuver-
ability, its workspace must be taken into consideration
during treatment planning and delivery. The robot’s
workspace is the total volume within which the robot
can maneuver without touching any other object or
interfering with any lines of sight for the imaging
system. The planning system accounts for the robot’s
workspace to ensure that the robotic arm can move
through the entire treatment safely.
The treatment dose for CyberKnifeÒ is typically
prescribed to 80% isodose line and the maximum
dose is always is represented by the 100% isodose
line. A plan is considered ideal if 95% of the tumor
volume is covered by the prescription dose. In some
cases, it may be very difficult to achieve this goal due
to the proximity of critical organs and the larger
penumbra of the larger cones which are frequently
used for lung treatment.
3.3 Treatment Delivery
At the start of every treatment the X-ray image
guidance system is used to align the patient using an
adjustable treatment table. Corrections for small
329
target movements are then accomplished through
automatic registration of the DRRs from the 3D
patient model with live images acquired using the
X-ray imaging system. The registration process
provides the additional translational and rotational
corrections that are needed to precisely align each
treatment beam with the target. The robotic manipu-
lator uses this information to reposition the linac such
that the radiation beam is precisely aligned with the
target. During treatment the robot systematically
moves through the nodes and delivers the beams.
Approximately every 30–60 s throughout treatment
the system acquires images, confirms target location,
and performs any necessary alignment corrections.
This interval can be adjusted based on expected target
movement (i.e., a longer interval can be used for brain
metastases while a shorter interval would be used for
a lung tumor). If a large correction is needed based on
image registration, the system automatically pauses to
allow for patient repositioning by the operator. With
the newest system, repositioning is performed by the
RoboCouchTM, by automatically manipulating the
treatment couch position.
3.4 Quality Management
One of the goals of a well-designed quality manage-
ment program is to give high confidence that the
patients will receive the prescribed dose correctly.
For stereotactic radiosurgery treatments, quality
assurance takes on a special meaning because small
errors in radiation planning and delivery have the
potential of severely underdosing the target or over-
dosing a nearby critical structure. Thus, it is critical
that the CyberKnife physicist develops and imple-
ments a comprehensive QA program which is con-
sistent with the recommendations of the professional
societies and vendor’s recommendations and meets
the states’ regulatory guidelines. It is also important
that the institutional CyberKnife physicist consult
other experienced CyberKnife users in this regard.
Task Group 135 of the American Association of
Physicists in Medicine (AAPM) has developed a
comprehensive QA document which provides guide-
lines and suggested methods for ensuring technical
aspects of a quality treatment using the CyberKnife
radiosurgery system. This document discusses quality
assurance methods for the robot, accelerator, imaging
330
system, treatment planning software, tracking system,
synchrony, auto-QA (AQA), delivery quality assur-
ance (DQA), and end-to-end tests. This report also
discusses considerations for accuracy of radiation
delivery, room and patient safety, and special mea-
sures that need to be followed after software upgrades
and imager exchange. Finally, this report provides
prescriptive recommendations for daily, monthly, and
annual QA of the CyberKnife system. It is recom-
mended that the institutional physicist follows the
recommendations of this report when designing a
comprehensive QA program for CyberKnife radio-
surgery and complement these recommendations with
those provided by the vendor.
4 Clinical Applications
As with all radiosurgery techniques, lesions in the
brain (metastases, primary tumors, arteriovenous
malformations, etc.) can be easily and safely treated
using the CyberKnifeÒ robotic radiosurgery system.
Given the large volume of data from various treat-
ment platforms for treatment of those conditions that
discussion will be saved for subsequent chapters.
4.1 Spinal and Paraspinal Tumors
As discussed previously, the CyberKnifeTM robotic
radiosurgery system was one of the first systems to
allow for the delivery of radiosurgical doses outside
the cranium. To that end, spine metastases were one
of the first areas of treatment to utilize the machine’s
capability. A prospective series by Gerszten and
colleagues published in 2004 reviewed the outcomes
of 125 spine cases treated using robotic radiosurgery
(Gerszten et al. 2004). Eighty-six percent of the
lesions were malignant and 62% were previously
irradiated using conventional techniques. The doses
delivered ranged from 12 to 20 Gy prescribed to the
80% isodose line in a single fraction. Ninety-four
percent of patients with tumor-related pain experi-
enced improvement in their symptoms by 1 month
post-treatment. The authors updated this series in
2007 with a total of 500 patients (Gerszten et al.
2007). Two-thirds of the patients in this cohort were
treated for painful spinal metastases. For those pat-
ents, 86% experienced long-term improvement in
R. E. Wegner et al.
their symptoms. When assessing local control as an
outcome, 90% of treated lesions exhibited long-term
control on follow-up imaging. There were no episodes
of radiation myelitis. Another prospective series uti-
lized the ability of the CyberKnifeÒ radiosurgery
system to fractionate treatment (Gagnon et al. 2009).
Two hundred patients with spinal tumors (75% were
metastatic) were treated in this manner using 3–5
fractions. Patients in this study reported their pain on
the 100-point visual analog scale (VAS). After treat-
ment pain, scores dropped by an average of 19 points,
with approximately 40% of patients becoming pain
free. Similar to the other series, treatment was well
tolerated with no evidence of treatment-related
myelitis or neurological injury.
4.2 Lung Cancers
With the inherent ability of the CyberKnifeÒ radio-
surgery system to track tumor movement and com-
pensate appropriately, the treatment of lung lesions in
medically inoperable patients became an active area
of clinical research and application. A Japanese multi-
institutional study enrolled 257 patients with stage
T1-2N0M0 non-small cell lung cancer who were
either medically inoperable or refused surgical inter-
vention (Onishi et al. 2007). Various dose fraction-
ation schemes were used ranging from 1 to 14
fractions with total doses to the isocenter between 30
and 84 Gy. All patients were evaluated with a chest
CT 3 months after completion of treatment. Eighty-
six percent of patients had a response to treatment
on imaging. Ten percent of patients developed
symptomatic pulmonary complications related to
treatment, with 50% of those being grade 2 or higher.
Actuarial local control at 5 years approached to 85%
in this study. A similar but smaller group of patients
was treated at Georgetown University (Vahdat et al.
2010) with a response to therapy assessed by PET/CT.
Patients were treated to 42–60 Gy in three fractions.
With a median follow-up of 43 months, the 2 year
local control was 95% based on PET/CT assessment.
Lung metastases can also be effectively treated using
the CyberKnifeÒ robotic radiosurgery system. A ser-
ies of 100 patients treated at our institution included
19 patients with lung metastases (Pennathur et al.
2009). The doses used in this population ranged from
20 to 60 Gy in 1–3 fractions. Local control was
Robotic Image Guided Radiation Therapy
achieved in 71% of the entire cohort. For patients
with lung metastases the 2 year overall survival was
excellent at 84%. No significant toxicity was reported,
helping to further support the safety and efficacy of
CyberKnifeÒ robotic radiosurgery for the treatment of
lesions in the lung.
4.3 Prostate Cancers
With emerging data that prostate cancer may have a
lower a/b than initially estimated, and therefore
respond better to larger fractions of radiation, hypo-
fractionation has become another treatment option for
localized prostate cancer (Dasu 2007; Yeoh et al.
2006). Robotic radiosurgery is an ideal way to deliver
highly conformal doses of radiation to the prostate
while limiting excessive dose to the rectum and
bladder. Investigators at Stanford treated 41 men with
low-risk prostate cancer to a total dose of 36.25 Gy in
five fractions using the CyberKnifeÒ (King et al.
2009). With a median follow-up of 33 months there
were no documented PSA failures and no grade 3 or
greater rectal toxicity. Two patients (5%) did develop
grade 3 late urinary toxicity. The largest series reports
outcomes in 304 men with clinically localized pros-
tate cancer (Katz et al. 2010). Eighty-five percent of
the men in this study were treated using the Stanford
regimen. With a median follow-up of 30 months, four
patients (1%) experienced a biochemical failure.
There was only one episode of grade 3 late urinary
toxicity and no grade 4 toxicity. Given the slow
growing nature of prostate cancer, a longer follow-up
is needed to help further characterize the safety and
efficacy of CyberKnifeÒ robotic radiosurgery for the
treatment of prostate cancer.
4.4 Pancreatic Cancers
CyberKnifeÒ robotic radiosurgery has also been used
in the treatment of resected and locally advanced
pancreatic cancer. Koong et al. (2004) established the
feasibility of using the CyberKnifeÒ robotic radio-
surgery system for locally advanced pancreatic cancer
in a phase I dose escalation study which achieved
100% local control with no treatment limiting
toxicities at 25 Gy in a single fraction. A follow-up
study combined conventionally fractionated 5-FU
331
chemoradiotherapy with a boost using robotic radio-
surgery resulting in 94% local control, but with an
increase in toxicity compared to radiosurgery alone
(Koong et al 2005). A more recent study from the
same group combined full dose gemcitabine with
single fraction SBRT resulting in 81% local control
and 100% 1-year freedom-from local-progression.
While acute toxicities were minimal, a significant
number of subjects (47%) experienced Grade 2 or
greater late toxicities, primarily duodenal ulcers
(Schellenberg et al. 2008). A retrospective review
from our institution evaluated one of the largest
experiences to date in 71 subjects with pancreatic
cancer treated with CyberKnifeÒ robotic radiosurgery
(Rwigema et al. 2010a). With a median follow-up of
12.7 months the freedom-from-local-progression at
6 months and 1 year was 72 and 49%, respectively.
Treatment-related toxicity was minimal with only
three patients experiencing acute grade 3 toxicities
(4%) and no late toxicity. Another study from our
institution examined outcomes in 24 patients treated
post-operatively with CyberKnifeÒ robotic radiosur-
gery (Rwigema et al. 2010b). Sixty-six percent of the
patients had positive margins and the remainder had
close margins of 1–2.5 mm. The median follow-up
for this cohort was 1 year. The freedom-from-local-
progression at 6 months and 1 year was 95 and 66%,
respectively. There was no acute or late grade 3 and 4
toxicity, and two patients (8%) had late grade
1–2 toxicity, again demonstrating that when done
properly, CyberKnifeÒ robotic radiosurgery can be
delivered to targets in the upper abdomen in a safe
and efficacious manner.
4.5 Head and Neck Cancers
More recently, SBRT has become a treatment option
for patients with recurrent head and neck cancers that
are not amenable to surgical resection. Such patients
have typically received prior radiation doses exceed-
ing 70 Gy, meaning that re-irradiation with conven-
tional techniques represents a significant risk in terms
of normal tissue toxicity. Investigators at the Henry
Ford Health System reported outcomes in 44 patients
treated with either single fraction or fractionated
SBRT for head and neck tumors; 21 (48%) of these
tumors were recurrent in a previous radiation field
(Siddiqui et al. 2009). The one year local control was
332
Fig. 3 A typical treatment plan for re-irradiation of recurrent head and neck cancer. In this case, 44 Gy was delivered over five
fractions to the 80% isodose line (thick orange line). The shaded red volume represents the planning target volume
60% for patients with recurrent head and neck tumors.
There were five incidents of grade 3 or greater
toxicity in patients with recurrent tumors (16%
overall). Our institution has reported outcomes in a
large cohort of 85 patients, all of whom had recurrent,
previously irradiated squamous cell head and neck
cancers (Rwigema et al. 2010c). The majority of these
patients were treated with fractionated SBRT using
CyberKnifeÒ robotic radiosurgery. The median dose
was 35 Gy with a range of 15–44 Gy. Through sta-
tistical analysis, it was determined that doses of
[35 Gy resulted in improved local control. With a
median follow-up of 6 months the 1 year actuarial
local control was in excess of 50%. There were only
four episodes (5%) of acute grade 3 toxicity and no
grade 3–5 late toxicity. CyberKnifeÒ robotic radio-
surgery has also been used in combination with
cetuximab for treatment of recurrent head and neck
R. E. Wegner et al.
cancers. A case–control study compared 35 patients
treated with SBRT alone to 35 patients treated with
combined cetuximab and SBRT (Heron et al. 2010).
With the addition of cetuximab, the median overall
survival improved from 15 to 25 months without an
increase in grade 3–4 toxicity. Figure 3 shows a
typical treatment plan for re-irradiation using the
CyberKnifeÒ. These data show that CyberKnifeÒ
robotic radiosurgery is safe and efficacious when used
to treat recurrent, previously irradiated head and neck
cancers.
4.6 Liver Lesions
There have been a handful of studies evaluating the
feasibility of treating liver lesions with SBRT.
A phase I/II trial found that liver metastases treated
Robotic Image Guided Radiation Therapy
with 60 Gy in three fractions over 3–14 days was well
tolerated with an actuarial local control rate of 93%
(Kavanagh et al. 2006). The authors updated this trial
in 2009 with a total of 47 patients with 63 metastases
(Rusthoven et al. 2009). At the time of publication
local control at 1 and 2 years was an impressive 95
and 92%, respectively. With the update, there was
only one episode of grade 3 skin reaction and no
grade 4 or 5 toxicity. A similar phase I trial was
conducted at the Princess Margaret Hospital with
escalating doses from 27.7 to 60 Gy in six fractions in
70 patients with 143 tumors (Lee et al. 2009). The
rate of grade 3 toxicity in this cohort was 10%,
manifesting as liver enzyme elevation, thrombocyto-
penia, and abdominal pain. One patient developed a
grade 5 small bowel obstruction. The 1-year local
control rate was 71%.
The experience of SBRT with hepatocellular car-
cinoma is more limited due to the disease’s multifocal
nature and tendency to develop in the setting of
cirrhosis. These factors create a liver which is more
susceptible to radiation injury. A recent study exam-
ining 18 tumors (all less than 36 mm in diameter)
treated with a preferred schedule of 48 Gy in eight
fractions revealed a local control rate of 83% at 2 years
(92% if allowing for re-irradiation). The overall
survival rate at 2 years was 39% (Taguchi et al. 2007).
A study conducted in the Netherlands examined the use
of SBRT in the treatment of 45 liver metastases and 11
hepatocellular carcinomas. In the HCC group, the
actuarial local control at 1 year was 75% (Mendez
et al. 2006). All of the above data suggest that SBRT is
a safe, effective way to deliver non-invasive, ablative
local therapy to lesions within the liver.
4.7 Adrenal Metastases
SBRT has also been used to treat adrenal metastases,
both for palliation and local control. One of the
largest studies evaluating the treatment of adrenal
metastases with SBRT was reported by the University
of Rochester. A total of 30 patients, the majority with
lung primaries (n = 20), were treated with SBRT at
prescribed doses ranging from 16 Gy in four fractions
to 50 Gy in ten fractions with a median dose of 40 Gy
(Chawla et al. 2009). The 1-year survival, local con-
trol and distant control rates were 44, 55, and 13%,
respectively. A study from Hokkaido University
333
reported significantly better results, in which ten
patients treated with SBRT at a prescribed dose of
48 Gy in eight fractions had an actuarial overall sur-
vival rate and freedom-from-local-progression rates at
12 months of 78 and 100%, respectively (Jang et al.
2009). At our institution we have treated nine adrenal
lesions (four from non-small cell lung cancers, two
from small cell lung cancer and three from hepato-
cellular carcinomas) either in a single fraction of
16 Gy or over three fractions to a total dose of 27 Gy
(Torok et al. 2011). No acute or late treatment-related
toxicity was observed which seems to further support
that SBRT is well tolerated for the treatment of
adrenal metastases. The median survival in this cohort
was 8 months and the actuarial local control rate at
1 year was 63%. Overall, SBRT for adrenal metas-
tases is a safe and non-invasive treatment modality,
but will still need further review to discern its true
benefits and optimal dose scheduling.
5 Summary
The CyberKnifeÒ robotic radiosurgery system has
undergone significant technical advances over the
past 20 years. The system continues to provide a
unique and innovative method for providing frame-
less radiosurgical treatment for both intracranial and
extracranial targets.
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 Cranial Stereotactic Radiosurgery
Joseph R. Simpson, Robert E. Drzymala, Keith M. Rich,
and Brigitta G. Baumert

Contents 6 Practical Physics and Dosimetry Issues................ 351

6.1 Selecting a Stereotactic Frame.................................. 351
6.2 Choosing Localization Images.................................. 354
1 Introduction.............................................................. 335 6.3 Working with Auxiliary Images ............................... 354
2 Origins of Radiosurgery ......................................... 336 7 Quality Assurance.................................................... 354
3 Descriptive Overview: Rationale, Dose 8 Dosimetry and Commissioning of Treatment
Prescription, and Normal Tissue Tolerance ........ 336 Units .......................................................................... 355
3.1 Rationale .................................................................... 336 8.1 Periodic Checks ......................................................... 356
3.2 Dose Prescription and Normal Tissue Tolerance..... 338 8.2 Mechanical Checks.................................................... 356
8.3 Safety Procedures ...................................................... 357
4 Components for Cranial Stereotactic
Radiosurgery ............................................................ 339 9 Summary of Published Treatment Results .......... 357
4.1 Stereotactic Device.................................................... 339
4.2 Irradiation Source ...................................................... 339 10 Conclusions ............................................................... 359
4.3 Medical Imaging........................................................ 339 References.......................................................................... 359
4.4 Computerized Treatment Planning ........................... 340
5 Specific Methods and Treatment Units ................ 342
5.1 Leksell Gamma Knife ............................................... 342 Abstract
5.2 Linear Accelerators (Linac) ...................................... 345 Presently, in any centers around the world, radi-
5.3 Charged Particle Therapy.......................................... 351
ation can be wielded like a surgical instrument, or
loco-regional chemotherapy agent in modern,
precisely focused intracranial treatment techniques
called stereotactic radiosurgery (SRS), fractionated
J. R. Simpson (&)  R. E. Drzymala radiosurgery (fSRS) and stereotactic radiotherapy
Department of Radiation Oncology, (SRT). This chapter presents a practical overview
Washington University School of Medicine,
4921 Parkview Place, Campus Box 8224,
of the rationale, methodology, equipment, and
St. Louis, MO 63110, USA personnel required to successfully perform cranial
e-mail: jsimpson@radonc.wustl.edu stereotactic radiosurgery, fractionated radiosurgery
K. M. Rich and stereotactic radiotherapy
Department of Neurological Surgery,
Washington University School of Medicine,
660 South Euclid Avenue, Campus Box 8057,
St. Louis, MO 63110, USA
B. G. Baumert 1 Introduction
Department of Radiation-Oncology (MAASTRO)
and GROW (School for Oncology The practice of radiation therapy has evolved substan-
and Developmental Biology),
University Medical Center Maastricht (MUMC), tially over the past 60 years. It is now routine to
Maastricht, The Netherlands accurately deliver well-calibrated doses of ionizing

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 335
DOI: 10.1007/174_2011_327, Ó Springer-Verlag Berlin Heidelberg 2012
336
radiations with precise conformality, in either single or
multiple fractions to targets deep within the cranium and
the body. Advances in medical imaging, immobiliza-
tion techniques, software tools, and computer hardware
have enabled stereotactic radiosurgery (SRS), to become
widely available. High resolution imaging techniques,
external and internal frames of reference and restriction
of target motion, or radiation beam-on sequencing
(gating) to correct for target and normal organ motion,
allow highly conformal treatment strategies to be
incorporated into the multimodality management of
cancer and other susceptible conditions. These proce-
dures are more complex than standard conformal
radiotherapy and provide improved target coverage with
greater sparing of normal tissues. This chapter provides a
clinical overview of the current techniques and devices
available for intracranial stereotactic radiosurgery
(SRS), fractionated radiosurgery (fSRS), and stereotac-
tic radiotherapy (SRT).
2 Origins of Radiosurgery
Lars Leksell, a Swedish neurosurgeon, pioneered the
idea of intracranial stereotactic radiosurgery. In 1968,
after more than a decade of trials, the first commer-
cially available dedicated radiosurgical device called
the ‘‘Gamma Knife’’ was introduced in Stockholm,
Sweden (Leksell 1968). The Gamma Knife allowed
the delivery of a single, large dose of highly confor-
mal irradiation via the use of 201 fixed cobalt sources
stereotactically aimed at a center point directed at
sites inside the skull. The Gamma Knife offered
alternative treatment options for a number of neuro-
surgical procedures associated with significant mor-
bidity or mortality (Leksell 1951). Clinical disorders
initially treated with stereotactic radiosurgery inclu-
ded acoustic schwannomas, pituitary adenomas,
meningiomas, arteriovenous malformations, single
metastatic tumors, and trigeminal neuralgia. In addi-
tion, certain other functional conditions, such as
essential tremor or Parkinson’s disease, were suc-
cessfully treated with radiosurgery in selected situa-
tions (Leksell 1968). Once the efficacy of Gamma
Knife radiosurgery was demonstrated other radiation
sources, particularly modified linear accelerators were
incorporated into stereotactic systems capable of either
single or fractionated intracranial treatments (Dunbar
J. R. Simpson et al.
et al. 1994). Subsequently, more detailed imaging
methods (computed tomography, magnetic resonance
imaging, positron emission tomography, and bi-plane
angiography) for target localization were developed.
These spawned a variety of additional techniques for
radiosurgical treatment. The principles of and a
number of practical methods for stereotactic cranial
irradiation are presented in this chapter.
3 Descriptive Overview: Rationale,
Dose Prescription, and Normal
Tissue Tolerance
3.1 Rationale
The central goal in stereotactic irradiation is to
maximize dose in the target and minimize it in the
surrounding neural tissue. There are several basic
principles common to all stereotactic procedures.
Stereotactic radiosurgery, fractionated stereotactic
radiosurgery, and stereotactic radiotherapy each
require patient immobilization and repositioning with
a stereotactic frame, a thermoplastic mask, or a
frameless system to direct precise radiation beam
targeting. By convention, traditional stereotactic
radiosurgery refers to a single treatment and
fractionated radiosurgery applies to up to five
fractions. Stereotactic radiotherapy typically means
multiple conventional-sized fractions and doses,
Traditional stereotactic radiosurgery requires a
positioning accuracy of \1 mm, while fractionated
radiosurgery, with non-invasive methods, is consid-
ered able to achieve an accuracy of about 2–3 mm.
Whereas the Leksell stereotactic frameÒ is used for
Gamma Knife radiosurgery, the Gill-Thomas-Cosman
(GTC) frame has been frequently employed for linac-
based radiosurgery or fractionated stereotactic radio-
therapy (Kooy et al. 1994). It was modified to allow the
treatment of extracranial head and neck tumors
involving the skull base, nasopharynx, and paranasal
sinuses (Kassaee et al. 2003), and also used with an eye
fixation device to permit fractionated radiosurgery.
A commercial thermoplastic mask system (BrainLAB)
has become increasingly popular for linac-based
radiosurgery (Dieckmann et al. 2003). This mask
system can also be used for stereotactic radiotherapy to
treat larger targets such as cavernous sinus meningio-
mas employing CT–MR image fusion with tight
Cranial Stereotactic Radiosurgery
Table 1 Examples of stereotactic timelines (a) single-treatment SRS (b) SRT and (c) fractionated SRS
SRS (a) SRT (b)
Stereotactic frame Imaging and Tx planning (Day 1:
placement (30 min) 60 and 60–120 min, respectively)
Pre-Tx imaging Pre-Tx imaging (30 min per Fx)
(30–90 min)
Tx planning Tx isocenter adjustment (5 min per
(15–120 min) Fx)
Patient treatment Patient treatment (20–45 min per
15–150 min 1 Fx) Fx)
conformal margins and conventional doses. (Selch et al.
2004a, b) Radiosurgery prescriptions represent maxi-
mum levels of time-dose contraction. Single fraction
schedules have been established for both benign and
malignant tumors, AVMs, and functional disorders.
These range from 12 Gy for acoustic schwan-
nomas, to 20–24 Gy for small metastases, to 75 Gy
for essential tremor. A variety of schedules for
fractionated radiosurgery have emerged. Choroidal
melanomas were treated with 70 Gy in five fractions
over 10 days (Emara et al. 2004). Larger metastases
were given a dose schedule of 35 Gy in four fractions
to the isocenter over 4–6 days (Aoyama et al. 2003),
or 40 Gy in five fractions on consecutive days
(Lindvall et al. 2005). Non-invasive skull fixation has
allowed patients to avoid the discomfort of repeated
invasive fixation for metachronous metastases.
The Laitinen stereoadapter with a conventional linac
is another technique for treatment of larger arterio-
venous malformations (Lindvall et al. 2003). At Johns
Hopkins a custom-fitted thermoplastic mask attached
to the metal base frame of the Brown-Roberts-Wells
(BRW) frame was adopted for fractionated treatment
of acoustic schwannomas (Williams 2002, 2003).
Whereas mask systems are often considered less
accurate than invasive frames, Kim et al. (2003)
reported a mean isocenter accuracy within 0.53 mm
for frameless stereotactic radiotherapy in 43 patients
using image guidance from three 2-mm gold markers
implanted in the cranium, allowing them to achieve
a high degree of accuracy comparable to framed
stereotactic radiosurgery.
Stereotactic irradiation thus requires a stereotactic
device, sensitive and highly accurate three-dimensional
imaging, high speed computer treatment planning, and a
radiation source. The radiation modalities have included
high-activity 60Co gamma rays, photons from low to
337
fSRS (c)
Imaging and Tx planning (Day 1: 60 and 120 min, respectively)
Patient treatment repositioning (10–15 min per Fx)
Patient treatment (10–60 min per Fx). Depends on the number
of isocenters or shots and the dose rate of the irradiator
medium energy linear accelerators, and charged particle
beams, such as protons and carbon ions.
Stereotactic radiosurgery, fractionated radiosur-
gery, and stereotactic radiotherapy reflect a division
based on the radiobiological intent of the therapy.
Radiotherapy is effective when it can destroy the
growth potential of a mass of tumor cells while limiting
toxicity to normal cells within and surrounding the
tumor. The intent of SRS is radioablation of small
tumors, destroying their growth potential with a single,
high-dose of irradiation. Fractionated radiosurgery
attempts to reduce normal tissue toxicity by the use of a
small number of fractions for treatment of larger ste-
reotactic targets, or those located too close to critical
normal tissues for adequate dose falloff from a large
single radiation dose. The technique may also be useful
when further dose escalation than feasible with a
single fraction is required for successful tumor control.
Stereotactic radiotherapy uses a stereotactic system, and
radiation beams with or without intensity modulation, to
allow tighter margins than conventional conformal
irradiation to further spare normal brain tissue from the
toxicity of even conventional fraction sizes and
total doses. In non-neoplastic conditions such as the
treatment of arteriovenous malformations or essential
tremor, radiosurgery is used more like a scalpel by
creating the desired result by virtue of the specific late
vaso-occclusive tissue effects of high dose fractions.
Although the techniques of SRS and fSRS depend
greatly on the equipment used, the (see flowchart in
Table 1) general flow of frame-based radiosurgery
begins with stereotactic frame placement. The invasive
frame is rigidly fixed to the patient’s skull under
awake sedation and regional nerve blocks with local
anesthesia, providing superior immobilization of
the patient’s head, as well as providing the basis
for a highly reliable stereotactic coordinate system.
338
Table 2 Example of dose prescriptions for various conditions:
typically 50% for the Gamma Knife and 80% for the linear
accelerator
Condition Dose at 50% or at 80%
Isodose line in Gy
Acoustic schwannoma 12–13
AVM 18–24
Malignant glioma 16–24
Meningioma 14–16
Atypical or anaplastic 16–22
Metastases 16–24
OCD 60–75
Pallidotomy 75
Trigeminal Neuralgia 40–45
Experienced application of frames may be done with
limited discomfort to the patient. If a repeatable and
relocatable stereotactic frame is used instead, it can
provide a platform for fractionated stereotactic radio-
surgery and stereotactic radiotherapy at appropriate
time intervals. The relocatable frame usually has
diminished immobilization and may also degrade tar-
geting accuracy relative to the fixed application of
stereotactic frames. In cases, where a frameless tech-
nique is employed, the stereotactic frame is replaced by
highly accurate direct ‘‘stereotactic’’ imaging on the
treatment system or with a stereo optic camera system.
After application of the stereotactic frame, CT
and/or MR volumetric imaging is routinely obtained
and, in selected cases, orthogonal planar angiograms
are required for accurate target localization during
computerized treatment planning. If fiducials are
included in the images, the spatial relationship
between image pixels and the stereotactic coordinates
can be determined mathematically. In this way, the
treatment beam configuration can be precisely speci-
fied at the desired anatomical locations during treat-
ment according to the dose distribution developed
during the planning process.
3.2 Dose Prescription and Normal Tissue
Tolerance
An extremely wide range of doses is used in stereotactic
irradiation. SRT doses are usually 1.8–2.0 Gy per frac-
tion to standard total doses, while fSRS and SRS doses
J. R. Simpson et al.
per fraction are much higher and fewer, i.e. 3.5–75 Gy
calculated at 50% isodose line for Gamma Knife plan-
ning and 80% isodose line for most linac prescriptions
(Table 2). Certain normal intracranial structure toler-
ance doses are always considered in prescribing treat-
ment: i.e. the optic nerves and chiasm are considered to
tolerate no more than 8–10 Gy for single fraction treat-
ment (Stafford et al. 2003; Leber et al. 1998). The facial
nerve also appears more sensitive, with a tolerance
considered to be around 14 Gy. Since many intracranial
treatment prescriptions employ single doses greater than
these levels, careful attention to the nearby location of
such sensitive organs is essential.
Evaluation of the intracranial treatment plan is
performed by collaboration among the radiation
oncologist, neurosurgeon or skull base surgeon, and
medical physicist. Consideration is given to the type
of target treated, conformity of dose to the target,
and dose to nearby neural tissue using both dose
volume histograms and isodose contours. Usually,
the goal is to cover [95% of the target volume with
the prescription dose as conformally as possible. One
‘‘conformity index’’ is the volume of tissue in the
dose matrix containing the target that receives
the prescription dose divided by the target volume
(Monk et al. 2003). Ideally, it should be less than
2:1 according to the model for variables contributing
to acute or chronic grade 3, 4, or 5 toxicity. Simi-
larly, RTOG protocol 90-05 used the PIV/TV ratio
(a measure of dose conformity of the treatment
relative to the target where PIV is the prescription
isodose volume (in mm3) and TV the tumor volume
(in mm3 Shaw et al. 1996). At the Gamma Knife
Center of Saint Louis, we typically strive for a
conformality index of B1.5:1. Other computations
for conformity have been proposed. (Paddick 2000;
Paddick and Lippitz 2006) In terms of prescribed
dose, RTOG 90-05 provides some guidance for
avoiding chronic late toxicity based on size for
metastases or gliomas after prior radiation therapy:
In that study no chronic late toxicity was seen for
tumor B2 cm in diameter up to 24 Gy, while B3
and B4 cm tolerated 18 and 15 Gy respectively
(Shaw et al. 1996). Appropriate quality assurance
(QA) tests on the treatment day are required to
verify the alignment and proper function of the
treatment device prior to treatment. Finally,
the patient is treated according to the plan on the
treatment couch or chair, under the guidance of the
Cranial Stereotactic Radiosurgery
stereotactic device, monitored by the stereotactic
team. In the United States, current Nuclear Regula-
tory Commission Guidelines (CFR Part 35) require
the presence of an authorized medical physicist and
an authorized user (radiation oncologist) throughout
the treatment with a Gamma Knife unit.
4 Components for Cranial
Stereotactic Radiosurgery
4.1 Stereotactic Device
The term, ‘‘stereotaxy,’’ and its adjectival forms,
stereotaxic and stereotactic, have a Greek and Latin
etymology, in which stereo refers to three dimensions
in space and taxis means ‘‘to arrange.’’ In this context,
the word implies the use of a device that can precisely
direct radiation to a specific site within the body. In
the traditional approach to stereotactic radiosurgery, a
mechanical device, the stereotactic frame (Leksell
1951), is attached to the patient’s head (Fig. 1). Once
applied to the head, the frame is also used to immo-
bilize the target. Less invasive mechanical, optical,
and radiographic methods, developed more recently,
can be reliably reapplied for fractionated treat-
ment (Ashamalla et al. 2003). Such optical and
radiographic methods are ‘‘frameless’’ stereotactic
techniques. The stereotactic devices in these cases
may include a bite block that can be located in space
with a stereo-optical camera (Bova et al. 1998; Kai
et al. 1998), a stereo-pair of kilo voltage fluoroscopy
units (Chang and Adler 2001), or a combination of
various imaging and tracking methods (Yin et al.
2002). In each case, the basic purpose of the stereo-
tactic device is to provide an accurate coordinate
system within which to direct a radiation beam to the
target. The targeting precision for a stereotactic pro-
cedure is assumed to be on the order of 1 mm (Lutz
et al. 1988); however, sub-millimeter precision may
be achieved with the use of many current stereotactic
devices (Bova et al. 1998). Baumert assessed the
repositioning accuracy of fSRS for different dental
fixations (Fig. 2) using sequential CT scanning.
She concluded that the reproducibility of patient
positioning using a re-locatable head mask system
combined with a bite block is within the reported
range for similar devices and is preferable to a simple
upper jaw support (Baumert et al. 2005).
339
Fig. 1 The original leksell stereotactic frame with X-ray tube
attached
4.2 Irradiation Source
In addition to highly accurate positioning of radiation
beams, high dose rate, and rapid dose falloff outside the
target volume are crucial for efficient and safe dose
delivery. Accurate positioning is achieved through the
use of a stereotactic device; high dose rate by high
activity Co sources, replaced after 5–6 years, or the
purchase of a linear accelerator capable of delivering
dose rates of 600–1000 cGy/min, and rapid dose fall-
off is accomplished either with secondary collimation
close to the patient (Fig. 3) or with a micro-multileaf
collimator capable of intensity modulation (Benedict
et al. 2001; Cosgrove et al. 1999) (Fig. 4). Close col-
limation combined with non-parallel–opposed beams
with multiple trajectories provides a high degree of
dose conformality to the target volume (Figs. 5, 6).
Commercially available machines to perform stereo-
tactic radiosurgery currently include the Leksell
Gamma Knife, Accuray CyberKnife, Varian Trilogy
and True Beam, BrainLab Novalis, Elekta Synergy,
HiArt Tomotherapy, and various charged particle units.
4.3 Medical Imaging
All stereotactic procedures are image-based, employ-
ing computed tomography (CT), magnetic resonance
(MR) imaging, bi-plane angiography, positron
emission tomography (PET), or other medical imaging
modalities such as MR spectroscopy. Selection of the
appropriate imaging modalities is of paramount
340
Fig. 2 Example of fixation
with a stereotactic mask for
stereotaxy. Modified
BrainLab design at Maastricht
University Medical Centre
Fig. 3 Proximal beam collimation enhances dose fall-off in
the penumbra of the beam
importance to visualize patient anatomy. Clinicians
use these images to define the anatomic target and
volume to treat with the prescription of radiation.
Imaging is critical in the differentiation of normal tis-
sues or critical structures from targeted tissue and
determination of stereotactic coordinates on which
the radiation beams will focus. In many cases,
co-registration or fusion of imaging modalities
provides distinction of target and normal brain helpful
in subsequent computerized treatment planning and
quality assurance (QA) checks (Lefkopoulos et al.
2001); the latter are covered in another section.
Neuro-images, verified with respect to their spatial
accuracy, are transferred to a computerized treat-
ment planning system. The imaging modality
employed determines the accuracy of target volume
and normal structure localization with respect to the
J. R. Simpson et al.
Fig. 4 The BrainLab m3 collimator
stereotactic coordinate system. Poor resolution may
result, such as with PET imaging or MR spectros-
copy, or from spatial distortions, as may be found
with high resolution MRI due to internal artifacts or
poor shim of the MRI machine’s magnet. Once the
appropriate imaging is completed, and the target is
verified, the data are sent to the treatment planning
computer for treatment planning. The commonly
accepted method now is to transfer images in DICOM
3.0 format (http://medical.nema.org).
4.4 Computerized Treatment Planning
The location of the stereotactic device is identified on
the images to establish the spatial relationship of the
image set with respect to the stereotactic and treatment
coordinate systems. Development of the treatment plan
includes specification of the arrangement, size, shape,
and weight of the beams utilized to deliver the desired
Cranial Stereotactic Radiosurgery
Fig. 5 Example plans for
brain metastases with multiple
conformal fields
Fig. 6 Treatment plan with
mMlc (m3)
prescription dose. In addition, it includes dose limits for
nearby normal neural
structures, accomplished by selective blocking or
arc-shaping. The treatment plan thus specifies the
location, and shape of the dose distribution, intended to
maximize dose in the target volume and minimize dose
to surrounding tissue.
A computerized treatment planning system with
software customized for the radiation source and its
341
stereotactic device is usually sold as part of the SRS or
fSRS equipment package. There are common features
of SRS and SRT treatment planning systems that
should be noted. In addition to the common peripherals
found on radiotherapy treatment planning systems, the
stereotactic treatment planning system must have the
appropriate software and hardware needed to take
full advantage of the superior anatomic localization
provided by the stereotactic device and multimodality
342
Fig. 7 Gamma Knife model U (a) device and (b) device with patient
medical imaging. Current software should accomplish
treatment planning tasks in a user-friendly manner
that allows conformal plan generation in real-time.
As stereotactic radiosurgery is usually given in one
session, usually on the same day as the imaging, there
must be sufficient computing power and sufficient
graphics capability to calculate isodose distributions
and display them within a few seconds. Disk space must
allow storage of data for a reasonable number of
patients, typically requiring 80 MB each. Furthermore,
convenience demands that the treatment planning
computer be connected to the diagnostic imagers via a
PACS system or other network for rapid transfer of
images. Most present radiotherapy planning systems
can accept transfer of images that are formatted using
the ACR-NEMA DICOM standard (Low et al. 1995;
Neumann 2002; Warrington et al. 1994). A wide vari-
ety of media, CD, DVD, can also be accepted by
modern treatment planning systems in order to transfer
DICOM 3.0 standard formatted image sets. In some
systems, the radiotherapy data via extension of the
standard, DICOM RT (http://medical.nema.org) can
also be imported and exported.
5 Specific Methods and Treatment
Units
5.1 Leksell Gamma Knife
The Leksell Gamma KnifeTM (Elekta, Inc., Stock-
holm, Sweden) was the first dedicated commercially
available radiosurgery device (Fig. 7). It was initially
J. R. Simpson et al.
designed to provide highly accurate radiation treat-
ment of intracranial targets with the goal of causing
ablative lesions for functional neurosurgery (Leksell
1968). The treatment indications were expanded to
include vestibular schwannomas (1969), pituitary
adenomas (1969), AVMs (1970), and later metastatic
tumors (1986). The manufacturer specifies an overall
treatment accuracy of 0.3 mm. The system has three
basic components: (1) a spherical source housing; (2)
three or four collimator sizes; and (3) a couch with
electronic controls (see image of the model C in
Fig. 8). Different models of the Gamma Knife
developed over the years vary mainly in the number
and pattern of the source distribution within the
housing, the couch path, hydraulic or electric
motor driven couch movement, and whether the
treatment is computer controlled with automatic
patient positioning.
The source housing contains the 192 (Perfexion
model) or 201 (Models U, B, and C) Co-60 gamma-ray
emitting sources, which are distributed in radial
arrangement. The emitted gamma photons have an
average energy of 1.25 MeV and decay with a half-life
of 5.26 years; therefore, the sources are usually
exchanged every 5 years. Each source is constructed
so that the Co-60 pellet is encapsulated within a wel-
ded stainless steel tube, which is enclosed in a stainless
steel jacket and finally a bushing (see image of dis-
assembled source in Fig. 9). The bushing assembly is
placed in the source housing at a specified location to
evenly distribute the individual source activities.
The radiation beam from each source converges to the
‘‘unit center point (UCP)’’ which is approximately
Cranial Stereotactic Radiosurgery
Fig. 8 a Gamma Knife model C and b Gamma Knife Perfexion
Fig. 9 A Gamma Knife source and bushing assembly
40 cm away from each source. The UCP is analogous
to the isocenter of a linac and is the location where
the target volume must reside during irradiation.
This is accomplished by the three-axis coordinate
system with respect to the Leksell frame. Each source
has an activity of approximately 30 Ci, when newly
installed, and the 201 sources combined provide a
dose rate of about 350 cGy/min at the UCP.
Along the path to the UCP, the radiation beam
from each source of a Model U, B, or C Gamma Knife
is collimated twice, once by a primary collimator and
then by one of four secondary collimator helmets. The
patient is secured to the couch and helmet via the
343
Leksell stereotactic frame. For each helmet, 201
tungsten collimators define circular apertures that
project a specific beam diameter of 8, 14, or 18 mm at
the UCP. Not until the primary and secondary colli-
mators align, when the couch docks the helmet in the
source housing, does a therapeutic radiation dose
reach the patient. In order to conform the radiation
dose to the shape of the target in the patient, various
combinations of aperture diameters, aperture blocking
(plugging), irradiation times, and head positions are
utilized. Head positions must allow placement of the
target at the UCP and include specification of the
three axial coordinates (x, y, and z) and neck flexion
344 J. R. Simpson et al.

Fig. 10 A close-up view of the Gamma Knife model C

automated positioning system (APS)
Fig. 11 Internal chamber of the Gamma Knife Perfexion unit

or extension given by the gamma angle. A specific

combination of these four parameters defines a ‘‘shot’’
in Gamma Knife terminology.
A major advance in the Gamma Knife design was
made by introducing computer control of the treatment
steps with the Model C. The automatic positioning
system (APS) is a pair of computer-driven motors with
feedback monitoring that moves the patient’s head into
the proper location prior to irradiation (see Fig. 10 for a
close-up view of the APS motors). Since target vol-
umes for SRS are relatively small, the patient can be
positioned without human intervention in many cases;
however, when multiple target volumes are widely
separated, which can occur when treating multiple
Fig. 12 Gamma Knife Perfexion collimation system
metastases, the controlling software requires the ther-
apist to observe the patient within the room during long
traverses. Computerization of the Gamma Knife also restriction was removed with introduction of the
permits integration of a record-and-verify system. Gamma Knife Perfexion model and its ExtendTM
For example, the Gamma Knife model C, with its Accessory.
current software version, monitors various treatment Gamma Knife PerfexionTM is a major change in
parameters: helmet aperture, patient position including design from the previous models with automated
gamma angle, and treatment time. There was only patient positioning, segmented source blocking,
manual checking of helmet plugging for Gamma Knife source movement for patient shielding between shots,
models U, B, and C. and an enlarged internal patient cavity for extended
Although the Gamma Knife is well-suited for tar- access to peripheral cranial anatomy (see Fig. 11).
gets in the cranium, the Models U, B, and C did not Unlike Models U, B, and C, the Perfexion unit moves
have sufficient room within the helmet to provide the entire patient on the couch to each stereotactic
extracranial treatments, with the exception of a few x, y, z coordinate. The sources are arranged radially,
superiorly located head and neck sites. Furthermore, and divided into eight moving sectors with 24 sources
the Gamma Knife requires the use of the Leksell each (see Fig. 12). Each sector is independently
stereotactic frame, invasively fixed to the patient’s selectable, thereby providing various sector combi-
skull. It was therefore not designed to provide frac- nations for aperture size or blocking at each shot
tionated treatments (Walton et al. 2000). This position during treatment.
Cranial Stereotactic Radiosurgery
Fig. 13 Volunteer mounted in the Elekta ExtendTM reposi-
tionable frame
With introduction of its associated ExtendTM
System accessory (Fig. 13), Gamma Knife Perfexion
has an increased reach into the upper c-spine.
The Extend System consists of a non-invasive carbon
fibre stereotactic frame, along with a head mould and
vacuum-assisted bite block, and specialized software
to control positioning accuracy. The Extend frame is
accurately repositionable, such that multiple treat-
ments can be administered to the same region using a
single treatment plan, thereby allowing for stereo-
tactic fractionated radiosurgery or radiotherapy.
The Gamma Knife delivers an elliptical isodose
distribution similar to an oblate spheroid with a
single ‘‘shot’’. This is because the cobalt sources are
not evenly distributed over a hemisphere. Figure 14
shows orthogonal views of the isodoses resulting
from a single 14-mm shot. Rotating the patient’s
head in the transverse axis (‘‘gamma angle’’) relo-
cates the isodose distribution relative to anatomical
structures. This is a useful technique for avoiding the
optic chiasm during a pituitary treatment (Fig. 15) or
for directing the major axis of the ellipsoid along the
trigeminal nerve (Fig. 16). Adjusting the ‘‘gamma
angle’’ is also helpful to avoid collisions between the
skull or stereotactic frame and the inside of the
collimator helmet. The computerized treatment
planning system specific to the Gamma Knife,
Gamma Plan, allows the selection of the collimator
aperture sizes, shot positions, treatment times, and
plugging patterns appropriate for each patient.
Aperture plugging is a unique feature of the Gamma
Knife, which allows some of the 201 collimators in a
345
helmet to be replaced with solid tungsten plugs to
block the radiation in appropriate patterns for
Models U, B, and C. The Perfexion model greatly
improves the ease of blocking as it allows for
independent automated blocking for each of the
eight sectors. Each sector contains 24 sources in the
Perfexion unit. Utilizing aperture plugging or
blocking, one can distort the ellipsoidal isodose
distribution of the unplugged source configuration in
a variety of directions. This provides an additional
parameter to increase isodose distribution confor-
mality to the target shape or to avoid organs at risk
adjacent to the target. A comparison of an unplugged
helmet of a Model B or C unit (left) with a plugging
pattern that shapes the isodose distribution into a
butterfly shape (right) in the coronal plane is shown
in (Fig. 17). This plugging pattern reduces dose to
the optic chiasm and nerves. Achieving a highly
conformational treatment plan is accomplished
through the use of multiple overlapping shots with
the Gamma Knife. Each shot may have its own
position, collimator aperture size, treatment time,
gamma angle, and plugging pattern. Figure 18 shows
a multiple shot plan for a meningioma.
5.2 Linear Accelerators (Linac)
The conventional linac is the most commonly avail-
able source for SRS and SRT by virtue of its ubiq-
uitous presence in the radiation therapy department;
however, special stereotactic accessories must be
obtained and fitted to the conventional linac for SRS,
fSRS, or SRT; these include a secondary collimator
system, a patient positioning and immobilization
system, and a stereotactic device.
Figure 19a shows a conventional linear accelerator
with stereotactic accessories attached. Observe the
secondary collimator housing that hangs from the
wedge slot and the BRW stand pinned to the couch
bearing. Figure 19b shows a detailed view of the
commercially available collimation system fabricated
by BrainLAB, Inc. Note that the collimator inserts
have circular apertures. The aperture diameters range
from 10 to 30 mm in 2-mm increments for this set of
inserts. During treatment, an insert resides in the
collimator housing, approximately 25 cm from the
linac isocenter. This arrangement provides a sharper
penumbra than is otherwise achieved with a block
346
Fig. 14 Isodose curves from a single 14-mm aperture with a Gamma Angle of 110°
placed at a larger distance, while maintaining
sufficient clearance, so that the housing will not
collide with the patient.
5.2.1 Converging Arc Technique
One of the first methods developed for linac radiosurgery
was the converging arc technique. This method utilizes a
combination of couch and gantry arc angles about one or
more isocenters placed within the target volume. For
equally weighted and uniform arc lengths in combina-
tion with equally spaced couch angles, the result is an
ellipsoidal isodose distribution around an isocenter.
Figure 20 shows resulting isodose distributions for
a combination of nine equally weighted converging
arcs, 100° in length, each using couch angles that
separate the arcs by 20° varying the couch angle arc
lengths and arc weights allowing customization of the
J. R. Simpson et al.
shape of the prescription isodose in a highly confor-
mal manner. Figure 21 shows a convergent 5-arc
plan. The use of multiple isocenters provides addi-
tional control over the dose distribution, albeit with an
increase in dose heterogeneity in the target volume.
The system shown in Fig. 22 demonstrates a patient
positioned on the couch with his head and frame
attached to the couch. In older approaches when the
patient’s head is supported independently from the
body, one must apply additional safety measures to
ensure that the couch cannot collapse under the patient.
Additional couch supports have been used as a pre-
ventive measure (Drzymala et al. 1994). Collision of
the gantry with the stand is also a concern and rotational
limit switches prevent such movements.
In order to provide sub-millimeter beam pointing
accuracy, the mechanical tolerance of the stereotactic
Cranial Stereotactic Radiosurgery
Fig. 15 Isodose curves from a single 14-mm aperture with a Gamma angle of 70°
linear accelerators isocenter must be tighter than that
specified for a conventional radiation therapy linac.
The radiation beam’s central ray and the gantry
rotation axis must remain aligned with the couch
rotation axis to within a fraction of a millimeter over
all rotational angles that are used clinically. In order
to achieve this level of mechanical accuracy for the
conventional linac, realignment and modifications
may be necessary (Lutz et al. 1988; Friedman and
Bova 1989). The University of Florida team, for
example, developed an additional gantry to house the
stereotactic collimators (Friedman and Bova 1989).
5.2.2 Novalis BrainLAB
The BrainLAB Novalis system (Novalis, Heimstetten,
Germany) was a cooperative development project
between Varian Medical Systems, Inc. and BrainLAB,
347
AG. Novalis permanently integrates the BrainLAB
stand-alone m3 MLC collimator (Fig. 4) into the head
of a Varian 600C linac (see Fig. 23). As with the stand-
alone m3, Novalis is limited to approximately a 10 cm2
radiation field, which must be patched together to
obtain larger field sizes. Because of the integrated m3,
Novalis can provide dynamic intensity-modulated
radiotherapy as well. The Novalis system is more than
a radiation device, however. Included with the system
are various positioning, tracking, and immobilization
devices for the patient, such as on-board stereoscopic
kilovoltage X-ray imaging with additional infrared and
video motion-tracking systems (Verellen and Soete
2003; Yan 2003). The manufacturer reports an overall
treatment accuracy of 1–2 mm. A specialized treat-
ment-planning system is also included (Grebe 2001;
Grosu et al. 2003; Hamm 2004; Solberg 2001)
348
Fig. 16 Gamma Knife plan for trigeminal neuralgia
The results are similar when using a conventional linac
with a circular or oval stereotactic collimator. Because
of its mini-multileaf collimator, the Novalis system can
combine beamlet-based IMRT (see ‘‘Linac-Based
Image Guided Intensity Modulated Radiation
Therapy’’ for a description of IMRT) with stereotaxy.
This results in high-dose conformity with sharp dose
gradients. The Novalis Tx treatment planning system is
one example that allows integration of CT, PET, MR
(Fig. 24) including specialized MR sequences such as
fiber tractography, as well as providing a system for
remote collaboration among treatment team members
(Novalistxradiosurgery.com 2009).
5.2.3 Varian Trilogy
The Varian Trilogy system is a common radiosur-
gery system adapted for use with selected Varian
linear accelerators (see Fig. 25). Components of
J. R. Simpson et al.
Trilogy include on-board kilovoltage imaging
orthogonal to its megavoltage imaging system and
the Millennium 120 multileaf collimator. Imaging
during rotation of the gantry can provide a cone-
beam reconstruction of the treatment volume for
final positioning of the patient on the treatment
couch. The manufacturer claims stereotactic
accuracy with Trilogy.
5.2.4 HiArt Tomotherapy
The Helical Tomotherapy HiArt System (Tomo-
therapy, Inc., Madison, WI) has been used by some
clinicians for intracranial stereotactic radiosurgery.
This unique treatment delivery system incorporates
on-board volumetric megavoltage imaging to verify
patient positioning in the 1 mm range (see Fig. 26).
Treatment delivery is dynamic, similar to CT
imaging, in which the 6 MV X-ray, linear
Cranial Stereotactic Radiosurgery 349

Fig. 17 The effect of

plugging or blocking of
anteriorly and posteriorly
directed sources in Gamma
Plan

accelerator rotates around the patient during inward 5.2.5 Elekta Synergy
couch travel. A binary multileaf collimator modu- The Elekta Synergy image-guided radiation therapy
lates the radiation beam, thereby providing IMRT (IGRT) system reportedly addressed the organ motion
technique. challenge for both cranial and extracranial targets by
350 J. R. Simpson et al.

Fig. 18 Gamma Plan multiple shot treatment plan

Fig. 19 BrainLab (a) collimator mount with collimator and (b) circular collimators
Cranial Stereotactic Radiosurgery
Fig. 20 Convergent arc
treatment plan
integrating image guidance into the treatment work
flow, allowing imaging the patient in treatment
position just prior to therapy. Elekta Synergy S
incorporates the tools of 3D volumetric cone-beam
imaging, for soft tissue visualization, 2D real-time
fluoroscopic-like imaging for moving targets, and 2D
kV imaging for standard planar imaging. This was
advertised to enhance the clinician’s confidence in
delivering SRS and SRT.
5.2.6 Accuray CyberKnife
Whereas most linac stereotactic units are based on a
gantry mounted linear accelerator (Das et al. 1996;
Delannes et al. 1990), an exception is the CyberKnife
(Chang et al. 1998; Gerszten et al. 2002; Gerszten and
Welch 2004; Ishihara et al. 2004; Kuo et al. 2003;
Murphy 2004; Rock et al. 2004), described in ‘‘Robotic
Image Guided Radiation Therapy’’ in this volume, the
CyberKnife that employs a compact linac on a robotic
arm and does not require a defined isocenter by design.
5.3 Charged Particle Therapy
Detailed discussions of the other devices used for
stereotactic irradiation, the charged-particle accel-
erators, can be found in ‘‘Proton Therapy’’ and
351
‘‘Physical, Biological and Clinical Background for
the Development of Light Ion Therapy’’ in this
volume. The reader is also referred to other resources
on this topic (Levy et al. 1999). One of the first
applications of proton therapy was, however, for
intracranial stereotactic radiosurgery.
6 Practical Physics and Dosimetry
Issues
Both stereotactic radiosurgery and stereotactic radio-
therapy require patient immobilization and reposi-
tioning with a stereotactic device: an invasive frame,
a non-invasive frame, or otherwise frameless system
to direct precise radiation beam targeting. The goal of
stereotactic radiosurgery and stereotactic radiotherapy
is to position the radiation dose relative to patient
anatomy with an accuracy of about 1 mm or less.
6.1 Selecting a Stereotactic Frame
Application of stereotactic frames to the head, such as
Leksell and BRW stereotactic frames provide rigid
immobilization and the localization-coordinate
system. They are primarily used for single treatment
352
Fig. 21 Convergent arc (5 arcs) Treatment plan for acoustic neuroma
Fig. 22 BrainLab couch-mounted head support
therapy. Application of stereotactic frames is a
technique utilized in a number of neurosurgery
procedures. With proper sedation and regional nerve
J. R. Simpson et al.
Fig. 23 The novalis treatment system
blocks to the supraorbital and occipital nerves, the
actual application of the frame may be accomplished
with minimal discomfort. Complications while apply-
ing the frame such as infections at the pin sites are
uncommon. Patients should be monitored for oxy-
gen saturation and vital signs as with any out-patient
procedure done with sedation. Occurrences such as
syncope from vasovagal episodes are not common but
Cranial Stereotactic Radiosurgery 353

Fig. 24 Imaging modality integration on the BrainLab treatment planning system

Fig. 25 Trilogy system with on-board imaging

354
Fig. 26 Tomotherapy unit (a) cover in place and (b) cover removed
may occur especially in patients with a prior history.
Application of stereotactic frames is not practical for
use with fractionated stereotactic radiotherapy of
larger lesions and disease encompassing critical nor-
mal tissues. A relocatable frame is typically selected
for this approach because the design allows for
repositioning of the patient at different times without
re-simulation. Relocatable frames usually employ
body moulds and bite blocks. Verification of relo-
catable frame accuracy and precision is of primary
importance.
6.2 Choosing Localization Images
CT and MR (T1 and/or T2 weighted) images are
standard choices for volumetric localization of targets
because of their potentially high spatial resolution
required by stereotactic treatments. Fiducials may be
contained in these images for stereotactic guidance.
MR imaging of the brain provides superior target
identification over CT, but MR suffers from potential
spatial distortion. These qualities should be balanced,
perhaps by spatially comparing the coincidence of
anatomy after co-registration. Imaging parameters are
optimized for stereotactic accuracy and the size of the
anatomical target. Recommendations for these
modalities are: contiguous images, 2.5 mm or finer
resolution in the patient’s longitudinal axis; the
smallest field of view that contains the appropriate
patient anatomy and the stereotactic accessories, such
as fiducials for a pixel size of 1 mm or finer in the
J. R. Simpson et al.
axial plane. Other restrictions may be imposed by the
manufacturer, such as eliminating gantry tilt and
having square pixels in the axial plane. Patients
with cardiac regulating devices present a particular
challenge where in use of magnetic fields would be
contraindicated. An interesting solution for locating
the trigeminal nerve in these patients is CT cistern-
ography (Rosenbaum and Drayer 1977).
6.3 Working with Auxiliary Images
Auxillary imaging modalities may be indicated in
specific clinical situations, for example, anatomic res-
olutions often poorer with modalities such as positron
emission tomography (PET). However, PET imaging
may provide invaluable target localization based on
function information that may be unavailable with
standard CT or MR imaging co-registered to advanced
imaging modalities allowing for more accurate locali-
zation of the desired target than with either study alone.
With the development of advanced imaging modalities
such as diffusion weighted MR, diffusion tensor MR,
Bold MR and SPECT, co-registration of image studies
will likely become the standard practice.
7 Quality Assurance
Maintaining the highest accuracy for stereotactic
radiosurgery and stereotactic radiotherapy requires
careful assessment of error at each step in the
Cranial Stereotactic Radiosurgery
treatment process. This includes assessing the integ-
rity of the stereotactic device, spatial accuracy of the
imaging modality, accuracy of the computerized
treatment planning system, radiation beam charac-
teristics and alignment accuracy of the treatment
machine, and the positional accuracy of the patient in
the radiation beam. Final accuracy of the treatment is
ultimately the combination of all these potential
sources of error. Each stereotactic system is different
and requires the expertise of a board-certified medical
physicist to develop the appropriate quality assurance
program. Guidelines developed by the American
Association of Physicists in Medicine are published in
Task Group Report no. 42 (Schell et al. 1995).
Although written in 1995, the report remains appli-
cable at present. An independent dose calculation
algorithm for Gamma Knife radiosurgery is routinely
employed at the Saint Louis Gamma Knife Center
(Mamalui-Hunter and Drzymala 2010).
8 Dosimetry and Commissioning
of Treatment Units
Commissioning the treatment planning system requires
entry of beam data specific to the radiotherapy device
being used. There must be close cooperation between the
vendor and medical physicist staff to ensure accuracy of
the beam data for such a device which produced under
tight quality control, especially if its radiation beam has
practically invariant characteristics, such as the Gamma
Knife. Only further spot checks of the data may be
necessary. The vendor may perform this analysis as part
of the installation included in the purchase price. Data for
a linac-based device can be more variable and typically
requires the customer to measure the appropriate data,
especially if the system is assembled with components
from multiple vendors. Failure to accurately calibrate the
treatment planning system may result in future system-
atic errors with delivery of either too much or too little
radiation and severe subsequent complications that may
not be realized for extended periods of time.
The type of dosimetric data required for the treat-
ment planning system depends on the algorithm used.
An algorithm that is frequently used for intracranial
SRS treatment planning may be very simple. Since the
head appears quite homogeneous to a megavoltage
beam, tissue density correction is not necessary.
The algorithm utilizing the ratio of tissue phantom
355
ratios and off-axis ratio corrections (RTPROAR) to
each point in the dose calculation matrix is simple and
fast. The RTPROAR is therefore best used for SRS and
fSRS in the brain. A discourse on heterogeneity
correction algorithms for computerized treatment plan-
ning is beyond the scope of this chapter. We therefore
confine our discussion to the RTPROAR algorithm.
The RTPROAR algorithm calculates dose to each
point in a volume of interest according to the fol-
lowing formalism:
!
TPRðfscal ;dcal Þ
Dosep ¼ Dose Rateðfscal ;SPDcal ;dcal Þ 
TPRðfsp ;dp Þ
 2
SPDcal
 OAR  ;
SPDp
where Dose Rate is the output at the reference point
under calibration conditions, fs is the field size, SPD
is the radiation source to point distance, d is depth
from the surface, TPR is the tissue–phantom ratio,
and OAR is the dose rate at an off-axis point relative
to the central axis.
The subscripts, cal and p, refer to the calibration
reference point and the arbitrary point under treatment
conditions, respectively. An inspection of the formal-
ism shows that the beam data needed for commis-
sioning the RTPROAR algorithm is threefold for each
collimator used: tissue-phantom ratios over the range
of clinical depths, profiles taken orthogonally with
respect to the central axis of the beam over the range of
clinical depths, and the dose rate at the beam specifi-
cation point. One beam energy (Co-60 gamma rays or
6-MeV X-rays) is usually commissioned for SRS and
fSRS; therefore, the amount of data required may not
be too extensive. Examples of TPRs and OARs for the
6-MeV X-ray beam of a linac are shown in Fig. 27. The
TPR data contains within it the radiation scatter and
attenuation properties of the beam, with water density
typically assumed, whereas the OAR data results from
the flatness and symmetry of the radiation beam as well
as the penumbra defined by the secondary collimator.
Since SRS and fSRS field sizes are small as 0.4 cm,
measurement of accurate calibrated dose rate is
challenging and has been a major source of treatment
error. The use of finite size ionization chambers and the
lack of lateral equilibrium have an impact on accurate
calibration. Dosimeters that utilize radiochromic
film (Kellermann et al. 1998; Mack et al. 2003;
Ramani et al. 1994), radiographic film (Robar and
356
Fig. 27 Tissue phantom ratios (TPRs) and off-axis ratios (OARs)
Clark 1999), micro-chambers (Duggan and Coffey
1996; Li et al. 2004), diodes (Fidanzio et al. 2000;
McKerracher and Thwaites 1999; Somigliana et al.
1999), BANG gel (Ertl et al. 2000; Foroni et al. 2000;
Oldham et al. 2001; Scheib and Gianolini 2002), and
1-mm3 thermoluminescent dosimeters (Ertl et al. 1996)
have been reported. We recommend that the output of
each collimated field size be calibrated with a sensor of
the highest spatial resolution and sensitivity available
and by more than one method, if possible. Figure 28
shows the typical relative dose rates obtained for the
conventional linac with a stereotactic collimation
system and the Gamma Knife.
The absolute dose rate for the reference field must
be determined using an appropriately small dosimeter
having calibration directly traceable to the National
Institute for Standards and Technology via an
Accredited Dosimetry Laboratory. A nationally rec-
ognized calibration protocol must be followed. There
are a number of reports that address the topics of small
beam calibration (Alfonso et al. 2008). At the time of
this writing, AAPM Task Group 178 had formed and
was in the process of reviewing calibration protocols
for the Gamma Knife. Most importantly once the
calibration is established, we highly recommend
obtaining confirmation by a third party, such as the
Radiological Physics Center (http://rpc.mdanderson.
org/RPC/home.htm).
8.1 Periodic Checks
Periodic checks of the treatment machine, its accesso-
ries, and associated procedures, should be performed
daily, weekly, monthly, or annually, depending on the
J. R. Simpson et al.
criticality of the issue and the time between expected
failures.
For example, in order to assure that each treatment
has sub-millimeter imaging accuracy, the images used
to localize the target should be checked for spatial
accuracy on a per-treatment-day basis. As the CT or MR
scanner used for SRS and SRT target localization may
not be under the supervision of the physicist in the
radiation oncology department, if the radiology depart-
ment does not specify the tight spatial tolerances needed
for stereotactic imaging, good quality control may be
hard to maintain. One simple solution to this problem is
to compare the consistency of fiducial marker positions
in patient treatment images with that expected from a
model of the stereotactic localization frame; another is
to fuse a suspect image set of the patient on MRI with
highly accurate one, such as CT, and to check their
co-registration. A more detailed analysis can be per-
formed using an anthropomorphic phantom on an
annual basis (Drzymala and Mutic 1999). Frameless
stereotactic techniques are dependent on imaging during
treatment and may require sophisticated image quality
and alignment tests on a frequent basis.
8.2 Mechanical Checks
If the radiation device is not dedicated to stereotactic
procedures and the accessories are reassembled prior to
treatment, as is the case for a conventional linac,
alignment of the radiation beam with the patient-
positioning system or lasers will need confirmation prior
to treatment. A radiographic alignment-verification
procedure has been published for the conventional linac
(Low et al. 1995; Warrington et al. 1994).
Cranial Stereotactic Radiosurgery
Linac Stereotactic Collimators
a 0.98
Relative Output (10x10cm2)
0.96
0.94
0.92
0.9
0.88
0.86
0.84
0 10 20 30
Aperture Diameter (mm)
Fig. 28 Relative output factors
8.3 Safety Procedures
An important tool for quality assurance of patient
treatment is a quality checklist. A list of critical items
and the sequence in which these are to be performed
is invaluable for maintaining efficiency and rigorous
adherence during treatment (Drzymala et al. 1994).
An understanding of the role of each member of the
stereotactic treatment team in the overall procedure is
of paramount importance. In-depth knowledge
requires specific training and periodic drills for
team members. This is especially true for emergency
procedures where speed is essential. An annual
refresher of the safety drill is required of all users at
our center, in St. Louis.
9 Summary of Published Treatment
Results
The geometrical aim of stereotactic radiotherapy can
be defined as the tailoring of radiation dose to the
treatment volume in three dimensions.
With the increasing availability of different ste-
reotactic treatment techniques, the question arises of
choosing the right technique for each tumor entity.
A classical indication for SRS in the treatment of
solitary brain metastases often preferable to surgery
although no prospective comparative studies for this
specific question have been conducted (O’Neill et al.
2003; Rades et al. 2009). A retrospective comparison
found a significantly better local control compared to
357
Gamma Knife Models B, C
b 1.02
1
0.98
Relative Output
0.96
BrainLab 0.94 Gamma Knife
0.92
0.9
0.88
0.86
40 0 10 20
Aperture Diameter (mm)
surgery (82 vs. 66%; P = 0.006) (Rades et al. 2009).
Generally, SRS is recommended for patients with a
good prognosis defined by oligo brain metastases (1–3
or 4) who have stable systemic primary tumor and
disease or reasonable systemic treatment options. SRS
is a widely accepted option for recurrent brain
metastases after whole-brain radiotherapy. One-year
local control rates after SRS are reported in the range
of 64–90% (Aoyama et al. 2006; Lutterbach et al.
2003; Rades et al. 2007). However, the addition of
whole-brain radiotherapy to increase local control of
brain metastases is under discussion and several
randomized trials have shown increased local control
at the radiosurgery site if WBRT is added (Aoyama
et al. 2006; Kocher et al. 2011; Linskey et al. 2010).
Additionally, level one evidence is available showing
that SRS along with WBRT leads to significantly
longer patient survival compared with WBRT alone
for patients with single metastatic brain tumors in
good clinical condition (Karnofsky performance
status C70) (Linskey et al. 2010). The recent results
are reported with comparable local control rates by
SRT in the treatment of large brain metastasis com-
pared to the classical treatment of brain metastases by
SRS.
Few data are available on fractionated SRS for
large brain metastases. For classical radiosurgical
treatment of brain metastases, local control is
dose-dependent (low control below 15 Gy), as for
fractionated SRS where also dose levels seem to
influence the outcome. A recent review showed that
an equivalent biological effective dose (BED12) of at
358
least 40 Gy needs to be used to achieve a 12-month
local control rate of 70%. For single dose radiosur-
gery this translates into 21 Gy or more and for frac-
tionated fSRS, two fractions of 11.6 Gy or three
fractions of 8.5 Gy (Wiggenraad et al. 2011). Actu-
arial tumour control for large metastases up to 5 cm
average diameter was reported with 75% at 9 months
with 3 9 8 Gy (Marchetti et al. 2011), 70–76% at
12-months with 5 9 6 Gy and 3 9 10 Gy (Higuchi
et al. 2009; Narayana et al. 2007; Ernst-Stecken et al.
2006)
SRT with or possibility of providing a high level of
dose conformity can improve the efficacy of treatment
by decreasing normal tissue toxicity and increasing
tumour control. SRT therefore is increasingly used
for the treatment of recurrent brain tumors such as
glioma, medulloblastoma, and also brain metastases.
Several reports describe outcomes after re-irradiation
in glioma with a median of 9 months in selected
patient groups with not overly large recurrent lesions
and good performance status (Fogh et al. 2010;
Combs et al. 2005a, b Ernst-Stecken et al. 2007;
Grosu et al. 2005; Nieder et al. 2006; Shepherd et al.
1997). Hypofractionation with a fractionation scheme
of 3–5 Gy is preferably used as it is reported to have
less toxicity (Fogh et al. 2010; Shepherd et al. 1997)
Response is dose dependent and at least a total dose
30–35 Gy for local control appears needed. Re-irra-
diation with brachytherapy resulted in similar survival
rates but is usually not favored due to high re-oper-
ation rates. Survival after radiosurgery was about
10 months and this modality caused re-operation rates
ranging from 0 to 22% (Cho et al. 1999; Combs
et al. 2005a, b; Patel et al. 2009; Shrieve et al. 1995).
A review of the available literature on re-treatment
with SRT (single dose and fractionated) suggested
that a cumulative dose of first radiotherapy and
re-irradiation of 100 Gy equivalent in 2 Gy fractions
to normal tissue is associated with a low risk of
radionecrosis (Mayer and Sminia 2008).
Another well-established indication for single-dose
SRS is for treatment of arterio-venous malformations
(AVM). Generally, AVMs are treated by SRS which
are difficult to resect. A median prescribed dose of
20 Gy to the target margin is recommended. Overall
median obliteration rates at 3 years are 70%.
(54–92%) (Starke et al. 2008). Time to obliteration
after SRS takes median 1–3 years. As for brain
metastases best obliteration rates are reached for
J. R. Simpson et al.
small AVM (\3 or 10 cm3). For larger AVM,
recently fractionated SRS has also been proposed and
reported (Lindvall et al. 2010), or alternatively, the
use of single-dose stereotactic light-ion radiation
therapy with Li, Be, or C (Andisheh et al. 2009). It is
postulated that the unique physical and biological
characteristics of light-ion beams are of considerable
advantage for the treatment of AVMs due to the
densely ionizing beams (Andisheh et al. 2009).
Skull base meningiomas are often located near
critical cranial nerves, important vascular structures
and the brainstem. Several stereotactic choices are
available. These tumors often show concavities within
the planning target volume, in which organs at risk
such as the brainstem, the pituitary, are located and
are therefore often irregularly and complexly shaped.
SRT based on multiple static fields is often suited
to the treatment of convex or ovoid-shaped
lesions, ideally combined with intensity modulation.
The Literature results report a high tumour control
rate in the range of 85–100% at 5 years with a low
long-term toxicity (Brell et al. 2006; Jalali et al. 2002;
Milker-Zabel et al. 2005; Minniti et al. 2007; Selch
et al. 2004a, b; Torres et al. 2003; Henzel et al. 2006).
Usually SRS is indicated for small meningiomas
less than 3 cm in maximum diameter and at a distance
of at least 3–5 mm from the optic apparatus due to a
high risk of long-term visual complications. A classic
indication in meningiomas for SRS is, for example,
small falcine meningiomas. As for SRT, control rates
for SRS (independent of application by Gamma Knife,
linear accelerator, CyberKnife, or proton SRS) are
reported to be greater than 85% (Henzel et al. 2006;
Colombo et al. 2009; Han et al. 2008; Hasegawa et al.
2007; Kondziolka et al. 2008; Sheehan et al. 2010;
Vernimmen et al. 2001; Zachenhofer et al. 2006).
The use of SRT and SRS has already proved quite
useful. Tumor control and improvement or stabilisa-
tion of symptoms can be maintained with a smaller
volume irradiated without increasing local recur-
rences as shown for example in paediatric low grade
glioma and optic nerve sheath meningioma. SRT is
the primary treatment for optic nerve sheath menin-
gioma as published evidence reports on overall visual
control rate of 91.5% maintained for the period of
follow-up (Andrews et al. 2002; Baumert et al. 2004;
Liu et al. 2002; Milker-Zabel et al. 2009; Paulsen
et al. 2011). SRT can thus be recommended as the
treatment of choice. Most literature published reports
Cranial Stereotactic Radiosurgery
conventionally fractionated SRT as small fractions
are presumed to better spare the optic nerve which is
part of the target volume. The single dose needed to
treat the meningioma exceeds the tolerance dose of
the optic nerve.
10 Conclusions
Stereotactic radiosurgery, fractionated radiosurgery,
and stereotactic radiotherapy are three valuable,
distinct, and increasingly applied techniques combining
sophisticated intracranial imaging with stereotactic
guidance high-dose rate irradiation and computer treat-
ment planning for precise radiation treatment programs
given either as a single large fraction, up to five mod-
erately large fractions, or multiple conventional-sized
fractional and total doses with maximal sparing of
adjacent normal tissues. Several devices and treatment
schedules have been tested and reported in the literature,
substantiating the validity of these approaches. They
have substantially increased our knowledge of tumor
response and normal tissue tolerance in a quantitative
sense, and provided useful primary, adjunctive, and
salvage treatments for a large number of patients. Fur-
ther progress is eagerly anticipated in combining these
techniques with other targeted therapies to enhance our
increasingly sophisticated anti-cancer armamentarium.
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 Stereotactic Body Radiotherapy
L. Chinsoo Cho, Valérie Fonteyne, Wilfried DeNeve,
Simon S. Lo, and Robert D. Timmerman

Contents 3.4 SBRT for Lung Oligometastases .............................. 378

3.5 Ongoing Clinical Trials............................................. 378

1 Introduction.............................................................. 364 4 Liver .......................................................................... 379

1.1 Radiobiology of Ablative Hypofractionated 4.1 SBRT for Hepatocellular Carcinoma........................ 379
Radiotherapy .............................................................. 364 4.2 Clinical Studies and Trials........................................ 380
1.2 History of Hypofractionation .................................... 365 4.3 Radiation-Induced Liver Disease in Patients
with HCC................................................................... 382
2 Technical Aspects .................................................... 368 4.4 Liver Oligometastasis ................................................ 383
2.1 Immobilization and Target Motion Issues Related 4.5 Future Directions ....................................................... 387
to SBRT ..................................................................... 368
2.2 Positioning and Immobilization ................................ 369 5 Spinal Metastases SBRT ......................................... 387
2.3 Respiratory Tracking Control Techniques 6 Genitourinary SBRT ............................................... 390
and Simulation........................................................... 369 6.1 SBRT for Prostate Cancer......................................... 390
2.4 Physics and Dosimetry of SBRT .............................. 370 6.2 SBRT for Renal Cell Carcinoma.............................. 394
2.5 Treatment Devices..................................................... 370
7 Conclusion ................................................................ 395
3 Lung .......................................................................... 372
3.1 SBRT for Primary Lung Malignancies..................... 372 References.......................................................................... 395
3.2 Evaluation of Treatment Response ........................... 376
3.3 Side Effects................................................................ 377
Abstract
Stereotactic body radiation therapy (SBRT) com-
L. C. Cho (&)
Department of Radiation Oncology,
bines the latest advancements in image guidance,
University of Minnesota Medical Center, planning, and treatment delivery to direct tumor-
420 Delaware St, SE MMC-494, Minneapolis, icidal doses to the target. This is accomplished
MN 55455, USA with acceptable sparing of normal tissues which
e-mail: choxx106@umn.edu
was not practical or feasible with traditional
V. Fonteyne
W. DeNeve techniques. Over the last decade, SBRT is evolving
Department of Radiotherapy-Oncology,
Ghent University Hospital, De Pintelaan 185,
and in some areas has been established as the
9000 Ghent, Belgium contemporary standard of care. This is especially
S. S. Lo
the case in inoperable non-small cell lung cancers,
Department of Radiation Oncology, where it has emerged as highly effective with
Case Western Reserve University, successful results that have been reproduced
University Hospitals Case Medical Center, around the world. Several other applications of
11100 Euclid Avenue, Lerner Tower B 181,
Cleveland, OH 44106, USA
SBRT require continued studies and careful design
of additional prospective studies. The technique
R. D. Timmerman
Department of Radiation Oncology,
demands the latest developments in patient immo-
University of Texas Southwestern Medical Center, bilization, dosimetry planning, and delivery of the
5801 Forest Park Road, Dallas, TX 75390-9183, USA

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 363
DOI: 10.1007/174_2011_263, Ó Springer-Verlag Berlin Heidelberg 2012
364
intended dose to the target using near real-time
imaging and precise assessment of expected tumor
motion during the treatment. In addition, dosimet-
ric parameters must spare a significant portion of
functional subunits in the adjacent normal tissues.
A careful consideration in selection of eligible
patients cannot be stressed enough. Increased
efficacy combined with convenient fractionation
schedule remains highly attractive for patients.
Long-term results with favorable outcomes with
similar or reduced treatment-related morbidity will
further accelerate the acceptance of SBRT.
1 Introduction
Stereotactic body radiation therapy (SBRT) combines
the latest advancements in image guidance, planning,
and treatment delivery to direct ablative tumoricidal
doses to the target. This is accomplished with
acceptable sparing of normal tissues which was not
practical or feasible with traditional techniques. In
order to achieve a successful SBRT treatment, a high
degree of confidence in tumor location at the time of
treatment delivery is required. The technique
demands a near real-time imaging and precise
assessment of expected tumor motion during the
treatment. In addition, dosimetric parameters must
spare a significant portion of functional subunits in the
adjacent normal tissues.
1.1 Radiobiology of Ablative
Hypofractionated Radiotherapy
SBRT utilizes large dose per fraction in shortened
total treatment time. This raises concern for late
effects in classical radiobiology since large dose per
fraction treatment, also called hypofractionation, is
more likely to increase the risk of late toxicities. Late
effects can result in significant pathologic changes to
the treated tissue. Irradiated normal tissues may
become devitalized by a poorly understood mecha-
nism that leads to fibrosis, scarring, and even ulcer-
ation with poor wound healing.
In contrast to the ‘‘early effects’’ of radiation often
associated with damage to exposed epithelial sur-
faces, late effects are more often associated with
L. C. Cho et al.
vascular injury (Gillette et al. 1989). Although early
effects mostly display acutely inflammatory respon-
ses, late effects are associated with chronic inflam-
mation. Some late effects on a patient can be quite
devastating to quality of life or even lethal.
The linear-quadratic (LQ) model assumes two
components of cell killing by radiation, one that is
proportional to dose (D) and the other that is pro-
portional to the square of the dose (D2). A general
description of the LQ survival curve and the resulting
surviving fraction (S) is described by the equation
below where a and b represent constants:


S  exp aD b D2
According to this equation, the cell survival curve
continuously bends with a given dose. This is in
contrast to experimental observations that describe a
final straight line after 7 or more logs of cell killing.
At conventionally fractionated doses, this discrepancy
may not be of consequence. However, at the high
doses per fraction typical in SBRT, the LQ model
probably overestimates cell killing and its predictive
model in this dose range has been questioned
(Guerrero and Li 2004). For instance, the universal
survival curve (Park et al. 2008) and generalized LQ
models (Wang et al. 2010a) address radiobiology in
the ablative dose range. There is some suggestion that
the mechanism of cell kill in ablative radiation dose
range is different from that in conventional radiation
(Garcia-Barros et al. 2003; Fuks and Kolesnick 2005).
In an animal model, the delivery of ablative radiation
resulted in a significant increase in T-cell priming in
draining lymphoid tissue, leading to reduction or
eradication of the primary tumor or distant metastasis
in a CD8+ T-cell dependent fashion (Lee et al.
2009b).
Each SBRT treatment session is significantly
longer than traditional therapy (e.g., anterior–poster-
ior portals) due to the higher doses per fraction,
multiple non-coplanar beam arrangements, and
intensity modulation. This increase in treatment time
may have a clinically significant impact on tumor
control. Increases in irradiation times have been
shown to result in a significant increase in tumor cell
survival when delivering a range of doses to U-87MG
human glioma cells (Benedict et al. 1997). As a
result, modification of the LQ model has been pro-
posed by correcting for intrafraction radiation repair
Stereotactic Body Radiotherapy
(Curtis 1986). Based on these data, every effort
should be made to minimize the treatment delivery
time per session without compromising accuracy.
Target dose heterogeneity is inherent to SBRT,
allowing for dramatically higher doses to be delivered
to portions of the target compared with the adjacent
normal tissues. Differences in treatment technique can
result in a substantial difference in biological effec-
tiveness despite equivalent reported prescription
doses, thus making it difficult to compare the clinical
results from one center to another. The equivalent
uniform dose is one proposed method of accounting
for this dose heterogeneity by quantifying the radio-
biological effect of inhomogeneous dose distributions
(Kavanagh et al. 2003). Clinical studies should care-
fully document these variables to allow a more
accurate comparison of prescribed doses between
reported experiences. Additional efforts to develop
accurate models of cell survival at high doses per
fraction may also aid in providing a guideline for dose
optimization (Timmerman et al. 2007).
Hypofractionated treatments are more convenient
for patients and caregivers. In some applications, it is
commonly used to administer palliative treatments.
Many have argued that hypofractionation can result in
unacceptable late complications. However, there is
evidence to indicate that some experiences of hypo-
fractionated radiotherapy have been very positive
(Andrews et al. 2004). Although the debate regarding
late effects from hypofractionated radiotherapy con-
tinues, the more recent safer application of hypo-
fractionation as in SBRT has been greatly aided by
technological innovation in radiation therapy. The
integration of improved hardware, planning systems,
and radiation quality has helped in the implementa-
tion of modern hypofractionation and SBRT.
1.2 History of Hypofractionation
The history of radiotherapy began with hypofrac-
tionated therapy. Many physicians who first used
radiotherapy for cancer were surgeons who were
accustomed to single-session interventions. Even
early on, the technical challenges of hypofractionated
radiotherapy were appreciated by radiotherapy pio-
neers including Friedrich Dessauer from Frankfurt
who formulated the ideas of multibeam or multi-
source irradiation (Dessauer 1921).
365
In 1905, Claudius Regaud began experiments
irradiating testes and this work subsequently led to the
‘‘Law of Bergonie and Tribondeau’’ (Bergonie and
Tribondeau 1906). This law formed a biological basis
for fractionation. However, even by the 1920s, mul-
tiple fractionated treatments were still less popular
than short-course hypofractionated treatments. Cou-
tard believed in both protracted and hypofractionated
approaches. He believed that the choice of fraction-
ation should depend on the initial volume of the tar-
get. The larger the volume of the target, the greater
the need for fractionation (Coutard 1924). Multiple
seminal presentations in the late 1920s by Coutard
describing the results of his experiments convinced
the medical community to adopt more protracted
radiotherapy for the following decades (Coutard
1929, 1930, 1932). Radiation oncologists across the
world soon abandoned hypofractionation as a method
for curative treatment.
Many years later in the early 1950s, a neurosur-
geon, Lars Leksell, rejuvenated hypofractionated
radiotherapy. Leksell had developed and improved a
system for accurately localizing a coordinate within
the skull called ‘‘stereotaxy.’’ Leksell’s arc-quadrant
frame allowed him to guide surgical instruments
toward three dimensional (3D) coordinates for the
purpose of biopsy, resection, and therapy. Leksell,
working with a radiation physicist, Borge Larsson,
created the first Gamma Knife (Elekta AB, Stock-
holm, Sweden) (Leksell 1951) to deliver curative
radiotherapy in a single session. Leksell broke from
the conventionally fractionated radiotherapy regimen
by using large-dose single sessions. He achieved
clinical success in an area that was felt to be intolerant
to radiotherapy, the central nervous system. Leksell’s
stereotactic radiosurgery (SRS) technique damaged
such a small amount of normal tissues that the patient
did not suffer clinically apparent toxicity, even as a
late event. Leksell’s SRS technique is widely accep-
ted as an effective treatment for brain tumors of rea-
sonable sizes. In certain situations, SRS has obviated
the need for invasive surgery.
The parallel development of intraoperative radio-
therapy (IORT) resulted in a wealth of clinical data.
Because of logistics involved in the technique, a single
treatment is often employed to avoid prolonged expo-
sure to anesthesia and to minimized infection. Under-
standing that some organs during IORT may be exposed
to high doses, early investigators in intraoperative
366
Table 1 Selected single-fraction intraoperative dose tolerance in a canine or rabbit model
Structure End point Tolerance
dose (Gy)
Anastamoses–intestinal Low risk dehiscence 30.0
Bile ducts Stenosis with secondary 20.0
biliary cirrhosis
Duodenum-partial wall Wall fibrosis/obstruction 45.0
Esophagus Ulcerative esophagitis in 30.0
circumferential wall 100%
(6 cm)
Nerve–phrenic Neuropathy in 0% 40
Trachea Necrosis in 0% 40
radiotherapy appropriately followed patients for
toxicity. Furthermore, these investigators performed
numerous experiments in larger laboratory animals
to gather dose-tolerance data for various structures
to a single fraction. Selected findings from single-
fraction IORT are shown in Table 1. The table
illustrates the structure irradiated with IORT and the
tolerance dose reached prior to the clinical end
point. IORT, however, is not entirely similar to
SBRT. For example, SBRT would rarely be used in
a situation in which a surgical anastomosis lies
within the target area. Furthermore, the surgical
procedure inherent to IORT may affect radiation
tolerance. For example, surgical exposure may
devascularize tissues, making them more prone to
subsequent injury or wound-healing problems that
affect radiation tolerance. Because SBRT is gener-
ally performed noninvasively, SBRT tolerance for
the same endpoints found in the Table 1 may be
different. Finally, SBRT may be fractionated beyond
the single fraction typical of IORT.
Dose tolerance for SRS and SBRT is far from
being clearly defined. For brain radiosurgery, the dose
is usually limited in eloquent areas like the thalamus
or brainstem as compared with other sites. Most
importantly, brain SRS complications are avoided by
selecting patients with relatively small tumors (e.g.,
3–4 cm). Unlike the relatively radio-intolerant brain,
tissues in the body may be more tolerant. For exam-
ple, parallel organs may remain functional so long as
their inherent reserve is respected by strict avoidance
L. C. Cho et al.
Observation Type of Reference
period radiation
1 year 11 MeV Tepper et al. (1983)
electrons
1.5 years 11 MeV Sindelar et al. (1982)
electrons
1.5 years 11 MeV Sindler et al. (1982)
electrons
6 weeks 9 MeV Barnes et al. (1987);
electrons Sindelar et al. (1988)
1 year 12 MeV Barnes et al. (1987)
electrons
1 year 12 MeV Barnes et al. (1987)
electrons
of high or intermediate dose volume using modern
technology. However, serial tissues like the spinal
cord or esophagus may be irreversibly damaged by
the ablative dose of SBRT. This may be particularly
important if the organ is irradiated, circumferentially.
Modern SBRT is a relatively newer radiotherapy
technique in which clinical trials using SBRT have
been forced to formulate a starting point of normal
tissue dose constraints. One such formulation of
SBRT dose constraints is listed in the ongoing Radi-
ation Therapy Oncology Group (RTOG) 0915 RTOG
protocol, a randomized phase II study comparing two
different SBRT dose regimens for medically inoper-
able patients with peripheral stage I non-small cell
lung cancer (NSCLC) (RTOG 2010). The patients are
randomized between a single treatment of 34 Gy
versus 4 fractions of 12 Gy (48 Gy). The dose con-
straints used in the protocol for 34 Gy 9 1 and
12 Gy 9 4 are outlined in Tables 2 and 3, respec-
tively. These constraints are not validated by long-
term follow-up. Rather, they are derived in some cases
by toxicity observation, conversions using mathemat-
ical models, and in other cases by educated guessing.
These constraints will be modified as new clinical data
accumulates. RTOG is collecting patient dosimetry
information in 3D for all patients enrolled to SBRT
trials with the hope of eventually making formal
comparisons of toxicity outcome data. In the end,
normal tissue constraints for hypofractionated radio-
therapy will be replaced by solid clinical outcome
data. Some patients will develop complications by
Stereotactic Body Radiotherapy 367

Table 2 Dose constraints for single treatment of 34 Gy from RTOG-0915

Serial tissue Volume (cc) Volume max (Gy) Max point dose (Gy) Endpoint (C grade 3)
Spinal Cord \0.35 \1.2 10 Gy 7 Gy 14 Myelitis
Esophagus \5 11.9 Gy 15.4 Stenosis/fistula
Brachial plexus \3 14 Gy 17.5 Neuropathy
Heart/pericardium \15 16 Gy 22 Pericarditis
Great vessels \10 31 Gy 37 Aneurysm
Trachea and large Bronchus \4 10.5 Gy 20.2 Stenosis/fistula
Rib \1 22 Gy 30 Pain or fracture
Skin \10 23 Gy 26 Ulceration
Stomach \10 11.2 Gy 12.4 Ulceration/fistula
Parallel tissue Critical Critical volume Endpoint (Cgrade 3)
volume (cc) dose max (Gy)
Lung (right and left) 1500 7 Basic lung Function
Lung (right and left) 1000 7.4 Pneumonitis

uncertainty of tolerance limits related to hypofrac-
tionated treatments. By thorough ongoing assessment
practices and early reporting of toxicity, however, as
few patients as possible will be exposed to such
misadventures.
1.2.1 Degrees of Hypofractionation
Cellular division is a very complicated process reg-
ulated by a variety of genes. Because damage to any
one of these genes can disrupt the process, cell divi-
sion can be disrupted by a relatively modest dose of
radiation. In contrast, cellular function, such as the
secretion of a hormone, is usually only coded by one
or a few genes. In order to affect the cellular function
such as secretion of hormones, higher dose of radia-
tion is required. For example, growth control of a
pituitary adenoma is achieved at a relatively modest
dose, but to stop the secretion of a hormone from
a hormone-secreting pituitary adenoma requires a
much higher dose. Radiotherapy doses that both dis-
rupt clonogenicity and cellular function are termed
ablative.
Not all hypofractionated radiotherapy is ablative.
In general, ablation occurs at dose levels above 8 Gy.
Below this dose range, cells have more capacity to
repair sublethal damage. More conventional hypo-
fractionated radiotherapy is delivered on the shoulder
portion of the classical survival curve. Doses in the
range of 2.25–8 Gy per fraction, have been used
commonly for palliative treatment. More recently,
investigators began using hypofractionated regimen
to deliver curative treatment for common diseases like
prostate cancer (King et al. 2009). Although hypo-
fractionation is commonly used to expedite the pal-
liation of symptoms caused by advanced cancers, in
some cases, such hypofractionation has a biological
rationale for improving the therapeutic ratio. A sum-
mary of the degrees of hypofractionated radiotherapy
and their effects is shown in Table 4.
Approximately 15 years ago, a similar review of
the topic of hypofractionation would have been lim-
ited to IORT, SRS, and the more moderate hypo-
fractionated regimens associated with breast and
prostate cancer. With the increasing use of SBRT to
treat a number of cancers, the topic has dramatically
broadened with dose per fraction of over 30 Gy.
Implementing hypofractionation within any daily
dose beyond conventional for curable patients
remains an extremely contentious topic. Clinical
practice may be ahead of prudent assessment of
effects, particularly for SBRT.
Phase I/II trials for tumors of the lung, liver, spine,
and prostate provide evidence that SBRT may provide
clinical results that rival surgery while avoiding some
of the undesirable morbidities associated with that
invasive approach. Further clinical study in the form
of multi-institutional phase II trials is currently
underway, and ultimately collaborative national level
phase III trials will be necessary to firmly establish
SBRT as a noninvasive alternative to surgery.
368 L. C. Cho et al.

Table 3 Dose constraints for fractionated SBRT treatment (12 Gy 9 4) from RTOG 0915
Serial tissue Volume (cc) Volume max (Gy) Max point dose (Gy) Endpoint
(Cgrade 3)
Spinal cord \0.35 \1.2 20.8 Gy (5.2 Gy/fx) 13.6 Gy 26 Gy (6.5 Gy/fx) Myelitis
(3.4 Gy/fx)
Esophagus \5 18.8 Gy (4.7 Gy/fx) 30 Gy (7.5 Gy/fx) Stenosis/fistula
Brachial plexus \3 23.6 Gy (5.9 Gy/fx) 27.2 Gy (6.8 Gy/fx) Neuropathy
Heart/pericardium \15 28 Gy (7 Gy/fx) 34 Gy (8.5 Gy/fx) Pericarditis
Great vessels \10 43 Gy (10.75 Gy/fx) 49 Gy (12.25 Aneurysm
Gy/fx)
Trachea and large \4 15.6 Gy (3.9 Gy/fx) 34.8 Gy (8.7 Stenosis/fistula
Bronchus Gy/fx)
Rib \1 32 Gy (8 Gy/fx) 40 Gy (10 Gy/fx) Pain or fracture
Skin \10 33.2 Gy (8.3 Gy/fx) 36 Gy (9 Gy/fx) Ulceration
Stomach \10 17.6 Gy (4.4 Gy/fx) 27.2 Gy (6.8 Ulceration/
Gy/fx) fistula
Parallel tissue Critical Critical volume dose max (Gy) Endpoint
volume (cc) (C grade 3)
Lung (right and left) 1500 11.6 Gy (2.9 Gy/fx) Basic lung
function
Lung (right and left) 1000 12.4 Gy (3.1 Gy/fx) Pneumonitis

Table 4 Fractionation Options

Type of radiotherapy Typical dose per Characteristics
fraction (Gy)
Conventional 1.5–2.0 High cumulative doses, less apt to cause ‘‘late effects’’
fractionated
radiotherapy
Hypofractionated [2.0–8.0 Most commonly used for palliative treatment for patients near end of life,
radiotherapy increasingly used for curative treatment in breast and prostate cancer therapy
Ablative radiotherapy [8.0 Stops both cellular division and cellular function, overwhelms tumor repair,
more likely to cause ‘‘late’’ effects

are designed to account for this uncertainty, this is

2 Technical Aspects
2.1 Immobilization and Target Motion
Issues Related to SBRT
SBRT must limit the volume of normal tissue that is
irradiated to spare potentially catastrophic toxicities.
In comparison to stereotactic radiotherapy to the
brain, tumor motion during treatment presents a sig-
nificant challenge for SBRT. Unlike the convention-
ally fractionated radiotherapy, where larger portals
considered an unacceptable approach when using
doses common to SBRT. Thus, accurate delivery of
dose with minimal dosimetric margin is necessary for
stereotactic ablation.
There are essentially two approaches to account
for tumor motion: minimization of target motion via
immobilization (e.g., abdominal compression or
breath hold techniques), or alternatively to account
for physiologic tumor motion via tracking or gating.
In targeting thoracic or upper abdominal targets,
active or passive breath-hold techniques fix the
Stereotactic Body Radiotherapy
tumor in a stable position for a short period of time.
The treatment is then activated during the short
period of breath-hold. Another immobilization
approach is the use of abdominal compression that
limits diaphragmatic excursion, and thereby the
respiratory motion of the tumor. This substantially
restricts tumor motion allowing for smaller treatment
margins.
Both gating and tracking often rely on surrogate
markers for tumor, although in the ideal situation the
tumor would be directly tracked for image guidance.
A surrogate for tumor motion may include fiducial
markers near or in the tumor correlated to all phases
of the respiratory cycle. The treatment hardware then
allows the radiation beam to ‘‘track’’ or follow the
tumor by moving the accelerator, the aperture, or the
patient. Gating similarly requires real-time assess-
ment of the respiratory cycle, and activation of the
beam at a particular phase of the respiratory cycle
(e.g., end-inhale or end-exhale), while maintaining
the radiation beam in a fixed position.
SBRT is an image-based treatment. All salient
anatomical organs of interest are defined with CT,
MRI, positron emission tomography (PET), or
angiography with or without image fusion, or with
any other imaging studies that may be useful in
localizing the target volumes. Both high 3D spatial
accuracy and tissue contrast definition are very
important imaging features for using SBRT to its
fullest potential. CT remains the most useful, spa-
tially undistorted, and practical imaging modality for
SBRT. It permits the creation of 3D renditions of
both the target volume and the patient during the
treatment planning process. However, partial volume
averaging, pixel sizes, slice thickness, distance
between slices, timing of CT with respect to contrast
injection, image reformatting for the treatment
planning system, and potential intrascan organ
movement may affect treatment delivery. In some
cases target tissues and normal tissue structures may
be better visualized by alternative imaging tools
such as MRI. The considerations enumerated for CT
also apply to the use of MRI. Additional caution is
warranted in MRI because of magnetic susceptibility
artifacts and image distortion. As such, use of MRI
must be verified with CT images. Techniques such
as combining MRI with CT images via image fusion
can be used to minimize geometrical distortions
inherent in MR images (Potters et al. 2010).
369
2.2 Positioning and Immobilization
The frame-based stereotaxy fiducials are rigidly
attached to non-deformable objects reliably coregis-
tered to the target. Given potential changes in the
location of tumors relative to external frames, frame-
based method is usually verified with some form of
pretreatment image guidance to confirm proper tumor
relocalization. Frameless stereotaxy uses the fiducials
that are registered immediately before or during the
targeting procedure. Examples of frameless stereotaxy
include image capture of 1 or more metallic fiducials
placed within a tumor, using surrogate anatomy such
as bone whose position is well established in relation
to the target, or using the target itself as a fiducial.
The patient is positioned appropriately with respect to
the stereotactic coordinate system used, ensuring that
the target is within physically attainable fiducial
space. The treatment position should be comfortable
enough for the patient to hold still for the entire
duration of the SBRT procedure. Immobilization may
involve use of a body aquaplast mold, a thermoplastic
mask, a vacuum mold, a vacuum pillow, immobili-
zation cushions, etc.
2.3 Respiratory Tracking Control
Techniques and Simulation
A variety of methods may be used to treat a tumor
affected by respiratory motion. These techniques may
include respiratory gating, tumor tracking, organ
motion dampening, or patient-directed methods. Once
the patient is properly positioned, bony landmarks
registering the patient within the stereotactic coordi-
nate system being used are identified and marked by
the radiation oncologist. There should be a quality
control (QC) program for the method of respiratory
motion control used and the clinical tolerances should
be explicitly determined. Abdominal compression, if
used, is applied to a degree that is tolerable to the
patient and limits target movement. The degree of
limitation of tumor and diaphragm movement may be
verified by fluoroscopic examination or 4-D CT scan.
CT simulation is performed with the patient in the
treatment position, and the errors added by the fusion
algorithm are quantified and included in the uncer-
tainty shell produced by the clinical target volume
(CTV) to planning target (PTV) expansion. Any of
370
several types of respiratory control or gating systems
may be used, such as abdominal pressure or active
breath control. Simulation is performed with the
respiratory control device activated. MRI simulation
or fusion of MRI and CT images may be necessary as
well (Potters et al.)
2.4 Physics and Dosimetry of SBRT
SBRT requires tight conformality of the prescription
isodose shell to the tumor volume, with rapid, even, and
isotropic dose falloff allowing for coverage of micro-
scopic extensions of disease. This dosimetric distribu-
tion is accomplished by using multiple non-opposing,
non-coplanar beams (Curtis 1986; Nesbitt et al. 1995;
Benedict et al. 1997; Kavanagh et al. 2003; Timmerman
et al. 2007) or arcs spread in a large solid angle with
fairly equal weighting to minimize entrance dose and
ultimately the volume of normal tissue irradiated to a
clinically significant dose. The proportion of the total
dose contributed by scatter is relatively small with this
technique. Beam directions are chosen to minimize the
volume of tissue where the beams intersect. A critical
factor in deciding the number of beam directions to use
and the relative beam weighting to the isocenter is the
entrance dose to keep the dose-maximum (d-max) to a
modest level. This will prevent severe acute and late skin
toxicity while keeping a uniform isotropic dose falloff.
Each beam aperture just coincides with the PTV outline,
leading to a prescription isodose line of 60–80% pro-
viding 95% PTV coverage, lower than what is typically
seen with traditional dosimetry. Potent doses are admi-
nistered with doses ranging from 6 to 30 Gy per fraction
over a short course of 1–5 fractions.
Evaluation of SBRT plans requires multiple con-
siderations. Three primary criteria are reviewed to
optimize the quality of the SBRT plan: (1) the con-
formality index, (2) high-dose spillage, and (3) inter-
mediate-dose spillage. The conformality index is
defined as the ratio of the volume of the prescription
isodose surface that provides 95% coverage to the
PTV volume. This assumes that 99% of the PTV is
receiving 90% of the prescription dose. It is recom-
mended that this ratio be kept to less than 1.2 to
minimize the volume of normal tissue receiving an
ablative dose.
High-dose spillage takes into account the volume
and location of the tissue that receives an ablative
L. C. Cho et al.
dose. It is recommended that any dose greater than
105% of the prescription dose occurs primarily within
the PTV, allowing no more than 15% of the pre-
scription dose to be delivered to the normal tissue
surrounding the PTV. Care must be taken to avoid
high dose ‘‘spillage’’ into any adjacent serial func-
tioning normal tissues since it would essentially
transect the organ in a similar fashion to a surgeon’s
scalpel. Similar to high-dose spillage, intermediate-
dose spillage is defined by both location and volume.
This intermediate dose causes the majority of the
toxicity associated with SBRT. There are two meth-
ods of evaluating intermediate dose spillage. One
criterion is to keep the dose to any point 2 cm away
from the PTV surface (D2 cm) below a limit that is a
function of PTV volume. A intermediate-dose con-
formality ratio defined as the ratio of the 50% isodose
coverage to the PTV (R50%) is also reported. For
example, a restriction may be placed to contain 50%
isodose surface to with a 2 cm expansion of the CTV.
The region of tissue receiving this dose is minimized
to limit the global damage to adjacent parallel func-
tioning organs. Thus careful consideration of the
conformality index, high dose ‘‘spillage,’’ and inter-
mediate-dose conformality ratio optimize the quality
of the SBRT plan by keeping compact dosimetric
margins, and should be used in combination with
known normal tissue dose-volume absolute limits. An
example of SBRT for lung cancer is illustrated in
Fig. 1.
2.5 Treatment Devices
There are many commercially available hardware
facilities capable of delivering stereotactic body
radiation therapy. Advanced image guidance is a
common feature found in treatment units discussed
below. Image guidance has minimized the uncertainty
associated with tumor localization, and it is now
possible to define tumor position in near real-time.
The treatment delivery units mentioned also allow
integration of patient immobilization and respiratory
control devices. The Novalis Shaped Beam Surgery
unit (BrainLAB AG, Feldkirchen, Germany) uses a
6–20 MV linear accelerator with micro-multileaf
collimators ranging in leaf widths of 3–5.5 mm. Two
orthogonal X-ray cameras delineate bony landmarks
or implanted fiducial markers whose position is then
Stereotactic Body Radiotherapy
Fig. 1 SBRT for lung
cancer. a The figure illustrates
a patient being treated in a
stereotactic body frame with
abdominal compression to
restrict respiratory
movements. b, c The axial
and coronal dosimetry show
rapid reduction in delivered
dose away from the target.
The prescription isodose line
is in red (85%)
compared with their expected position on digitally
reconstructed radiographs generated from the CT
simulation. Patient positional shifts are then used to
align the patient in the treatment position. A new
device, Vero SBRT System (known as ‘‘TM2000’’ in
Japan), is a joint product of MHI (Mitsubishi Heavy
Industries Ltd., Tokyo, Japan) and BrainLAB. It uti-
lizes a rotating inline 6 MV C-band LINAC with
MLC mounted on orthogonal gimbals built into the
ring structure. An electronic portal imaging device
(EPID) and two kV imaging devices are also inte-
grated in the ring. TomoTherapy HiArt System
(TomoTherapy Inc, Madison, WI) uses intensity
modulated radiotherapy (IMRT) delivered throughout
helical rotations using a binary multileaf collimator.
The patient couch moves continuously during the
treatment session. Radiation detectors are present
opposite the multileaf collimators (MLC) allowing for
megavoltage CT of the patient during treatment.
The Varian Trilogy (Varian Medical Systems, Inc.,
Palo Alto, CA) and Elekta Synergy (Elekta AB,
371
Stockholm, Sweden) have an integrated gantry-
mounted cone beam CT and treatment head to provide
near real-time image guidance for repositioning. The
Siemens Primatom (Siemens AG, Munich, Germany)
has a similar system with a separate CT scanner
linked to a linear accelerator via a shared tabletop.
The CT gantry travels along rails. Once image
acquisition is completed the tabletop rotates to the
linear accelerator for treatment delivery, thereby
providing a near real-time localization. The Cyber-
Knife (Accuray Inc., Sunnyvale, CA), uses a frame-
less image-guided process to direct a lightweight
linear accelerator mounted on a robotic arm along 6
spatial axes providing broader translational and rota-
tional movement than possible with a standard linear
accelerator. Two orthogonal diagnostic X-ray cam-
eras are mounted on the ceiling and provide real-time
imaging for tracking. Implanted fiducials or reliable
bony landmarks are used to localize the tumor and
deliver treatment in real-time. Multiple isocenters can
be used during one treatment. It is not clear whether
372
any one of these systems is superior to the others.
Rather, a combination of training and experience is
likely to result in the delivery of high quality SBRT.
3 Lung
3.1 SBRT for Primary Lung Malignancies
Surgery is the standard treatment for early stage lung
cancer. In cases of medically inoperable patients with
early stage (T1-2 N0 M0) lung cancer, treatment
options include conventional radiotherapy or obser-
vation. The outcomes after conventional fractionated
radiotherapy (CFR) are suboptimal. CFR fails to
durably control the primary lung tumor in 60–70% of
patients (Armstrong and Minsky 1989; Kaskowitz
et al. 1993; Dosoretz et al. 1996). More than half of
patients ultimately die from progressive lung cancer
with the observation only approach (McGarry et al.
2002; Raz et al. 2007) and 2-year survival rates are
less than 40% with either approach.
The inferior survival rate seen with CFR compared
with the surgical series is related to both the poorer
local control seen with the conventional technique
and the multiple comorbidities in the medically
inoperable population. CFR dose escalation in an
attempt to improve local control and survival is lim-
ited by accelerated tumor repopulation, increased
risks of toxicity, and logistical difficulties associated
with extending treatment for a population burdened
by multiple medical problems. SBRT theoretically
provides the biologic advantages of dose escalation
while avoiding the disadvantages of CFR dose esca-
lation outlined above. SBRT has been well received
by the medical community as the definitive treatment
for patients with early stage medically inoperable
lung cancer. SBRT offers a promising, noninvasive
alternative for the definitive management of stage I
lung cancers and pulmonary metastases in patients
with prohibitive medical comorbidities.
There are many retrospective studies of SBRT for
lung cancer. The mixture of patient population (some
with metastatic cancers) with varying degrees of
comorbidities, differences in fractionation, and dif-
ferent clinical end points preclude exact comparison
between studies. However, it has been shown in
several retrospective studies that SBRT for primary
lung tumors is more effective than conventionally
L. C. Cho et al.
fractionated treatment for medically inoperable
patients (Blumgart and Fong 1995; Uematsu et al.
1998; Hof et al. 2003; Lee et al. 2003; Onimaru et al.
2003; Onishi et al. 2004; Wulf et al. 2004; Timmerman
et al. 2005; Baumann et al. 2006; Fritz et al. 2006;
Hara et al. 2006; Brown et al. 2007; Pennathur et al.
2007; Ricardi et al. 2007; Scorsetti et al. 2007; Baba
et al. 2010; Dunlap et al. 2010). Local control is
approximately 90% using various fractionations and
total doses. A commonly used total number of frac-
tions in these studies was 5 or less. Table 5 summa-
rizes the published results of SBRT retrospective
studies.
There are now multiple single-institution studies
that have shown SBRT as an effective treatment for
early stage lung cancer in medically inoperable
patients. Validation of efficacy and safety data must
involve prospective trials. The first phase I SBRT dose-
escalation trial was conducted at Indiana University.
This prospective study treated 47 patients with T1-2 N0
non-small cell lung cancer without restriction on tumor
location (Timmerman et al. 2003). Each treatment
course was administered over 3 fractions with a starting
dose of 8 Gy per fraction. Patients were stratified into 3
dose escalation groups based on T stage and size
(T1, T2 \5 cm, and T2 5–7 cm). A total of 10 local
failures were seen with a median follow-up of
15.2 months. Nine of the 10 local failures occurred at
doses B16Gy, (Timmerman et al. 2003; McGarry et al.
2005) suggesting a dose response. The maximum tol-
erated dose was 22 Gy 9 3 for T2 tumors larger than
5 cm, and was not reached at 20 Gy 9 3 for T1 tumors
or at 22 Gy 9 3 for T2 tumors smaller than 5 cm. The
treatment dose was prescribed to the margin of the PTV
which was often 80%. A follow-up phase II trial from
Indiana University evaluated the efficacy and safety of
the dose levels established in the previous phase trial in
70 patients with Stage I non-small cell lung cancer.
With a median follow-up of 17.5 months, the local
control was 95%, which appears at initial impression to
be comparable in outcome to definitive surgical
resection (Ginsberg and Rubinstein 1995). Severe
toxicity occurred at a median of 10.5 months in 17% of
those patients with peripheral lesions versus 46% with
central lesions. In an update of this phase II study, after
a median follow-up of 4.2 years, 3-year local control
was 88%, regional failure was 9%, 3-year overall sur-
vival was 43%, and 3-year cause-specific survival was
82% (Fakiris et al. 2009). There was no difference in
Stereotactic Body Radiotherapy 373

Table 5 Retrospective studies of SBRT for early stage primary NSCLC

Author/ Number of Stage Radiotherapy F/U Local Outcomes
Institution patients (months) control
(Country)
Uematsu 50 I 50–60 Gy in 36 94% 66% 3-year OS
(Uematsu 2001) 5–10 fx (combined number
National for both medically
Defense operable and
Medical inoperable cases)
College (Japan)
Lee (Lee et al. 28 19 Metastatic 10 Gy 9 3–4 18 N/A 39% CR, 43% PR
2003) 9 ‘‘Primary Lung’’ Separate Primary
U of Ulsan Stage I Lung Cancer
(S Korea) outcome not
reported
Hof (Hof et al. 10 I 19–26 Gy 9 1 14.9 80% 64% 2-year OS
2003)
German Cancer
Research
Center
(Germany)
Onimaru 45 I (\6 cm) 48–60 Gy 17 69.6% 47% 2-year OS
(Onimaru et al. in 8 fx for
2003) 48 Gy
Hokkaido U 100%
(Japan) for
60 Gy
Wulf (Wulf 20 T1-3 N0 M0 10 Gy 9 3 11 92% 32% 2-year OS
et al. 2004) 12–12.5 Gy 9 3
U of Wuerzburg
(Germany)
Onishi (Onishi 245 I 18–75 Gy in 24 86.5% 23.3% CR, 61.6%
et al. 2004) 1-22 fx PR
Multi- (operable ? medically 56% 3-year OS
Institution Inoperable)
(Japan)
Zimmerman 30 I 24–37.5 Gy in 18 93% 75% 2-year OS
(Zimmerman 3–5 fx
2005)
Technical U
(Germany)
Hara (Hara 59 I(\4 cm) 20–34 Gy 9 1 12 78% 41% 2-year OS
et al. 2006) (11 Primary (primary lung
Internaltional Lung cancer) tumors not analyzed
Medical Center separately)
(Japan)
Fritz (Fritz et al. 58 (33 I 30 Gy 9 1 18 94% 53% 3-year OS
2006) PrimaryLung
U of Marburg cancer)
(Germany)
Baumann 138 I 30–48 Gy in 33 88% 52% 3-year OS
(Baumann et al. 2-4 fx 26% 5-year OS
2006)
Kaolinska
Hospital
(Sweden)
(continued)
374 L. C. Cho et al.

Table 5 (continued)
Author/ Number of Stage Radiotherapy F/U Local Outcomes
Institution patients (months) control
(Country)
Brown (Brown 59 I 15–67.5 Gy in 1–33 89% 86% alive at 1–
et al. 2007) 1–5 fx No 33 months follow-
Cyberknife median up.
Centers of reported
Miami (USA)
Scorsetti 43 I 30.5 Gy in 14 – 53% 2-year
(Scorsetti et al. 1–4 fx
2007)
Istituto Clinico
Humanitas
(Italy)
Ricardi (Ricardi 54 (43 I 15 Gy 9 3 14.7 100% Survival N/A
et al. 2007) analyzed)
U of Turin
(Italy)
Pennathur 32 11-stage I (I-IV 20 Gy 9 1 15 N/A 91% 1-year OS for
(Pennathur included) Stage I
et al. 2007)
U of Pittsburgh
(USA)
Baba (Baba 124 I 44 Gy in 4 fx 26 80% 71% 3-year OS
et al. 2010) 48 Gy in 4 fx
Nagoya City U
(Japan) 52 Gy in 4 fx
Dunlap (Dunlap 40 I 60 Gy in 3–5 fx 12.5 83%
et al. 2010)
U of Virginia
(USA)
LC local control, OS overall survival, CSS cancer-specific survival, CR complete response, PR partial response, Gy gray,
fx fractions

local control or survival between T1 and T2 tumors, by
tumor volume, or by peripheral versus central location.
Koto et al. (2007) reported the results of a pro-
spective study from the Tohoku University in Japan
that included 31 patients with stage I lung cancer.
Twenty of 31 patients were medically inoperable and
10 refused surgery. The treatment consisted of 45 Gy
in 3 fractions. However, when the target volume was
close to a critical organ, 60 Gy in 8 fractions were
used. These doses were prescribed at the center of the
tumors. With a median follow-up of 32 months, the
3-year local control of T1 and T2 Tumors was, 77.9
and 40.0%, respectively. Five of 31 patients (16%)
developed Cgrade 2 acute pulmonary toxicity.
Nagata et al. (2005) treated 45 patients who were
medically inoperable or refused surgery for stage I
NSCLC. The treatment dose, 48 Gy in 4 fractions was
prescribed to the isocenter of the beams. The entire
treatment was delivered over a median of 12 days.
With a median follow-up of 30 months, 97% local
control rate and a 5-year overall survival rate of 83%
were reported for patients with T1 N0 M0 staging on
presentation. In patients with T2 N0 M0 staged lung
cancer, the local control rate was 100% with a 5-year
overall survival rate of 72%.
A report from a phase II trial from Scandinavia of
SBRT for 57 medically inoperable stage I NSCLC
utilizing 45 Gy in 3 fractions prescribed to the
periphery of the PTV showed a 3-year overall sur-
vival rate of 60%, 3-year cause-specific survival rate
of 88%, and a 3-year progression-free survival (PFS)
rate of 52% at a median follow-up of 35 months
(Baumann et al. 2009). This study excluded patients
with centrally located tumors. The median overall
treatment time was 5 days (4–15 days). Although
there was no statistically significant difference in
Stereotactic Body Radiotherapy
survival between patients with T1 or T2 tumors, the
estimated risk of all failure (local, regional, or distant
metastases) was increased in patients with T2 (41%)
compared with those with T1 (18%) tumors
(p = 0.027).
The latest results from Italy of a phase II trial of
SBRT for medically inoperable (56) or those patients
who refused surgery (6) with stage I NSCLC (43 with
T1 and 19 with T2 tumors) have been reported by
Ricardi et al. (2010). The study included patients with
tumors up to 5 cm. A pathologic confirmation of
NSCLC was obtained in 64.5% of patients while the
remainder had clinical evidence of lung cancer. The
SBRT dose was 15 Gy 9 3 (45 Gy total) prescribed
to the 80% isodose line covering the PTV. The entire
treatment was delivered in a week (Monday–
Wednesday–Friday). At a median follow-up of
28 months, the 3-year local control, cause-specific
survival, and overall survival rates were 87.8, 72.5,
and 57.1%, respectively.
The RTOG 0236 phase II trial was a multi-
institutional prospective study evaluating the dose
levels established in the Indiana phase I trial in
patients with T1, T2 B 5 cm, and T3 (chest wall
lesions) B5 cm that excluded any tumors located
within the ‘‘zone of the proximal bronchial tree’’
(see Fig. 2) to avoid the severe toxicities seen with
centrally located tumors. In the recent publication
of the RTOG 0236 prospective study, a high rate
of primary tumor control was seen. The 3-year
local control rate was 97.6% (Timmerman et al.
2010). Thereby, the stereotactic body radiotherapy
technique as delivered in the RTOG 0236 resulted
not only in more than double the rate of primary
tumor control but also doubled the overall survival
rate compared to previously reported results from
conventional treatment (Armstrong and Minsky
1989; Dosoretz et al. 1993; Kaskowitz et al. 1993).
The overall survival rate was 55.8% at 3 years for
the RTOG 0236 study. In comparison, series
reporting results from conventional radiotherapy
for similar patient groups report 2-year to 3-year
overall survival rates in the 20–35% range (Haffty
et al. 1988; Kaskowitz et al. 1993; Dosoretz et al.
1996).
A prospective, risk-adapted, SBRT trial was
reported from Belgium (Bral et al. 2010). This study
included 40 patients with solitary tumors up to 6 cm,
with stage T1-2N0M0, located both in the periphery
375
Fig. 2 Outline of the ‘‘zone of the proximal tree’’ (in red).
Patients with gross tumors within the boundary of this zone
were ineligible for the RTOG 0236 study
(23) as well as in the central zone (17) as defined by
the RTOG 0236 study. The treatment dose was tai-
lored according to the location of the tumor. The
tumors located in the periphery received 60 Gy in 3
fractions and the tumors in the central zone received
60 Gy in 4 fractions. With a median follow-up of
16 months, the 2-year local progression free survival
(LPFS) was 84%. The LPFS was significantly corre-
lated with the initial tumor stage (T1 versus T2,
p = 0.006). Tumors [4 cm in diameter had LPFS
dropped to 75%. The 2-year overall survival was
52%. The dose reduction for centrally located lesions
did not increase the risk of local failure. The authors
concluded that a biologic equivalent dose (BED) of
150 Gy (18 Gy 9 3) may be required to achieve an
acceptable local control. The adapted schedule did not
lower the crude incidence of lung toxicity for
peripherally or centrally located lesions, but it affec-
ted the severity of the toxicity. Pulmonary toxicity
remained location dependent even at lower doses. The
2-year lung toxicity-free survival was 74%
(SE = 8%).
In a recent update of the Georgetown University
SBRT study, Vahdat et al. (2010) reported a pro-
spective study using CyberKnife to treat twenty
medically inoperable, biopsy proven, patients with
stage IA NSCLC. The prescription dose ranged from
376 L. C. Cho et al.

Table 6 Prospective trials of SBRT for stage I NSCLC

Author/Institution Number Stage Radiotherapy Median 2-year 3-year 2-year 3-year
of follow–up LC (%) LC (%) OS (%) OS (%)
patients (months)
Koto (Koto et al. 31 I 15 Gy 9 3 32 – 77.9 – 71.7
2007) (T1)
Tohoku University 7.5 Gy 9 8 40 (T2)
(Japan)
Nagata (Nagata et al. 45 I, B4 cm 12 Gy 9 4 30 – 97 – 83
2005)
Kyoto University
(Japan)
Fakiris(Fakiris et al. 70 I, B7 cm 20 Gy 9 3 50.2 – 88.1 – 42.7
2009) (T1)
Indiana University 22 Gy 9 3
(USA) (T2)
Baumann (Baumann 57 I 15 Gy 9 3 35 – 92 – 60
et al. 2009)
Karolinska
University Hospital
(Sweden)
Ricardi (Ricardi et al. 62 I, B5 cm 15 Gy 9 3 28 87.8 72.5
2010)
University of Torino
(Italy)
Timmerman 55 I, \5 cm 18 Gy 9 3 34.3 – 97.6 – 55.8
(Timmerman et al.
2010)
RTOG 0236 (USA)
Bral (Bral et al. 2010) 40 I, B6 cm 15 Gy 9 4 16 84 – 52 –
University Hospital or (LPFS)
Brussels (Belgium) 20 Gy 9 3
Vahdat (Vahdat et al. 20 IA 42–60 Gy in 43 95 – 90 –
2010) 3 fx
Georegetown
University (USA)
LC local control, OS overall survival, CSS cancer-specific survival, Gy gray, LPFS local progression free survival, fx fractions

42 to 60 Gy in 3 fractions to cover 95% of the PTV.
With a median follow-up of 43 months, the 2-year
local control and overall survival rates were 95 and
90%, respectively. The results of prospective SBRT
trials for non-small cell lung cancers are listed in
Table 6.
3.2 Evaluation of Treatment Response
The accumulation of data using SBRT for the treat-
ment of stage I NSCLC allows post-SBRT radio-
graphic changes to be better understood. Three
dimensional non-opposing and non-coplanar beams in
SBRT converge at the center of the lung tumor to
create a highly conformal isodose distribution and a
steep gradient of the radiation dose outside the plan-
ning treatment volume (PTV). As a result of this type
of isodose distribution, predominant radiographic
changes typically originate from both the area of the
lung tumor and the rim of normal lung tissue sur-
rounding the tumor and consolidation/collapse of lung
parenchyma distal to the airways and vessels near the
treated tumor may be seen. Radiographic changes can
occasionally result from the intermediate dose asso-
ciated with the entrance and exit of beams.
Five patterns of early radiographic changes,
including diffuse consolidation, diffuse ground-glass
Stereotactic Body Radiotherapy
opacity, patchy consolidation and ground-glass
opacity, patchy ground-glass opacity, and no change,
were described (Trovo et al. 2010; Linda et al. 2009).
For late changes, four patterns, including modified
conventional pattern, mass-like pattern, scar-like
pattern, and no changes, have been described (Trovo
et al. 2010; Linda and al 2009). CT findings of post-
SBRT fibrosis and tumor recurrence may appear
similar at one single time point, and serial studies are
needed to monitor the changes. Treatment-related
fibrosis may initially progress and will then become
stable radiographically. In general, an opacity or
nodule associated with tumor progression would
continuously enlarge.
Fluorodeoxyglucose (FDG)-positron emission
tomography (PET), which has superior sensitivity and
specificity, has been used in an attempt to better
evaluate treatment response. Hoopes et al. from
Indiana University evaluated the treatment response
using FDG-PET in 58 patients treated in their phase I/
II study of SBRT for medically inoperable stage I
NSCLC. SBRT dose ranged from 24 to72 Gy in 3
fractions (Hoopes et al. 2007). Pre-SBRT PET was
performed in 57 of the 58 patients. Post-SBRT PET,
usually done to address concern for possible recur-
rence, was performed in 28 of the 58 patients. Pre-
SBRT PET scan did not predict for overall survival or
local control. In addition, moderate PET activity was
sometimes seen for 2 years after treatment without
other evidence of recurrence. In a pilot trial from
Indiana University, 14 patients with medically inop-
erable stage I NSCLC treated with SBRT in the phase
II trial were followed prospectively with FDG-PET at
2 weeks, 6, and 12 months after treatment. At a
median follow-up of 30.2 months, there was no local
failure. The median tumor maximum standardized
uptake values [SUV (max)] before SBRT, at 2 weeks,
6, and 12 months were 8.70, 6.04, 2.80, and 3.58,
respectively. Patients with low pre-SBRT SUV were
more likely to develop initial increase in SUV while
patients with high pre-SBRT SUV frequently had
decrease in SUV shortly after treatment (Henderson
et al. 2010). Six (43%) of 13 patients with primary
tumor SUV(max) [3.5 at 12 months after SBRT
remained free of local disease failure upon further
follow-up. Thus post-SBRT PET studies cannot
independently and reliably predict tumor persistence
or progression. For many medically inoperable
patients, post SBRT biopsy may be poorly tolerated or
377
contra-indicated. The current RTOG 0915 protocol
recommends but does not require PET scans at
12 weeks and 12 months after treatment in addition to
PET before SBRT.
3.3 Side Effects
Although various radiobiologic models provide radi-
ation oncologists with some guidance, the full effects
of radiation associated with SBRT cannot be
explained by a mathematical formula. The safest
approach is to refer to dose-volume constraints
determined from well conducted prospective phase I
studies that addressed dose–response relationships.
Central tumor location is a well-known factor
predicting severe toxicities when a regimen of
20–22 Gy 9 3 fractions (60–66 Gy) is used (Timm-
erman et al. 2006). A range of toxicities associated
with SBRT for stage I NSCLC has been reported.
Hoppe et al. from Memorial Sloan-Kettering Cancer
Center evaluated the risk factors leading to severe
skin toxicities in 50 patients with Stage I NSCLC
treated with regimens of 60 Gy in three fractions or
44–48 Gy in four fractions (Hoppe et al. 2008).
Factors predicting grade 2 or higher acute skin tox-
icity included the use of only 3 beams, distance from
the tumor to the posterior chest wall skin of less than
5 cm, and a maximum skin dose of 50% or higher of
the prescribed dose. RTOG trials for stage I NSCLC
mandate that the contouring of skin, defined as a
concentric ring starting 5 mm from the body surface,
as an organ-at-risk, in an attempt to detect hotspots in
the skin during treatment planning (Lo et al. 2009).
Chest wall pain and rib fractures have occurred in
patients receiving SBRT for peripheral NSCLC close
to the chest wall. Voroney et al. reported that pain and
rib fracture after SBRT was observed in a significant
portion of patients with tumors close to the chest wall
(Voroney et al. 2009). The 2-year Kaplan–Meier
estimate of rib fracture was 48%. Dunlap et al.
determined that the chest wall volume receiving more
than 30 Gy was predictive of severe pain and/or rib
fracture after lung SBRT. A chest wall volume of
35 cm3 receiving 30 Gy when delivered in 3–5 frac-
tions was correlated with 30% risk of developing
severe chest wall toxicity (Dunlap et al. 2010).
In patients with stage I NSCLC at apical locations,
brachial plexus morbidity may be observed. Data
378
pertaining to brachial plexus tolerance to radiation
therapy in the ablative dose range is limited. Forquer
et al. from Indiana University, reported 36 patients
with apical lesions who were treated with SBRT in
3–4 fractions. Apical tumors were defined as tumors
with epicenter of the mass superior to aortic arch.
Grade 2–4 brachial plexopathy developed in 7 out of
36 (19%) patients after a median of 7 months (range
6–23 months) (Forquer et al. 2009). The 2-year risk of
brachial plexopathy for maximum brachial plexus
dose [26 Gy was 46 versus 8% for doses B26 Gy.
Based on the results of the study, the authors rec-
ommended that the maximum dose to the brachial
plexus should be kept below 26 Gy in 3–4 fractions.
With accumulation of data from well conducted stu-
dies, more information regarding early and late toxi-
cities associated with SBRT is forthcoming.
3.4 SBRT for Lung Oligometastases
Patients with oligometastases, defined as a small
number of metastatic lesions limited to an organ, may
be candidates for curative treatment because long-
term survival may be possible (Milano et al. 2008a, b;
Specified 1997). SBRT can be performed for olig-
ometastases in the lung and in the liver in hopes of
improving patients’ prognosis (Milano et al. 2008a, b;
Norihisa et al. 2008; Kim et al. 2009; Rusthoven et al.
2009a, b). Blomgren et al. (1995) first reported that 14
metastatic lung tumors in 10 patients treated with
SBRT achieved 92% local control. Similarly,
Uematsu et al. (1998) reported that 43 metastatic lung
tumors in 22 patients treated with SBRT achieved
98% local control. Nagata et al. (2002) using SBRT
with 48 Gy in four fractions to the isocenter reported
that nine metastatic lung tumors in nine patients
achieved 67% local control. Norihisa et al. (2008)
using SBRT at 48–60 Gy in four to five fractions
prescribed to the isocenter reported that 43 metastatic
lung tumors in 34 patients achieved a 2-year local
control rate of 90% and a 2-year overall survival rate
of 84.3%. However, these promising studies are
retrospective.
Milano et al. reported the results of a phase II trial
using SBRT to a dose of 50 Gy in 10 fractions in the
treatment of oligometastatic disease (Milano et al.
2008a, b). Lung metastases were treated in 41% and
thoracic lymph nodes in 20% of patients. Local
L. C. Cho et al.
control for all treated lesions was 67% at 2 years.
Similarly, Hof et al. reported actuarial LC of 74% at
2 years after 61 patients with 71 lung metastases were
treated with single-fraction SBRT to an isocenter dose
of 12–30 Gy (Hof et al. 2003). Hoyer et al. also
reported an actuarial 2-year LC rate of 86% in a phase
II trial of SBRT to a dose of 45 Gy in 3 fractions for
treatment of colorectal metastases, primarily involv-
ing the lung and liver (Hoyer et al. 2006).
In 2009, Rusthoven et al. (2009a, b) reported a
phase I/II prospective study of SBRT for patients with
1–3 enlarging metastatic lung tumors. Sixty-three
metastatic lung tumors in 38 patients were treated
with SBRT with dose escalated from 48 to 60 Gy
with a phase II dose of 60 Gy. All treatments were
delivered in 3 fractions. The study achieved a 2-year
local control rate of 96% and a 2-year overall survival
of 39%. The median follow-up was 15.4 months. This
result was inferior to that of surgery according to the
International Registry of Lung Metastases (Specified
1997). One of the important reasons for a poorer
prognosis in SBRT is that this prospective study
included patients with extrapulmonary lesions. When
the treatments are limited to similar patients, the
overall survival may be better and might be equiva-
lent to surgery.
3.5 Ongoing Clinical Trials
The combined experiences of multiple centers and
prospective trials have confirmed that local control is
excellent with the different SBRT dose regimens. The
current RTOG standard dose for peripheral tumors,
54 Gy in 3 fractions (heterogeneity corrected),
showed a 3-year primary tumor control of 98%
(Timmerman et al. 2010). While other fractionation
regimens might cause less toxicity, it is unlikely that
any of them would demonstrate improved tumor
control. The currently active RTOG 0915 phase II
randomized study will compare two different SBRT
fractionation schedules (34 Gy in 1 fraction versus
48 Gy in 4 daily fractions) for patients with stage I
peripheral NSCLC. Similarly, RTOG 0813 is a phase
I/II study, with seamless transition from phase I to
phase II, investigating SBRT dose-escalation frac-
tionation schedules (from 50 Gy up to 60 Gy in 5
fractions) in medically inoperable patients with early
stage centrally located NSCLC. The Trans-Tasman
Stereotactic Body Radiotherapy
Radiation Oncology Group (TROG) in Australia is
conducting a phase III trial (TROG09.02) comparing
3D-CRT (60–66 Gy in 30–33 fractions) and SBRT
(54 Gy in 3 fractions) to determine whether SBRT is
more effective, results in improved survival, and is
equally safe as 3D-CRT. Another study, the Scandi-
navian Stereotactic Precision and Conventional
Radiotherapy Evaluation (SPACE) trial, is a phase II
randomized study comparing 3D-CRT (70 Gy in 35
fractions) with SBRT (45 Gy in 3 fractions). SBRT
may be equally effective as surgery when the effec-
tiveness of SBRT is compared to the historical surgical
results. There are now studies assessing its effective-
ness in operable patients with early stage disease, as
well as studies comparing SBRT and surgery in early
stage operable patients. The Japan Clinical Oncology
Group (JCOG) completed a phase II trial (JCOG 0403)
of SBRT of 48 Gy in 4 fractions for patients with stage
IA NSCLC, including a treatment arm for operable
patients. Preliminary report showed 3-year overall
survival and progression-free survival rates of 76 and
68.5%, respectively (Nagata et al. 2010). RTOG 0618
is a phase II trial of SBRT for patients with operable
stage I disease, utilizing a regimen of 54 Gy in 3 frac-
tions. In the Dutch ROSEL (Radiosurgery or Surgery
for Early Lung cancer) study, patients with stage IA
NSCLC will be randomized to either surgery or SBRT
and evaluated for local and regional tumor control,
quality of life, and treatment costs at 2 and 5 years. The
Lung Cancer STARS (STereotActic Radiotherapy
versus Surgery) international randomized study,
sponsored by Accuray, will compare CyberKnife-
based SBRT with surgical resection in stage I NSCLC.
The primary endpoint is overall survival at 3 years. The
results of these trials will help further define the role of
SBRT in the management of stage I NSCLC.
4 Liver
4.1 SBRT for Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most common
primary liver cancer in the world (Parkin et al. 2001).
HCC is ideally managed by a multidisciplinary team
consisting of a gastroenterologist, surgical oncologist,
liver transplantation team, interventional radiologist,
medical oncologist, and radiation oncologist. Unfor-
tunately, only 30–40% of patients may benefit from
379
radical treatments such as surgical resection, ortho-
topic liver transplantation (OLT), or percutaneous
ablation (Cardenes 2009). Surgical resection is
offered to non-cirrhotic patients or cirrhotic patients
who have normal bilirubin, tumor diameter \5 cm,
and no portal hypertension. OLT can potentially
produce excellent results with 5-year survival rate of
70% for patients with tumors \5 cm or with up to 3
tumors \3 cm, and absent vascular or extrahepatic
spread (Cardenes 2009). Unfortunately, due to various
factors such as the lack of liver donors, OLT may be
delayed for [6 months, which puts patients at risk for
tumor progression, rendering them ineligible for OLT
in the future. ‘‘Bridging treatments’’ such as trans-
arterial chemoembolization (TACE) or radiofre-
quency ablation (RFA) have been used to control
tumor prior to definitive treatment. Unfortunately,
palliative treatments are often administered because
most patients with HCC are not candidates for
curative treatment. TACE, selective intra-arterial
hepatic radioembolization, systemic and intra-arterial
chemotherapy, high dose 3-D radiotherapy, and
other systemic agents have been used for treatment
of HCC. However, only TACE and sorafenib
(Nexavar) have been proven to show survival benefit
in Child-Turcotte-Pugh class A patients in random-
ized trials (Cardenes 2009). Patients with unresec-
table HCC have poor disease control and survival.
Conventionally fractionated radiation therapy for
HCC is ineffective. SBRT has been used for the
management of HCC (Lo et al. 2010) and has
demonstrated a high rate of local control with a low
incidence of severe toxicity and radiation induced
liver disease (RILD).
However, the importance of distinction between an
HCC arising in the background of dysfunctional liver
and a metastasis found in otherwise normal liver
parenchyma must be stressed. The liver tolerance and
dose-volume relationship may be vastly different.
Imaging studies of the liver must accurately iden-
tify the location and the volumetric characteristics of
the target tumor and surrounding normal tissues. For
SBRT contouring of the treatment target, MRI or dual
phase CT is used to outline the gross tumor volume in
the liver. When (Kelsey et al. 2005) compared
radiographic dimensions of tumors by CT and MRI
with true pathologic extent, both MRI and CT were
equally useful in the prediction of the true tumor size.
The size of the tumor was overestimated by CT or
380
MRI in 81% of the cases and underestimated in 19%
(Kelsey et al. 2005). The study authors concluded that
the addition of 0.5 and 1.0 cm margin to the visible
gross tumor would cover the true tumor extent in 93
and 100% of the cases, respectively. However,
microscopic extension was not examined in this study
and the effect of tissue processing on the true
dimensions of the tumors is unclear. A study by Wang
et al. analyzed 149 patients with HCC who underwent
resection with at least 1 cm margin around the tumor
(Wang et al. 2010b). The microscopic extent of the
tumor and various clinical parameters including labo-
ratory values, degree of liver cirrhosis, gross extent of
the tumor, and histology were correlated. Tumor
microinvasion between 0.5 and 4 mm was found in
seventy-nine (53%) patients and the degree of micro-
invasion was inversely correlated to lower platelet
counts and directly correlated to higher alpha fetopro-
tein levels, larger tumor size, portal vein invasion, and
advanced stage. In patients with tumor size B5 cm, the
extent of microinvasion was B2 mm in 96.1% of the
cases. In patients with alpha fetoprotein \400 lg/l,
the extent of microinvasion was B2 mm in 94.5% of
the cases. Thus it appears that a 0.5 cm margin
expansion to create a CTV from a gross tumor volume
may be adequate. In some institutions, a clinical target
volume expansion is not performed, and the clinical
target volume (CTV) equals the gross tumor volume
(GTV) (Cardenes et al. 2010).
Even without a GTV expansion, the surrounding
0.5 cm may be adequately covered by the SBRT
prescription. If a 4-D CT is used for treatment plan-
ning, an internal target volume (ITV) is often created
to account for different tumor positions at different
respiratory phases. A PTV is generated from an ITV
by the expansion of a margin that anticipates daily
set-up errors. In the absence of 4-D CT, the PTV is
generated by expansion of the GTV by 0.5 cm axially
and 1 cm in the cranio-caudal dimensions (Cardenes
et al. 2010).
Similar to SBRT treatments for lung tumors, pre-
treatment verification of tumor position can be
achieved with the use of a megavoltage (used in
Siemens Primus, TomoTherapy, and Oncor systems)
or kilovoltage cone beam CT (used in Varian Trilogy,
Novalis TX, and Elekta Synergy) or stereoscopic
X-rays (used in Novalis TX and CyberKnife). Kilo-
voltage (KV) cone beam CT provides more superior
soft tissue resolution than megavoltage conebeam CT.
L. C. Cho et al.
However, KV cone beam CT is more subject to
artifacts from metallic implants. CyberKnife, a linear
accelerator mounted on a robotic arm, allows for real-
time tumor tracking. Insertion of 3–6 metal fiducials
is required if CyberKnife system is used to treat HCC.
Since HCC is a highly vascularized tumor, there is a
need for added caution in placement of fiducials.
Because SBRT requires accurate and precise
positioning, strictly reliable and reproducible immo-
bilization is necessary. Therefore, patients selected
for SBRT for HCC must be able to lie still in the
immobilization device for a potentially extended
period of time, depending on the technology used. For
example, the entire treatment duration of a single
fraction may last up to a couple of hours, depending
on the dosimetry and technology employed. Also,
patients must have a well-delineated liver tumor seen
on planning dual phase CT or MRI. In addition, in
order to fully verify the IGRT setup, the target must
be readily visible on the pre-treatment KV or MV CT
scans.
Several entry criteria have been used in prospec-
tive trials. Overall, unresectable HCC patients that
belong to Child-Turcotte-Pugh class A or class B with
low Child-Turcotte-Pugh scores (\8) are considered
suitable candidates for SBRT. In terms of tumor
dimensions, a diameter of 6 cm has been used as the
upper limit in the phase I trial led by Indiana Uni-
versity (Cardenes et al. 2010). In addition, the tumor
should be at a distance of at least 5 mm from serial
organs such as the stomach or small bowel wall.
4.2 Clinical Studies and Trials
There are several studies describing the use of SBRT
for the treatment of HCC. Some reports include
patients with liver metastases. Some of the early
experiences of SBRT for liver tumors were reported
by Blomgren et al. (1995). The SBRT dose pre-
scription of 30 Gy was to the periphery of the PTV in
1–3 fractions. Local control was noted in almost all of
11 patients treated after SBRT. However, there was
10% severe toxicity. A fever B38.5°C developed in
all patients after SBRT and two developed ascites as a
result of liver failure and died. Another patient died of
unclear cause after SBRT to a large HCC. In the study
by Wulf et al. (2006), 4 patients with HCC were
treated with SBRT. At a median follow-up of
Stereotactic Body Radiotherapy
15 months (2–48 months), all (100%) patients
achieved local control. Choi et al. (2006) treated 20
patients with HCC. There were 15 patients with
Child-Turcotte-Pugh class A and 5 with Child-Tur-
cotte-Pugh class B disease with an average tumor size
of 3.8 cm. The SBRT dose regimen was 50 Gy in 5
or10 fractions prescribed to the 85–90% isodose
line. At a median follow-up of 23 months
(3–55 months), the overall response rate was 80% and
the 1- and 2-year overall survival rates were 70 and
43.1%, respectively. There was no grade 3 or higher
toxicity.
A phase I/II trial of SBRT for liver metastases and
HCC from the Netherlands (Mendez Romero et al.
2006) treated 45 lesions in 25 patients. There were 11
patients with HCC. Patients with liver metastases,
HCC not associated with cirrhosis, and HCC \4 cm
received 37.5 Gy in 3 fractions, and patients with cir-
rhosis and/or HCC C4 cm received 25 Gy in 5 frac-
tions or 30 Gy in 3 fractions, prescribed to the 65%
isodose line. The local tumor control rates for all
tumors were 94 and 82% at 1 and 2 years, respectively.
Acute toxicity grade C3 was seen in 4 patients total
and one Child-Turcotte-Pugh class B HCC patient
developed liver failure with infection and died.
Tse et al. (2008) from University of Toronto
treated 31 patients with unresectable Child-Pugh A
HCC and 10 patients with intrahepatic cholangiocar-
cinoma (IHC) in a phase I trial of individualized
SBRT for HCC and intrahepatic cholangiocarcinoma.
All patients received a six-fraction SBRT regimen in
2 weeks. Radiotherapy dose was customized by the
volume of liver irradiated, and the estimated risk of
liver toxicity was based on a normal tissue compli-
cation model (NTCP). The median dose was 36 Gy
(24–54 Gy). No RILD or grade 4/5 toxicities were
seen within 3 months after SBRT. The 1-year in-field
tumor control was 65% for all patients. Median sur-
vival was 11.7 months and 1-year overall survival
rate was 48% for HCC patients. Sixteen (76%) out of
21 HCC patients with elevated baseline alpha feto-
protein had a reduction of the alpha fetoprotein level.
Five patients with HCC had their liver function
decline from Child-Turcotte-Pugh class A to class B
within 3 months after SBRT.
In a phase I trial of SBRT for HCC led by Indiana
University, Cardenes et al. enrolled 17 patients with
25 tumors. Each patient had 1–3 unresectable Child-
Turcotte-Pugh’s class A or B HCC tumors (average
381
volume of 34 ml, range of 8–95 ml). The starting
dose was 36 Gy in 3 fractions with a 2 Gy per frac-
tion increment and the radiation dose was escalated to
48 Gy in 3 fractions in Child-Turcotte-Pugh class A
patients without causing dose-limiting toxicities
(defined as CTCAE Events v3.0 grade 3 or greater).
Grade 3 hepatic toxicities occurred in two Child-
Turcotte-Pugh class B patients when the dose was
escalated to 42 Gy in 3 fractions. The radiation dose
was then scaled down to 40 Gy in 5 fractions for
Child-Turcotte-Pugh class B, and one of five patients
treated with this dose level developed liver failure.
A Child-Turcotte-Pugh score of C8 was the most
important factor associated with more than one grade
3 or higher liver toxicity or death within 6 months
after treatment. Using the RECIST criteria, the com-
plete response, partial response, and stable disease
rates were 25, 56, and 19%, respectively. The local
control rate was 100% and 1- and 2-year survival
rates were 75 and 60%, respectively, at a median
follow-up of 24 months, The overall survival rates
were 100 and 60% for Child-Turcotte-Pugh classes A
and B patients, respectively. After SBRT, 6 patients
underwent OLT and complete response, partial
response, stable disease were observed in 2, 3, and 1
patients. Table 7 summarizes the outcomes of SBRT
trials for HCC.
Takeda et al. (2008) reported results of 16 patients
(14 with Child-Turcotte-Pugh class A and two with
class B cirrhosis) with solitary HCC treated with
SBRT with or without TACE. Fourteen patients
TACE 13 days (range of 5–40) before SBRT. The
doses ranged from 35 to 50 Gy given in 5–7 fractions.
All patients were alive after a median follow-up time
of 611 days. Complete response was observed in
eight patients and seven others had stable disease.
One had marginal recurrence and six had out-of-field
recurrence. There was no severe toxicity observed.
Choi et al. (2008) treated 31 patients with unresec-
table small HCC or advanced HCC with portal vein
thrombosis with a combination of CyberKnife-based
SBRT (30–39 Gy in 3 fractions) and TACE. With a
median follow-up of 10.5 months, an overall response
rate of 71.9% was noted. The median survival times
for patients with unresectable small HCC and
advanced HCC with portal vein tumor thrombosis
were 12 months and 8 months, respectively. No
patient experienced grade 4 toxicity but one patient
experienced grade 3 liver enzyme toxicity.
382
Table 7 SBRT trials for hepatocellular carcinoma
Investigator Number of Dose
patients
Mendez-Romero 8 5 Gy 9 5 or
et al. (2006) 10–12.5 Gy 9 3
(The Netherlands)
Tse et al. (2008) 31 24–54 Gy in 6
(Canada) fx
Cardenes et al. (2010) 17 8–16 Gy 9 3
(USA)
Gy gray, OS overall survival, fx fraction
Approximately one in five patients with advanced
HCC who are eligible for liver transplantation are
subsequently found to be ineligible due to local tumor
progression (Sandroussi et al. 2009). SBRT has also
been used as a bridging therapy before OLT. Al
Hamad et al. from McGill University reported clinical
outcomes of Child-Turcotte-Pugh class C patient with
HCC who underwent SBRT to prevent local tumor
progression while waiting for liver transplantation.
The patient received 50 Gy in 5 fractions using
respiratory gating. The patient had a complete radio-
logic and serologic response without deterioration of
liver function (Al Hamad et al. 2009). The patient
subsequently underwent liver transplantation and only
scarring was observed in the removed liver. However,
patients with Child-Turcotte-Pugh class C patients are
generally not candidates for SBRT given the high risk
of radiation-induced liver disease (RILD). Sandroussi
et al. from University of Toronto also used SBRT as a
bridging therapy for HCC in 10 patients who had
either failed prior local therapies or in whom poor
liver function and anatomical constraints precluded
other local therapies. SBRT doses and volumes were
individualized to spare normal liver parenchyma in
order to prevent patients from being removed from
the transplant list. Tumor diameter ranged from 2.5 to
10.8 cm. The median radiation dose was 33 Gy in one
to six fractions. The uninvolved liver received a
median dose of 13.3 Gy (range of 1.8–16.5 Gy).
Planned SBRT was completed in nine of the ten
patients; the remaining patient underwent liver
transplantation after a single fraction of SBRT. There
were minimal complications and none of the treated
tumors developed progression. With a median follow-
up of 14 months, local control rate was 100%. Two
patients were delisted because of out-of-field pro-
gression. Five underwent transplantation, and tumor
L. C. Cho et al.
Median follow-up Local 1-year OS 2-year OS
(months) control (%) (%) (%)
12.9 Crude 92 75 40
17.6 Infield 65 48 –
24 100 75 60
necrosis and fibrosis were observed on the explanted
liver with the untreated liver parenchyma spared. All
transplanted patients survived without evidence of
cancer (Sandroussi et al. 2009).
4.3 Radiation-Induced Liver Disease
in Patients with HCC
In patients with HCC, RILD is the most important
toxicity for SBRT of the liver. This is in part due to
presence of cirrhosis in most cases. The radiation-
induced liver damage is divided into classic and non-
classic clinical presentations. Classic RILD consists
of anicteric hepatomegaly, ascites, and elevated
alkaline phosphatase that is greater than twice the
reference value, generally seen 2 weeks to 3 months
after radiotherapy. Non-classic RILD presentation
consists of elevated transaminases more than 5 times
the upper limit of reference values or CTCAE v3.0
grade 4 levels in patients with baseline transaminases
levels [5 times the upper limit of normal within
3 months after completion of radiotherapy. It also
may be indicated by worsening of Child-Tucotte-
Pugh score by C2, in the absence of classic RILD
occurring 1 week to 3 months after radiotherapy
(Pan et al. 2010). Non-classic RILD has been
observed in patients with HCC who have poor base-
line liver function.
Dawson et al. (2002) used the Lyman-NTCP
model to analyze the risk of RILD after radiotherapy
in a comprehensive review that incorporated a large
number of patients from the University of Michigan.
The analysis included patients with primary liver
cancer and those with liver metastases. Nineteen
(9.4%) of 203 patients developed RILD after
radiotherapy. Factors important for predicting the
Stereotactic Body Radiotherapy
development of RILD included the mean liver
radiotherapy dose, presence of primary liver cancer,
use of concurrent continuous infusional hepatic artery
fluorodeoxyuridine or bromodeoxyuridine, and male
gender. When the treated effective liver volume
was \1/3, the incidence of RILD was almost nonex-
istent. The risk is estimated to be \5% when the
whole liver effective volume was treated to an abso-
lute dose of \32 Gy for primary liver cancer (based
on 1.5 Gy per fraction, b.i.d.). No cases of RILD were
observed when the mean liver dose was than 31 Gy.
This analysis has greatly influenced the current
practice pattern of limiting the radiotherapy dose of
30 Gy to the entire liver and limiting only 1/3 of the
liver parenchyma to higher doses.
Many Asian hepatic radiotherapy studies included
mostly HCC or primary liver cancer patients and a
majority of patients had hepatitis B or Child-Turcotte-
Pugh class B cirrhosis. In this group of patients with
underlying liver disease, the tolerance of liver to
radiotherapy is lower and is less predictable when
applying the University of Michigan model (Cheng
et al. 2005; Liang et al. 2006; Xu et al. 2006; Kim
et al. 2007; Cardenes 2009; Pan et al. 2010). In
addition, the University of Michigan model largely
focuses on liver toxicities after conventional or b.i.d.
fractionated radiotherapy.
With highly conformal techniques such as 3D-
CRT or IMRT, conventional fractionation can spare a
large portion of the normal liver parenchyma sur-
rounding the targeted tumor. It is uncertain whether
the mathematical models used in conventional frac-
tionation are still applicable in SBRT of liver tumors.
In the University of Toronto phase I trial from where
the SBRT dose was based on estimated prediction of
liver toxicity, no RILD or treatment-related grade 4 or
5 toxicities were observed. However, five patients
with HCC had decreased Child-Turcotte-Pugh scores
within 3 months after SBRT (Tse et al. 2008). In the
Indiana University phase I study, no dose-limiting
toxicities were observed in patients with Child-Tur-
cotte-Pugh class B liver disease when a more pro-
tracted regimen of 40 Gy in 5 fractions instead of
42 Gy in 3 fractions was used (Cardenes et al. 2010).
The recently published Quantitative Analyses of
Normal Tissue Effects in the Clinic (QUANTEC)
contains nonuniform liver recommendation for SBRT
delivered in three to six fractions to achieve 5% or
less risk of RILD (Pan et al. 2010). The mean normal
383
liver dose, defined as liver minus GTV, differed
according to primary versus metastatic liver tumors.
For primary liver tumors, the mean normal liver
dose \13 Gy in three fractions, \18 Gy in six frac-
tions, or \6 Gy for primary liver cancer with Child-
Turcotte-Pugh class B in 4–6 Gy per fraction was
recommended for classic or nonclassic RILD. For
metastatic liver tumors, mean liver dose \15 Gy in
three fractions or \20 Gy in 6 fractions was recom-
mended. When the critical volume model is
used, C700 ml of normal liver should recei-
ve B15 Gy in 3–5 fractions. The critical volume
model in patients with HCC and cirrhosis of the liver
needs greater vigilance. In addition, long-term liver
injury or biliary duct system damage pattern is less
well understood due to the relative absence of long
term follow-up data on such patients.
4.4 Liver Oligometastasis
The liver may harbor metastases from various pri-
mary sites including lung, breast, bladder, gastro-
intestinal organs and even melanomas (Dawood et al.
2009). In colon cancer, the liver is often the first site
of metastasis. Approximately 15–25% of colorectal
cancer patients will have liver metastases at the time
of presentation and 50–70% of patients may subse-
quently develop liver metastasis (Kemeny 2006;
Lochan et al. 2007) Although surgery is the standard
of care for liver metastasis, 80–90% of lesions are
unresectable at presentation (Small et al. 2007).
The high rate of unresectable liver metastasis is
partly due to recent use of extensive imaging studies
including MRI and FDG-PET imaging (Small et al.
2007). Upstaging prevents unnecessary surgery and
also expedites initiation of alternative therapy. With
improved patient selection for surgery, reported
5-year survival rates up to 60% are seen (Lochan et al.
2007). After careful selection of patients, surgery is
safe and specialist centers are reporting mortality
rates of less than 1%. For patients with unresectable
colorectal liver metastasis, a combination of systemic
agents is the mainstay of treatment with response
rates of up to 50% and a median survival of
20 months (Kelly and Goldberg 2005). Radiofre-
quency ablation (RFA) may be attempted in a
select group of patients with variable success. The
reported recurrence rates vary from 1.8 to 40%
384
Fig. 3 Liver SBRT. a The
liver SBRT treatment shows a
patient is a stereotactic body
frame with abdominal
compression. b, c show
dosimetry in axial and coronal
plane, respectively
(Curley et al. 1999; Solbiati et al. 2001; Donckier
et al. 2003).
Definitive attempts to eradicate visible metastases
have been technically challenging and radiation
therapy for liver metastases has often been per-
formed to palliate pain associated with tumor pro-
gression. However, with advancement of treatment
techniques along with accumulation of toxicity data,
radiotherapy has become a useful tool to deal with
liver metastases. It became evident that otherwise
normal liver may tolerate significant radiotherapy
dose directed at a limited volume. For example,
Emami et al. have shown that when only two-thirds
of the liver is irradiated doses up to 35 Gy are tol-
erated and when only one-third of the liver is irra-
diated the dose tolerance increases to 50 Gy (Emami
et al. 1991).
Advancement in 3D and IMRT treatment planning
has allowed the escalation of the dose to one-third of
the liver to 66–72.6 Gy in 1.5–1.65 Gy per fraction
(Borgelt et al. 1981; Leibel et al. 1987; Lawrence
L. C. Cho et al.
et al. 1992; Jackson et al. 1995; Dawson and Ten
Haken 2005) Unfortunately, adjacent normal struc-
tures, such as the intestines, biliary tree, and vascular
structures are at risk for significant damage with dose
escalation. SBRT offers further improvement in dose
escalation to the metastases without simultaneous
escalation of the dose given to the nearby critical
structures. Early applications of SBRT to liver
metastases have demonstrated promising results.
However, SBRT treatments must be performed cau-
tiously given the well-known challenges of organ
motion and limited tolerance of the liver parenchyma.
Patients with unresectable liver metastases with
adequate hepatic function are generally considered for
SBRT. Other patients with demonstrated progression
of primary disease or widespread systemic disease are
usually not considered for SBRT. The consideration
of number and size of metastases along with the
location within the liver may also influence the con-
sideration for SBRT. These factors are considered to
help predict the likelihood of devastating RILD. For
Stereotactic Body Radiotherapy 385

Table 8 Retrospective studies of SBRT for metastatic liver tumors

Investigator Number of patients SBRT dose Follow-up Outcome
(months)
Blomgren et al. (1998) 17 20–45 Gy in 2–4 fx 9.6 95% crude local control
Sato et al. (1998) 18 50–60 Gy in 5–10 fx 10 100% crude local control
Wulf et al. (2001) 20 30 Gy in 3 fx 9 61% local control at 2 years
Wada et al. (2004) 34 15 Gy 9 3 18 71% local control at 2 years
Katz et al. (2007) 69 30–55 Gy in 7–20 fx 14.5 57% local control at 20 months
Wurm et al. (2006) 3 74.8–79.2 Gy in 8–11fx N/A 100% local control
Gy gray, fx fractions

example, criteria for SBRT reported by Schefter et al.
(2005) included restrictions on the number of meta-
static liver tumors to three or less, the size of the
tumors to less than 6 cm and limiting the normal liver
that receives a specific dose. Approximately 700 cm3
of normal liver was allowed to receive up to 15 Gy in
3 fractions. For patients with grossly multiple lesions
or large lesions, this becomes a significant patient
selection issue. Figure 3 illustrates an example of
SBRT for liver metastasis with the patient immobi-
lized in a frame with abdominal compression.
The liver is considered a parallel functioning organ
capable of receiving high doses of radiation when a
sufficient volume of normal liver is spared.
There are many techniques to ensure that a specific
volume or percentage of normal liver receives less
than a specified dose. The earliest of these approaches
involved volumetric restriction on the amount of
normal liver tissues to be spared from specified
radiotherapy dose. A collaborative SBRT study from
University of Colorado and Indiana University rec-
ommended at least 700 cm3 of healthy liver tissue to
receive no more than 15 Gy over 3 fractions (Schefter
et al. 2005) Another approach is to limit the volume
of the normal liver that receives certain dose. The
percent volume of normal liver tissue receiving 15
and 21 Gy are designated as V15 and V21, respec-
tively. Commonly used V15 and V21 limits in 3
fraction SBRT include less than 50 and 30%,
respectively (Dawson and Ten Haken 2005; Rustho-
ven et al. 2009a, b). When single-fraction liver SBRT
is planned, similarly defined V7 and V12 are often
used. Another approach uses tolerance-based dose
prescription using the NTCP model (Dawson et al.
2006). Table 8 lists retrospective studies that admin-
istered SBRT for patients that included liver
metastases.
Blomgren et al. (1998) from Karolinska Hospital
in Stockholm, Sweden reported one of the earliest
experiences using SBRT for liver tumors. Investiga-
tors treated a combination of 17 primary tumors and
21 liver metastases with SBRT. The prescribed dose
ranged from 20 to 45 Gy (mean 34.1 Gy) in 2–4
fractions. Crude local control with a 9.6-month mean
follow-up was 95%. There were two cases of
hemorrhagic gastritis. There are also SBRT studies
that have applied hypofractionated regimen using
more than 5 fractions. In the SBRT report by Sato
et al. 50–60 Gy was delivered in 5–10 fractions (Sato
et al. 1998). With a median follow-up of 10 months,
the crude local control rate was 100% and only one
patient out of 18 experienced a transient elevation in
serum transaminases. Wulf et al. from Germany
delivered a total dose of 30 Gy in 3 fractions to 23
liver metastases in a report that also included primary
tumors and some lung tumors (Wulf et al. 2001).
Actuarial local control of liver metastases was 76% at
1 year and 61% at 2 years with no grade 3 or higher
toxicities. Wada et al. from Japan reported their
experience administering SBRT. They delivered
45 Gy in 3 fractions to 5 liver metastases in addition
to various other sites including primary liver and lung
lesions (Wada et al. 2004). Local control of combined
liver lesions was approximately 85% at 6 months and
71% at 18 months. At 18 months the local control for
tumors less than 3 cm was 95% and the local control
for tumors [3 cm was 58%. No serious adverse
events were reported. Katz et al. delivered SBRT
doses of 30–55 Gy (median 48 Gy) with fractional
doses of 2–6 Gy to 174 liver metastases in 69 patients
(Katz et al. 2007). The mean number of lesions
treated per patient was 2.5 and the median survival
was 14.5 months. The actuarial overall in-field local
control rate of the irradiated lesions was 76 and 57%
386
at 10 and 20 months, respectively. No patient devel-
oped grade 3 or higher toxicity. Wurm et al. also
delivered a total dose of 74.8–79.2 Gy in 8–11 frac-
tions to 3 patients with 4 metastases (Wurm et al.
2006). SBRT was image guided and respiratory gated
for patients with liver and lung tumors. No patient
failed locally and there was no toxicity.
There are an increasing number of prospective
SBRT reports that included patients with metastatic
tumors. Herfarth and colleagues from Heidelberg,
Germany, conducted a phase I/II trial of single-frac-
tion SBRT for liver metastases (Herfarth et al. 2001,
2004). The SBRT dose was escalated from 14 to
26 Gy, with the 80% isodose prescription surrounding
the PTV. Median tumor volume was 10 cm3 (range
1–132 cm3). All patients tolerated the treatment well
without any major toxicity. Eleven patients experi-
enced intermittent loss of appetite or mild nausea for
1–3 weeks after treatment. None of the patients
developed clinically apparent RILD after SBRT. The
overall actuarial local tumor control rates were 75, 71
and 67% at 6, 12 ,and 18 months of follow-up,
respectively. There was a statistically significant dif-
ference in Kaplan–Meier estimates of local tumor
control between tumors treated with 14–20 versus
22–26 Gy. The investigators noted that local control
was improved in patients treated later in the study
suggesting that a ‘‘learning’’ phase may be involved.
For patients who were enrolled in the later part of the
study, the actuarial local tumor control rate was 81%
at 18 months. Stratification by size did not reveal a
statistically significant difference in the local control
rate. In a report of a phase II SBRT study that
included 64 patients with colorectal cancer metastases
by Hoyer et al. 44 patients with hepatic metastases
were treated with 15 Gy 9 3 fractions. They dem-
onstrated a 2-year local control rate of 86% and a
2-year overall survival rate of 38% (Hoyer et al.
2006). The SBRT treatments were well tolerated.
Dawson et al. (Dawson et al. 2006) conducted a phase
I/II study that included 79 patients with both primary
and metastatic hepatic malignancies. There were 34
patients with liver metastases. The prescription dose
was individualized to maintain the same estimated
risk of RILD, based on an NTCP model, with a
maximum permitted dose of 60 Gy in 6 fractions. The
median prescribed dose was 36.6 Gy (24.0–57.0 Gy)
in 6 fractions. No dose-limiting toxicity was
observed. The investigators from the same institution,
L. C. Cho et al.
Princess Margaret Hospital in Toronto, Canada, also
reported a phase I dose escalation study for patient
with liver metastases (Lee et al. 2009a). The dose of
SBRT ranged from 27.7 Gray to 60 Gy in 6 fractions.
There was no dose-limiting toxicity or other grade
3–5 liver toxicity seen. However, there were two
grade 3 liver enzyme changes and one grade 4
thrombocytopenia observed. The 1-year local control
rate was 71% with a median overall survival of
17.6 months. In a prospective study that incorporated
121 patients with oligometastases, Milano et al.
(2008a, b) treated 54 patients with five or fewer
metastases to the liver. The 2-year overall survival
and local control rates were, 50 and 67%, respec-
tively. The respective 4-year overall survival and
local control rates were 28 and 60%. No patient
experienced grade 3 or higher toxicity and the
detailed toxicity analysis was done by Katz et al.
(2007).
Mendez Romero et al. from Netherlands used
SBRT to treat 25 patients with 45 primary and met-
astatic liver lesions (Mendez Romero et al. 2006).
Patients with metastases, HCC without cirrhosis, and
HCC \ 4 cm with cirrhosis were mostly treated with
12.5 Gy 9 3. One and 2-year local control rates were
94 and 82% for all patients and 100 and 86% for
patients with metastases. Survival ranged from 92%
overall at 6 months to 70% overall at 18 months.
There were three patients who experienced acute
grade C3 toxicity.
Goodman et al. performed a single-fraction phase I
dose escalation study for primary and metastatic liver
tumors (Goodman et al. 2010). The prescribed radi-
ation dose was escalated from 18 to 30 Gy at 4 Gy
increments. All patients tolerated the treatment
without developing a dose-limiting toxicity. Acute
grade 1 toxicity was observed in 9 patients, acute
grade 2 toxicity in 1 patient and late grade 2 gastro-
intestinal toxicity in 2 patients. For patients with liver
metastasis, the 1 and 2-year overall survival rates
were 61.8 and 49.4%, respectively.
In the previously mentioned phase I SBRT study
for liver metastases from University of Colorado and
Indiana University, Schefter et al. (2005) incremen-
tally escalated the SBRT dose to 60 Gy in 3 fractions
without reaching maximum tolerated dose. The tumor
diameter ranged from 0.4 to 5.8 cm. During the phase
I study, the total dose was safely escalated from 36 to
60 Gy. The phase II dose was 60 Gy in 3 fractions.
Stereotactic Body Radiotherapy
Table 9 Prospective trials of SBRT for metastatic liver tumors
Investigator Number of patients
Herfarth et al. (2001) 37
Hoyer et al. (2006) 64
Lee et al. (2009a) 68
Milano et al. (2008a, b) 121
Mendez-Romero et al. (2006) 25
Goodman et al. (2010) 26
Rustoven et al. (2009a, b) 47
Gy gray, fx fractions
On subsequent recent updates, (Kavanagh et al. 2006;
Rusthoven et al. 2009a, b) one of 47 patients expe-
rienced grade 3 or higher toxicity. Actuarial in-field
local control rates at one and two years after SBRT
were 95 and 92%, respectively. The prospective
studies are outlined in the Table 9.
There are very few reports of RILD following
SBRT for liver metastases. Clinically relevant mor-
bidities include nausea/vomiting, anorexia, fever, and
chills. There can be grade 2 toxicities such as ascites
(Mendez Romero et al. 2006), and increased serum
transaminases (Katz et al. 2007) grade 3 complica-
tions may include gastritis (Kavanagh et al. 2006),
elevated c-GT (gamma-glutamyl-transpeptidase)
(Sato et al. 1998; Uematsu et al. 1998; Mendez
Romero et al. 2006), and occasionally skin toxicity
(Kavanagh et al. 2006) The absence of frequent
catastrophic complications may be due to careful
treatment planning by the investigators who have
administered SBRT. However, there have been
reports of some concerning complications. These
experiences underscore the need for careful consid-
eration to limit irradiation of sensitive neighboring
normal tissues. For example, Blomgren et al. in the
early days of liver SBRT, noted a patient who expe-
rienced hemorrhagic gastritis as well as another
patient with duodenal ulcer after treatment (Blomgren
et al. 1998). Hoyer et al. also reported complications
including colonic ulceration and duodenal ulceration
after liver SBRT when part of the intestine recei-
ved [30 Gy in 3 fractions (Hoyer et al. 2006).
While precise dose constraints are lacking,
Schefter et al. urge extreme caution when dealing
with nearby structures such as the duodenum
(Schefter et al. 2005) Point doses to the duodenum
387
SBRT dose Follow-up (months) Local control
14 Gy 9 1 6 67% at 18 months
26 Gy 9 1
15 Gy 9 3 51.6 79% at 2 years
27.7–60 Gy in 6 fx 10.8 71% at 1 year
5 Gy 9 10 41 67% at 2 years
12.5 Gy 9 3 13 82% at 2 years
18–30 Gy 9 1 17 77% at 1 year
20 Gy 9 3 16 92% at 2 years
should not exceed 30 Gy total in 3 fractions (Hoyer
et al. 2006; Kavanagh et al. 2006).
4.5 Future Directions
SBRT appears to be a promising non-invasive therapy
for carefully selected patients with unresectable HCC.
It may also serve as a bridging therapy for patients
with HCC awaiting liver transplantation. Currently,
there is an ongoing confirmatory phase II trial of
SBRT enrolling patients with HCC who are not can-
didates for surgery. Patients with 1–3 lesions B6 cm,
without active hepatitis and with adequate liver
function are eligible. Child-Turcotte-Pugh class A and
B patients will receive 16 Gy 9 3 and 8 Gy 9 5,
respectively. Trials combining systemic therapy and
SBRT for HCC are also under development.
5 Spinal Metastases SBRT
The incidence of spinal metastases and metastases in
general will likely increase due to improved local
control of the primary tumor as a result of more
aggressive therapies along with better imaging tech-
niques resulting in higher detection rates of (spinal)
metastases. The role of radiotherapy in the palliation
of symptomatic bone metastases is well established as
radiation therapy alleviates metastatic bone pain
efficiently in the majority of patients (Bates 1992).
Besides pain control, external beam radiotherapy
helps in preventing local disease progression and
subsequent pathologic fractures. The optimal dose for
treating symptomatic bone metastases remains
388
unknown. There is however strong evidence indicat-
ing that single fraction radiotherapy is as effective as
multifraction radiotherapy in relieving metastatic
bone pain despite an increased retreatment rate and
slightly higher incidence of pathological fractures
after single fraction radiotherapy (Wu et al. 2003; Sze
et al. 2004). Studies reported that 4 Gy was less
effective than 8 Gy (Hoskin et al. 1992), 6 Gy gives
similar results as 8 Gy but is insufficiently studied
(Jeremic et al. 1998). Nowadays, a single fraction of
8 Gy is the treatment of choice for alleviating
bone pain because of its greater convenience for
the patient and radiotherapy unit and lower cost
(Wu et al. 2003).
The aim of implementing SBRT in the treatment of
spinal metastases is to increase the dose at the level of
the lesion without exceeding the maximum tolerated
dose of the spinal cord and cauda equine thanks to the
ability of creating sharp dose falloffs.
The hypothesis that increasing the biological
equivalent dose for spinal metastases results in
improved clinical response and tumor control and
reduced retreatment rates however still has to be
proven. Moreover, one must be aware of the potential
risks of increasing the dose to bone metastases, such
as radiotherapy-induced fractures. Exceeding the
maximum tolerated dose of the myelum can result in
unacceptable toxicity particularly, radiotherapy-
induced myelopathy.
Until now only prospective and retrospective
studies on SBRT for spinal metastases are published
with as endpoints pain control, (radiographic) local
control,and radiotherapy-induced toxicity. An over-
view of these clinical trials, published in the last
5 years by single institutions is presented in Table 1.
In general, local tumor and rapid (often within
1 week) pain control rates of 80% and more are
reported with acceptable toxicity. As is the case for
conventional fractionated radiotherapy, the local
control rate after radiosurgery is influenced by the
histology of the primary tumor (Gerszten et al. 2007;
Sheehan et al. 2009). Spinal radiosurgery is most
often used to treat metastases of renal cell carcinoma,
carcinomas of the breast, lung, colon, and prostate
gland, spinal plasmacytoma, and primary and sec-
ondary sarcomatous tumors of various types. The
localisation of the spinal metastases seems to have no
significant influence on the tumor volume control
(shrinkage or size stabilisation) (Sheehan et al. 2009).
L. C. Cho et al.
Although the optimal treatment schedule is unknown,
there are studies suggesting that there is a dose-
response relation favouring higher doses (Yamada
et al. 2008; Ryu et al. 2008).
Two distinct patterns of failure are described in the
literature. On one hand, recurrence occurs in the bone
adjacent to the site of previous treatment. In the study
of Nguygen for example, 3 recurrences occurred in
the pedicles and 1 relapse was observed in the pos-
terior elements of the vertebra as they did not include
these sites routinely in the target volume unless
grossly involved (Nguyen et al. 2010). On the other
hand, relapse is reported in the epidural space adja-
cent to the spinal cord most likely due to the limited
radiation dose to the tumor constrained by the dose to
the spinal cord (Chang et al. 2007; Nguyen et al.
2010). As progression in adjacent vertebral bodies is
rare it is justified to limit the stereotactic treatment to
the involved spinal level.
External beam radiotherapy or stereotactic radio-
therapy can be offered as an alternative for surgery for
patients presenting with metastatic spinal cord com-
pression. Again, the optimal treatment schedule
remains unclear. In general, a multifraction regimen
(10 9 3 Gy) is preferable in these cases as it allows
for larger dose and thus greater reduction in tumor
size (6). Again there are no data indicating that
increasing the dose improves neurological outcome.
In a recent publication of Rades et al. the contrary was
even stated for fractionated radiotherapy as they did
not found a significant difference in neurological
outcome after dose escalation [30 Gy for metastatic
spinal cord compression in patients with relatively
radioresistant tumors (Rades et al 2010). Despite
absence of evidence of improved outcome after dose
escalation, high dose SBRT has been implemented in
the treatment of metastatic epidural compression.
Today, only small single institution data with low
quality of evidence are published. The largest study
was published by Ruy et al. In this study 62 patients
with metastatic epidural compression were treated
with a single fraction of 12–20 Gy. After a median
follow-up of 11.5 months the neurological function
improved or remained stable in [74% of patients
(Ryu et al. 2008). Jin et al. treated 24 patients with
multiple myeloma and epidural spinal cord com-
pression at 1 level. A dose of 10–18 Gy was given in
1 fraction. Seventy-one percent of the patients pre-
senting with extremity weakness and sensory deficits
Stereotactic Body Radiotherapy
had complete neurological recovery 1–6 months after
radiosurgery (Jin et al. 2009). Patients without neu-
rological deficit at the moment of presentation
remained ambulant after radiosurgery.
The feasibility of a combined treatment of surgical
decompression followed by a single fraction radio-
surgery was demonstrated in a small study published
by Moulding et al. Twenty-one patients received
postoperative radiosurgery to a dose of 18–24 Gy.
Local control was maintained in 81% of patients after
radiosurgery with an estimated 1-year local failure
risk of 9.5%. The local control rate increased with
higher radiotherapy doses (1-year local failure risk of
6.3 versus 20.0% for those receiving a dose [24 Gy)
(Moulding et al. 2010).
The intrafraction motion of the target volume
remains a point of concern in case of frameless ste-
reotactic radiotherapy for spinal metastases due to
long treatment times. In order to determine the opti-
mal intrafraction imaging frequency as well as the
appropriate safety margins several studies were set
up. Murphy et al. treated patients with radiosurgery
for intracranial as well as extracranial spinal lesions.
For both type of lesions, fixed alignment (i.e. beam
alignment is established once at the beginning of the
treatment) requires three times larger margins when
compared to dynamic alignment (i.e. intrafraction
beam alignment correction each time that the target
position is measured). The estimated margins for
optimal target coverage were 3.6–4.5 and 1.2–1.6 mm
for fixed and dynamic alignment, respectively (Mur-
phy 2009).
A similar study was performed by Hoogeman et al.
For patients treated for spinal metastases in supine
position, the systematic error increased linearly in the
superoinferior, left–right and anterior–posterior
direction to on average 0.7 mm at a 15-min interval.
For the prone group, the systematic error for the three
components of direction increased linearly to
1.1–1.3 mm at a 15-min interval. The 3D systematic
error increased to 1.2 and 2.2 mm for the supine- and
prone-treated patients, respectively. The random dis-
placements for the prone-treated patients were sig-
nificantly higher than for the other groups, namely
1.6 mm, probably caused by respiratory motion
(Hoogeman et al. 2008). Ma et al. detected non-ran-
dom intrafraction target motion for all target loca-
tions. However, the largest non random intrafraction
target motion was measured for the targets located at
389
the level of the cervical spine. The average time
needed to maintain the target motion to within 1 mm
of translation or 1° of rotational deviation was 5.5,
5.9, and 7.1 min for cervical, thoracic, and lumbar-
sacrum locations (Ma et al. 2009). In general, we can
conclude that repeat intrafraction imaging and
patients setup correction with a 5-min interval can
reduce the setup error as a result of intrafraction
movement adequately. In the absence of a tracking
system with dynamic alignment the intrafraction
motion has to be taken into account by use of safety
margins. Extra vigilance is indicated for patients
treated for cervical lesions or patients treated in the
prone position as a result of increased intrafraction
movement reported for these lesions.
The incidence of radiotherapy-induced myelopathy
after radiosurgery is low even in reirradiation settings.
However, there still is much uncertainty regarding the
maximum tolerated dose of the spinal cord and cauda
equine. So far, no case of radiotherapy-induced
myelopathy was described for cumulative doses
of B60 Gy in 2-Gy equivalent dose. Based on a large
review performed by Kirckpatrick et al. the following
spinal cord constraints were formulated. For con-
ventional fractionation (i.e. 2 Gy/day) including the
full cord cross-section, total doses of 50, 60 ,and
69 Gy are associated with risk of 0.2, 6, and 50% of
myelopathy respectively. For reirradiation of the full
cord cross-section at 2 Gy per day, spinal cord tol-
erance increases with C25% 6 months after prior
conventionally fractionated radiotherapy. For partial
cord irradiation (as is the case for radiosurgery) a
maximum cord dose of 13 Gy in a single fraction or
20 Gy in 3 fractions appears safe with a \1% risk of
cord injury (Kirkpatrick et al. 2010).
Frequently reported spinal cords constraints, which
appear to be safe, are: a maximum of 10 Gy to 10% of
the spinal cord volume (in a previously untreated cord
with no concurrent chemotherapy) which is defined as
6 mm above and below the radiosurgery target (Ryu
et al. 2008) and maximum dose constraints of
12–14 Gy at any point of the spinal cord (Yamada
et al. 2008; Wu et al. 2009). Based on the dose-
analysis of 5 patients with radiotherapy-induced
myelopathy Sahgal et al. formulated more stringent
constraints. In case of single fraction radiosurgery the
maximum dose to a point of the thecal sac is set at
10 Gy. For treatments up to 5 fractions a normalized
2-Gy-equivalent biologically effective dose calculated
390
Table 10 SBRT for Spinal Metastases
Indications for radiosurgery
Good performance status
Expected survival of [3 months
Certainty of diagnosis
Limited spinal involvement (typoically 2 contiguous levels)
Small (B50 mm3) well described lesions
Tumor recurrence after conventional radiotherapy or surgery
Radioresistant lesions that would benefit from a radiosurgical
boost
Residual tumor after surgery
Lesions requiring difficult surgical approaches
Significant medical comorbidities precluding open surgical
invention
Minimal spinal cord compression
Lesions not requiring open spinal stabilization techniques
No evidence of biomechanical instability to the spine
using a/b value of 2 for late toxicity of 30–35 Gy to
the thecal sac is associated with a low risk of mye-
lopathy (Sahgal et al. 2010). In order to avoid radio-
therapy-induced myelopathy the dose to the spinal
cord must be limited taking into account the immo-
bilisation technique and performed image guidance.
Additionally, rat models have shown that the simul-
taneous administration of chemotherapy can increase
radiosensitivity of the spinal cord. Criteria that can be
used for selecting candidates for spinal stereotactic
radiotherapy are summarised in Table 10.
Based on the above-mentioned literature one can
only conclude that SBRT for spinal metastases is
feasible regarding acute toxicity. Long-term outcome
and toxicity data after high dose SBRT for spinal
metastases are not available but mandatory. There are
no clear guidelines concerning the optimal treatment
dose or constraints for adjacent organs. In the absence
of randomised trials indicating that high dose SBRT is
superior to a single fraction of 8 Gy in alleviating
pain or prolonging pain control or that dose escalation
results in better neurological outcome SBRT cannot
be advocated as the standard treatment for spinal
metastases. There is an urgent need for well-designed
controlled studies evaluating SBRT for spinal
metastases of one specific primary tumor site and
treated with fixed dose parameters before practical
conclusions can be drawn regarding the place of
L. C. Cho et al.
SBRT in the treatment of spinal metastases with or
without spinal cord compression.
6 Genitourinary SBRT
6.1 SBRT for Prostate Cancer
Based on the analysis of external beam radiotherapy
(EBRT) and brachytherapy data, Brenner and Hall
hypothesised that the a/b ratio for prostate cancer is
low as a result of the presence of a small proportion of
cycling cells in prostate cancer. According to them,
the a/b ratio for prostate cancer is 1.5 Gy (0.8, 2.2)
indicating a high sensitivity to fractionation (Brenner
and Hall 1999). Since then other publications have
supported the hypothesis of a low a/b ratio (Fowler
et al. 2001) for prostate cancer. The concept of a low
a/b for prostate cancer has encouraged the use of
hypofractionated treatment schedules in order to
increase therapeutic outcome. This, together with the
knowledge that most prostate cancers are diagnosed at
an early stage makes patients presenting with local-
ised prostate cancer suitable candidates for stereo-
tactic radiotherapy (SBRT). Clinical data on the
implementation of SBRT for prostate cancer are
scarce. The limited experience of SBRT for prostate
cancer has resulted in a variety of dose and fraction-
ation schemes. The planning objectives for organs at
risk are often derived from HDR brachytherapy pro-
tocols. Published series have predominantly included
low risk patients. For intermediate and high risk
prostate cancer SBRT is most often performed as a
boost after conventional radiotherapy.
In a recent large clinical study reported by Katz
et al. 304 patients with prostate cancer were treated
with SBRT to a dose of 35 Gy or 36.25 Gy in 5
fractions in 5 consecutive days. The majority of
patients had low risk prostate cancer (69%).
According to the Phoenix definition for biochemical
failure all patients treated to 35 Gy (n = 50) were
free of biochemical relapse at a median follow-up of
30 months. After a median follow-up of 17 months 4
patients (2 low risk and 2 high risk patients) treated to
36.25 Gy (n = 254) failed biochemically. There was
no acute grade 3 or 4 RTOG toxicity. One patient
treated to a dose of 36.25 Gy developed late grade 3
urinary toxicity. At a median follow-up of 18 months
87% percent (198/228) of patients maintained erectile
Table 11 Summary of publications on SBRT for prostate cancer
Number Inclusion Median Dose Toxicity Acute toxicity Late Erectile Clinical outcome
of criteria follow- prescription scoring toxicity dysfunction
patients up system
(months)
Katz et al. 50–254* Low-int- 30–17* 5 9 7 Gy/ EPIC/ 4% G2 GU-GI/4.7% G2 GU & 1% G2 10% decrease for 4 biochemical
(2010) high risk 5 9 7.25 Gy RTOG 3.6% G2 GI* GU/5.8% both levels relapses in high dose
G2 GU group (36.25 Gy)
and 0.5%
G3 GU;
Stereotactic Body Radiotherapy

2.9% G2
GI*
Friedland 112 Low risk 24 5 9 7 Gy AUA, 1 patient with G3 RBL, increase NR 82% maintained 3 patients with
et al. RAS, of RAS score to 4.6 (SD = 2.9) erectile function biochemical relapse:
(2009) SHIM (1.8 pretreatment); mean AUA 2 patients with biopsy
score increased from 8.9 to confirmed local
12.8, 1 patient required TURP relapse, 1 patient with
posttreatment distant metastases
King et al. 41 Low risk 33 5 9 7.25 Gy IPSS, NR 24% G2 NR No biochemical
(2009)** RTOG and 5% failure
G3 GU;
15% G2
Madsen 40 Low risk 41 5 9 6.7 Gy AUA, 21% G2 GU, 1% G3 GU; 13% 20% G2 23% developed Actuarial 4-year
et al. RTOG/ G2 GI GU; 7.5% ED freedom from relapse
(2007) CTC G2 GI was 90% (the
Phoenix definition)
and 70% (ASTRO)
Wiegner 32 Low risk 35.5 5 9 7.25 Gy EPIC NR NR 33% increase of NR
and King ED after
(2010)** treatment; age
(\70
or C70 years) is a
determinant of
ED (p = 0.008)
(continued)
391
Table 11 (continued)
392

Number Inclusion Median Dose Toxicity Acute toxicity Late Erectile Clinical outcome
of criteria follow- prescription scoring toxicity dysfunction
patients up system
(months)
Aluwini 10 Low-int 5.1 4 9 9.5 Gy IPSS, 20% G1-2 GI symptoms; 50% 33% G1-2 NR NR
et al. risk RTOG, G1-2 GU symptoms after GU
(2010) EORTC 2 weeks
Fuller 10 Low-int NR 4 9 9.5 Gy IPSS, Median-maximum IPSS NR NR No biochemical
et al. risk RTOG increase from baseline: 10-22 failure
(2008) points respectively; 60%
G1–G2 proctalgia and fecal
urgency resolving in 83%
4 weeks posttreatment
Morgia 6 NR NR 4 9 9.5 Gy IPSS Mainly presence of urgency, NR NR No biochemical
and De dysuria and frequency and failure
Renzis rectal irritative complaints
(2009) 2-4 months posttherapy
*The first and second number represent data for patients treated with 35 and 36.25 Gy, respectively;
**Data from the same group of patients.
int intermediate risk, NR not reported, EPIC Expanded prostate cancer index composite, RTOG Radiation Therapy Oncology Group, AUA American Urological Association
prostate symptom score, RAS rectal assessment score, SHIM Sexual Health Inventory for Men, IPSS International prostate symptom score, EORTC European Organization for
Research and Treatment of Cancer, CTC common toxicity criteria, G1-2-3: grade 1-2-3, GU genito-urinary, GI gastro-intestinal, TURP transurethral resection of the prostate,
ED erectile dysfunction
L. C. Cho et al.
Stereotactic Body Radiotherapy
Fig. 4 SBRT for prostate
cancer. The patient was
treated on TomoTherapy to
deliver 50 Gy to the PTV with
reduction of the dose to the
bladder and the rectum. A
rectal balloon was used to
spare a significant portion of
the lateral and posterior
rectum. Multiple CT images
were acquired during the
treatment to confirm the
stability of the setup
function either with or without medication (Katz et al.
2010). Friedland et al. reported the toxicity and
clinical outcome of 112 low risk prostate cancer
patients treated with SBRT to 35 Gy delivered in 5
fractions in 5 consecutive days. Acute gastro-intesti-
nal and urinary side effects were generally mild and
resolved shortly after treatment. One patient required
TURP post therapy and 1 patient developed grade 3
rectal blood loss. After a follow-up of 3 years, erectile
function was maintained in 82% of patients who were
sexually potent before treatment. At a median follow-
up of 24 months 2 patients developed a biopsy-con-
firmed local relapse. One patient developed distant
metastases (Friedland et al. 2009). The results of other
published but small single-institution trials are sum-
marized in Table 11 (Katz et al. 2010; Wiegner and
King 2010; Aluwini et al. 2010; Friedland et al. 2009;
King et al. 2009; Morgia and De Renzis 2009; Fuller
et al. 2008; Madsen et al. 2007).
Several randomised trials have indicated that by
increasing the dose to the prostate better biochemical
control is obtained. In order to avoid toxicity, further
dose escalation can be obtained by focusing the dose
on the intraprostatic lesion. SBRT can be used to
perform this boost. The feasibility of such an
approach was reported by Miralbell et al. In this study
50 patients were treated with conventional EBRT to a
dose of 64 Gy in 2 Gy fractions followed by a
boost of 2 fractions of 5, 6, 7, or 8 Gy to the
dominant tumor region. This was delineated based
on information obtained by rectal examination, site
of positive biopsies, and magnetic resonance images
393
(T2 sequences). The reported 5-year probabilities
of C grade 2 late urinary and late low gastroin-
testinal toxicity-free survival were 82.2 ± 7.4 and
72.2 ± 7.6%, respectively. Increasing the dose did
not result in higher toxicity rates. The 5-year bio-
chemical disease–free survival and disease-specific
survival were 98 ± 1.9 and 100%, respectively indi-
cating that for patients presenting with low risk
prostate cancer this approach may be considered an
alternative to high-dose-rate brachytherapy (Miralbell
et al. 2009).
The safe delivery of very large doses per fraction
requires effective patient immobilisation, and precise
target localisation. Prostate motion, both interfraction
and intrafraction prostate movement, and setup errors
have necessitated the use of margins by expanding the
treatment volume. Interfraction movement can be
addressed by the utilization of daily prostate imaging
using ultrasound, CT, KV- or portal-imaging of
implanted fiducials. The reported treatment time for
stereotactic radiotherapy for the prostate is 20–40 min
enhancing the need to detect and control the intra-
fraction motion. For 47 patients with implanted
fiducial markers, orthogonal portal images were
obtained before and after each fraction of stereotactic
radiotherapy resulting in a time interval of approxi-
mately 20–30 min. The average intrafractional pros-
tate movement was 2.0 mm or less. For 6 patients
localizing radiographs at 6-min intervals for 24 min
were obtained. The relative motion of the bony
landmarks and prostate markers was calculated,
demonstrating that most patient and organ movement
394
occurs early and a settling-in period is advisable
before treatment (Madsen et al. 2003). A stereotactic
body immobilization system has the ability to
immobilize prostate patients with satisfactory setup
accuracy for fractionated stereotactic conformal
treatment and IMRT. Reported random and system-
atic errors in the anterior–posterior, lateral and supe-
rior-inferior direction are in the range of ±3 mm
(Wang et al. 2004). The margins that are nowadays
used in most stereotactic radiotherapy protocols for
prostate cancer to compensate for setup errors and
prostate movement are within the range of 3–5 mm
which appears to be safe. As is the case for conven-
tionally fractionated external beam radiotherapy for
prostate cancer there is no consensus on rectal prep-
aration and bladder filling in stereotactic radiother-
apy. Some authors advocate the use of low fiber diets
and pre-treatment laxatives (Aluwini et al. 2010) or
anti flatulent medication after each meal (Madsen
et al. 2003). However, so far none of these approaches
was proven to be superior.
Based on a growing number of data one can con-
clude that SBRT for prostate cancer is technically
feasible. Figure 4 illustrates an example of SBRT for
prostate cancer. The patient was treated on Tomo-
Therapy to deliver 50 Gy to the PTV with significant
sparing of the bladder and the rectum. The particular
example divides the rectum into four parts for plan-
ning purposes; anterior, laterals (right and left), and
the posterior. A balloon is introduced to spare much
of the lateral and posterior rectum and multiple CT
images are acquired to confirm the stability of the
treatment position. SBRT for prostate cancer seems
promising regarding biochemical control and toxicity.
However, these data must be evaluated carefully and
interpreted as being preliminary as a result of lack of
data on long-term disease control, survival, and
chronic toxicity.
6.2 SBRT for Renal Cell Carcinoma
Renal cell cancer is considered to be a radioresistant
tumor. Therefore surgery remains the standard treat-
ment of choice for patients with renal cell cancer. For
patients presenting with advanced renal call cancer the
treatment options are limited. Published local control
rates up to 90% with stereotactic radiotherapy for
brain metastases of renal cell cancer are encouraging
L. C. Cho et al.
resulting in an increased interest for high fraction-dose
radiotherapy for renal cell cancer. The feasibility of
performing SBRT on renal tissue is proven both on
canine (Chan et al. 2000) and porcine (Ponsky et al.
2003) models.
Beitler et al. were the first to report on SBRT for
primary renal cell cancer. Nine patients with medical
inoperable renal cell cancer were treated with SBRT
to a dose of 40 Gy in 5 fractions given over a median
period of 15 days. Four of the 9 patients survived with
a median follow-up of 26.7 months. There was no
local relapse. Toxicity was mild with nausea and
vomiting being the most prevalent. The authors con-
cluded that SBRT is a valuable treatment option for
patients presenting with small (B3.4 cm) node-nega-
tive, organ-confined renal cell cancer (Beitler et al.
2004).
The potential role of SBRT for both primary renal
cell cancer and extracranial metastases of renal cell
cancer has been published by Teh et al. In their study,
16 patients (2 patients with inoperable renal cell
cancer and 14 patients with extracranial metastases of
renal cancer) were treated with SBRT to doses rang-
ing from 24 to 40 Gy in 3–6 fractions in 1–2 weeks
(most frequent used prescription: 3 9 8 Gy). Thirteen
patients (93%) who were treated with SBRT for extra-
cranial metastases achieved significant pain relief
resulting in a decreased use of analgesics. Imaging
post SBRT revealed excellent local control up to
87%. For patients treated for primary RCC, tumour
size remained unchanged but improvement of pain
was observed without changes in the renal function
post SBRT. There was no significant (grade 2 or
higher) toxicity (Teh 2007).
Wersall et al. confirmed these encouraging results
by publishing their 5-year clinical experience with
SBRT in the treatment of RCC. Fifty patients had
metastasised RCC resulting in 162 lesions treated
with SBRT. Different doses and fractionation sched-
ules were prescribed in function of the treatment site
and organs at risk lying in the vicinity of the lesions.
The fractionation schedules most frequently applied
in this study were 8 Gy 9 3–4, 10 Gy 9 3–5 and
15 Gy 9 2–3. Thirty percent (in particular small lung
metastases) and 22% of the treated metastatic sites
showed total tumor regression and tumor regression
of [50% after 3–36 months, respectively. Local
progression was seen in 3 lesions resulting in a local
control rate of 90% taking into account those patients
Stereotactic Body Radiotherapy
from whom there was no post treatment CT scan
available. The median survival time decreases for
patients presenting with more than 3 lesions at the
start of treatment (median survival: 37 months and
19 months for patients with B3 or [3 metastases at
referral, respectively). Toxicity was present in
approximately 40% of patients, mainly grade 1–2
toxicity (50%). Grade 5 toxicity (fatal gastric
hemorrhage 4 months after therapy) was seen in 1
patient treated for a metastasis in the pancreas. Five
patients developed radiation pneumonitis and
required steroid treatment (Wersall et al. 2005). The
prior study also treated patients for metastases from
RCC to the contralateral kidney to a dose of 30–40 in
10 Gy fractions. An update of the outcome of this
patient group was published in 2008 by Svedman
et al. One patient had local recurrence requiring
retreatment after a period of 54 months. Four patients
developed transient grade 1–2 toxicity (nausea, fati-
gue, and local pain). None of the patients needed
dialysis (Svedman et al. 2008).
The reported results on local control and main-
tenance of renal function indicate that SBRT can be
considered as an alternative for surgery for patients
with inoperable renal cell cancer. In the metastatic
setting, SBRT could be offered to patients present-
ing with a limited number of metastases before
initiating systemic therapies. However, although the
clinical results of SBRT for renal cell cancer are
promising both in the primary and metastatic setting
more mature data are imperative before imple-
menting SBRT for RCC into daily practice outside
clinical studies. Longer follow-up is needed to
confirm that an aggressive therapy for metastasised
RCC is beneficial.
7 Conclusion
SBRT is evolving and in some areas has been estab-
lished as the contemporary standard of care. The SBRT
for inoperable non-small cell lung cancers has emerged
as highly effective and the successful results have been
reproduced around the world. There are other appli-
cations of SBRT that will require continued studies and
careful design of additional prospective studies. In all
the sites treated, SBRT demands the latest development
in patient immobilization, dosimetry planning, and the
safe and accurate delivery of the intended dose to the
395
target. A careful consideration in selection of eligible
patients cannot be stressed enough. Increased efficacy
combined with convenient fractionation schedule
remains highly attractive for patients. Long-term
results with favorable outcomes with similar or reduced
treatment related morbidity will further accelerate the
acceptance of SBRT.
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 Physics and Clinical Aspects
of Brachytherapy
Bruce Thomadsen, Jack Venselaar, and Zuofeng Li

Contents 4 Sources Used in Clinical Brachytherapy............ 407

4.1 High-Energy Photon Emitters ................................. 407
4.2 Low-Energy Photon Emitters.................................. 408
1 Introduction............................................................ 402 4.3 Intermediate-Energy Photon Emitters..................... 408
2 Classifications of Brachytherapy ......................... 402 5 High Dose-Rate Remote-Afterloading
2.1 Permanent Versus Temporary Implants ................. 402 Brachytherapy........................................................ 409
2.2 Interstitial, Intracavitary/Intraluminal, Surface 5.1 Equipment and Operating Principles ...................... 410
Applications ............................................................. 403 5.2 Electronic Brachytherapy ........................................ 410
2.3 Loaded Applicators, Manual Afterloading
and Remote Afterloading ........................................ 403 6 Dose Calculations in Brachytherapy................... 411
2.4 Low-Dose Rate, High-Dose Rate, Medium Dose 6.1 The Superposition Principle.................................... 411
Rate and Pulsed Dose Rate..................................... 404 6.2 Source Strength Units ............................................. 411
6.3 Single Source Dosimetry ........................................ 413
3 Physical Characteristics of Brachytherapy
Sources .................................................................... 404 7 Pragmatic Interstitial Dosimetry ......................... 417
3.1 Activity and Decay.................................................. 404 7.1 Paris System ............................................................ 417
3.2 Specific Activity...................................................... 406 7.2 Paterson–Parker System .......................................... 418
3.3 Effective Energy...................................................... 406 7.3 Quimby System ....................................................... 419
7.4 ICRU 58 Reporting Recommendations .................. 419
7.5 Image-Based Reporting Quantities ......................... 421
8 Example Implants.................................................. 422
8.1 Breast Implant ......................................................... 422
8.2 Esophageal Application........................................... 423
9 Process of Brachytherapy Treatment Planning
and Delivery ........................................................... 424
B. Thomadsen (&) 9.1 Brachytherapy Planning .......................................... 425
Departments of Medical Physics, 9.2 Source and Applicator Preparation......................... 426
Engineering Physics, 9.3 Applicator and Catheter Insertion........................... 426
Biomedical Engineering and Industrial 9.4 Source and Applicator Localization ....................... 427
and Systems Engineering, 9.5 Treatment Planning and Quality Assurance Review
University of Wisconsin, Madison, of Brachytherapy Treatment Plan........................... 428
WI 53705, USA 9.6 Source Loading and Treatment Delivery ............... 429
e-mail: thomadsen@humonc.wisc.edu
10 Radiation Protection and Regulatory
J. Venselaar Compliance in Brachytherapy ............................. 429
Department of Clinical Physics, 10.1 Licensing, Authorization and Report of Medical
Institute Verbeeten, 5000 LA, Events....................................................................... 430
Tilburg, The Netherlands 10.2 Radiation Safety Concerns in Permanent Implants 430
Z. Li 10.3 Safety and Regulatory Issues in HDR
Department of Radiation Oncology, Brachytherapy.......................................................... 431
University of Florida Proton Therapy Institute, References.......................................................................... 431
University of Florida, Jacksonville,
FL 32206, USA

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 401
DOI: 10.1007/174_2011_361,  Springer-Verlag Berlin Heidelberg 2012
402
Abstract
Brachytherapy was the original intensity-modulated
radiotherapy, providing the ability to deliver high
doses to custom-shaped targets while preserving
normal, neighboring structures. Brachytherapy has
many manifestations, for example permanent
implants and treatments using high-dose rate and
remote afterloaders. The treatments may be exe-
cuted by placement of needles or catheters into a
tumor or placement of the sources in body cavities
near the tumor. The choice of sources, approaches
and techniques should be dictated by the patient’s
presentation. The rate of treatment delivery affects
both the biological results of the radiation and the
physical facets of therapy. Biologically, low-dose
rate treatments tend to be relatively gentler to
normal tissues but high-dose rate approaches
provide more stable and precise dose distribu-
tions. Most commonly, dose distribution calcula-
tions follow the protocol of Task Group 43 of the
American Association of Physicists in Medicine,
computing the doses or dose rates in space from
each source separately and adding them together
to obtain the composite. At the time of writing,
commercial treatment planning systems have just
begun to incorporate computational algorithms
that can include the effects of tissue composition
and density. Brachytherapy has moved from
simple localization using planar images from
radiographs that identify source positions and
skeletal anatomy to volume imaging that also
shows soft tissues and allows identification of
target and normal tissue structures. Physiological
and molecular imaging can further enhance the
ability to shape target volumes, just as with
external-beam treatments. Treatment planning
entails decisions on the approach to the brachy-
therapy. The classical systems, such as the Paris
or Manchester systems, provide guidance for
source or needle distributions that results in more
controlled dose distributions from the modern
optimization routines. These systems, along with
other measures of implant quality, also serve as
benchmarks for quality-assurance evaluations of
an application.
B. Thomadsen et al.
1 Introduction
Brachytherapy uses sealed radioactive sources for the
treatment of cancers or other diseases by placing the
sources in close proximity to a treatment target vol-
ume, either by directly inserting them into the tumor,
or by loading them into instruments, appliances or
applicators that were previously inserted into the
target volume or body cavities near the tumor
(afterloading). Brachytherapy may be used alone,
such as with early stage prostate and breast cancers,
or in combination with external-beam radiation ther-
apy to deliver a boost dose to the target, as in many
gynecological tumors, later-stage prostate cancer, and
some head and neck cancers. Following the surgical
removal of the gross tumor, brachytherapy may be
used to deliver a tumoricidal radiation dose to the
tumor bed where microscopic diseases remain. Due to
the rapid falloff of dose with distance from the sour-
ces, brachytherapy allows the delivery of very high
tumor doses while retaining excellent sparing of
neighboring critical organs. Compared with surgery,
brachytherapy does not create a tissue deficit, thereby
allowing potentially better cosmetic results.
2 Classifications of Brachytherapy
Brachytherapy can be classified according to various
criteria, including implant duration, approach used to
insert the sources into the patient, technique used to
load the sources and the rate at which radiation dose
is delivered to the target. These classifications hold
significance not only as medical terms, but also in the
selection of radioactive sources for a given brachy-
therapy treatment.
2.1 Permanent Versus Temporary
Implants
Permanent brachytherapy implants are those where the
sources inserted into the patient, remain permanently
in the patient. Common permanent brachytherapy
procedures include treatment of the prostate, some
Physics and Clinical Aspects of Brachytherapy
head and neck cancers, lung, and sarcomas. 125I, 103Pd
and 131Ca sources are commonly used for permanent
implants, although 198Au sources have also been used
occasionally (Crusinberry et al. 1985; Hochstetler et al.
1995). As is discussed later, sources used for perma-
nent implants need to have low energy, short half-lives
or a combination of both, so that the radiation exposure
received by people that have either frequent or close
contact with the patient is limited.
Temporary brachytherapy implants are those where
the sources are implanted in the patient for a
pre-determined length of time and then removed.
Treatment times of temporary implants range from
a few minutes, when the high dose-rate (HDR)
afterloading technique is used, to a few days for low
dose-rate (LDR) treatments. Patients receiving LDR
treatments may need to be admitted into the hospital for
the duration of the treatment, in which case radiation
exposure to hospital workers may be a concern.
2.2 Interstitial, Intracavitary/
Intraluminal, Surface Applications
Depending on the approach used to insert the brachy-
therapy sources into the patient, brachytherapy can be
classified into interstitial, intracavitary/intraluminal,
or topical/mold treatments.
In interstitial brachytherapy, sources are intro-
duced into the tissue, often with the use of needles
and catheters. Correspondingly, brachytherapy sour-
ces used for interstitial treatment need to have small
dimensions to fit into the needles and catheters.
Interstitial treatments are used for tumors such as
prostate cancer, breast cancer, and sarcomas.
In intracavitary brachytherapy treatments, sources
are loaded into applicators positioned into cavities
within the body adjacent to the target tissue. Site-
specific applicators are designed to fit into cavities
and place the sources near the target tissues. Exam-
ples include the tandem and ovoid applicators for
treatment of cervical cancer, the cylinder applicator
for vaginal cancer and the nasopharyngeal applicator.
The applicators remain in the patient during the
treatment and are removed at the completion of the
403
treatment, hence intracavitary brachytherapy treat-
ments are usually temporary treatments.
Surface applications place sources on some spac-
ing material, called a mold, which in turn is placed on
the patient’s surface. Surface applicators most often
treat skin lesions or conditions in the eye.
2.3 Loaded Applicators, Manual
Afterloading and Remote
Afterloading
Depending on the timing of source insertion relative
to the surgical procedure to insert the applicators or
needles, brachytherapy can be divided into three
classifications:
• Loaded applicators, in which the sources are already
in the applicator when it is inserted into the patient.
• Manual afterloading, where the applicators are
inserted into the patient in the procedure room, with
the sources loaded into the applicator after the
patient returns to their room.
• Remote afterloading, where the applicators are
inserted into the patient in the procedure room as
with manual afterloading, but with a computer-
controlled device used to load the sources auto-
matically after all staff leave the treatment room,
eliminating exposures to other persons.
Except as noted, loaded applicators are rarely used
nowadays due to the radiation exposure to staff in the
operating room, recovery room, imaging facilities, and
during transportation. Eye plaque applicators containing
125
I or 103Pd seeds for treatment of ocular melanoma fall
into the classification of loaded applicators, but when
handled correctly, personnel exposures remain low.
Permanent implants fall somewhere between loaded
applicators and manual afterloading, illustrating that the
classifications provide some useful guidance but should
not be taken as all-encompassing. The use of after-
loading techniques, either manual or remote (computer
controlled), minimizes radiation exposure to hospital
personnel, in addition to providing an opportunity for
the treatment planner to optimize the source strength
and loading distribution based on a retrospective review
of the applicator positioning relative to the target tissue.
404
2.4 Low-Dose Rate, High-Dose Rate,
Medium Dose Rate and Pulsed Dose
Rate
The biological effects of radiation depend on the rate
of delivery, as discussed in ‘‘Practical Time–Dose
Evaluations, or How to Stop Worrying and Learn to
Love Linear Quadratics’’. One of the determining
factors is the half-time for repair of sublethal damage.
In high dose-rate radiotherapy, brachytherapy or
external beam, the patient receives the dose over a
short duration with respect to this half-time. With a
half-time of about 1.5 h, an HDR treatment should be
completed within about 0.5 h. If that is the case,
differences in the actual dose rates across the treat-
ment volume have little effect on the biological
effectiveness, although absolute doses carry different
biological effectivenesses. It must be noted that there
is no absolute dose rate that corresponds to a high
dose-rate range, although the International Commis-
sion on Radiation Units and Measurements has pro-
posed that 12 Gy/h would be a guide (ICRU 1985).
On the other extreme, low dose-rate treatments fall
in a dose-rate range where the biological effectiveness
remains mostly independent of both dose and dose
rate. Most treatments with dose rates between 0.40
and about 0.80 Gy/h satisfy this requirement.
Between HDR and LDR treatments is a wide range
of doses, from about 1.0 to about 12 Gy/h, referred to
as medium dose rate (MDR), where the biological
effectiveness depends on both the absolute dose and
the dose rate. This makes brachytherapy difficult
because the physical isodose surfaces in a treatment
plan do not indicate the biological effect in any easy
and nice way.
Remote afterloading HDR brachytherapy units
equipped with a high-activity 192Ir source can deliver
an entire treatment fraction in minutes. At such high-
dose rates, the advantage of normal tissue repair
associated with LDR is lost, hence HDR treatments
must be fractionated, delivering a smaller total dose
relative to their LDR counterparts. This has led to the
development of the pulsed dose rate delivery, in
which the overall treatment time is equivalent to a
traditional low dose-rate treatment at 40–80 h. The
sources, however, are only inserted into the patient for
mins during each hour of treatment, resulting in a
higher instantaneous dose rate, though the same
dose delivered within each hour as traditional
B. Thomadsen et al.
LDR treatments. Several authors (Brenner et al.
1996, 1997; Chen et al. 1997; Visser et al. 1996)
have demonstrated biological equivalence of PDR
relative to LDR treatments. For more information
about pulsed dose-rate treatments, see ‘‘Principles
and Clinical Applications of Pulsed Dose Rate
Brachytherapy’’.
3 Physical Characteristics
of Brachytherapy Sources
The radioactive material used in a brachytherapy
source has three basic characteristics:
• The rate at which its strength decays (often
described by its half-life);
• How much radioactivity can be obtained in a given
mass of the radioactive source (specific activity);
and
• The energies and types of the radiation particles
that are emitted from the source (energy spectrum).
These physical characteristics will guide the clin-
ical utilization of brachytherapy sources. Table 1 lists
the common radioactive sources used in brachyther-
apy, together with their physical characteristics.
3.1 Activity and Decay
The nuclei of radioactive materials have reasons to be
unstable. For further discussion of these reasons, the
interested reader is directed to any nuclear physics
textbook. To become more stable, the nuclide
undergo transitions, most often undergoing either a
beta decay or an internal conversion. Some brachy-
therapy sources make use of the electrons resulting
from the beta emissions, such as 90 Sr eye applicators
or 90 Y-labeled microspheres. However, these spe-
cialized treatments will not be covered in this chapter
and the interested read is refered to Thomadsen et al.
2005 or Baltas et al. 2007. Accompanying these
transitions, the atoms emit energy in the form of
photons, either c rays if the change to a more stable
form leaves the nucleus with excess energy, or X-rays
if energy comes from excited electrons. The number
of transitions to the more stable state per unit time
defines the activity of the source.
Beginning with a collection of radioactive nuclei,
as the nuclei undergo transition, the total number of
Physics and Clinical Aspects of Brachytherapy 405

Table 1 Common brachytherapy sources and their physical characteristics

Element Isotope Energy Half- HVL- Exposure Source form Clinical application
(MeV) life lead rate
(mm) constant
(Cd)a
Sealed sources of historic significance
226
Radium Ra 0.83 1626 16 8.25b Tubes and needles LDR intracavitary and
(avg) years interstitial
222
Radon Rn 0.83 3.83 16 8.25b Gas encapsulated in Permanent interstitial;
(avg) days gold tubing temporary molds
60
Cobalt Co 1.25 5.25 11 13.07 Encapsulated spheres HDR intracavitary
years
Currently used sealed sources
252
Californium Cf 2.4 2.65 – – Tubes High-LET LDR
(avg) years intracavitary
neutron
137
Cesium Cs 0.662 30 6.5 3.28 Tubes LDR intracavitaryl
years
131
Cesium Cs 0.030 9.69 0.030 0.64 Seeds Permanent implants
days
198
Gold Au 0.412 2.7 6 2.35 Seeds Permanent interstitial
days
125
Iodine I 0.028 59.6 0.025 1.45 Seeds Permanent interstitial
days
192
Iridium Ir 0.397 73.8 3 4.69 Seeds in nylon ribbon; LDR temporary interstitial;
(avg) days metal wires; intracavitary; HDR
encapsulated source on interstitial and intracavitary
cable
103
Palladium Pd 0.020 17 0.013 1.48 Seeds Permanent interstitial
days
90
Strontium/ Sr/90Y 2.24 28.9 – – Plaque Treatment of superficial
Yttrium bmax years ocular lesions
169
Ytterbium Yb 0.093 32 0.48 1.80 Seeds LDR temporary interstitial
days
90
Yttium Y 2.24 64 h – – Microspheres Intra-arterial treatment for
bmax liver cancer
Unsealed radioisotopes used for radiopharmaceutical therapy
131
Iodine I 0.61 8.06 – – Capsule NaI oral Thyroid cancer
bmax days solution
0.364
MeV c
32
Phosphorus P 1.71 14.3 – – Chromic phosphate Ovarian cancer seeding;
bmax days colloid instillation; peritoneal surface; PVC,
Na2PO2 solution chronic leukemia
145
Samarium Sm 0.043 340 0.060 0.885 Lexidronam Diffuse bone metastases
days
89
Strontium Sr 1.4 51 – – SrCl2, IV solution Diffuse bone metastases
bmax days
Adapted from: Williamson (1998b) LDR low-dose rate; HDR high-dose rate
a
No filtration in units of R cm2 mCi-1 h-1
b
0.5 mm platinum filtration; units of R cm2 mg-1 h-1
406
radioactive nuclei decrease, each transition reducing
the number by one. In each time period, for example,
each second, the same fraction of the radionuclei
undergo transition. Thus, over time the activity of the
collection decreases, or decays exponentially. With an
activity at time 0 of A0, the activity of the source at
time t, A(t), is given by Eq. 1.
AðtÞ ¼ Ao ekt ð1Þ
where k is the decay constant. The decay constant
describes the fractional rate at which the activity
decays. Of particular use in brachytherapy is the time
it takes for the source strength to decay to half its
initial value, i.e., A(T1/2) = A0/2, where T1/2 is the
half-life of the source. The half-life relates to the
decay constant as
lnð2Þ 0:693
T1=2 ¼ ¼ ð2Þ
k k
A source’s half-life is a fundamental quantity of the
radioactive nuclide of the source. Common brachy-
therapy sources have half-lives ranging from days to
years. The length of a given brachytherapy source’s
half-life determines its shelf life, namely, whether a
source can be stored and used repeatedly over a long
period of time. Sources with longer half-lives, such as
137
Cs and 192Ir sources can be used for treatment of
multiple patients before replacement, thereby reduc-
ing the cost of each treatment. Sources with shorter
half-lives, such as 125I and 103Pd sources, need to be
purchased and received for an intended implant pro-
cedure date. Exceptions are very large implant pro-
grams that use enough shorter half-lived sources that
they can keep them on hand for use as needed. The
half-life of a brachytherapy source also affects the
implant dose calculation. The decay of the source over
the planned treatment duration may not need to be
accounted for explicitly if the source has a sufficiently
long half-life. For example, 137Cs sources with a half-
life of 30 years, may be assumed to exhibit a constant
activity during the treatment period of a few days,
whereas the dose calculation of an implant using 125I
sources, with a half-life of 59.8 days needs to consider
the decay of the sources during the implant.
A source’s half-life, together with its average
energy, determines its suitability for use in permanent
or temporary implants. When brachytherapy sources
are permanently inserted into a patient and the patient
B. Thomadsen et al.
is released from the hospital, the radiation exposure
around the patient can pose a risk to people within
short distances from the patient. Sources with shorter
half-lives can reduce these risks because the radiation
exposure around the patient decreases rapidly with
time. If necessary, the patient can be hospitalized in a
private room for a short period of time. For sources
with low energies, the patient provides shielding from
the implant’s radiation.
3.2 Specific Activity
The strength of a brachytherapy source for practical
applications is limited by its specific activity. The
specific activity is the ratio of activity contained
within a unit mass of the source. When a parent
nuclide is activated within a neutron flux field, the
number of radioactive nuclides per unit mass that may
be obtained is limited by the neutron flux field
strength, the parent nuclide’s neutron cross section,
and the source half-life. This is important for brach-
ytherapy applications that require small source
dimensions as well as high source strengths. The
popularity of the 192Ir source in modern brachyther-
apy is partly due to its high specific activity and high
neutron cross section, thereby making it suitable as an
HDR remote-afterloading source. The small size of
the source makes it useful for both interstitial and
intracavitary brachytherapy treatments.
3.3 Effective Energy
The effective energy of a brachytherapy source
determines the penetrability of the photon particles
emitted from the source. The high-energy photon
sources allow higher radiation dose to tissues at larger
distances from the sources, such as the pelvic nodes in
the treatment of cervical cancer. On the other hand,
the high-energy photons require thicker shields for
protection of hospital personnel. As noted above,
permanent brachytherapy treatments often use low-
energy photon emitting sources, such as 125I and
103
Pd because the photons from these sources are
mostly attenuated by the patient tissue resulting in
very low radiation exposure rates around the patient.
Patients treated with these sources can be released
from the hospital without concern for the radiation
Physics and Clinical Aspects of Brachytherapy
exposure to members of the public from the implanted
sources. When high-energy sources, such as 198Au,
are used for permanent implants, the patient needs to
be confined in the hospital until the radiation exposure
outside the patient satisfies the allowed limits.
125
I and 103Pd sources can be shielded by a thin
lead foil, making them useful for treatments of shal-
lowly located or superficial tumors such as ocular
melanoma.
The energy of a radionuclide affects its penetra-
tions, generally with higher energy photons pene-
trating more than those of lower energy. The
penetration is often characterized by the half-value
layer, HVL, which is the thickness of a material
that reduces the intensity of the radiation by a factor
of two.
4 Sources Used in Clinical
Brachytherapy
The use of radioactive sources for treatment of
malignancies started shortly after the discovery of
radium in 1898 by the Curies. 226Ra sealed first in
glass tubes and then in platinum tubes or needles was
used for interstitial and intracavitary temporary
treatments. 222Rn, the daughter product of 226Ra, in a
gas form sealed within a gold seed, was later used for
permanent implants, due to its short half-life. While
neither source is currently used clinically, much of the
current brachytherapy treatment derives the dose
specification and prescription parameters from the
earlier clinical experiences using 226Ra and 222Rn
sources. Their historical importance therefore cannot
be ignored.
4.1 High-Energy Photon Emitters
1. Radium-226: 226Ra was the first radionuclide
isolated, and the first used in brachytherapy treat-
ments. 226Ra has a half-life of 1620 years. The
c-rays from radium and its decay products range in
energy from 0.05 to 2.4 MeV, with an average
energy of about 0.8 MeV when enclosed in a
0.5 mm thick platinum jacket. The active 226Ra
sources consist of a radium salt (sulfate) mixed
with filler (usually barium sulfate), which is
encapsulated in platinum cylinders to form radium
407
tubes or needles. Radium tubes have a platinum
wall thickness of 1.0 mm, are typically 22 mm
long, and contain from 5 to 25 mg of radium in
15-mm active lengths. Radium needles have a
wall thickness of 0.5 mm and are often classified
for their strengths per centimeter of length:
Full-intensity needles with 0.66 mg of radium per
centimeter of length and half-intensity needles
with 0.33 mg of radium per centimeter.
2. Radon-222: 222Rn, with a half-life of 3.83 days
and average energy similar to that of radium, is a
gas produced when radium decays. The radon gas
was extracted and encapsulated in gold seeds,
which were used for permanent brachytherapy.
Both 226Ra and 222Rn have been replaced by arti-
ficially produced radionuclides discussed below.
3. Cesium-137: 137Cs, a fission by-product, is a
popular radium substitute because of its 30-year
half-life. Its single c-ray of 0.662 MeV is less
penetrating in lead with HVLPb = 0.65 cm, than
the c-rays from radium with HVLPb = 1.4 cm.
In tissue, however, the penetration is very similar,
particularly near the sources. Modern 137Cs intra-
cavitary tubes have been the mainstay for intra-
cavitary treatment of gynecological malignancies.
The radioactive material is distributed in insoluble
glass microspheres, posing less of a hazard from a
ruptured source than the radon gas and the radium
powder under the pressure from the build-up of
helium due to the alpha decay in a radium tube.
The 137Cs source material is then sealed in stain-
less steel encapsulation cylinders with a diameter
of about a 2.65 mm, physical length of about
20 mm and active lengths between 14 and 20 mm,
depending on the vendor’s design.
4. Iridium-192: The 74-day half-life 192Ir, with an
effective c-ray energy of about 0.38 MeV, is the
most widely used source for temporary LDR
interstitial implants and HDR remote afterloading.
In Europe, 192Ir has been used in the form of a wire
containing an iridium–platinum radioactive core
encased in a sheath of platinum. In the United
States, 192Ir is available as small sources, often
called seeds, 0.5 mm diameter by 3 mm long with
an active 192Ir core cylinder contained in stainless
steel or platinum encapsulation. The seeds are
inserted in a 0.8 mm-diameter nylon ribbon and are
usually spaced at intervals specified for a given
case, but frequently 0.5 or 1 cm center-to-center.
408
Fig. 1 192Ir sources in nylon ribbon. Picture courtesy of Best
Medical, Inc
192
Ir ribbons and wires can be trimmed to the
appropriate active length for each catheter. Figure 1
shows iridium sources in a ribbon.
5. Gold-198: Metallic 198Au seeds, with a 2.7-day
half-life and a 0.412 MeV c-ray, are available for
permanent implants. Gold-198 seeds are 2.5 mm
long and 0.8 mm in outer diameter, and have
0.15 mm-thick platinum encapsulation.
4.2 Low-Energy Photon Emitters
1. Iodine-125: 125I seeds emit several conversion
X-rays with energies between 27 and 32 keV and a
35.5 keV c-ray (7% of the time) with a half-life of
59.7 days, and are readily shielded by a few tenths
of a millimeter of lead, having an HVLPb =
0.002 cm. Many designs of 125I seeds are currently
available, all having an outer cylindrical encapsu-
lation of titanium 4.5 or 5 mm in length and 0.8 mm
in diameter, as shown in Fig. 2. Iodine-125 seeds
are used mostly for permanent implant treatments
of cancers of the prostate, lung, and sarcomas, as
well as the temporary implant treatment of ocular
melanoma when affixed in an eye plaque.
2. Palladium-103: 102Pd is an alternative to 125I.
103
Pd emits 20–23 keV characteristic X-rays with
a half-life of 16.9 days. Because with 103Pd the
doses are delivered in a shorter time, 103Pd is
thought to have a greater biological effect than 125I
(Ling 1992; Ling et al. 1995; Nath et al. 2005;
Antipas et al. 2001; Wuu et al. 1996; Wuu and
Zaider 1998) and could, in theory, prove more
effective against more aggressive tumors. So far,
no differences have been seen between the clinical
effects of 125I and 103Pd. Implants that use 103Pd
B. Thomadsen et al.
Fig. 2 GE Medical model 6711 125I seed. (Rivard et al. 2004)
Fig. 3 Theragenics model 200 103Pd seed. (Rivard et al. 2004)
may be more sensitive to errors in source
positioning due to the reduced penetration of the
low-energy X-rays and from the effects of edema
during the days shortly after the implantation
procedure, when most of the dose is delivered.
These errors can be substantial (Dawson et al.
1994; Nath et al. 2000). Figure 3 shows a diagram
of the Theragenics model 200 103Pd seed.
3. Cesium-131: 131Cs emits X-rays between 29.4 and
34.4 keV and has a half-life of 9.7 days, and is
thought to combine the advantages and disadvan-
tages of 125I and 103Pd for permanent implants
(Murphy et al. 2004; Yue et al. 2005). Cesium-131
sources match the external dimensions of 125I and
103
Pd seeds.
4.3 Intermediate-Energy Photon
Emitters
Interest in use of ytterbium-169 as a brachytherapy
source dates back to the early 1990s (Mason et al.
1992; Perera et al.1994; Das et al. 1995). 169Yb has an
average energy of approximately 90 keV, with a half-
life of 31 days. The average energy of 169Yb falls
within a region of Compton scattering interaction in
tissue, where the ratio of scattered photon energy to
primary photon energy is nearly at a maximum. The
169
Yb sources can therefore deliver a higher dose to
points distant from the source in comparison with
Physics and Clinical Aspects of Brachytherapy 409

traditional brachytherapy sources, such as 137Cs and

192
Ir, which is considered an advantage for gyneco-
logical cancer treatments. At the same time, radiation
shielding for 169Yb is much easier than for 137Cs and
192
Ir, due to its lower energy and smaller half-value-
layer value in lead (see Table 1).

5 High Dose-Rate
Remote-Afterloading
Brachytherapy

High dose-rate, remote-afterloading technology,

conventionally using high activity 192Ir sources and a
computer-controlled mechanism to drive the source
into a set of implanted applicators and catheters
sequentially, has become the dominant approach for
brachytherapy treatment of gynecological and breast
cancers. HDR treatments, compared with manually
loaded brachytherapy treatments, offer the advantages
of significantly lowered radiation exposures to
patient-care personnel because the radiation source is
housed in a shielded source safely built into the
remote afterloader unit located in a shielded treatment
room. The source is only driven out of the safe for
patient treatment and machine quality assurance tests,
while all patient care personnel are safely outside the
treatment room. The radiation sources for HDR units
are typically of small dimensions, an example of
which is shown in Fig. 4, along with an HDR unit.
During a treatment, the source is driven out of the
HDR unit, and steps through pre-determined posi-
tions, called dwell positions, within each treatment
catheter, stopping at each dwell position for a pre-
calculated length of time, called dwell time, to deliver
the planned treatment dose distribution. The HDR
technology therefore offers significant flexibility in Fig. 4 a A high dose-rate remote afterloading unit. b The
customizing the source dwell times at all dwell source for the treatment unit in a. Pictures courtesy of Varian
positions, equivalent to using a large number of Medical Systems, Inc. All rights reserved
sources of various strengths, to achieve optimized
dose distribution for the treatment. Various optimi- treatments, especially with the help of automatic
zation algorithms are available in all HDR treatment- optimization algorithms, provide unprecedented
planning systems that greatly facilitate tailoring of the capabilities in sculpting dose distributions, they are
dose distribution to the treatment target (Ezzell and fundamentally limited by the physical limits of
Luthmann 1995; Ezzell 2005; Edmundson 1994; applicator and catheter locations, and cannot be
Van der Laarse 1994; Lessard and Pouliot 2001; relied upon to correct applicator and catheter posi-
Milickovic et al. 2002; Lahanas et al. 2003). It is tioning errors. The dose distributions resulting from
noted, however, that while the flexibility of source an optimization algorithm should be reviewed in
dwell time and position optimization in HDR detail for dose homogeneity, especially for the
410
presence of large-volume hot spots. Manual reop-
timization, repositioning of the applicators and
insertion of additional catheters are sometimes the
only remedy for an implant to achieve acceptable
dose distributions.
5.1 Equipment and Operating Principles
A typical HDR remote-afterloading unit comprises a
high-activity source containing up to 444 GBq (12Ci)
of 192Ir, a shielded source safe, a stepping motor to
drive the source out of the safe to positions in appli-
cators with a precision of about 1 mm, computer-
controlled timer for dwell times, an emergency motor,
and a backup battery for retraction of the source
into the shielded safe in the event of a power failure.
A check cable, driven by a separate motor, is included
for testing the integrity of the applicator/catheters and
their secure connection to the machine prior to driving
the active source out of the source safe. Many dif-
ferent applicators and catheters may be connected to
the unit through the indexer, which automatically
selects the current channel of source travel based on
the treatment plan. Transfer tubes of various designs
specific to the applicator or catheter in use connect to
the indexer and serve as source conduits between the
HDR unit and the applicators. Multiple safety inter-
locks are integrated into the system to perform addi-
tional tests on source travel speed and position
accuracy, and retract the source into the source safe in
the event of unexpected source travel speed and
positions, to prevent the source from being stuck
within damaged applicators and catheters.
An HDR system is usually equipped with its own
treatment planning system for the calculation of source
dwell positions and dwell times, which after approval,
are digitally transferred to the treatment delivery unit.
While a conventional brachytherapy treatment planning
system may be modified to calculate the dose distribu-
tions from given HDR source dwell positions and dwell
times, they usually lack the capabilities of automatic
source dwell position and dwell-time optimization and
digital interface with the HDR delivery unit and are
therefore unable to provide the advantages afforded by
an HDR-specific treatment planning system.
Because of the high activity of the source used,
HDR units must be housed within a shielded treat-
ment room so that the radiation exposure outside the
treatment room during source-out sessions remain
B. Thomadsen et al.
below regulatory limits. The HDR treatment rooms
may be either dedicated to HDR treatments or shared
with an external-beam radiation treatment room.
In the former case, the HDR treatment room may be
designed to allow outpatient surgical procedures to
further improve the efficiency of applicator insertion,
simulation, and treatment delivery, by installation
of appropriate surgical and imaging equipment
(Kubo et al. 1998).
5.2 Electronic Brachytherapy
An alternative to the radionuclide-based HDR unit is
one using an electronic X-ray source. Two such
units are available commercially. The INTRABEAM
(Carl Zeiss Meditec, Jena, Germany), shown in
Fig. 5a, is primarily used for intraoperative brachy-
therapy. The stand supports an electron accelerator
that projects 50 keV electrons through a long tube
with a target at the end. The target becomes a mostly
isotropic X-ray source. Various applicators fit over
the tube, applicable for the particular anatomic site
under treatment. Treatments would be delivered in a
single fraction during surgery.
Figure 5b shows the Axxent system by Xoft
(Sunnyvale, CA), a device designed to replace the
conventional HDR unit. This unit uses a very small
X-ray tube on the end of a long cable that moves through
a treatment volume, pausing at dwell positions for
specified dwell times, just as a 192Ir source would.
As with the INTRABEAM unit, the Axxent system
operates at 50 kVp. One advantage of the system com-
pared with a conventional HDR unit is the minimized
shielding requirements. The electronic system requires
no shielding in the walls and the treatment site in the
patient can be covered with a shielding material so that
personnel can remain in the room during the treat-
ment. Disadvantages of the electronic system includes
the source size being too large to pass through
interstitial catheters, restricting the use to intracavi-
tary applications, and an uncertain radiobiological
effectiveness compared with the more conventional,
higher energy brachytherapy, a problem shared with
all the low-energy radionuclides as well. Due to the
limited life span of the current model of the Xoft
sources, the user must regularly replace the minia-
turized X-ray tube catheter, however, the exchange
procedure takes little time.
Physics and Clinical Aspects of Brachytherapy
Fig. 5 Electronic brachytherapy units. a The INTRABEAM
system, showing the stand and tube assemble on the left and a
schematic of the X-ray generator (electron gun, beam deflectors,
drift tube, and target) on the right. Pictures courtesy of Carl Zeiss.
b The Axxent system, clockwise from upper left: the control unit,
the catheter containing the X-ray source and the cooling system,
the X-ray tube against a figure and a schematic of the end of the
catheter with the X-ray tube. Pictures courtesy of Xoft, Inc
6 Dose Calculations in Brachytherapy
6.1 The Superposition Principle
The clinical calculation of dose distribution from
brachytherapy sources, as is currently practiced, is
based on the superposition principle, i.e., the total
dose distribution, at a given point of interest, from a
group of brachytherapy sources is equal to the sum of
the dose to that point by each of the brachytherapy
sources in the group, or
411
X
D_ ðx; y; zÞ ¼ D_ i ðx; y; zÞ; ð3Þ
i¼1;...;n
where D_ i (x, y, z) is the dose contribution from the ith
source to point of interest (x, y, z).
The superposition principle assumes that the dose
distribution to a point of interest is not affected by the
presence of other sources or applicators (as discussed
below). In reality, this assumption is only an approxi-
mation. The accuracy of this assumption, called the
interseed effect, intersource effect, or intersource
shielding, depends on the average energy of the sour-
ces, the specific source design, as well as the distances
of the points of interest to the sources. For low-energy
sources, such as 125I and 103Pd seeds used in permanent
prostate implants, this assumption has been shown to
overestimate dose by several percents (Meigooni et al.
1992; DeMarco et al. 1999; Zhang et al. 2005; Chibani
et al. 2005). For high-energy photon emitting sources,
such as 137Cs and 192Ir, the intersource effect is negli-
gible. However, shielding effects from the applicators
(and especially shields present in these applicators),
often used with these HDR sources, reduce the dose.
For radiation shielding resulting from other sources or
by an applicator, the attenuation of water should be
replaced with that for the high-Z material over the
shielding path-length. The material may be a stainless
steel applicator or tungsten protection shields. The
photoelectric effect is largely responsible for the
attenuation differences in comparison to water (e.g.,
Markman et al. 2001). This, and several other effects
influencing dose calculation outcome, were exten-
sively discussed in a Vision 20/20 article in Medical
Physics journal by Rivard et al. (2009a, b).
Assuming that the superposition principle holds for
a clinical application, the brachytherapy dose calcu-
lation problem reduces to the calculation of single
sources, i.e., calculation of the radiation dose distri-
bution around a single brachytherapy source. Once
such dose distribution parameters are obtained, they
can be tabulated for a manual calculation or for
computerized isodose distribution calculation for an
implant using a group of sources.
6.2 Source Strength Units
Brachytherapy source-strength specification protocols
have evolved since its inception. Historically, the
412
earliest unit for brachytherapy source strength was
based on the mass of radium, which was used to
define the unit of curie (Ci) for activity:
1 g radium ¼ 1 Ci ¼ 3:7  1010 disintegrations=s:
The SI unit Bq (bequerel) was introduced in order to
obtain consistency in the definitions of units and is
defined as 1 disintegration/s. Thus, 1 Ci = 3.7 91010
Bq or 37 GBq. Similarly, 1 mCi = 37 MBq.
While the quantity activity, as defined in terms of
elemental disintegration rate, is a measurable physical
quantity, it cannot be easily applied to brachytherapy
source strength specifications because the dose dis-
tribution around an encapsulated brachytherapy
source depends on the attenuation and scattering of
the photons by the encapsulation material. Specifica-
tion of source strength based on the elemental disin-
tegration rate is usually referred to as contained
activity in the brachytherapy literature, and holds little
interest to brachytherapy physicists except in the case
of regulatory compliances, where many countries, the
United States included, require accounting for radio-
active material possession in terms of this quantity.
Brachytherapy source strength specifications are
usually based on quantities that can be measured out-
side of the encapsulated source. The following units are
often encountered in the brachytherapy literature:
1. Milligram-radium-equivalent (mgRaEq): High-
energy brachytherapy sources with average energy
higher than 300 keV have dose distribution charac-
teristics similar to that of radium and are often
referred to as radium substitute sources. One
mgRaEq of the radium substitute source is defined to
be the amount of the radium substitute source that
gives the same exposure rate at 1 m as a 1-mg radium
source encapsulated in 0.5 mm platinum in the same
measurement geometry. The quantity mgRaEq has
had a long use history in clinical brachytherapy. The
product mgRaEq and the implant time, mgRaEq h,
have been used as a prescription quantity for many
temporary implants, such as in tandem-and-ovoids
implants for the treatment of cervical cancer.
2. Apparent activity (A): Apparent activity is defined
similar to mgRaEq, with the exception that instead
of an encapsulated radium source, the reference
source is an unshielded point source of the same
radionuclide. Thus, a brachytherapy source with an
apparent activity of 10 MBq gives rise to the same
B. Thomadsen et al.
exposure rate at 1 m as an unencapsulated source
of the same isotope of 10 MBq activity. Since it is
not based on radium sources, apparent activity can
be applicable to low-energy, non-radium-substitute
sources such as 125I and 103Pd sources.
3. Air-kerma strength (SK): Both milligram-radium-
equivalent and apparent activity are associated with
historical variations in their conversion to exposure
in air through the use of the exposure rate constant.
In addition, calculation of dose in water, as is
required for brachytherapy applications, requires an
additional conversion factor between exposure in air
and dose to water. The National Council on Radia-
tion Protection and Measurements (NCRP) recom-
mended specifying source strength in exposure rate
at a stated reference point, usually taken as 1 m.
(NCRP 1974) As the convention turned from using
exposure to air kerma, this specification method
shifted to expressing the source strength in terms of
the air-kerma rate at 1 m, (CFMRI 1983; BCRUM
1984) given the name reference air-kerma rate
(RAKR), with the symbol K_ R (ICRU 1985). RAKR
is used by ICRU and is widely accepted for clinical
dosimetry in all European countries. The American
association of physicists in medicine (AAPM) rec-
ommended the use of the air-kerma strength (SK),
defined as the air kerma in free air along the trans-
verse axis of an encapsulated source, measured at a
large distance from the source such that the source
can be approximated by a point source. (Nath et al.
1987) SK has the units lGy m2 h-1, which are
numerically equal to cGy cm2 h-1, often repre-
sented with the symbol U, and its measured value
should be traceable to a primary standards dosimetry
laboratory PSDL like the National Institute of
Standards and Technology NIST. Both the air-
kerma strength and the RAKR correct the mea-
surement to eliminate the effects of scatter and
attenuation, effectively simulating the source being
in vacuum except for the small mass of air required
for transfer of energy at the measurement distance.
The two quantities, SK and K_ R differ only in that the
RAKR specifically refers to the air-kerma rate at
1 m while the air-kerma strength incorporates the
distance in the quantity by the m2 in the units.
Nowadays, the use of the quantities milligram-
radium-equivalent and apparent activity is strongly
discouraged.
Physics and Clinical Aspects of Brachytherapy
6.3 Single Source Dosimetry
6.3.1 Point Source Dosimetry
Based on general principles, the dose rate in Gy/h at
distance r from a point source is described as:
A  C  fas ;W ðrÞ  Fm
D_ W ðrÞ ¼ ð4Þ
r2
in which A is the apparent activity, usually in Ci; C is
the air-kerma rate per unit apparent activity, conven-
tionally in Gy/h at 1 m; fas,W is the conversion factor to
give dose per air kerma for the medium; and Fm (r)
accounts for absorption and scatter effects in the med-
ium at distance r compared to the same point in vacuo.
For source strengths specified in K_ R or SK, the
following expressions can be used (see for more
details, e.g., Baltas et al. 2007):
 W  
_DW ðrÞ ¼ K_ R ð1  ga Þ len r0 2
fas;W ðr Þ ð5aÞ
q a r
 W  2
l 1
D_ W ðrÞ ¼ SK ð1  ga Þ en fas;W ðr Þ; ð5bÞ
q a r
where ga is the fraction of electron energy liberated
by photons in air that is lost due to radiative processes
such as bremsstrahlung and fluorescence. The term
 W
len=
q a is the ratio of the mass-energy absorption
coefficient of water to that of air.
6.3.2 Line Source Dosimetry
A real source has finite dimensions compared to an
idealized point source. The most common shape of a
brachytherapy line source is a cylinder, either as a
closed end capsule or as a wire cut to a specified
length. Wall material, wall thickness, the details of
the design, and the choice of the active material
influence the resulting dose distribution. In the cap-
sule, Bremsstrahlung photons are generated by beta
particles that may contribute to the dose, and the
capsule may act as a filter for the radiation emitted by
the bare source material. Therefore, the photon energy
spectrum of a realistic source can deviate substan-
tially from that of a bare source. Especially, con-
struction details along the source long axis may lead
to a significant anisotropy in dose deposition.
Calculation of the dose from a line source
including the effects of the attenuation of the jacket
413
uses the Sievert integral. This process divides the
source material into infinitesimal portions and inte-
grates from end to end of the source, accounting for
the oblique filtration through the jack along each ray.
This method is accurate to within 2–8% for 137Cs
sources, but is less accurate at low- and intermediate-
photon energies (e.g., less than 0.4 MeV). Since this
approach does not currently used by commercial
dosimetry computers and a complete discussion of its
many aspects would fill most of a chapter, the inter-
ested reader is referred to (Shalek and Stoval 1969).
A look-up table summarizing the dose distribution
surrounding a line source can be a useful tool for quality
assurance. A point in an away–along table is identified
by its distance away from the source normal to the
transverse axis of the source, and its distance along the
longitudinal axis of the source from the center to that
normal. Table 2 shows such a table for the 3M model
6500 Cs-137 source. Using these tables, the medical
physicist is able to validate the calculations by the
dosimetry computer at points around the source. Away
and along tables have been published for many source
types, both in print (Quimby 1944; Venselaar and
Pérez-Calatayud 2004; Baltas et al. 2007) and on the
internet at the ESTRO web site (http://www.estro.org/
estroactivities/Pages/TG43HOMEPAGE.aspx). This
web site also has postings of brachytherapy source
dosimetry papers and dosimetry parameters compiled
into spreadsheet format. Carleton University similarly
has a web-based database listing brachytherapy
dosimetry parameters for a variety of low- and high-
energy brachytherapy sources (http://www.physics.
carleton.ca/clrp/seed_database/).
6.3.3 TG-43 Formalism
The dosimetry approach of AAPM Task Group No.
43 (TG-43) forms the current standard for brachy-
therapy dosimetry (ICWG 1990; Nath et al. 1995;
Rivard et al. 2004; Rivard et al. 2007). The formalism
relies on superposition of single-source dose distri-
butions obtained in a liquid water phantom with a
fixed volume for radiation scattering. Based on the
assumption of cylindrically symmetric source dose
distributions, the TG-43 brachytherapy dosimetry
formalism utilizes a polar coordinate system with
respect to the source long-axis (z-axis) with the
coordinate system origin located at the center of
radioactivity as shown in Fig. 6a. Dose deposition at
point P(r,h), with radial distance r and polar angle
 414

Table 2 Away–along dose distribution table for 3M model 6500 Cs-137 source
Distance along (cm) Distance away (cm)
0.00 0.25 0.50 0.75 1.00 1.50 2.00 2.50 3.00 3.50 4.00 5.00 6.00 7.00
7.00 0.0193 0.0189 0.0184 0.0180 0.0179 0.0178 0.0176 0.0170 0.0164 0.0156 0.0147 0.0129 0.0111 0.0094
6.00 0.0269 0.0263 0.0254 0.0249 0.0248 0.0247 0.0241 0.0231 0.0218 0.0204 0.0189 0.0160 0.0134 0.0112
5.00 0.0397 0.0386 0.0370 0.0365 0.0365 0.0359 0.0344 0.0322 0.0297 0.0272 0.0247 0.0201 0.0162 0.0131
4.00 0.0638 0.0614 0.0586 0.0584 0.0582 0.0559 0.0517 0.0468 0.0416 0.0367 0.0323 0.0249 0.0193 0.0151
3.50 0.0848 0.0811 0.0774 0.0773 0.0766 0.0719 0.0648 0.0570 0.0495 0.0428 0.0369 0.0276 0.0209 0.0162
3.00 0.118 0.112 0.107 0.107 0.105 0.0949 0.0824 0.0700 0.0591 0.0497 0.0420 0.0304 0.0226 0.0172
2.50 0.176 0.164 0.159 0.156 0.149 0.128 0.106 0.0863 0.0702 0.0575 0.0475 0.0332 0.0241 0.0181
2.00 0.290 0.265 0.257 0.246 0.225 0.178 0.137 0.106 0.0827 0.0657 0.0530 0.0359 0.0257 0.0189
1.50 0.580 0.516 0.489 0.427 0.360 0.249 0.176 0.128 0.0957 0.0737 0.0581 0.0383 0.0268 0.0196
1.00 – 1.580 1.135 0.799 0.582 0.34 0.217 0.149 0.107 0.0807 0.0625 0.0403 0.0278 0.0202
0.50 – 6.569 2.468 1.345 0.852 0.426 0.252 0.165 0.116 0.0855 0.0654 0.0415 0.0284 0.0205
0.00 – 7.806 3.039 1.594 0.973 0.462 0.266 0.171 0.119 0.0872 0.0664 0.0420 0.0286 0.0206
–0.50 – 6.566 2.466 1.343 0.851 0.425 0.252 0.165 0.116 0.0855 0.0654 0.0416 0.0285 0.0205
–1.00 – 1.590 1.136 0.803 0.584 0.340 0.217 0.149 0.108 0.0807 0.0625 0.0403 0.0278 0.0202
–1.50 0.547 0.498 0.489 0.428 0.360 0.249 0.176 0.128 0.0958 0.0738 0.0582 0.0384 0.0269 0.0196
–2.00 0.273 0.251 0.256 0.247 0.226 0.178 0.137 0.106 0.0828 0.0657 0.0530 0.0360 0.0256 0.0189
–2.50 0.166 0.154 0.155 0.156 0.149 0.129 0.106 0.0863 0.0702 0.0575 0.0475 0.0333 0.0241 0.0181
–3.00 0.112 0.106 0.104 0.106 0.104 0.0949 0.0824 0.0701 0.0591 0.0497 0.0420 0.0304 0.0226 0.0172
–3.50 0.0802 0.0767 0.0745 0.0759 0.0760 0.0719 0.0648 0.0571 0.0495 0.0428 0.0369 0.0276 0.0209 0.0162
–4.00 0.0604 0.0582 0.0561 0.0570 0.0575 0.0557 0.0517 0.0468 0.0416 0.0367 0.0322 0.0248 0.0193 0.0151
–5.00 0.0376 0.0366 0.0352 0.0353 0.0358 0.0357 0.0344 0.0323 0.0298 0.0271 0.0246 0.0200 0.0161 0.0131
–6.00 0.0255 0.0250 0.0242 0.0239 0.0242 0.0244 0.0240 0.0231 0.0218 0.0204 0.0189 0.0160 0.0134 0.0111
–7.00 0.0183 0.018 0.0175 0.0172 0.0173 0.0175 0.0174 0.0170 0.0164 0.0156 0.0147 0.0128 0.0111 0.0094
-1 2 -1
Unit of the entries is cGy h /((Gy m 9h ) source strength. (From: Williamson 1998a)
B. Thomadsen et al.
Physics and Clinical Aspects of Brachytherapy 415

approximation, is used if no orientation can be deter-

mined, such as prostate implant reconstruction from
CT images.
SK should be traceable to a primary standards
dosimetry laboratory (PSDL) such as the National
Institute of Standards and Technology (NIST) (Seltzer
et al. 2003). The dose rate constant K has units of
cGy h-1 U-1. The other dosimetry parameters from the
equations take the value of unity at the reference point.
The geometry function, G(r,h) accounts for the
variation of the dose just from the location of the points
due to simplified field theory. In the 1D case the func-
 2
tion reduces to the inverse-square approximation, rr0 .
The ro in the numerator comes from the value of r at the
reference point, removing the dependence for that point
and reintroducing the dependence for the point of
interest. The 2D formalism approximates the distribu-
tion of radiation emissions as a line-segment L, so

b
GL ðr; hÞ ¼ ; ð8Þ
L  r  sinðhÞ

where

b ¼ b2  b1 ð9Þ
Fig. 6 a Coordinate system of TG43 dose calculation formal-
ism. (Figure coutesy MJ Rivard) b The definition of the in Fig. 6b. The geometry function contains the
quantity b greatest part of the dose rate variation.
Dose rate variations on the perpendicular bisector,
h expressed relative to the origin and source long- h0, other than due to geometry, are accounted for by
axis, is given by: the radial dose function, g(r). The point-source radial
dose function is given by
GL ðr; hÞ
D_ ðr; hÞ ¼ SK  K   gL ðr Þðr; hÞ ð6aÞ  2
GL ðr0 ; h0 Þ D_ ðr Þ r
gP ðrÞ ¼  ; ð10aÞ
_Dðr0 Þ r0
r 2
0
D_ ðr Þ ¼ SK  K  gP ðr Þ  /an ðr Þ ð6bÞ
r whereas the line-source radial dose function is
The dose at a reference point P(r0,h0), positioned at
D_ ðr; h0 Þ GL ðr0 ; h0 Þ
r0 = 1 cm and h0 = 908 is gL ðrÞ ¼  : ð10bÞ
D_ ðr0 ; h0 Þ GL ðr; h0 Þ
D_ ðr0 ; h0 Þ ¼ SK  K ð7Þ The last factors in Eq. 10a remove the effects of
The calculation first determines the dose rate at the geometry from the radial dose function so that it only
reference point (Eq. 7), and then, for each factor, reflects the variation in attenuation and scatter as a
removes the value of that factor at the reference point function of distance from the source.
and reintroduces the value for the point of interest. Calculating dose rate to the rest of the plane uses
Equation 6a presents the two-dimensional approx- the anisotropy function, either for the 1D case,
imation for cases in which the source orientation is  2
known, for example, an implant using a gynaecolog- D_ ðr Þ r
/an ðr Þ ¼  ð11aÞ
ical template, while Eq. 6b, the one-dimensional _Dðr;Þ r0
416
or the 2D
D_ ðr; hÞ GL ðr; h0 Þ
FL ðr; hÞ ¼  : ð11bÞ
D_ ðr; h0 Þ GL ðr; hÞ
Again, the last factors remove the geometric
dependence. These dosimetry parameters are
explained in much greater detail in the cited AAPM
TG-43 reports, along with reporting criteria and
good practice recommendations for dosimetry investi-
gators obtaining these parameters using measurements
and/or Monte Carlo (MC) methods. Several other
publications may be helpful as well (Venselaar and
Pérez-Calatayud 2004; Baltas et al. 2007; Rivard 2005).
6.3.4 Determination of Dosimetry
Parameters
Due to the fact that there are usually several dosimetry
publications on a given brachytherapy source model
leading to different data sets, there is a potential for
disparity in dose calculation among different institu-
tions. These data sets are incorporated in dosimetry
computer files and are also used in treatment planning of
patients on cooperative group clinical trials. Potential
for confusion of which data to use could cause vari-
ability in clinical practice and unnecessary variations in
administered dose or even serious dose-calculation
errors. Addressing this problem, the AAPM prepares
consensus dosimetry data sets for sources that satisfy the
requirements of having a NIST standard and two inde-
pendently derived, peer-reviewed sets of the dosimetry
parameters, one using a simulation-based approach like
Monte Carlo. The data for a given source are reviewed
by a panel, and possibly recalculated if discrepancies
occur between the two published data sets. (Rivard et al.
2009a, b) The approved data sets appear on the Radio-
logical Physics Center’s web site. (RPC 2011) The
consensus data sets should be used whenever possible.
Where none exist for a given source type, the user bears
the responsibility to verify the parameters before use in
patients (Rivard et al. 2009a, b).
6.3.5 Model-Based Dosimetry Calculation
Algorithms
The TG 43 formalism gives the dose rate in water,
without any accounting for the effects of the actual
tissue involved. In commercial planning software
packages for external-beam radiotherapy, correction
for heterogeneities has been a topic of interest for
B. Thomadsen et al.
many years following the clinical introduction of
3D-based patient modeling with CT scanning. This
has led to sophisticated and accurate model-based
dose calculation algorithms (MBDCAs) such as
collapsed-cone convolution (CC), superposition-
convolution, Monte Carlo (MC) methods, and grid-
based Boltzmann solvers (GBBS).
For brachytherapy the photoelectric effect is domi-
nant at the low-energy end and the photon interaction
processes are less forgiving of tissue composition than
with higher energy brachytherapy sources or external-
beams, the interactions for which are more determined
by the Compton processes. Thus, the all-water
approximation for dose calculations is worse at low
energies and at intermediate energies than at high
energies (e.g., with E [ 200 keV). Implants near the
skin–air interface and in cases with high-Z shielding are
examples of cases requiring correction for inhomoge-
neities. These differences become accentuated for the
electronic brachytherapy sources where mean photon
energies are generally in the order of 30 keV and for the
low-energy radioactive sources. The report of AAPM
Brachytherapy Subcommittee TG-186 provides a
thorough literature review of this field and guidance for
the early adoption of MBDCAs. (Beaulieu et al. 2011)
The report presents descriptions of the different mod-
eling approaches (CC, MC, GBBS), and guidelines for
benchmarking using a series of realistic cases.
6.3.6 Total Delivered Dose Calculations
The calculation procedures in the previous sections lead
to a result in terms of a dose rate from a source or from a
multiple source implant at a given point, e.g., the dose
prescription point. If the half-life of the radionuclide is
long compared with the treatment time, t, the dose
rate will approximate a constant and the dose will simply
be the dose rate times the duration, Dðr Þ ¼ D_ ðr Þ  t:
However, if the dose rate is not constant but changes
according to the radioactive decay of the radionuclide,
this simple statement modifies into an integration pro-
cedure of the product of dose rate and time.
Given the half-life value of a radioactive isotope,
T1/2, and the initial dose rate D_ 0 ðrÞ at point r from the
source, the total dose delivered to point r in the time
interval [0, t] can be calculated as
Zt lnð2Þt

D ðr Þ ¼ D_ o ðrÞ T1=2 dt; ð12aÞ
0
Physics and Clinical Aspects of Brachytherapy
 
T1=2 lnð2Þt
¼ D_ o ðrÞ 1e T1=2
ð12bÞ
lnð2Þ
 0:693t 
¼ 1:443 D_ o ðr ÞT1=2 1  e T1=2 ð12cÞ
For short treatments using sources with large
lnð2Þt
half-lives, the term e T1=2 can be approximated by
(1 – ln(2) 9 t / T1/2), resulting in Dðr Þ ¼ D_ ðr Þ  t;
as above. Treatments using low-dose rate, short
half-lived isotopes, such as 125I or 103Pd seeds for
temporary implants, such as eye plaques with treat-
ments over five days, incur radioactive decay in situ,
and the integral equation must be used.
Of particular interest is the use of these shorter
lived sources for permanent implants, in which the
integration must be performed from 0 to ‘infinity,’
meaning total decay. Then, the total dose delivered to
a point of interest is given by
Dðr Þ ¼ 1:443 D_ o ðrÞT1=2 ð13Þ
Because of the special importance of the term
1.433 9 T1/2, it is defined as the mean life of an
isotope, i.e., s.
7 Pragmatic Interstitial Dosimetry
Brachytherapy treatments using interstitial technique
insert brachytherapy sources within the target volume,
in order to deliver a prescribed target dose with
acceptable dose distribution homogeneity. Prior to the
development of computerized treatment planning
techniques, several classical implant systems were
developed to calculate, for a given target volume, the
total activity of the sources, number of sources, and
the source distribution within the target volume, for a
given prescription dose. The relationship between the
target dimensions and the total activity often was
given in tabular form, with rules for source distribu-
tion specified for which the tables applied. While the
importance of these classical systems has been
reduced with the use of computerized treatment
planning, they remain fundamental in the planning of
interstitial brachytherapy treatments, both to help
guide the pattern of source distribution within the
target volume for appropriate dose distribution
homogeneity, and to ensure the technical consistency
417
of treatment delivery for all patients. In addition, the
classical implant systems often serve as tools for
independent quality assurance checks of computer-
generated treatment plans.
7.1 Paris System
The Paris System allows treatment of a volume with
adequate accuracy and homogeneity without compli-
cated calculations, using uniform-strength, rectilinear,
and parallel sources in one or more planes. Rules
determine the length of the source wires, number and
separation of the needles, and the number of planes,
and only a small sampling of the rules follow here
(Pierquin et al. 1978; Pierquin and Marinello 1997).
The geometry of the implant is determined in advance
based on clinical evaluation of the target volume. The
number of planes depends on the thickness of the
volume. If this thickness exceeds 12 mm, there should
be more than two planes. The arrangement in squares
or triangles (see Fig. 7a) depends on the shape of the
target volume. With the help of the ratio of treated
thickness to spacing in the chosen source arrangement,
the minimum spacing between the sources and the
number of required sources is determined. The active
length of the sources is calculated from the ratio of the
treated length to active length. Table 3 assumes that
the sources have the same active length, but deviations
may occur due to the shape of the target volume.
Following the rules of the Paris System, large
volumes with high doses can be avoided. These
‘hyperdose sleeves’, volumes with doses [200% of
the prescription dose referred to as high-dose volumes,
should be avoided to reduce the probability of exces-
sive tissue reaction from the treatment. The dimen-
sions of these local hot spots, V200, are determined on
the computer-generated dosimetry (See Fig. 7).
The rigid needle technique was developed in an era
with limited possibilities for 3-dimensional target
delineation. Not surprisingly, many modifications to
this approach were made since its origin. Instead of
rigid needles, many have used flexible tubes to guide
the sources, thus allowing better adaptation to the
target volume and greater comfort to the patient. One
marked advance was the move to 192Ir sources in
ribbons or a stepping source remote afterloader, either
HDR or pulsed dose rate (Van der Laarse et al. 1991,
1994). Any of these approaches allowed improved
418
Fig. 7 a Examples of needle placement and basal dose point
locations: top row––single-plane implant; middle row––trian-
gular-pattern, double-plane implant; bottom row––square-
pattern, double-plane implant. For the double-plane implants,
the dashed lines show the perpendicular bisectors for each side,
with the basal dose points located at their intersections.
b Definition of treated and ‘hyperdose’ volumes (with dose
[200% of the prescription dose) for an implant arranged in
square pattern. (Fig. 7b from Pierquin and Marinello 1997, used
with permission)
optimization of the source strength along a catheter or
needle. Optimization also allowed reduction of the
active lengths of the source trains, leading to better
sparing of the surrounding critical structures, such as
the skin of the breast. All these changes were paral-
leled by the coming of modern imaging techniques for
target definition and implant reconstruction. All the
B. Thomadsen et al.
technological advancements notwithstanding, the
Paris System provided guidelines to produce a rela-
tively uniform dose distribution from a set of uni-
form-strength source wires. Following the guidelines
leaves less work for the optimizer to do, usually
resulting in a more uniform dose distribution.
One of the most enduring parts of the Paris System
is the prescription specification method. For this sys-
tem, in the transverse plane passing through the middle
of the implant, the local minimum dose in the region
bounded by three needles for tiangular-patterened
implants or four needles for rectangular-patterened
implants, defined a basal dose. The average of all the
basal doses through the implant determined the basal
dose (BD). The prescription would be to the reference
dose, RD = 85% of the BD. While the BD charac-
terized the dose through the implanted volume, the RD
surrounded the implant, falling just outside of the
needle perimeter (See Fig. 8).
7.2 Paterson–Parker System
The Manchester system, developed by Paterson and
Parker in 1934, aimed to deliver a dose that was
uniform within 10% of the prescribed or stated dose
on designated dosimetric planes for planar implants or
within a treated volume (Paterson and Parker 1934,
1938). The system provided rules for positioning
sources with differential strengths, based on the size
of the target volume. The Patterson–Parker dose
tables gave the cumulative source strength required to
deliver a specified dose as a function of the treated
area (planar implants) or volume (Williamson 1998b).
For a single-plane, the dose specification applies to a
plane 0.5 cm on either side of the plane of the nee-
dles, so that the treatment covers a slab of tissue 1-cm
thick. For a two-plane implant, the dosimetric plane
falls 0.5 cm from an implant plane towards the other
needle plane, not at the midplane for any separation
between the planes other than 1 cm. All planar
implants used an interneedle spacing of 1 cm. A two-
plane implant provides adequate dose uniformity up
to a separation of needle planes of 2 cm. Larger
volumes required volume implants in the form of
cylindrical or multiplane implants, or with permanent
sources, eliptical implants. The original system
applied to radium needles but also works well with
192
Ir sources. For each of the implant types, the ideal
Physics and Clinical Aspects of Brachytherapy 419

Table 3 Predictive relationships in the Paris System for rectilinear sources equal in length
Patterns Ratio of treated length to Ratio of treated thickness Ratio of lateral margin Ratio of safety margin
active length to spacing to spacing to spacing
2 lines 0.7 0.5 0.37 –
N lines in 1 0.7 0.6 0.33 –
plane
N lines in 0.7 1.55-1.60 – 0.27
squares
N lines in 0.7 1.3 – 0.20
triangles
Adapted from Gerbaulet et al. (2002)

allowing a higher dose at the center of the treatment

Fig. 8 An example of simulated crossing needles using
iridium sources
application used crossing needles perpendicular to the
needle planes at the needle tips and ends to prevent
the reduction of dose near the ends of the source
strength. With 192Ir sources in ribbons or HDR remote
afterloaders, the crossing needles can be simulated
by adding an additional position at the end of the
loading pattern for a needle or catheter, as shown
in Fig. 8. Table 4 provides a summary of some of the
Manchester loading rules. Again, using the distribu-
tion rules to guide an implant provides a good starting
point for the computer’s optimization routine. More
complete discussions of the Manchester system can
be found in Thomadsen and Hendee (1999).
volume than near the periphery, assuming that the
center of a tumor required higher doses for treatment
(Quimby 1952). In contrast to the Quimby approach,
the Manchester system specified that the dose within
the treated volume fell within 10% of the prescribed
dose. The periphery of an implant likely has the
lowest dose, corresponding to 10% below the nominal
dose for a Manchester implant. A Quimby volume
implant, unlike a Manchester implant, specifies the
dose approximately 0.25 cm outside of the implanted
volume, similar in concept to the Paris System. Thus
for a Quimby volume implant, the dose through the
target is always higher than the prescribed dose.
However, for a planar implant, the Quimby system
specifies the dose at the center of the target plane,
which with uniform strength loading, will be the
highest dose in that plane. Even with an implant with
a computer optimization to produce a relatively uni-
form dose throughout a volume, there will be regions
of high dose near the sources. Understanding this
unavoidable increase in dose in the target volume may
be responsible, at least in part, for the success of
brachytherapy, and recognizing the volumes in excess
of about twice the prescribed dose may not improve
tumor control but may increase toxicity, the Quimby
approach has mostly disappeared in practice.
7.4 ICRU 58 Reporting
Recommendations

In 1997, the ICRU published its report no. 58 on the

7.3 Quimby System dose and volume specification and reporting of
interstitial brachytherapy (ICRU 1997). The report is
This system, developed by Quimby in 1932, is based on specification, recording, and reporting; it is not a
on applying a uniform distribution of source strength, description of a system or approach to brachytherapy.
420 B. Thomadsen et al.

Table 4 Manchester implant rules

Planar implants
Area of the plane (cm2) Fraction of the source material on the periphery Fraction of the source material on the interior
\25 2/3 1/3
25–100 1/2 1/2
[100 1/3 2/3
Volume implants
Distribution rules for a Manchester cylindrical implant
Section Minimum no. of needles Parts
Belt 8 4
Core 4 2
End As needed 1 ea.(crossed at active end)
2 ea. (crossed at physical end)
Planar implants: Needles should be about 1 cm apart; 1-plane implant covers a thickness of 1 cm; 2-plane implant cover between
1 and 2 cm; For 2-plane implants, the source material should be divided between the planes; Full-strength = 0.66 mg/cm and;
Half-strength = 0.33 mg/cm
Spherical implants: Spherical implants find the most application in permanent seed placements. In the spherical case, the division
of the radioactive material follows;
Shell (the outer surface): 6 parts
Core: 2 parts
The material in the core should be distributed as uniformly as possible, and for both divisions, the separation between seeds should
remain between 1 and 1.5 cm

Continuing the conceptual path set forth by the ICRU
report no. 50 (ICRU 1993), the report defines the
gross target volume (GTV) as the tumor volume
visible on imaging or clinically palpable target vol-
ume, and the clinical target volume (CTV) as the
volumes of potential tumor spread or microscopic
diseases. The treated volume is that volume of tissue,
based upon the implant as actually achieved, which is
encompassed by an isodose surface selected or
specified by the radiation oncologist as being appro-
priate to achieve the purpose of the treatment. The
dose value at this surface is the minimum target dose.
For brachytherapy treatments, the planning target
volume (PTV) is considered to be identical to the
CTV, as no source positioning uncertainties within
the target volume is included. Furthermore, the report
recommends the description of the source patterns of
the implant and the calculation of the TRAK value, as
it is analogous to the old mg h concept, proportional
to the integral dose to the patient, and can also serve
as a useful index for radiation protection of person-
nel. A clear description of the time pattern of the
implant should be recorded to provide the informa-
tion about dose and time for the calculation of
instantaneous and average dose rates in continuous
low dose rates, and PDR and HDR fractionation
schemes.
The report defines dosimetric concepts similar to
those used in the Paris System, renaming the basal
dose points as central dose points and the Basal Dose
becomes the mean central dose (MCD). It expands on
the Paris System by allowing for the use of multiple
central planes when the implant is such that one
central plane may not intersect all implanted needles.
Furthermore, it recommends the reporting of the low-
dose (LD) volume, defined as the volume of the CTV
receiving \90% of the prescription dose, and the
high-dose (HD) region, defined to be the tissue
receiving greater than 150% of the MCD. ICRU
report 58 also recommends reporting of the dose
homogeneity index (DHI) of the implant, defined to
be the ratio of the minimum target dose (MTD) to the
MCD, echoing the Paris System concept of implant-
ing a target such that 85% of the average basal dose
should cover the target and therefore be used as the
prescription dose.
The report was issued at the edge of modern
brachytherapy. Clinical experience with miniaturized
interstitial HDR, and later PDR, 192Ir afterloading
techniques was still limited, and even more relevant,
Physics and Clinical Aspects of Brachytherapy 421

Fig. 9 Size of the clinical target volume (CTV) according to

ICRU 58. As a minimum, the three physical dimensions of the
CTV to be reported are the three maximum diameters measured
in orthogonal directions. They are noted as length L along the
needle direction, width W perpendicular to L in the plane of the
needles, and height H, orthogonal to L and W

the potentials of modern imaging technology using

CT, MR and ultrasound and dosimetry based on
image-based targets were yet to be elaborated. Since
then, functional MRI and PET scanning have been
added to the toolbox of the oncology clinician. The
lack of target information is reflected in the limited
depth of the report when discussing volume defini-
tions for CTV (see for example Fig. 9), descriptions
of organs at risk and dose-volume concepts for
reporting, although the added value of 3-dimensional
information was recognized, and tables of parameters
for reporting with ‘‘3D or multiplane computation
needed’’ included in the report. The report was largely
based on the implant geometry, rather than on the
clinical structures.

7.5 Image-Based Reporting Quantities

The current practice with image-identified targets and
sensitive structures uses other descriptors of implants.
All the evaluation quantities begin with a dose vol-
ume histogram (DVH), a display of how a function of
the volume varies with the dose (or dose rate) in the
implanted volume. Figure 10 shows several forms the
DVH can take. Some of the more common and most
useful are described below.
Fig. 10 Natural, differential, and cumulative dose-volume
histograms (DVH) of an interstitial APBI HDR treatment plan.
a Natural DVH. b Differential DVH. c Cumulative DVH.
(From: Li 2005)
yDx––The dose to which x of the volume of
structure y is raised. Sometimes x is absolute
volume and sometimes the percent of the structure.
422
For example CTVD90% is the dose covering 90% of the
CTV, while rectumD0.1cc is the minimum dose covering
the hottest 0.1 cm3 of the rectum. While in these
examples little confusion is likely, some cases may be
ambiguous––all cases should include the designator
for the ‘‘x’’ with units of volume or percentages. In
addition, the dose, D needs to be clarified as whether
the value is an absolute dose or a percentage of the
prescribed dose.
yVx––The fraction of structure y raised to dose x.
The ‘‘x’’ may be a fraction of the prescription dose, for
example CTVV90% is the fraction of the CTV raised to
90% of the prescribed dose, or it may be an absolute
dose, such as CTVV60Gy. Further uncertainties come
with the volume; sometimes V is absolute volume and
sometime the fraction of the region of interest. Again,
indications of units or percentage are required.
Relative dose homogeneity index (HI)––The frac-
tion of the target volume receiving a dose between the
prescription dose and the high-dose level (Saw and
Suntharalingham 1988). Often the high-dose level is
taken as 150% of the prescription dose, and
HI ¼CTV V100% CTV V150% ð14Þ
where the volumes are the percent of the CTV raised
to at least the percentage of the prescription dose
given. With no volume exceeding 150% the value is
unity. As the volume that exceeds 150% increases, the
HI decreases.
Dose non-uniformity ratio (DNR)––The ratio of
the high-dose volume taken at least to the target dose
(Saw and Suntharalingham 1988).
DNR ¼CTV V150% =CTV V100% ð15Þ
Small numbers indicate that little volume exceeds
the high-dose level.
Conformation Number (CN) (van’t Riet et al. 1997)
(also known as Conformality Index, COIN) (Baltas
et al. 1998)––A measure of the conformance between
the prescribed dose distribution and the target, given by
CTV V100% CTV V100%
CN ¼  ð16Þ
V100% CTV V
where V100% is the volume enclosed by the pre-
scription isodose surface, CTVV is the volume of the
CTV, and each of the volumes in Eq. 16 are absolute.
The COIN index defined by Baltas was later
B. Thomadsen et al.
expanded by Milickovic et al. (2002) to include
organs at risk (OARs), leading to a COIN index being
the product of three components, c1, c2 (the two ratios
in Eq. 16) multiplied by c3:
CN ¼ c1  c2  c3
CTV V100%
c1 ¼
V100%
CTV V100% ð17Þ
c2 ¼
CTV V
NYOAR
 
OARi VðDOARi [ i Dcrit
c3 ¼ 1
i¼1 OARi V
where OARi V is the volume of the ith organ at risk
and iDcrit is the critial dose for the OAR above which
should be avoided.
COIN in this form assumes that the PTV, the
OARs, and the surrounding tissue are of equal
importance. Values close to unity are best. The first
factor considers how efficiently the dose distribution is
used, moving towards unity as the prescription isodose
matches the CTV. The second factor addresses cov-
erage of the CTV by the prescription isodose. The
third factor considers exessive dose to organs at risk.
If there are more than one OARs defined in the plan-
ning process, C3 is the product of each ratio.
Maximum significant dose (MSD)––The isodose
surface with the highest dose that encompasses more
than one source. This is another, but different, mea-
sure of the excessive dose in an implant. In general,
MSD should remain less than 1.5 times the prescribed
dose. As the MSD increases above that, the likelihood
of toxicity increases.
8 Example Implants
8.1 Breast Implant
There are several different techniques of applying a
brachytherapy boost dose to the female breast.
A typical example is the use of rigid needles
implanted in a regular triangular or square pattern,
with a dosimetry system based on the Paris System.
Needles are supposed to be straight, equidistant, and
may contain linear sources such as the 192Ir wire
sources of uniform linear activity. The Paris System
Physics and Clinical Aspects of Brachytherapy
Fig. 11 a Unoptimized versus b optimized dose distribution
Paris System breast. In the optimized case the dwell positions
are all within the target volume. Reprinted from Radiotherapy
and Oncology 45 (1): Anacak et al. (1997), with permission
from Elsevier
provides rules for the choices for the number of layers
of needles, the needles itself, the spacing between the
needles, and the active length of the source wires
(Pierquin and Marinello 1997). These choices are
guided by the clinical examination of the size of the
target volume. Because no crossing needles are used,
the active length of the sources must be longer than
the length of the target. The needles were usually
fixated using a template with a grid of holes from a
repository. The basic rules of the Paris System were
discussed in Sect. 7.1.
Figure 11a shows the dose (rate) distribution of a
simple, single-plane implant calculated according to
these rules. The normalization was performed on the
basal dose points. The average dose rate of all basal
dose points is called the basal dose rate DB and is set
equal to 100% (MCD). The experience of the appli-
cation of the Paris System in these implants led to the
general rule to define the dose prescription to the
target on the isodose (rate) line of 85% of the value of
DB. In this way, the entire target volume in general
receives at minimum the prescription dose. The 85%
isodose line extends well outside the pattern of the
needle implant. A quick estimation of the size of this
extension follows from the ‘rules’. Figure 11b shows
the implant optimized for a remote afterloader. In this
case, the dwell positions all remain within the target.
Figure 12 illustrates a typical technique used for
loading sources into catheters in a patient.
Breast brachytherapy has become much more
widespread with accelerated partial breast irradiation
(see ‘‘Accelerated Partial Breast Irradiation’’).
423
Fig. 12 Technique used to insert flexible catheters for inter-
stitial accelerated breast irradiation. a Inserting a needle
through a tumor. b Inserting a catheter through the needle.
The needle will then be pulled through the tumor, leaving the
catheter in place. c Placing buttons on the ends of the catheter
to hold it in place. d Illustration of a template to guide the
placement of the catheters and hold them in place during
treatment (Courtesy of J. Venselaar.)
8.2 Esophageal Application
Afterloading brachytherapy for treatment of advanced
obstructive broncheal tumors uses applicators with a
small diameter of about 1.7 mm. However, for
esophagus tumors it is prefered to perform an appli-
cation with an intraluminal applicator with a diameter
as large as possible, due to the reduced dose gradient
over the esophageal wall and therefore the lower
contact doses to the mucosa. For patient comfort,
HDR-brachytherapy with its short treatment duration
is a common practice. The applicators are often single
catheters, allowing the treatment of cylindrically or
elipitically shaped PTVs. Applicators are available
with diameters between 6 mm and 20 mm. In a wide
esophageal lumen, the larger applicators are used
preferentially, whereas applicators with small diam-
eters are reserved for obstructing lesions. Attention
must be paid to potentially irregular contact with the
mucosa. Generally, the applicators carry a smaller
424
Fig. 13 Commercial available esophagus tube used for end-
oluminal treatment. Reproduced courtesy Nucletron
tube fitting the inner diameter of the applicator. The
applicator is moved over a guide wire that is first
inserted in the lumen under imaging guidance. The
outer surface of applicators usually carries a scale in
cm similar to endoscopes. Endoscopy is normally
used to identify the upper and lower extensions of a
target in the esophagus, which can then be marked
under fluoroscopy. Figure 13 shows an esophagus
applicator set commercially available from one of the
vendors of the afterloading equipment.
The position of the applicator can be verified with
fluoroscopy or on CT images. The tip of the appli-
cator should reach several centimetres beyond the
distal end of the visible tumor to cover the length of
the PTV adequately. The length of the PTV (PTL) is
determined taking into account tumor length, safety
margins for subclinical extension and positional
uncertainties as e.g. catheter displacement. The dose
distribution should include coverage of the entire
PTL. The radial depth of treatment comes from the
visible tumor on the localization images (gross tumor
volume) plus the margin for subclinical disease,
giving the CTV. In the radial direction, no margin
around the CTV to form a PTV is required because
there is unlikely significant movement in that
direction with the proper tube size. The dose at the
tube-mucosa interface must be considered and may be
the limiting factor in the delivery of the prescription
dose to the radial extent of the CTV.
Considerable experience has been gained using this
technique as a boost to external-beam therapy without
CT guidance. Using radiographic localization, the
Treated Length should include the PTL at the depth of
B. Thomadsen et al.
the prescription point (intersection with the 90% iso-
dose). The length of the reference volume (reference
volume length: RVL) includes the PTL at the refer-
ence depth (intersection with the 90% isodose). Most
often, when small diameter applicators are used such
as in endoluminal bronchus applications, doses are
prescribed and reported at a reference point 10 mm
from the source axis. For the esophagus, there is a
practice to use dose prescription and reporting that
reflects the individual situation in a patient related to
the applicator and the esophageal lumen. Often, a
reference point at 5 mm from the applicator surface, or
at 5 mm tissue depth is chosen. Three-dimensional
imaging may reveal tumor extension and then mini-
mum peripheral dose can be reported for the parts of
the tumor volume receiving the lowest dose.
Taking the different historical reference points, the
reported reference doses, and the dose gradients,
doses vary significantly, in particular when taking into
account the different diameters of the applicators used
(2–20 mm.) With a 5–10 Gy reference dose per
fraction, the dose to the lumional surface falls
between 10 and 30 Gy. It is now generally recom-
mended to record and report the dose at 5 mm tissue
depth (reference depth) from the lumen-applicator
surface (lumen-applicator radius + 5 mm) and at the
lumen-applicator surface, indicating the dose gradient
in the tumor and the normal tissue and the dose at the
lumen/tumor surface. Figure 14 gives samples of dose
distributions for three applicators.
9 Process of Brachytherapy
Treatment Planning and Delivery
The successful delivery of a brachytherapy treatment
is a coordinated effort among hospital personnel
across a wide spectrum of expertise, including the
radiation oncologist, surgical oncologist, radiation
physicist, medical dosimetrist, radiation therapist, the
nursing staff of radiation oncology, surgery, recovery,
and hospital floor units, and other support personnel.
Careful planning, scheduling, and communication for
a brachytherapy treatment are the keys to its suc-
cessful completion. Various pre-surgery patient tests
and exams must be performed before considering the
patient eligible for the surgical insertion of brachy-
therapy applicators. The results of such tests must be
Physics and Clinical Aspects of Brachytherapy
Fig. 14 Dose distribution and reporting for different applicator
diameters of 6, 10, 15 mm. The prescribed depth (PD), the
reference depth (RD), and the applicator surface (AS) are
indicated, in addition to the diameter and the radius of
the applicator (3, 5, 7.5 mm). The length of the reference
volume (RVL) is defined as the length of the 90%-isodose at
the reference depth of 5 mm. The active source length (ASL) is
also given, which is always longer than the RVL. The RVL
should enclose the PTL as tightly as possible. (Gerbaulet et al.
2002)
communicated to the radiation oncologist and radia-
tion physicist in a timely manner, such that adequate
time remains for the ordering, shipping, and receipt of
the sources to be used for the patient if needed. In an
institution that provides a large number of brachy-
therapy treatments, such as permanent prostate
implant or HDR partial breast treatment, it is often
helpful to have a radiation oncology staff member
designated for the overall scheduling of patients. Such
a person must coordinate with the radiation oncologist
and the operating room (OR) staff for the surgical
aspects of the treatment, in addition to coordinating
the activities germane to the brachytherapy aspects of
the treatment, as discussed below. Checklists can be
helpful to document the timely completion of each of
the landmark events in the overall brachytherapy
treatment, identifying the information required and its
recipients at the completion of these landmark events.
425
The order of the steps of the brachytherapy process
varies with the actual treatment. For example, imag-
ing for the dose calculation follows the applicator
insertion for a tandem and ovoids application for
cervical cancer but precedes the needle insertion for a
permanent prostate implant. Notwithstanding the
order, most procedures use most of the steps.
9.1 Brachytherapy Planning
While often used interchangeably, treatment planning
and dosimetry form very different and distinct steps in
a brachytherapy procedure. The term ‘‘dosimetry’’
itself may refer to dose calculations for a brachy-
therapy procedure either before or after its execution
or it could mean making in vivo measurements. The
goal of treatment planning for a brachytherapy pro-
cedure is to determine such aspects of the treatment as
the type of procedure, the appropriate applicators and
sources required for the treatment, the geometry of
the application such as needle or source positions and
whether high or low dose rate or permanent approach
will be used.
Planning does not always result in a physical iso-
dose plan for the intended treatment, but determining
the underlying principles of an isodose distribution,
i.e., establishment of the relation between sources and
the dose distribution, is always a part of planning.
For example, the planning for an HDR interstitial
treatment would estimate the number of catheters
required for the treatment, as well as the spatial dis-
tribution and arrangement of the catheters. Such
specifications of catheter number and distribution
can typically be based on one of the classical implant
systems that established predictable relations between
the catheter distributions and the resultant dose distri-
butions. Rules and nomograms exist for specific tech-
niques, such as with the permanent prostate implants,
which are based on clinical experience and pretreat-
ment volume measurements, e.g., ultrasound imaging
for prostate implants. For HDR applications, post-
implant treatment planning can be used for optimizing
the dose distribution to mitigate the effects of minor
needle misplacements. However, optimization cannot
make a poor implant good, careful planning of not only
how the implant should look but also how to control the
implant to follow the plan becomes essential.
426
9.2 Source and Applicator Preparation
The applicators and sources specified in planning are
subsequently prepared. Such preparation may be as
simple as making sure that the tandem and ovoids
applicators, the associated surgical instruments such as
dilation sets and sounding rulers (a pliable sound used
to measure uterine depth and angle), and the sources
are available. Custom applicators and templates may
need to be fabricated or acquired for the more complex
treatments. In all cases, the applicators and instruments
are collected and sterilized so as to be ready for the
procedure. A member of the nursing or radiation
therapist staff should be designated for this task.
Many interstitial brachytherapy treatments require
acquisition of sources as specified in planning for the
treatment. Regulatory agencies require that an insti-
tution’s radioactive material license be on file with a
source vendor before the vendor may ship the sources
to the institution. The radiation physicist or radiation
safety officer should ensure that this has been done
prior to source ordering.
A secure room must be available for temporary
storage of the sources, equipped with a shielded
source safe, an L-block shield, source handling tools,
and source assay instruments, as source preparation is
typically performed in this room. During source
receipt and preparation, the radiation physicist per-
forms radiation contamination tests on the source
packaging to ensure its integrity. These tests include
an inspection of the physical condition of the pack-
aging, removable of radiation contamination wipe
tests, and measurement of radiation exposure rates at
the package surface and 1 m away from the package.
Records of the results of these tests must be
maintained.
The custody of the sources, upon receipt in the
institution and through to final source disposal, should
be ensured. Regulatory bodies at both the national/
federal and state levels require that the chain of cus-
tody for radioactive materials be maintained, and the
location of sources is known at all times. A source
inventory is performed at the receipt of the sources in
comparison with the source order. Any discrepancies
must be investigated through communication with the
vendor, and, in the event that a source is deemed to
have been lost, reported to regulatory authorities
immediately. Source accounting is further performed
through the entire process of source preparation, with
B. Thomadsen et al.
the locations of the sources and the times when the
sources are moved between locations documented.
The strengths of the sources must be confirmed to
be in agreement with the values ordered and the values
used for treatment planning. The AAPM recommends
that the institution perform an independent source
strength assay, using a dosimetry system with sec-
ondary traceability to a NIST/ADCL standard in the
United States or National standards in other countries
(Kutcher et al. 1994; Nath et al. 1997). Source strength
assay is typically performed using a well-type ioni-
zation chamber and electrometer system. This system
should be calibrated at the ADCL every 2 years, and
its constancy verified using a long-half-life source,
such as a 137Cs source, at the beginning of each day
when the system is to be used for source strength
assay. Similar guidelines have been published by
Venselaar and Pérez–Calatayud on behalf of ESTRO
(2004). The users’ responsibilities in calibration were
in a report of the AAPM low energy brachytherapy
source calibration working group (Butler et al. 2008).
9.3 Applicator and Catheter Insertion
The insertion of applicators is usually performed in an
OR or a procedure room under sterile or clean con-
ditions. Accuracy of applicator positioning is crucial
in realizing the planned dose distribution. The radia-
tion oncologist and physicist involved in the brachy-
therapy treatment should discuss in detail the catheter
insertion procedure prior to performing the procedure,
and ensure that each step of the procedure is well
understood by all persons in the OR to minimize
miscommunications and to achieve maximum effi-
ciency for the successful insertion of the applicator.
The aspects of the applicator insertion procedure in
the OR usually include the following:
1. Having the plan available in the OR where appli-
cable. The physicist should ensure that a plan for a
multiple catheter implant be available in an easily
interpretable format in the OR, so that the position
and depth of each catheter can be looked up
quickly and without ambiguity. In addition, the
physicist should be prepared to evaluate the posi-
tioning accuracy of catheters as they are inserted,
such that their dosimetric effect may be estimated,
and additional catheters may be inserted to achieve
the desired dose distribution.
Physics and Clinical Aspects of Brachytherapy
2. Confirmation of target and critical organ localiza-
tion. Surgical clips, markers, or other target
localization media, such as contrast solution in a
lumpectomy cavity for breast implant, should be
placed in the target volume, such that they can be
used to assess the adequacy of applicator insertion
by imaging later. Similarly, markers may be
placed near critical organs, such as blood vessels
and nerves, such that radiation doses to these
critical organs may be minimized.
3. Determination of catheter insertion approach on
the patient’s skin when applicable. For interstitial
implants, the catheter insertion approach may
depend on the surgical approach for gross tumor
removal. The entrance and exit points of the
catheters should be evaluated to allow accurate
catheter insertion, to minimize the number of
catheters used, and to facilitate ease of source
loading. If the treatment is to be delivered on an
outpatient basis in multiple fractions, the termi-
nation of catheters should allow for easy securing
of the catheters to avoid their movement within the
tissue, and to minimize the possibility of their
damage between treatment fractions. After the
catheter insertion approach has been selected, a
ruler should be used to measure the catheter
entrance and exit points on skin to facilitate the
accurate and efficient catheter insertion. Templates
provide excellent guidance for placement of cath-
eters when compatible with the treatment site.
4. Assessment of catheter insertion accuracy. As the
procedure proceeds, the accuracy of catheter
insertion should be periodically reviewed, using
imaging techniques appropriate for the procedure,
including fluoroscopic X-rays, ultrasound, and
other imaging techniques, such as CT or MRI for
CT/MRI-guided procedures. Catheters deviating
significantly from planned positions should be
re-inserted, or additional catheters inserted, so that
the desired dose distribution as planned may be
achieved. At the completion of applicator insertion,
a set of images should be obtained and reviewed, to
confirm that all the catheters were inserted cor-
rectly, and to serve as guidance for later dosimetry
calculations. For treatments delivered in multiple
fractions, the initial images of applicator and
catheter positioning are often useful to evaluate
the positioning of applicator and catheter insertion
of subsequent treatment fractions. Deviations of
427
subsequent applicator and catheter insertion from
the initial images should be evaluated. Repeated
imaging at each fraction is useful to identify inter-
fraction movement.
9.4 Source and Applicator Localization
Except for cases where the implant images obtained in
the OR are used directly for dose distribution calcula-
tions, such as in intra-operative high dose rate prostate
treatments (Kini et al. 1999), the dose distributions of
the implant are usually calculated based on images
acquired after the completion of applicator insertion.
The clinical practice in the last decade has moved
dramatically from planar-based radiographs towards
the use of CT and MR imaging. For tissue contouring
MR often is superior to CT, although for the advanced
model-based dose-calculation algorithms, the avail-
ability of 3D CT information is crucial.
For multiple-catheter implants, the individual
catheters must be labelled by identification numbers
prior to imaging. As appropriate for the imaging
modality used, markers are inserted into the catheters.
Coded markers are commonly used for radiographic
imaging. These same markers may not be suited for
CT scanning due to the scattering artefacts in the
images. MR markers are completely different from
those used for either radiographs of CT. The corre-
spondence between the radiographic markers and the
catheter numbering should be recorded for reference
during treatment planning.
Patient images need to be acquired to permit accu-
rate applicator and catheter localization and dose cal-
culations. For each type of brachytherapy implant, an
imaging protocol should be developed and adhered to,
with the parameters of these protocols chosen to min-
imize the imaging artifacts, and to allow accurate
applicator, target, and critical organ localization. Tests
must be performed to acquire the knowledge of the
accuracy of seed placement and seed reconstruction in
implant techniques (see e.g., Siebert et al. 2005, 2007).
Breathing artifacts in 3D imaging and even in orthog-
onal radiographs can significantly increase the uncer-
tainties in applicator and catheter localization accuracy,
as well as in the delineation of treatment target and
critical organs. Figure 15 shows an orthogonal pair of
radiographs for the HDR treatment of bile duct, where
the patient breathing motion artifact caused up to 1-cm
428
Fig. 15 Breathing motion artifacts in the X-ray images of a
bile-duct brachytherapy treatment. The catheter positions differ
by up to 1 cm between the two anteroposterior–posteroanterior
differences in the y-coordinates of the X-ray markers.
The physicist needs to evaluate the dosimetric conse-
quences of such imaging artifacts, and communicate
with the treating physician to arrive at the optimal
actions to be taken in the patient’s treatment.When
volumetric imaging is used for brachytherapy treatment
planning, the field of view (FOV), slice thickness, table
pitch, and gantry angle of the scans need to be reviewed
to assure that they conform to the scanning protocol
established for the particular brachytherapy treatment.
Deviations from the established scanning parameters
may reduce the accuracy of applicator, target and crit-
ical organ localization, and could result in significantly
increased dose calculation uncertainties.
When orthogonal or other types of planar radio-
graphs are used, the isocenter of the radiographs
should be placed near the center of the target volume.
The magnification factors of the radiographs and
gantry angles need to be confirmed. The coordinate
system used on a radiotherapy simulator may be dif-
ferent from the IEC coordinate system used in some
treatment planning systems. The conversion of gantry
angles between the two coordinate systems must be
done correctly to avoid significant source localization
errors. The technique used should allow clear and
unambiguous recognition of applicators, surgical
clips, and radiographic markers on the images. The
quality of images directly impacts the accuracy
B. Thomadsen et al.
images supero-inferiorly. a Anteroposterior image of bile-duct
HDR treatment, patient free breathing. b Same image as a,
except with patient holding breath. (From Li 2005)
of subsequent dose distribution calculations. It is
therefore important that treatment-site-specific imag-
ing protocols be developed, and that a physicist or
dosimetrist familiar with the treatment be present dur-
ing the imaging. More than in the past, deep knowledge
of all aspects of modern imaging technology and pro-
cedures including the awareness of the proper quality
assurance issues is crucial (Mutic et al. 2003; Cormack
2008). This is also true in situations where the team
makes use of equipment from other departments, such
as a radiology department. It should be part of the
education and training program of the medical physi-
cist. Figure 15 illustrates the problems that could arise
during localization imaging.
9.5 Treatment Planning and Quality
Assurance Review of Brachytherapy
Treatment Plan
The localization images of the brachytherapy implant,
once approved by the treating physician, are used for
calculation of dose distribution and treatment planning
of the implant. The volumes and the source applicators
and source positions are localized on the images, and
dose distributions are calculated based on the principle
previously discussed. It is critical that the numbering
of catheters on the images and the sources to be
Physics and Clinical Aspects of Brachytherapy
inserted into the catheters are identified accurately in
the treatment plan as miscorrelations in these param-
eters result in significant dose-calculation errors. The
source strengths and their spatial distributions may
be selected such that the calculated dose distributions
are optimized to conform the prescribed isodose to the
target and to minimize critical organ doses.
Following the completion of dose-distribution cal-
culations for a brachytherapy implant, the treatment
plan should be reviewed by a medical physicist for its
appropriateness for the treatment, accuracy, and dose
distribution quality and consistency with previous
similar treatments (Kubo et al. 1998; Li 2005). During
this review, the treatment prescription is reviewed for
appropriateness for the treatment by comparison with
institutional treatment protocols or national treatment
guidelines. The treatment-plan input parameters,
including imaging parameters, source localization
accuracy, and source calibration and dosimetric
parameters are evaluated for appropriateness and
accuracy. The dose distribution is reviewed for
homogeneity, adequate target dose coverage, and
acceptable critical organ doses. Automatic optimiza-
tion algorithms and parameters, when used, should be
reviewed for the appropriateness of their selections.
Dose volume histograms are useful tools and inspec-
tion of calculated measures of uniformity, quality, and
coverage parameters should be registered. Institutions
build their own expertise on these parameters when
treating larger numbers of similar cases. In the same
way, documentation of TRAK is useful as an indicator
of correct dose calculation in a cohort of similar
treatments with the same dose prescription.
For permanent seed implants, the treatment plan-
ning is often performed intraoperatively in the oper-
ating area. The same care is needed for the interactive
evaluation of the plans, but under time pressure.
Methods and practices used in institutions for intra-
operative imaging and planning techniques for the
prostate brachytherapy were extensively reviewed by
Polo et al. (2010).
9.6 Source Loading and Treatment
Delivery
Depending on the complexity of the treatment design,
source loading may occur either before or after
treatment planning is completed. In either case, the
429
loading of sources into applicators and catheters starts
delivery of the brachytherapy treatment. Similar to
the directives in other countries, in the United States,
federal and state regulations require that a written
directive for the treatment must be completed by a
physician authorized by the relevant regulatory bodies
prior to the start of treatment. Throughout the treat-
ment delivery process, the number of sources, source
loading pattern, source strengths, and source dwell
times must be verified to be in agreement with the
prescription. A record of the sources removed from
brachytherapy source storage room, and the time of
source removal, must be kept as required by regula-
tions and to ensure that all brachytherapy sources are
accounted for at all times. Appropriate radiation sur-
veys need to be performed, following the loading of
brachytherapy sources, to ensure that all areas in close
proximity to the patient room are free of radiation risk
to both patient care personnel and to visitors to the
hospital. The results of these radiation surveys,
together with appropriate warning signs and instruc-
tions, should be posted. A shielded radioactive source
container, together with source-handling tools, need
to be kept in the patient’s room for handling of
sources that may have dislodged from the patient.
When the treatment is completed, the sources are
removed from the applicators and catheters,
accounting for all implanted sources. The applicators
and catheters are subsequently removed. A radiation
survey of the treatment room is performed to ensure
that all radiation sources have been removed. The
sources are returned to the brachytherapy source
room, and the appropriate source inventory docu-
mentation is completed for regulatory compliance.
Afterloaders should be stored and locked away such
that unintended use is impossible.
10 Radiation Protection
and Regulatory Compliance
in Brachytherapy
Significant radiation protection issues exist with the
clinical practice of brachytherapy due to its use of
radioactive materials, which, unlike electrically acti-
vated radiation machines, cannot be turned off at will.
Radioactive materials implanted in patients produce
radiation exposures around the patient that must be
limited to avoid high radiation exposures to the public
430
and to patient care personnel. The sources need to be
under strict control to prevent their misplacement and
subsequent accident radiation exposure. Significant
errors in dose calculation and deviations in treatment
delivery from prescription and treatment plan may
cause irreparable harm to the patient.
The regulations for radiation and radioactive
materials vary tremendously between countries. In the
United States, the use of radioactive materials falls
under the jurisdiction of the nuclear regulatory com-
mission (NRC). The atomic energy act of 1954 cre-
ated the atomic energy commssion (AEC). To
separate the nuclear development from the regulatory
aspects of the AEC, in 1974 Congress split the AEC
into the Department of Energy to develop energy
sources and the NRC to regulate nuclear materials.
The NRC has entered into agreements with many
state agencies to delegate its authority to the indi-
vidual states, called agreement states. The agreement
states exercise their authorities in compliance with
NRC regulations, although such states often create
regulations that apply uniformly to all therapeutic
radioactive materials. Title 10, part 35 of the Code of
Federal Regulations (10CFR35) details the federal reg-
ulation requirements on the medical use of by-product
radioactive materials, including brachytherapy sources
(USNRC 2011).
10.1 Licensing, Authorization and Report
of Medical Events
A radioactive materials license is required for the
possession of brachytherapy sources. The NRC or an
agreement state grants this license after the applicant
institution has established radiation protection proce-
dures that satisfy requirements of the NRC or the
agreement states. For the most part, the regulatory
requirements include identification of a radiation safety
officer or the establishment of a radiation safety com-
mittee with members including representatives from
institution administration, authorized users, and other
interested parties in the institution’s radiation protection
program. The radionuclides, the maximum amounts,
and their clinical uses are specified in the license.
The NRC and the agreement states require that all
brachytherapy treatments be performed under the
supervision of an authorized user physician for any
brachytherapy treatment. Furthermore, the technical
B. Thomadsen et al.
aspects, such as source strength calibration and
machine quality assurance review for HDR units must
be performed under the supervision of authorized
medical physicists. The NRC specifies training
requirements for authorized users and authorized
medical physicists according to the specific modality,
including didactic classroom training and practical
clinical training.
The regulations define a medical event for brachy-
therapy in §35.3045. There are several criteria for a
medical event but the most relevent are:
• When there is a deviation of the total delivered
dose by more than 20% from the prescribed dose;
• When a fraction deviates from the prescribed dose
by more than 50%; or
• When the dose to any organ or tissue other than the
target exceeds that expected by the treatment plan
by more than 50%.
When a medical event occurs, the regulations
require reporting to the appropriate governing bodies,
the NRC or the appropriate agreement state agency,
as well as the patient and the patient’s referring
physician, via telephone within 24 h of the identifi-
cation of the event. A written report to the regulatory
agency is required within 15 days of the identification
of such events. The occurrence of a medical event
may trigger an investigational visit by the regulatory
agency, during which the root cause of, as well as the
proposed corrective actions for, the medical event are
reviewed. Such an investigational visit often reviews
the entire relevant radiation protection program at the
institution, including, for example, all modalities of
brachytherapy treatments, in order to identify other
potential weaknesses of the program.
10.2 Radiation Safety Concerns
in Permanent Implants
For permanent brachytherapy treatments, a primary
concern is the radiation exposure produced by the
radioactive sources that remain in the patient. As it is
often impractical to keep such patients hospitalized
under strict radiation-protection control, the NRC
permits release of patients with permanently implan-
ted brachytherapy sources, as long as the radiation
exposure levels from the sources near the patients are
sufficiently low. For prostate implants, radiation
exposure levels of less than 10 lSv/h (1 mrem/h) at
Physics and Clinical Aspects of Brachytherapy
1 m from the patient is sufficient for release of the
patient with written instructions given to the patient
on how to minimize radiation exposures to his family
members. Such written discharge instructions typi-
cally explain the radiation exposure risk associated
with the sources implanted in the patient, and ask the
patient to take precautions to further minimize such
risks, such as: sleeping in a separate bed from his
spouse for a given period of time; keeping a safe
distance ([1 m) from pregnant women and from
children, except for short periods (e.g., 30 min) per
day of close contact; and handling of sources that may
have migrated out of the prostate and into the bladder,
and subsequently discharged in urine.
All brachytherapy sources for permanent prostate
implants are encapsulated in thin titanium shells,
making them easily damaged. Damaged 125I seeds are
of particular radiation protection concern, as they may
release radioactive iodine into the environment. Such
sources must be handled with care to prevent trauma.
For sources embedded in absorbent sutures, extreme
care must be exercised to avoid damaging the sources
when cutting the sutures.
With the heightened security measures in recent
years, radiation monitors have been installed in
transportation checkpoints and public access areas.
The radioactive materials implanted in patients
receiving permanent prostate implant have the poten-
tial to activate such monitors. It is therefore advisable
that the patient be given a card, listing the procedure
performed on the patient, the radionuclide, the total
activity administered, its half-life, and the contact
telephone number of the radiation therapy center.
10.3 Safety and Regulatory Issues in HDR
Brachytherapy
The HDR brachytherapy treatments, due to its use of
high-activity radiation sources, are under even greater
regulatory oversight by the NRC and the agreement
states. The regulations require detailed daily and
periodic quality assurance tests of the treatment unit
performance, as well as associated radiation safety
control interlocks and equipment. In the United States,
authorized users, authorized medical physicists, as
well as treatment unit operators are required to
undergo annual radiation safety in-service training,
which includes aspects of the HDR source
431
characteristics, machine operating principles, and
emergency procedures in cases where the source is
stuck inside a treatment applicator or catheter. The
records of such annual training must be maintained.
The treatment planning system must be tested to
assure correction function and its dose-calculation
accuracy. An independent calculation check of a
treatment plan must be performed for each patient
planned on the treatment planning system. At the
initiation of an HDR treatment, the physical presence
of an authorized user, as well as an authorized medical
physicist, is required. Once the treatment has started,
the authorized user may be replaced by a physician
trained in the emergency removal of the treatment
applicators. Details for such checks can be found in
Thomadsen (1999).
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 Principles and Clinical Applications
of Pulsed Dose Rate Brachytherapy
Bethany Anderson, Christine Haie-Meder,
and Erik Van Limbergen

Contents Abstract
Pulsed dose rate (PDR) brachytherapy (BT) was first
1 Historical Background ............................................ 436 proposed in 1991 (Brenner and Hall Int J Radiat
2 Radiobiology............................................................. 436 Oncol Biol Phys 20(1):181–190, 1991), and has
been increasingly put into clinical use over the past
3 Practical Aspects...................................................... 438
two decades. This technique unites the benefits
4 Applicator Design and Treatment Planning ........ 440 of the modern stepping-source afterloading unit
4.1 Applicator Design...................................................... 440
(radiation safety and dose optimization) with the
4.2 Treatment Planning ................................................... 440
radiobiologic advantages of low dose rate (LDR)
5 Techniques and Clinical Outcomes by Disease BT. Almost every LDR or high-dose rate (HDR)
Site ............................................................................. 441
5.1 Cervical Cancer ......................................................... 441 technique can be adapted for PDR-BT, with
5.2 Vaginal and Vulvar Cancer....................................... 446 appropriate modifications of the applicator and
5.3 Anal Cancer ............................................................... 446 the dose schedule. Conservative continuous treat-
5.4 Esophageal Cancer .................................................... 447 ment regimens with overall dose and treatment
5.5 Breast Cancer............................................................. 448
5.6 Bladder Cancer .......................................................... 449 time equivalent to standard LDR-BT have been
5.7 Penile Cancer............................................................. 450 most widely accepted; however, ‘‘office hour’’ or
5.8 Prostate Cancer .......................................................... 451 ‘‘daytime’’ PDR-BT regimens have also been
5.9 Head and Neck .......................................................... 452 modeled and studied on a more limited basis. When
5.10 Soft Tissue Sarcoma.................................................. 452
5.11 Pediatrics.................................................................... 453 transitioning from HDR or LDR to PDR-BT, it is
5.12 Re-irradiation ............................................................. 454 recommended that changes in overall technique and
6 Ongoing Studies and Future Directions ............... 455
prescription method be introduced gradually, in a
step-by-step fashion. Careful attention to national
References.......................................................................... 456
regulations regarding issues such as shielding
requirements and availability of authorized user(s)
B. Anderson
Department of Human Oncology, during treatment is mandatory. PDR-BT has been
University of Wisconsin, 600 Highland Avenue, successfully applied to many tumor types, as
Madison, WI 53792 USA summarized in this chapter. One major use of the
C. Haie-Meder (&) technology has been for MRI-guided cervical
Institut Gustave Roussy, Brachytherapy Unit, cancer BT, which has been the subject of two large
114 rue Edouard Vaillant, 94800 Villejuif, France multi-institutional clinical trials (EMBRACE and
e-mail: christine.haie@igr.fr; Christine.HAIEMEDER@igr.fr
STIC-PDR (Cancer Radiother 10(6–7):402–409,
E. Van Limbergen 2006; Cancer Radiother 12(6–7):527–531, 2008)).
Department of Radiation Oncology,
University Hospital Leuven, Leuven, Belgium A multi-institutional German-Austrian trial of

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 435
DOI: 10.1007/174_2011_262, Ó Springer-Verlag Berlin Heidelberg 2012
436 B. Anderson et al.

accelerated partial breast irradiation delivered (LDR-BT). Stepping-source high dose rate (HDR)
via PDR or HDR-BT has also been conducted afterloading technology with highly active artificial
(Brachytherapy 1(3):149–153, 2010). nuclides was introduced in the 1970s. This allowed
improved radioprotection of staff and dose optimiza-
tion, but posed some risk for increased late toxicity
due to the rapid administration of large doses per
Abbreviations fraction.
APBI Accelerated partial breast irradiation In 1991, Brenner and Hall (Brenner and Hall 1991)
PDR Pulsed dose rate published a sentinel paper proposing conditions under
PDR-BT Pulsed dose rate brachytherapy which (BT) administered as a series of brief pulses
LDR Low dose rate could be biologically equivalent to traditional con-
MDR Medium dose rate tinuous LDR-BT. When administered in this fashion,
SCC Squamous cell carcinoma pulsed dose rate-brachytherapy (PDR-BT) offers
DFS Disease-free survival the same possibilities for radiation safety and dose
LC Local control optimization as HDR-BT, while maintaining the
EBRT External beam radiation therapy radiobiological advantages of LDR-BT. The princi-
MUPIT Martinez Universal Perineal Intersti- ples set forth in that paper have been applied to
tial Applicator clinical practice since the early 1990s. In the early
Ir Iridium PDR experience, many institutions used this tech-
OAR Organs at risk nology strictly to imitate conventional LDR-BT
HNC Head and neck cancer implants (i.e., identical dose and overall treatment
BED Biologically effective dose time), with minimal geometric dose optimization.
GEC-ESTRO Groupe Européen de Curiethérapie- Three dimensional (3D)-guided treatment planning
European Society for therapeutic offers the potential for further individualization of
radiation oncology dosimetry, and alternative fractionation regimens
ASTRO American Society for radiation have also been developed (i.e., ‘‘office hour’’ or
oncology ‘‘daytime’’ PDR-BT), as discussed in this chapter.
ABS American Brachytherapy Society General characteristics of PDR-BT as compared with
ASBS American Society of breast surgeons LDR and HDR are summarized in Table 1.
5-FU 5-Fluorouracil
DVH Dose volume histogram
LVSI Lymphovascular space invasion 2 Radiobiology
F Fraction
STIC Soutien aux Thérapeutiques PDR-BT is delivered by a single source that moves
Innovantes et Coûteuses stepwise through the implant, pausing to deliver
EMBRACE International study on MRI-guided treatment at numerous dwell points under the control
brachytherapy in locally advanced of a computerized afterloading unit. A low radiation
cervical cancer dose (typically 0.3–1 Gy) is delivered in this fashion
to the entire target volume, and then repeated several
times over the course of hours to days in a series of
‘‘pulses’’ to administer the total prescribed dose. The
1 Historical Background original objective of PDR-BT, as proposed by
Brenner and Hall (1991), was to give a series of short
Brachytherapy (BT) has been used to treat cancer HDR pulses, such that the overall treatment time and
since shortly after the discovery of radium by Marie average dose rate would be equivalent to LDR-BT
Curie and Henri Becquerel. Over the years, clinical (Fig. 1). In doing so, the advantages of a stepping-
experience has yielded a solid foundation of knowl- source afterloading unit (i.e., radioprotection of staff
edge regarding tumor control and normal tissue and dose optimization) could be realized while pre-
effects produced with low dose rate-brachytherapy serving the radiobiological advantages of LDR-BT.
Principles and Clinical Applications of Pulsed Dose Rate Brachytherapy
Table 1 Advantages and disadvantages of LDR, HDR, and PDR brachytherapy
Advantages
LDR Radiobiologically less damage to late-reacting
normal tissues
Several decades of clinical experience
HDR Dose distribution can be optimized by altering
fraction size and location
Typically outpatient treatment
No radiation exposure to medical staff
Critical organs may be temporarily displaced for
treatment, in certain cases
PDR Off-time each hour allows the patient to receive
nursing care and visitors
Less shielding of treatment rooms required, as
compared with HDR units
Dose distribution can be optimized by altering
pulse size and location
Dose rate (cGy/h) can be prescribed for each
patient
No radiation exposure to medical and nursing staff
Fig. 1 Examples of LDR and PDR schedules that deliver dose
at an average rate of 0.5 Gy/h. The biological effects of these
regimens may be very different. (Ref. Radiotherapy chapter
GEC-ESTRO handbook of RT) CLDR continuous low dose rate
The majority of PDR-BT teams continue to use
PDR to mimic LDR implants, although the 37 GBq
Ir-192 afterloader has also been used to administer
437
Disadvantages
Hospitalization required
May lead to radiation exposure to medical staff
May require pre-ordering and preparing sources
for each individual patient
Radiobiologic effect on late-reacting normal
tissues is inferior to LDR
Typically requires an increased number of
fractions, as compared with LDR or PDR
Hospitalization required
Majority of treatment is not supervised directly
(i.e., by physician and physicist), so an emergency
protocol must be developed to be initiated by
dedicated nursing staff. Authorized user(s) must be
on-call during treatments
Less clinical data currently available, when
compared with LDR and HDR
HDR-like treatment schedules (Izard et al. 2006).
There are many variables under the control of the BT
team, including the activation/deactivation of dwell
points within the applicator, the relative amount of
time spent by the source at each point (dwell weight),
the dose per pulse, and the time interval between
pulses. Theoretically, treatments may therefore be
prescribed along a continuum between traditional
LDR-BT and traditional HDR-BT.
The therapeutic ratio between PDR and LDR
depends on multiple factors, including total dose per
pulse, pulse interval, and tissue repair characteristics
(i.e., a/b ratio and DNA repair half-time). Repair
kinetics have a significant impact upon the radiobi-
ologic effect of PDR-BT because repair of sublethal
DNA damage within tumors and normal tissues is
incomplete between pulses. At this time, uncertainties
exist regarding DNA repair parameters that make
radiobiological modeling for PDR-BT challenging.
Experimental data suggest that this complex, dynamic
process may follow a multi-exponential model with
fast and slow phases of repair. For practical purposes,
438
the kinetics of sublethal damage repair is typically
described in an exponential fashion, with a repair
half-time (t‘). Repair t‘ values of 30–60 min are
typical for tumors and early-reacting normal tissues,
whereas late-reacting normal tissues have a longer
average repair t‘ of approximately 90 min.
Furthermore, experiments providing the basis for
theoretical calculations of PDR-BT have typically been
performed using ‘‘pulses’’ given with external beam
equipment. For example, 0.5 Gy may be given over
10 min at a dose rate of 0.05 Gy/min or at 0.1 Gy/min
in 5 min. This differs from the administration pattern of
PDR-BT, during which a single stepping source moves
through the entire area to be irradiated, delivering the
majority of the dose at approximately 0.2 Gy/min. This
has been aptly described as the ‘‘golf ball’’ effect
(Fowler and Van Limbergen 1997). Biologically
equivalent doses calculated without accounting for this
effect tend to overestimate the tolerance of late-react-
ing normal tissues.
Despite these challenges, most PDR protocols have
been modeled to mimic continuous LDR-BT (Brenner
and Hall 1991; Brenner et al. 1995). The linear-
quadratic model formulated for incomplete mono-
exponential sublethal damage repair is commonly
used in clinical practice, as a practical means to
compare regimens with different doses and dose rates
(Dale 1985). This model does not account for the
effects of dose and dose rate heterogeneity throughout
the treated volume, which are more pronounced in BT
than in EBRT. It is generally agreed that small pulses
should be given per hour. Treatment schedules
with pulse sizes of 0.5–1.5 Gy repeated every 1–3 h
are expected to reproduce the biologic effects of
conventional LDR to within 10%, unless the sur-
rounding late-reacting normal tissues have a very
short repair t‘ (Fowler and Van Limbergen 1997).
With larger pulse sizes and shorter repair times,
cytotoxic effects increase significantly in cells with
lower a/b ratios (i.e., late-reacting normal tissues), as
shown in Fig. 2.
PDR schedules have also been designed to allow
delivery of treatment exclusively during office hours
(or extended office hours). The first such set of ‘‘office
hour’’ or ‘‘daytime’’ schedules was calculated by
Visser et al. (1996), using the linear-quadratic
model with an incomplete repair formulation. These
regimens typically prescribe a larger dose per
fraction, with a longer interval between fractions.
B. Anderson et al.
To preserve the therapeutic ratio (i.e., maintain
equivalent tumor control probability without signifi-
cantly increasing the risk for late toxicity), longer
overall treatment times are required for treatment
regimens that deviate increasingly from traditional
LDR (Visser et al. 1996). Daytime treatment sched-
ules may allow clinicians to overcome logistical
barriers to the implementation of PDR-BT, and
therefore merit further investigation. Because of the
uncertainties in a/b and especially repair t‘ values,
and the relative lack of current evidence about clinical
outcomes, more conservative regimens simulating
continuous LDR-BT are still recommended outside
the context of a clinical study.
3 Practical Aspects
The typical PDR unit houses an active 18.5–37 GBq
Ir-192 source, welded at the tip of a 1.5 m-long steel
wire, as well as a dummy check source. Because the
source strength is 1/10 that of a typical Ir-192 HDR
afterloader (370 GBq), the amount of shielding
required for a PDR-BT treatment room may also be
correspondingly less. In some cases, a shielded
hospital room used to care for patients receiving
traditional LDR-BT may be converted for use with
PDR-BT without adding additional shielding, pro-
vided that the machine will be used to deliver
LDR-like regimens with comparable average hourly
absorbed-dose rate (Gy m2 h-1) and total treatment
absorbed dose (Gy m2) (Management of Radionuclide
Therapy Patients, Report No. 155: National Council
on Radiation Protection and Measurements 2006).
Regulations do vary significantly by region and coun-
try, however, so close attention to national policies is
required. For example, in France, shielding calcula-
tions must be performed as if the source would be
outside the PDR unit at all times, while in other coun-
tries estimated duty times are taken into account.
Clinical feasibility studies have shown that several
LDR-BT techniques can be adapted for PDR-BT
without significant technological difficulty (Gerard
et al. 1999; Peiffert et al. 2001). Koedooder et al. (2008)
analyzed the error messages that occurred among 1,300
PDR treatment sessions using stepping-source tech-
nology. Of 20,000 delivered pulses, only 0.2% was
disturbed by some type of error. The routine use of
dummy check runs minimized the percentage of errors
Principles and Clinical Applications of Pulsed Dose Rate Brachytherapy
Fig. 2 Biological effect of four different PDR schedules, each
delivering dose at an average rate of 0.5 Gy/h. When pulse
doses exceed 1 Gy, isoeffect to continuous LDR is only present
occurring during the active phase of treatment, i.e.
when the source was outside the afterloader. In this
institutional experience, no manual source withdrawal
was necessary. The authors do emphasize, however, the
need to proactively implement an emergency reaction
protocol, for which dedicated nursing or radiotherapy
technologist staff plays a crucial role. In the United
States, NRC regulations currently state that an autho-
rized medical physicist and an authorized user (or
trained physician under the supervision of an autho-
rized user) must also be physically present for the ini-
tiation of a PDR-BT treatment and immediately
available any time a treatment is being given (Code of
Federal Regulations. In: Commission USNR, ed. 10
CFR 35.6152002).
In the experience of Koedooder et al. (2008), error
frequency varied by disease site, due to the nature of
the applicators used. Implants containing several
439
when half-life of repair is longer than 30 min (Fowler and Van
Limbergen 1997)
flexible plastic catheters were more likely to have an
error, such as friction or obstruction during outdrive
or indrive of the dummy source. In the case of bladder
cancer implants, the authors maintained a low
frequency of errors by inserting flexible steel wires
into the catheters in between pulses, thereby
preventing them from kinking within the patient.
Problems with kinked or otherwise impaired catheters
impeding passage of the source have been encoun-
tered at other centers using PDR-BT (Peiffert et al.
2001; Blank et al. 2007). In nearly every case,
the implant may be delivered as initially intended by
manually-afterloading iridium wires, since the cathe-
ters used for PDR-BT are of slightly larger caliber
than those used for LDR-BT. Other solutions, such
as supplemental EBRT (Pieters et al. 2011) may
sometimes be necessary, however, particularly for
institutions without ready access to LDR Ir-192.
440
4 Applicator Design and Treatment
Planning
Many aspects of PDR-BT applicator placement and
treatment planning can be adapted with minor devi-
ation from protocols already in place for LDR or
HDR-BT. When transitioning from LDR or HDR to
PDR-BT, it is generally recommended that changes
be introduced in a stepwise fashion. Here, we describe
general principles, with particular attention to issues
which are unique to PDR-BT. Additional information
pertinent to specific disease sites can be found in the
corresponding sections of this chapter.
4.1 Applicator Design
The applicators used to deliver PDR-BT are funda-
mentally equivalent to those used to deliver LDR-BT.
Gynecologic PDR-BT may be performed using a
variety of intracavitary applicator types, such as tan-
dem and ovoids, tandem and ring, and tandem with a
customized vaginal mold. Interstitial PDR-BT
implants should be performed according to the
guidelines of a traditional LDR-BT system (i.e., Paris,
Manchester, Quimby). The majority of published
interstitial PDR-BT results to date have been achieved
by investigators following the Paris system. Dose
optimization is often beneficial to improve the quality
of the dose distribution, but cannot substitute for poor
quality catheter placement.
Minor modifications of BT applicators may be
required to allow passage of the Ir-192 source and to
enable appropriate CT/MRI imaging, if indicated. For
example, the caliber of interstitial catheters must be
slightly larger for PDR-BT than for manually-after-
loaded Ir-192 wires (i.e., 17.5 gauge vs. 19.5 gauge).
This seemingly insignificant change requires careful
planning prior to attempting to replace an LDR-BT
implant with PDR-BT, as many accessory compo-
nents such as templates and buttons may not be
compatible with the larger catheters. In certain cases,
catheter placement must also be thoughtfully altered
to allow unimpeded passage of the source. For
example, traditional loop implants performed for
LDR-BT of the tongue or oropharynx may be
replaced by two parallel tubes with increased dwell
B. Anderson et al.
times at the tips, depending on the techniques that are
used (Sethi et al. 1996).
4.2 Treatment Planning
As with HDR-BT, PDR treatment planning is com-
puter-based and may be performed using any imaging
method (i.e. digitized orthogonal X-rays, CT scan and
MRI). CT or MRI scans provide very valuable 3D
information concerning the position of the applicator
with respect to tumor and organs at risk (OAR), and
also reveal inadvertent events such as perforation of
the uterus, bladder, or small bowel.
After appropriate imaging and volume delineation,
if required, the treatment-planning process begins
with the creation of a plan using standard loadings
for each tumor type. Dwell points can be activated
at 1 mm for Flexitron, 2.5 or 5.0 mm intervals.
As described above (see Radiobiology), continuous
treatment regimens prescribing small, frequent pulses
are most widely accepted. At the Institut Gustave
Roussy, an initial PDR-BT plan is often prescribed in
0.5 Gy hourly pulses to standard reference points for
intracavitary implants, and in 0.4 Gy hourly pulses to
the 85% isodose (Paris system) for interstitial
implants. There are exceptions, however. The lip, for
example, is more tolerant for radiation therapy despite
being treated with an interstitial technique, and is
preliminarily planned at 0.5 Gy/hour.
The standard plan may then be modified or
‘‘optimized,’’ to achieve goals such as improving tumor
coverage, reducing dose or dose rate to normal tissues,
and decreasing the magnitude of hot and cold spots. For
example, dwell times toward the edges of an interstitial
implant may be increased to reduce the inward bowing
of isodose lines between planes. Dose optimization
cannot compensate for poor quality catheter placement
or inappropriate applicator type. However, the
3D-guided optimization process may alert the BT team
to the fact that tumor coverage is suboptimal with a
standard applicator, allowing for corrective steps to be
taken for the current or subsequent implants (i.e., the
addition of interstitial needles to an intracavitary
implant (Jurgenliemk-Schulz et al. 2009)).
Optimization may be performed manually, by
manipulating the source dwell positions and dwell
weights (i.e., doubling the relative dwell time at
Principles and Clinical Applications of Pulsed Dose Rate Brachytherapy
certain positions) in a step-by-step manner, then
evaluating the impact upon dose to tumor volumes
and OAR. This method is the most straightforward
and controllable, and allows the brachytherapist to
gain valuable experience with adapting a standard
loading pattern. Manual dose optimization is also
highly user-dependent, however, and practical
guidelines have not been clearly established. Some
treatment-planning systems also offer partially auto-
matic optimization tools (i.e., dragging isodose lines
for so called graphic optimization) or inverse-
planning software. Caution must be applied when
using such tools, as the resulting loading pattern and
dose distribution can deviate significantly from stan-
dard techniques, sometimes producing very large
high-dose areas that are not readily apparent on the
dose volume histogram (DVH). Chajon et al. (2007)
have compared the dose distributions achieved via
manual optimization with those produced by one
inverse planning simulated annealing (IPSA) software
program in cervical cancer PDR-BT. The treatment
plans calculated by IPSA had notably heterogeneous
dwell time values, which were considered clinically
unacceptable due to the significant deviation from
traditional—but gold-standard—LDR-BT dosimetry.
Two new constraints were therefore developed—a
maximum time constraint (Tmax) for the individual
dwell points, and a minimal volume dose constraint
(Vdummy) for artificial ‘‘dummy’’ structures extending
5 mm around each BT catheter. Plans generated by
IPSA utilizing these two constraints were compared
with manually optimized plans and found to have
significantly less average D2cc to rectum (58.2 vs.
57.9 Gy, p = 0.009), bladder (68.6 vs. 70.7 Gy,
p = 0.016), and vagina (95.6 vs. 100.2 Gy, p = 0.012),
with slightly higher overall implant quality, as
measured by the conformal index (mean 0.44 vs. 0.41,
p = 0.007). The mean overall planning time required
was approximately 90 min for each method,
as time saved by automatic dose optimization with
IPSA was spent creating dummy volumes around the
catheters.
During the optimization process, attention should
also be paid to other parameters which may influence
toxicity, including the implant volume and total ref-
erence air kerma (TRAK), which represents the
integral dose delivered to the patient (similar to
mg-hours of radium). TRAK values from different BT
schedules cannot be compared directly, because the
441
biological effectiveness depends on both dose rate and
fraction size.
5 Techniques and Clinical Outcomes
by Disease Site
At this time, there have been no prospective
randomized trials comparing PDR with LDR or
HDR-BT. A strong foundation of clinical experience
is building, however, across multiple disease sites.
The majority of this experience has been in Europe,
although a few cancer centers in North America and
elsewhere have also adopted the technology. For any
of the treatment sites, more information might be
found in the respective disease-specific chapters of
this book.
5.1 Cervical Cancer
In recent years, there has been growing interest in
PDR-BT for cervical cancer. For example, a survey of
Canadian radiation oncologists, published in 2009,
found that 9% were planning to switch from LDR to
PDR-BT (Pearce et al. 2009). A variety of applicators
may be used, such as tandem and ovoids, tandem and
ring, and tandem with a customized vaginal mould.
Interstitial implants may also be performed for
patients with locally advanced disease that extends
beyond the high-dose area of an intracavitary appli-
cators. Recently, applicators have been developed
which allow the placement of a limited number of
interstitial needles transvaginally into the parame-
trium (Jurgenliemk-Schulz et al. 2009; Kirisits et al.
2006a). The choice of applicator depends upon
institutional experience and extent of disease.
After placement of the applicator, imaging is per-
formed to calculate the dose distribution. In 2007,
ABS members were using CT (55%), plain films
(43%), or MRI (2%) to plan cervical cancer BT
(Viswanathan and Erickson 2010). PDR-BT may be
performed using digitized orthogonal X-rays, pre-
scribing dose to point A. CT or MRI-based planning
is highly recommended, if feasible, to permit dose
optimization (see below). Of course, this requires the
use of specially designed nonmetallic or titanium
applicators that do not produce significant image
distortion. MRI is superior to CT for visualizing the
442
tumor, particularly parametrial invasion and regres-
sion related to prior pelvic EBRT; however, CT and
MRI are equally useful for delineating the bladder,
rectum, sigmoid colon, other adjacent bowel, and
vagina.
For CT-guided planning, intravenous contrast is
preferred to improve visualization of the cervix and
the uterine vessels, which can help define the upper
aspect of the cervix in otherwise ambiguous cases.
For MRI-guided planning, the vagina may be
packed with gauze soaked in diluted gadolinium (i.e.,
1:10) to improve visualization, although this is not
needed with the customized vaginal mould. The Foley
catheter balloon should also be filled with 7 cc’s of
dilute gadolinium (i.e., 1:1). In lieu of the standard
‘‘dummy sources,’’ tubes filled with fluid are placed
into the BT catheters during MRI scanning. Such
tubes are commercially-available; alternately, in-
house tubes filled with materials such as peanut oil
(Lindegaard et al. 2008) or glycerin (Chargari et al.
2009) have been used. Certain aspects of applicator
reconstruction may still be challenging, such as
determining the precise location of the first dwell
positions in each source train. It may be helpful to use
information gained from other imaging methods (i.e.,
T1-weighted MRI, CT, or X-rays) and/or applicator
templates for some commercially-available applicator
sets (Chargari et al. 2009; De Leeuw et al. 2009;
De Brabandere et al. 2008; Kirisits et al. 2006b). The
dose distribution generated from CT or X-rays must
then be matched to MRI using points visible on both
imaging studies (i.e., tips and center of applicator,
probes and bony structures). Target volumes and
OAR are contoured on T2-weighted MRI images,
according to published GEC-ESTRO guidelines
(Potter et al. 2006; Haie-Meder et al. 2005) (Table 2),
which have been accepted in both Europe and the
United States (Viswanathan and Erickson 2010). The
systematic use of these recently defined concepts and
terms is encouraged, to facilitate communication and
comparison of the results achieved with different
institutional BT methods.
Regardless of the type of imaging used, a plan
prescribing dose to point A using standard loading is
generated first. Computerized treatment planning
software is then used to determine the dose to stan-
dard ICRU reference points and, for 3D planning, the
D2cc of OAR (bladder, rectum, sigmoid colon, small
bowel) and coverage of the HR-CTV and IR-CTV.
B. Anderson et al.
In this process, total dose prescribed from EBRT
and BT is calculated according to the ‘‘worst-case’’
scenario, for which OAR are assumed to have
received the full prescribed EBRT dose (i.e., often
45 Gy), and it is further assumed that the same 2 cm3
of each organ will receive the highest dose from
each BT fraction or during each delivered pulse.
GEC-ESTRO recommends calculating these doses in
EQD2, using a/b = 10 for tumor and a T1/2 of 1 h
and a/b = 3 for OAR, with a repair t‘ of 1.5 h
(Potter et al. 2006). An alternative method for esti-
mating the cumulative dose to target volumes and
OAR has also been investigated, wherein the BED
and EQD2 values of each voxel for each plan are
added and averaged (Van de Kamer et al. 2010).
The standard plan may be optimized using
information from CT or MRI to improve tumor
coverage and limit dose and/or dose rate to normal
tissues (Fig. 3). Several dosimetric analyses have
demonstrated the value of MRI-guided dose opti-
mization for PDR-BT in cervical cancer (Table 3)
(Jurgenliemk-Schulz et al. 2009; Lindegaard et al.
2008; De Brabandere et al. 2008; Tanderup et al.
2010; Jurgenliemk-Schulz et al. 2010). In this pro-
cess, the ‘‘pear-shaped’’ isodose distribution gener-
ated by standard loading is sculpted manually
(Jurgenliemk-Schulz et al. 2009; Lindegaard et al.
2008; De Brabandere et al. 2008) or graphically,
i.e., by dragging and dropping isodose lines while
visually controlling the effect on dwell times in
order to avoid excessive differences (Jurgenliemk-
Schulz et al. 2009). Automated dose optimization
using IPSA software has also been studied in the
context of cervical cancer BT (Chajon et al. 2007),
as described above (see Treatment Planning). In
some cases, clinical judgment must be used to
achieve a reasonable balance between tumor cover-
age and doses to OAR (Tanderup et al. 2010). As a
check, the TRAK may be compared between the
standard 2D plan and the optimized 3D plan, to
ensure that the optimization process has reallocated
radioactivity according to the patient’s anatomy,
rather than subtly increased the integral dose.
At this time, the dosimetric parameters that cor-
relate best with tumor control and morbidity have not
been definitively established. Examples of published
institutional treatment-planning goals for PDR-BT are
provided in Table 2. At some institutions, the pre-
scribed dose per pulse is reduced (and the total
Principles and Clinical Applications of Pulsed Dose Rate Brachytherapy 443

Table 2 Overview of GEC-ESTRO guidelines and examples of institutional optimization goals for 3D MRI-guided cervix
PDR-BT
Structure GEC-ESTRO definition Examples of institutional PDR-BT optimization goals
GTV Macroscopic tumor extension at time of BT (clinical
exam and high signal intensity masses on T2-weighted
MRI)
HR-CTV GTV, whole cervix, presumed extracervical tumor Total dose as high as possible and appropriate to
extension at time of BT (clinical exam and ‘‘grey eradicate all residual macroscopic tumor
zones’’ on T2-weighted MRI) (i.e., C80–90 Gy) (Haie-Meder et al. 2005)
D90 C 85 Gya/b10 (Lindegaard et al. 2008; De
Brabandere et al. 2008)
D90 = 84 Gya/b10 (Jurgenliemk-Schulz et al. 2009)
IR-CTV HR-CTV plus a safety margin of 5–15 mm, including Total dose to eradicate significant microscopic dose
areas involved with tumor at diagnosis and respecting (C60 Gy) (Haie-Meder et al. 2005)
natural anatomic borders V(60 Gya/b10) = 100% (De Brabandere et al. 2008)
3
Rectal Minimum dose to maximally irradiated 2 cm of D2cc B 75 Gya/b3 (Jurgenliemk-Schulz et al. 2009;
D2cc rectum, contoured as a solid structure Lindegaard et al. 2008)
D2cc B 75 Gya/b3, B0.6 Gy/h (De Brabandere et al.
2008)
D2cc B 70–75a/b3, B0.5 Gy/h (Chargari et al. 2009)
Bladder Minimum dose to maximally irradiated 2 cm3 of D2cc B 90 Gya/b3 (Jurgenliemk-Schulz et al. 2009;
D2cc bladder, contoured as a solid structure Lindegaard et al. 2008)
D2cc B 85 Gya/b3, B0.6 Gy/h* (De Brabandere et al.
2008)
D2cc B 80–85a/b3, B0.5 Gy/h (Chargari et al. 2009)
3
Sigmoid Minimum dose to maximally irradiated 2 cm of D2cc B 75 Gya/b3 (Jurgenliemk-Schulz et al. 2009;
D2cc sigmoid, contoured as a solid structure Lindegaard et al. 2008)
D2cc B 75 Gya/b3, B0.6 Gy/h (De Brabandere et al.
2008)
D2cc B 70–75a/b3, B0.5 Gy/h (Chargari et al. 2009)
Current recommendations for target definition, recording, and reporting of 3D gynecologic brachytherapy have been published in
more detail elsewhere (Potter et al. 2006; Haie-Meder et al. 2005). At this time, it is not clear what parameters correlate best with
early and late complications, so reporting of the D0.1cc, D1cc, and D2cc for OAR is recommended. Examples of published
institutional dose-planning goals for PDR-BT are provided; all doses are cumulative from EBRT and brachytherapy D90 dose
received by 90% of target volume; * subsequently increased to D2cc B 90 Gya/b3 (De Brabandere et al. 2008)

number of pulses correspondingly increased) if the
optimized plan demonstrates a high-dose rate to OAR
(Lindegaard et al. 2008; Chargari et al. 2009; De
Brabandere et al. 2008). For example, investigators at
the University Hospital Leuven have performed a
dosimetric analysis in which the maximum allowed
dose rate to D2cc of OAR was 0.6 Gy/hour (De
Brabandere et al. 2008). When the dose per pulse was
decreased to meet this constraint, the authors noted
that the corresponding reduction of the radiobiologi-
cally normalized dose was more pronounced in
OAR than in target volumes, thanks to the lower a/b
ratio of OAR. This demonstrates the possibility
for ‘‘radiobiological optimization’’ with PDR-BT,
although the authors do caution against significant
deviation from the reference dose rate of 0.5 Gy/hour.
It must be remembered that the pelvic contents are
mobile and may shift over even short periods of time,
due to factors such as bladder and bowel filling.
De Leeuw et al. (2009) assessed the impact of
applicator shifts on DVH parameters in a series of
nine patients undergoing MRI-guided PDR-BT for
cervical cancer with a tandem-ring applicator (18 total
BT fractions). On treatment day 2, a second MRI
scan was performed and the previously generated set
of dwell positions and times were applied, after
444
Fig. 3 PDR-BT for cervical cancer using a tandem and
customized vaginal mold. a Initial plan generated by prescrib-
ing 15 at 0.5 Gy per pulse to point A. b Manually optimized
repeating the process of applicator reconstruction and
contouring. They found that the average applicator shift
relative to pelvic structures was 5–6 mm in the ventral
direction and 3–4 mm cranially. On average, DVH
changes that occurred between days 1 and 2 were fairly
small: HR-CTV D90 decreased by 0.2 ± 2 Gya/b10,
bladder D2cc increased by 1 ± 3 Gya/b3, and rectum
D2cc increased by 0.5 ± 3.9 Gya/b3. For a given
patient, however, the impact of applicator shift could be
more pronounced, particularly when summing the
effects of both PDR-BT fractions. For example,
one patient had a total decrease in HR-CTV D90 of
7 Gya/b10, and one patient had a total increase in
bladder D90 of 12 Gya/b3. Based on applicator recon-
struction analysis, it appeared that some shifts occurred
during the 20 min of MRI scanning time, implying that
the mobility of pelvic organs could also impact
dosimetry with HDR-BT.
During treatment, pain may be managed with
epidural anesthesia or oral/intravenous anti-analge-
sics. As compared with LDR-BT, nursing care is
facilitated thanks to the fact that treatment is only
administered for a few minutes out of every hour.
B. Anderson et al.
plan showing improved coverage of the prescription volume
(IR-CTV) by the 15 Gy isodose line. CTV clinical target
volume; IR intermediate risk; HR high risk
Published clinical outcomes achieved with
PDR-BT for cervical cancer are summarized in
Table 4. In France, 801 patients have been enrolled
on a prospective, nonrandomized multicenter study
(STIC-PDR) comparing 3D PDR-BT with conven-
tional 2D LDR-BT for cervical cancer (Haie-Meder
and Peiffert 2006; Charra-Brunaud and Peiffert
2008). This study, which opened in 2005, had several
objectives—to reduce late side effects, to promote the
use of the current GEC-ESTRO guidelines, to collect
dosimetric and clinical data for subsequent correlation
with local control and side effects, and to assess the
economic impact of 3D-guided PDR-BT for cervix
cancer. Preliminary analysis suggested that physicians
did not greatly modify their prescription methods when
transitioning from LDR to PDR-BT, as there were no
significant differences in the treated volume, TRAK, or
dose to ICRU bladder and rectal points between the two
patient groups. Furthermore, although final BED
calculations had not yet been performed, the doses
delivered to target volumes in the 3D PDR-BT
group appeared to be lower than recommended by
GEC-ESTRO (Charra-Brunaud and Peiffert 2008).
Principles and Clinical Applications of Pulsed Dose Rate Brachytherapy 445

Table 3 Dosimetric studies of MRI-guided PDR-BT for cervix cancer

Institution No. Applicator Optimization method Key findings
pts
Aarhus University 21 Tandem-ring- Manual All DVH constraints were met in 3/21
Hospital ± interstitial patients with 2D planning vs. 16/21
(Lindegaard et al. parametrial needles or patients with MRI optimization
2008) multichannel vaginal (p \ 0.001)
cylinder MRI optimization increased HR-CTV
D100 (p \ 0.007)
MRI optimization decreased sigmoid
D2cc (p = 0.03)
Aarhus University 72 Tandem- Manual For small tumors (HR-
Hospital (Tanderup ring ± interstitial CTV B 31 cm3), standard plans
et al. 2010) parametrial needles or covered the HR-CTV well in 94% of
multichannel vaginal patients, but exceeded OAR
cylinder constraints in 72% of patients. After
MRI optimization, HR-CTV dose was
adequate in 92% of patients, and only
6% had excessive dose to OAR
For large tumors (HR-
CTV [ 31 cm2), MRI optimization
allowed adequate HR-CTV coverage
in more patients (72 vs. 25%), while
reducing the frequency of OAR
constraint violations (8 vs. 44%)
Compared with 2D planning, MRI
decreased mean TRAK by 10 ± 16%
(p \ 0.001)
University Hospital 16 Tandem-ovoids Manual ? radiobiological Compared with 2D planning, MRI
Leuven (De optimization increased average HR-
Brabandere et al. CTV D90 by 3 Gya/b10 while meeting
2008) all OAR dose constraints
For patients with excessive bladder
dose on 2D plan (10/16), average
bladder D2cc reduction was
7 ± 6 Gya/b3
For patients with excessive sigmoid
dose on 2D plan (7/16), average
sigmoid D2cc reduction was
7 ± 4 Gya/b3
University Medical 24 Tandem- Manual or graphical MRI optimization increased HR-CTV
Centre Utrecht ovoids ± interstitial D90 by 4–10 Gya/b10, compared with
(Jurgenliemk- parametrial needles 2D plans that were symmetrically
Schulz et al. 2009) downscaled to meet OAR constraints
(p \ 0.001, p = 0.003)
Loading interstitial needles for patients
with suboptimal tumor volume
coverage increased average HR-CTV
D90 by 5.4 ± 4.2 Gya/b10 (p = 0.005)
Multi-institutional 2 Tandem- Manual or graphical Institutional standard plans were quite
(Jurgenliemk- ring ± interstitial variable, but became more similar in
Schulz et al. 2010) parametrial needles terms of dose distribution and DVH
parameters after MRI dose
optimization
(continued)
446 B. Anderson et al.

Table 3 (continued)
Institution No. Applicator Optimization method Key findings
pts
Institut Gustave 30 Tandem-customized Manual versus IPSA Two novel constraints (Tmax and
Roussy (Chajon vaginal mold Vdummy) were required to limit dwell
et al. 2007) time heterogeneity for the IPSA
studied
Compared with manual optimization,
IPSA generated plans with
significantly less average D2cc to
rectum (58.2 vs. 57.9 Gy, p = 0.009),
bladder (68.6 vs. 70.7 Gy, p = 0.016),
and vagina (95.6 vs. 100.2 Gy,
p = 0.012), with slightly higher
conformal index (mean 0.44 vs. 0.41,
p = 0.007)
No difference in overall planning time
required
In all studies, standard plans were first generated using 2D imaging, then an MRI with the applicator in place was used to sculpt the
shape of the standard ‘‘pear’’ to improve coverage of tumor volumes and limit dose to adjacent OAR.
D100 dose received by 100% of volume, D90 dose received by 90% of volume, IPSA inverse planning simulated annealing, Tmax
maximum time constraint, Vdummy minimum volume dose constraint to dummy structures around brachytherapy catheters

Table 4 Clinical outcomes achieved with PDR-BT for cervix cancer

Institution BT method Planning Local Overall survival Late grade C 3
(no. pts) method control toxicity
University of California-San PDR (n = 42) 2D 86% at 65% at 2 years 14% at 2 years
Francisco (Swift et al. 1997) 2 years
St. Joseph’s Hospital PDR (n = 46) 2D 86% at 55% at 4 years 7% at 4 years
(Rogers et al. 1999) 4 years
Princess Margaret Hospital PDR (n = 57) 2D 84.2% 83% at 3 years 7.6% at 3 years
(Bachtiary et al. 2005) (crude)
LDR (n = 109) 88.9% 70% at 3 years, 7.4% at 3 years,
(crude) p = 0.25 p = 0.69
Institut Gustave Roussy PDR (n = 45) 3D, MRI-guided 95.6% 78% at 2 years 2.2% (crude)
(Chargari et al. 2009) (crude)

5.2 Vaginal and Vulvar Cancer
Seeger et al. (2006) have retrospectively reviewed the
outcomes of patients with primary or recurrent/meta-
static tumors involving the vagina (n = 13) or vulva
(n = 9) treated with interstitial PDR-BT at a single
institution. Two-dimensional-planning was used to
prescribe 0.4–0.7 Gy pulses to a median dose of
20.25 Gy for the vagina or 55.0 Gy for the vulva.
Treatment also included EBRT in 12 patients, surgery
in 13 patients, and chemotherapy in a few cases. By
6 months, a clinical complete remission was seen in all
patients with vaginal cancer and in seven out of nine
patients with vulvar cancer. With further follow-up,
only one more patient with vulvar cancer failed locally.
Five patients with vaginal cancer developed distant
metastasis while regional lymphadenopathy was seen
in six patients with vulvar cancer, including both in
whom no complete remission was achieved. Late tox-
icity was mild, with only one occurrence of necrosis.
5.3 Anal Cancer
In Europe, some centers routinely treat anal SCC with
concurrent chemoradiotherapy followed by an inter-
stitial, transperineal LDR-BT boost of 10–25 Gy
using the Paris system (Fig. 4). This BT technique
Principles and Clinical Applications of Pulsed Dose Rate Brachytherapy 447

EBRT ± 5-FU/cisplatin, followed 2–3 weeks later

by an interstitial PDR-BT implant of 10–25 Gy,
prescribed at 0.5 Gy/hour to the reference isodose
(85% of the basal dose). Needles were spaced at
1–1.2 cm intervals, and the volume receiving the
prescribed dose was 17–45 cm3. The treatments were
administered without significant technical difficulty,
and with good patient tolerance.
More recently, Bruna et al. (2006) retrospectively
reviewed the outcomes of 71 patients with anal SCC
treated from 1996–2002 with EBRT (36–50 Gy),
in some cases with induction and/or concurrent
chemotherapy (n = 47), followed by a PDR-BT
boost. Interstitial implants were performed according
Fig. 4 Applicator and three needles for interstitial, transperi- to the Paris system, with 1–2 rows of needles spaced
neal PDR-BT boost for anal cancer
1 cm apart (median 5 needles, range 3–12). An
average dose of 17.8 Gy (range 10–25 Gy) was
was first developed to treat perirectal lymph nodes, prescribed to the 85% reference isodose, without
and favorable clinical outcomes were published by optimization. The mean dose rate was 0.7 Gy/h
Papillon et al. (1989). In general, the implant should (range 0.5–1.5 Gy/h). With a median follow-up time
be performed within 2–4 weeks after completion of of 28.5 months, the actuarial 2-year OS rate was 90%,
chemoradiation (Belliere et al. 2003), and there is less 2-year DFS was 81%, and 2-year colostomy-free
toxicity if the volume can be limited to 5–6 needles, survival was 89%. Grade 3 complications developed
each 5–6 cm long, implanted in a single row (Peiffert in ten patients (14%) and two patients (3%) developed
et al. 1997). Ideal candidates, therefore, have residual grade 4 toxicities. In this relatively small series, dose
primary tumors less than approximately 1 cm thick, rate did not correlate with the development of severe
encompassing \50% of the anal circumference at the complications (P = 0.9).
time of BT. These principles can be applied to BT
implants performed for anal SCC using a PDR tech-
nique. Typically, little to no dose optimization is 5.4 Esophageal Cancer
required due to the good parallelism achieved with
rigid needles in these implants. In 1997, the ABS published consensus guidelines for
From 1993 to 1994, Roed et al. (1996) treated 17 incorporating BT (HDR or LDR) into the manage-
patients with EBRT (46 Gy at 2 Gy/F) followed ment of esophageal cancer (Gaspar et al. 1997). Since
1–2 weeks later by PDR-BT (25.2 Gy at 0.6 Gy/h). that time, BT has fallen out of favor as a component
The mean volume receiving C25.2 Gy was 161 cm3 of definitive chemoradiation at most centers in the
(range 20–400 cm3). Necrosis developed in 13 of 17 United States, due in part to the 12% fistula rate found
patients at a median of 16 weeks, and eight patients in a phase I/II study (RTOG 92-07) (Gaspar et al.
required a colostomy. The high toxicity rate seen in 2000). Other studies have reported lower fistula
this early experience has been attributed to the large rates, however, and EBRT with a BT boost may be
treated volume, large needle spacing (1.3–2 cm), and beneficial for selected patients (Flores et al. 1989;
prescription of dose to 5 mm beyond the outer row of Okawa et al. 1999). Withholding chemotherapy dur-
needles, which frequently resulted in a higher dose ing BT and individualizing the prescription dose and
than what would be given when respecting the rules depth may reduce the likelihood of fistula or other late
of the Paris system (Gerard et al. 1999). toxicity (Gaspar 1999). To date, there are no pub-
In 1995, French investigators launched a prospec- lished reports of PDR-BT as a component of the
tive, multi-institutional study to evaluate the feasi- definitive management of esophageal cancer.
bility of PDR-BT for boosting anal SCC (Gerard Endoluminal BT is a widely practiced method for
et al. 1999). Nineteen patients were treated with palliating dysphagia, which has demonstrated results
448 B. Anderson et al.

Table 5 Overview of APBI patient selection guidelines.

Age Tumor Histology EIC, LVSI Margins Nodes
(years) size
ASTRO ‘‘suitable’’ C60 B2 cm IDC and other No Negative pN0 (i-, i+)
(Smith et al. 2009) favorable histologies (C2 mm)
(ER+)
GEC-ESTRO ‘‘low [50 B3 cm IDC, mucinous, No Negative pN0
risk’’ tubular, medullary, (C2 mm)
(Polgar et al. 2010) colloid
ABS (Keisch et al. C50 B3 cm IDC EIC is relative Negative cN0
2007) contraindication
ASBS (2008) C45 B3 cm IDC or DCIS NR Negative pN0
(microscopic)
See individual society publications for additional details. IDC invasive ductal carcinoma, DCIS ductal carcinoma in situ, ILC
invasive lobular carcinoma, EIC extensive intraductal component, LVSI lymphovascular space invasion, NR not reported

superior to that of metal stent placement in a ran-
domized controlled trial with HDR-BT (Homs et al.
2004). Harms et al. (2005) published the outcomes of
16 patients treated with daytime, outpatient PDR-BT
to palliate dysphagia from unresectable, recurrent
esophageal cancer. Clips were placed endoscopically
at the upper and lower aspects of the tumor, and the
treatment volume extended 2 cm proximal and distal
to these clips. Treatment was delivered through an
endoluminal catheter measuring 6–10 mm in outer
diameter. Each fraction consisted of 5 Gy in 0.5 Gy
hourly pulses, prescribed 1 cm from the axis, inde-
pendent from catheter diameter, without optimization.
Most patients received four such fractions (20 Gy) at
1-week intervals; however, three patients with a
limited volume of disease received only three frac-
tions (15 Gy). During treatment, patients received
intravenous hydration and continuous suctioning of
saliva. Acute grade 3 dysphagia was noted in one
patient. Three patients experienced significant adverse
late events, all in the context of progressive locore-
gional disease, including trachoesophageal fistula
(n = 2) and fatal arterial bleeding (n = 1). The
median actuarial grade 2 dysphagia-free survival time
was 17 months.
5.5 Breast Cancer
Conservative guidelines for the selection of appropriate
patients for accelerated partial breast irradiation
(APBI) outside of clinical trial protocols have been
established by ASTRO (Smith et al. 2009), GEC-
ESTRO (Polgar et al. 2010), ABS (Keisch et al. 2007),
and the American Society of Breast Surgeons (ASBS
2008; see Table 5). Several phase III studies comparing
APBI with whole-breast EBRT are currently under-
way, with a projected total of nearly 12,000 patients
(Offersen et al. 2009), and are expected to provide
additional information regarding the merits of these
two techniques. BT may also be used to boost the
lumpectomy cavity in conjunction with whole-breast
EBRT, particularly in cases where superior target
coverage would be expected (Keisch et al. 2007).
Breast BT may be performed using interstitial
catheters, or with a variety of commercially-available
intracavitary applicators that contain one or several
internal catheters. The interstitial BT technique was
the first to be developed, and is the only method with
published results in PDR-BT at this time.
5.5.1 Accelerated Partial Breast Irradiation
Investigators at Örebro University have performed a
prospective clinical study of APBI delivered with
PDR-BT (Johansson et al. 2009). Fifty patients were
treated with sector resection followed by an intersti-
tial PDR-BT implant of 50 Gy, given in 0.833 Gy
pulses at 2 h intervals. The target was defined using a
unique method, wherein the ‘‘index point’’ or center
of the original tumor was identified, and the whole-
breast thickness was treated with a radius of at
least 3 cm around this index point. Planning was
performed using 3D reconstruction of orthogonal
films. At 5 years, the actuarial LC rate was 96%, DFS
Principles and Clinical Applications of Pulsed Dose Rate Brachytherapy
was 88%, and OS was 88%. Late side effects included
fibrosis (18% grade 2 and 8% grade 3), fat necrosis
(20%), and teleangiectasia (14% grade 2 and 8%
grade 3). The authors hypothesized that cosmetic
outcome may be improved if CT-based treatment
planning is used to decrease the treatment volume and
skin dose.
From 2000–2005, 274 patients were treated with
APBI via interstitial PDR (64%) or HDR (36%) BT
on a multicenter German-Austrian phase II trial
(Strnad et al. 2011). Participation was restricted to
patients with low-risk disease, similar to the current
GEC-ESTRO guidelines, although the minimum
patient age was 35 years, and either ER or PR posi-
tivity was required. Flexible afterloading catheters
were placed according to the Paris system, targeting
the tumor bed plus C2 cm in all directions, except to
spare 5–10 mm of tissue below the skin surface and
5 mm of tissue above the ribs. Dose was prescribed to
the reference isodose (85% of the mean central dose),
either 34 Gy at 4 Gy per fraction twice daily (HDR)
or 49.8 Gy in 0.6 Gy hourly pulses (median, PDR).
These regimens were calculated to be isoeffective for
late-reacting tissue (a/b = 3), according to the linear-
quadratic model. The 5- and 8-year actuarial local
recurrence-free survival rates (ipsilateral breast only)
were 99.7 and 95.0%, and the 5- and 8-year overall
survival rates were 96.6 and 96% (Strnad et al. 2011).
BT method (HDR vs. PDR) did not impact LC, DFS,
or OS. In a separate analysis, age \50 and lack of
antihormonal treatment (in ER or PR positive tumors)
were the only factors that predicted for ipsilateral
in-breast tumor recurrence (Ott et al. 2010). Overall,
cosmetic outcomes were excellent or good in
90.1% of patients (245/274) (Strnad et al. 2011). The
cosmetic outcomes of patients who enrolled on this
trial at Erlangen University Hospital (n = 171) were
analyzed in further detail to identify factors associated
with non-excellent cosmesis (Ott et al. 2009). Of 54
variables assessed, cosmetic status prior to BT, acute
toxicity (radiodermatitis), and late toxicity (hyper-
pigmentation, fibrosis and telangiectasia) correlated
with non-excellent cosmetic outcome. There were
also a higher percentage of patients who received
PDR-BT in the non-excellent group, whereas
the trend toward worse cosmesis prior to APBI in
PDR-BT patients did not reach statistical significance.
The authors suggest that a higher BED or catheter
movement during nocturnal pulses may explain the
449
higher percentage of PDR-BT patients in the nonex-
cellent group.
5.5.2 Tumor Bed Boost
Harms et al. have published their experience treating
113 patients with lumpectomy, followed by whole-
breast EBRT (median 50 Gy at 1.8–2 Gy/F) plus an
interstitial PDR-BT boost of 15–25 Gy given in 1 Gy
hourly pulses (Harms et al. 2002). The objective of
this regimen was to improve the outcome of patients
with risk factors for local control, such as close or
positive margins, lymphovascular space invasion
(LVSI), or T2 grade 3 tumors. A 15 Gy boost was
prescribed for patients with T2 grade 3 tumors,
whereas 25 Gy was initially chosen for patients with
close/positive margins or LVSI. This was subse-
quently lowered to 20 Gy when clinical reports of
heightened telangiectasias and soft tissue necrosis
with PDR-BT emerged. Treatment planning was
performed with digitally reconstructed isocentric
radiographs, using the catheter puncture sites and a
dummy chain fixed on the skin above the implant to
assess skin dose. During treatment, 10% of patients
had the active length of the catheters adjusted as
swelling decreased. At 5 years, the actuarial local
recurrence-free survival rate was 95%, and OS was
93%. Grade 3 skin or soft tissue toxicity developed in
10.8% of patients treated with a boost of B20 Gy and
54.6% of patients treated with [20 Gy (p \ 0.01). At
the time of last follow-up, the cosmetic outcome was
scored as excellent or good in 90% of cases by patient
assessment, and in 80% of cases by physician
assessment. The first fair or poor scores occurred
approximately 4 years after treatment.
5.6 Bladder Cancer
There are no prospective randomized trials com-
paring the outcomes of organ-sparing approaches with
radical cystectomy for bladder cancer. Currently,
surgical management is the standard approach in the
United States and Europe (Kuczyk et al. 2003),
however, multidisciplinary bladder-sparing regimens
are also used routinely and effectively at some centers
(see also ‘‘Bladder Cancer’’).
Blank et al. (2007) have reported the outcomes of
122 patients treated with EBRT (3 9 3.5 Gy or
20 9 2 Gy), followed within 10 days by cystotomy
450
Fig. 5 Interstitial brachytherapy for penile cancer.
a Schematic of two plane, six needle penile cancer implant,
showing the calculation of the isodose location as per the Paris
system rules (Crook et al. 2010). For PDR-BT, needles are
placed in the same fashion, and a treatment plan is created by
for placement of BT catheters in the tumor bed, along
with partial cystectomy for patients with tumors
located in a bladder diverticulum or invading
[10 mm (n = 37). Patients then received an LDR
(n = 99) or PDR (n = 23) BT boost of 20–70 Gy.
For PDR-BT, 20.8–59.3 Gy was prescribed in pulses
of 1.04 Gy separated by 2 h and 12 min. At 5 years,
the actuarial local relapse-free survival rate was 76%,
distant metastasis-free survival was 83%, and OS was
73%. BT technique (PDR-BT vs. LDR-BT) did not
correlate significantly with local control. After treat-
ment, urinary function deteriorated in six patients
(5%), ending in a crippled bladder in three.
5.7 Penile Cancer
Interstitial BT is an important organ-preserving
option for penile cancer patients. Crook et al. have
published the outcome of a series of patients treated
with LDR- and PDR-BT (Crook et al. 2005, 2009), as
well as a detailed description of the technique (Crook
et al. 2010). Appropriate patients for BT alone have
T1–T2 tumors measuring up to 3–4 cm, with no
invasion of the shaft, as this increases the risk for
dissemination. At Princess Margaret Hospital, elec-
tive inguinal lymph node dissection is recommended
for patients with moderately/poorly differentiated or
T3 tumors (Crook et al. 2009). Treatment begins with
B. Anderson et al.
activating dwell positions at 2.5–5 mm intervals along the
length of each catheter. b Photograph of an interstitial implant
for penile cancer. In this case, 4 needles were placed to cover a
small lesion on the ventral surface of the glans. More
commonly, coverage of the entire glans is required
circumcision, to reduce the risk for soft tissue com-
plications, and facilitate future clinical examinations.
Interstitial needles are then placed through the glans,
covering the entire thickness of the penis in almost
every case (Fig. 5). A rigid template is used to
maintain parallelism and spacing, ideally 14–18 mm.
The central needles must avoid the urethra, and the
peripheral needles should be no more than 2–3 mm
under the skin, to ensure sufficient dose coverage.
Needles are then exchanged for flexible plastic cath-
eters. The penis is supported for the duration of
treatment using a Styrofoam collar, which increases
the distance between the implant and the patient’s
body. Lead may be incorporated into this collar to
further reduce dose to the scrotum, if preservation of
fertility is desired. After appropriate imaging and
applicator reconstruction, a dose of 60 Gy is pre-
scribed to the 85% isodose in 0.4–0.55 Gy hourly
pulses. Typically, minimal dose optimization is
required thanks to the good parallelism achieved with
this technique.
Crook et al. (2009) have reported the outcome of
patients treated with PDR-BT (n = 41) or manually-
afterloaded LDR-BT (n = 26). Implants were per-
formed using the technique described above. For
PDR, a median dose of 60 Gy (range 55–65 Gy) was
delivered in 0.5–0.612 Gy hourly pulses. At 5 years,
the actuarial freedom from local failure was 87.3%
and the penile preservation rate was 88%. The authors
Principles and Clinical Applications of Pulsed Dose Rate Brachytherapy 451

Table 6 Overview of GEC-ESTRO guidelines for HNC brachytherapy (Mazeron et al. 2009)
Anatomic Patient Implant Safety Dose Result
site selection technique margin
Lip T1–3 Rigid needles 5–10 mm 60–75 Gy LDR or PDR LC 90–95%
N 2–10%
Buccal \4 cm Plastic tubes 5–10 mm 65–70 Gy LDR or PDR (25–30 Gy LC 80–90%
mucosa boost if 40–45 Gy EBRT) N \ 10%
Mobile T1–3 Plastic tubes 5 mm 65–75 Gy LDR or PDR (25–30 Gy LR [ 90%
tongue boost if 40–45 Gy EBRT) N 10–20%
Floor of T1–2 N0 Rigid needles or [5 mm 65 Gy LDR or PDR (10–25 Gy LC [ 90%
mouth plastic tubes boost if 46–50 Gy EBRT) N 10–20%
Oropharynx \5 cm Plastic tubes [10 mm LDR or PDR: 25–35 Gy boost Base of tongue
following 45–50 Gy EBRT LR 80–90% for T1–2,
65–80% for T3–4
N 25%
HDR: 21–30 Gy at 3 Gy/F or Faucial arch
21–24 Gy at 4 Gy/F as boost LC B 90% for T1–2,
following 45–50 Gy EBRT 67% for T3
N 20%
LC local control, N necrosis

noted a 52% reduction in the risk of local recurrence
for every unit increase in spacing. Due to the
effectiveness of salvage treatment, the cause-specific
survival was 83.6% at 5 and 10 years. Grade was a
significant predictor for regional and/or distant
recurrence. Late complications included soft tissue
necrosis (12% of patients) and meatal stenosis (9% of
patients).
5.8 Prostate Cancer
Dose-escalation has been proven to improve biochemi-
cal control in prostate cancer patients (Peeters et al.
2006; Kuban et al. 2008; Sathya et al. 2005). For patients
with intermediate- or high-risk disease who require
treatment beyond the prostate gland itself, 3D-confor-
mal EBRT with a BT boost is one method that has been
successfully applied at many cancer centers (Sathya
et al. 2005; Vicini et al. 2003). Investigators at the
University of Amsterdam have published their experi-
ence treating a cohort of 106 patients with EBRT (46 Gy
to whole pelvis or prostate plus seminal vesicles) fol-
lowed by a PDR-BT boost (Pieters et al. 2011). Novel
self-anchoring catheters developed for PDR-BT (Pieters
et al. 2006) were implanted into the periphery of the
prostate gland under ultrasound guidance, and CT-based
treatment planning was used to prescribe the dose to the
prostate and proximal seminal vesicles. Each treatment
plan consisted of 24 pulses. Initially, patients were
prescribed 24.96 Gy in 1.04 Gy pulses delivered
continuously, at 2.2 h time intervals (n = 42). Subse-
quently, the dose was escalated to 26.4 Gy in 1.1 Gy
pulses delivered every 2 h (n = 23), and finally to
28.8 Gy in 1.2 Gy pulses delivered every 2 h (n = 35).
Six patients were unable to complete BT due to prob-
lems with the catheters, and had the remaining dose
given via EBRT. At 5 years, the actuarial biochemical
DFS rate was 89.5% and OS was 96%. Morbidity data
were collected prospectively at each clinic visit, and a
subsequent longitudinal analysis of symptoms revealed
no accumulation of high-grade toxicity over time
(Pieters et al. 2010). Maximal gastrointestinal toxicity
(grade 2) was 12.0%, and maximal genitourinary
toxicity (grade 3) was 7.3%.
Izard et al. (2006) have published the early out-
comes of 165 patients treated with anti-androgen
therapy, EBRT (45–50.4 Gy), and an interstitial
PDR-BT boost of 18 Gy in three fractions, given at
least 6 h apart. This regimen was selected due to
machine availability, and the authors note that it
more closely resembles HDR-BT, with a dose rate of
5–10 Gy/hour (technically medium dose rate).
Toxicity was comparable to other HDR-BT series, and
with a median follow-up time of 36 months, the overall
biochemical recurrence-free survival rate was 88%.
452
This series demonstrates the potential adaptability of a
PDR-BT afterloader unit, however further clinical
study of such regimens is required.
5.9 Head and Neck
For certain anatomic subsites of squamous cell HNC,
BT may be used as monotherapy in early stage
disease, or as a means for boosting the primary
tumor in combination with EBRT. A recent publi-
cation from GEC-ESTRO provides detailed recom-
mendations regarding patient selection and technique
(see Table 6) (Mazeron et al. 2009). Acknowledging
the controversial nature of PDR schedules and dose
rates, the authors promote continuous 0.3–0.7 Gy
hourly pulses, to maintain the radiobiological
advantages of LDR-BT in late-reacting normal
tissues.
One of the first published series of PDR-BT for
HNC compared the outcomes of patients with tonsil
and soft palate tumors treated with PDR-BT (n = 19)
or twice daily HDR-BT (n = 19) against historical
controls treated with EBRT alone (n = 70)(Levendag
et al. 1997). The authors used radiobiologic modeling
(Brenner and Hall 1991) to determine PDR regimens
(1–2 Gy every 3 h) and HDR regimens (3–5.4 Gy
twice daily) for use alone or with 46–50 Gy EBRT.
The radiobiological effectiveness for tumor (BED10)
was calculated for these varying regimens and was
corrected for overall treatment duration (BEDcor10).
A dose–response relationship was observed, as
BEDcor10 correlated with LRFS and OS. PDR-BT and
twice daily HDR-BT produced equivalent outcomes
in terms of LRFS, OS, and severe late toxicity.
In France, a prospective multicenter study of
PDR-BT for HNC was initiated in 1995 and enrolled
30 patients (Peiffert et al. 2001). The objective was to
mimic the traditional LDR iridium wire technique;
therefore catheter placement and dosimetry were
performed according to the Paris system (continuous
0.5 Gy hourly pulses prescribed to the 85% isodose),
without dose optimization. By investigator opinion,
the quality of the implants was typically equal to
LDR-BT (n = 25), but was better in four patients and
worse in one patient. Catheter malfunction (kinking
or flattening) caused treatment interruption tempo-
rarily (B6 h) in seven patients, and permanently
in seven patients. In all cases of permanent PDR
B. Anderson et al.
treatment failure, implants were successfully com-
pleted via manual afterloading of Ir-192 wires to
deliver LDR-BT.
Ziemlewski et al. (2007) have reported the outcome
of 45 patients treated with PDR-BT for HNC, 42 of
whom were treated with curative intent. The total pre-
scribed BT dose was variable, with a median of 70 Gy
(range 42.5–70 Gy, n = 32) for interstitial BT alone
and 20 Gy (range 10.2–20 Gy, n = 10) for interstitial
BT as a boost after EBRT. Three patients received
contact BT to doses of 15, 30, or 50 Gy. Dosimetry was
most often performed using digitized orthogonal
radiographs (n = 43). All patients were prescribed
hourly pulses, typically 1 Gy/pulse (n = 38), however,
the dose was reduced to 0.6 Gy/pulse in previously
irradiated patients (n = 6) and increased to 2.5 Gy/
pulse in one elderly patient with poor performance
status. Severe acute toxicities included grade 3 der-
matitis (6.8%) and oral mucositis (13.6%), particularly
in patients with no dental care prior to BT (23% vs. 0%,
P = 0.44) Late grade 4 soft tissue and bone toxicity
occurred in seven patients (15.9%), and correlated with
larger treatment volume (P = 0.004). The authors
subsequently decreased their dose rate to B0.7 Gy per
hourly pulse, except for lip tumors.
5.10 Soft Tissue Sarcoma
The value of adjuvant BT after resection of soft tissue
sarcomas of the extremity and superficial trunk has
been demonstrated in a prospective, randomized trial
(Pisters et al. 1996). Contraindications to BT as the
sole local adjuvant treatment include positive margins,
skin ulceration, and low-grade disease (Nag et al.
2001). In some cases, a BT boost used in combination
with EBRT may be beneficial. The relative rarity of
this tumor type, along with its histologic and anatomic
variability, makes multidisciplinary input a key aspect
of patient management.
Historically, the majority of BT implants have
been performed using LDR techniques, with catheters
placed in a single plane at 1–1.5 cm intervals across
the surgical bed (without intentional inclusion of the
incision and drain sites) at the time of radical resec-
tion. The catheters are loaded no sooner than 5 days
after surgery, to reduce the likelihood for wound
complications. When used as monotherapy, a dose of
45–50 Gy is typically given at around 0.45 Gy/hour
Principles and Clinical Applications of Pulsed Dose Rate Brachytherapy
(range 0.35–0.6 Gy/h), whereas a 15–25 Gy BT boost
may be prescribed in combination with 45–50 Gy
EBRT (Nag et al. 2001).
Lazzaro et al. (2005) reported the outcomes of
42 consecutive patients treated with post-operative
PDR-BT for sarcoma of the extremity or trunk.
A single-plane implant of 2–14 catheters was placed at
the time of surgery, according to the Paris system, and
CT-based treatment planning was performed. PDR
monotherapy was prescribed at a median dose of 45 Gy
(range 45–60 Gy) in 18 patients. Twenty-four patients
received EBRT (median 50 Gy, range 40–66 Gy) fol-
lowed by a PDR-BT boost of 15 Gy median (range
10–29 Gy). The mean PDR-BT dose rate was 0.5 Gy/h
(range 0.3–1 Gy/h). At 3 years, the crude cumulative
incidence of any local recurrence was 10.9%, and the
actuarial OS rate was 83.9%, with six out of seven
deaths directly related to tumor progression. Acute
grade 3–4 dermatitis occurred in four patients, all of
whom received chemotherapy concurrently with
EBRT. Three patients required local wound care for
delayed healing, and one patient required intravenous
antibiotics for a wound infection. The authors describe
no grade 3 or higher late radiation toxicity.
Muhic et al. (2008) have also used PDR-BT to treat
39 patients with sarcomas deemed difficult to resect
via compartmental or wide local excision without
amputation. A total dose of 20 Gy was prescribed
at 5–10 mm from the catheters, and was given at
0.6 Gy/hour starting the day after surgery. EBRT was
started 2–4 weeks later, typically 50 Gy at 2 Gy/F,
although an additional boost of 10 Gy was required for
two patients with gross residual disease. At 5 years, the
actuarial local recurrence-free survival was 83%, dis-
tant metastasis-free survival was 66%, and OS was
76%. Although toxicities were not explicitly graded,
wound complications occurred in eight patients (21%)
and required surgical management in four cases, 49%
of patients had some degree of functional impairment,
41% developed edema, and 31% had persistent pain.
No patient, however, developed BT-related peripheral
nerve damage, severe fibrosis, or bone fracture.
5.11 Pediatrics
A limited number of cancer centers worldwide
utilizes BT as a component of local treatment for
pediatric tumors, particularly rhabdomyosarcoma.
453
Features such as rapid dose fall-off and lack of need
for PTV expansion make BT an attractive option for
pediatric patients, in whom the late effects of cancer
treatment can be significant. Due to the rarity and
diversity of these tumors, however, the majority of
practicing radiation oncologists today do not have
the opportunity to gain significant experience and
expertise in pediatric BT.
A multidisciplinary team of investigators at the
University of Amsterdam has developed an approach
consisting of ‘‘ablative surgery, mold technique with
afterloading BT and immediate reconstruction’’
(AMORE) for locally advanced or recurrent nonorbital
rhabdomyosarcoma of the head and neck (Blank et al.
2009). This is applied after 4–8 cycles of conventional
multiagent chemotherapy (as per contemporary active
European or North American protocols), in children
with initially unresectable or recurrent tumors. Exclu-
sion criteria include M1 disease, inoperable intracra-
nial tumor growth after chemotherapy, and (after
developing experience with the technique) encasement
of the carotid artery. After chemotherapy, the residual
tumor is resected, and a customized BT mold is created
for the tumor bed by implanting catheters into specially
cut and shaped 5 mm thick layers of thermoplastic
rubber. The mold is placed in the tumor bed and the
wound sutured closed. A dose of 40–50 Gy prescribed
5 mm from the surface of the mold is given via LDR or
PDR-BT, and then the mold is removed and surgical
reconstruction is completed. The treatment course ends
with additional chemotherapy, as dictated by the con-
temporary protocols.
Blank et al. (2009) have published the outcomes of
42 patients treated via the AMORE approach,
including 31 patients with primary disease (24 par-
amenigeal, seven nonparameningeal) and 11 patients
with recurrent or persistent disease after prior con-
ventional treatment, including EBRT (five paramen-
ingeal, six nonparameningeal). Since 2002, 13
patients have been treated with PDR-BT, prescribing
40–45 Gy in pulses of 1.25 Gy at intervals of 2 h,
6 min. At 5 years, OS was 73% for all patients, 70%
for patients with primary tumors, and 82% for patients
with recurrent/persistent disease. The 5-year DFS was
68% overall, 64% for patients with primary tumors,
and 82% for recurrent/persistent disease. The authors
attributed the favorable outcome in recurrent/persis-
tent tumors to proper patient selection for the
AMORE technique. No significant difference in
454
outcome was noted between LDR and PDR-BT.
Severe fibrosis, xerostomia, and radionecrosis were
not observed, and the patient group is being followed
to assess the full impact of treatment after puberty.
5.12 Re-irradiation
Locoregional recurrence within an irradiated area
poses a major management challenge across many
disease sites. If further local treatment is desired,
either from a curative or palliative standpoint, surgi-
cal resection is often preferred, but may not be fea-
sible or adequate as monotherapy. Over the years, BT,
external beam radiation therapy, intra-operative
radiation therapy, and hyperthermia have been
applied to these patients. Re-irradiation poses the risk
for significant late side effects, however, which are
classically associated with dose rate. PDR-BT offers
the potential to precisely prescribe the hourly dose
rate and optimize dose distribution, two features that
make it appealing in this context. As detailed below,
PDR-BT has been investigated as an option for re-
irradiating locally recurrent gynecologic (Jensen et al.
1998), breast (Niehoff et al. 2006), colorectal, and
head and neck cancers.
5.12.1 Gynecologic Cancers
From 1993–1996, Jensen et al. (1998) used
PDR-BT to treat 34 consecutive patients with
unresectable locally recurrent (n = 22) or locally
advanced de novo gynecologic cancers (n = 12).
Treatment was individualized, given the diversity of
cancer diagnoses and past treatments in this patient
population. The majority of patients received pelvic
EBRT (46 Gy at 2 Gy/F) followed 1–2 weeks later
by an interstitial PDR implant (30 Gy in 0.6 Gy
hourly pulses) using a MUPIT applicator. The
median treatment volume was 177.5 cm3 (range
70–650 cm3). CT-based treatment planning was
performed, and in 12 cases the BT treatment plan
was optimized to create a more homogeneous dose
distribution. The actuarial 1-year OS rate was 71%.
Twenty five patients (74%) were alive and in
complete remission 3 months after treatment, and
local control was maintained in 18 patients at the
time of last follow-up (median 14 months, range
3–40 months). Major acute complications occurred
in five patients, including two deaths. Ten patients
B. Anderson et al.
developed 17 late grade 3 complications, 16 of
which occurred in patients treated for recurrent
disease after radical hysterectomy. Larger treatment
volume ([200 cm3) correlated with an increased
risk of severe gastrointestinal complications, but not
with severe toxicity in general or with overall
survival.
5.12.2 Colorectal Cancer
Tepel et al. (2005) reported the outcomes of 46
patients with recurrent pelvic colorectal cancer who
were treated with extended surgical resection of the
primary tumor and any distant metastases, intersti-
tial PDR-BT (n = 23) or HDR-BT (n = 23), and
45 Gy pelvic EBRT, if standard EBRT doses were
not given during the initial treatment course
(n = 25). Six months of 5-FU/leucovorin was
administered in 26 patients. BT catheters were
placed at the time of resection, 8–12 mm apart in a
single plane over the surgical bed, which was
marked with clips. CT or MRI-guidance was used
to optimize the dose distribution, allowing the
prescription dose to extend B10 mm from the lat-
eral tubes and up to four times the prescription dose
on the surface of the plastic tubes. Dose rate (PDR
vs. HDR) was determined by machine availability.
HDR patients received 2.5 Gy twice daily, whereas
PDR patients received 1 Gy every 2 h during the
daytime; resulting in a total daily dose of 5 Gy for
both groups. Procedure-related complications
occurred in eight patients (17.4%), including pre-
sacral necrosis, fistulas, and dehiscence of the rectal
stump. No grade 3–4 early radiation toxicity was
noted. Significant late toxicity developed in 10
patients (22%), including perineal necrosis, fistula,
and urethral stenosis. At 5 years, the OS rate was
23%, DFS was 20%, and LC was 33%. There was
no significant difference in outcome achieved with
HDR vs. PDR, except for superior local control in
PDR patients when BT was given without EBRT
(P = 0.026). DFS and LC were better for patients
who underwent an RO resection, and those who
received EBRT after BT.
5.12.3 Breast Cancer
Niehoff et al. (2006) compared their outcomes with
interstitial HDR versus PDR-BT (technique selected
by machine availability) in 32 patients who were
re-irradiated for breast or chest wall recurrences, and
Principles and Clinical Applications of Pulsed Dose Rate Brachytherapy
found no difference in treatment results between the
two groups. Harms et al. (2001) treated 58 patients
with gross or microscopic residual disease on the
chest wall using split-course PDR-BT (typically
20 Gy 9 2) delivered via an external mold. An initial
complete response was achieved in 28 out of 30
patients with gross disease. The 3-year local recur-
rence-free survival was 71% for patients with gross
disease and 75% for patients with microscopic dis-
ease. Grade 3 acute dermatitis developed in 16% of
patients, and late toxicities included grade 3 skin
toxicity (50%), grade 4 skin toxicity (7%), and grade
4 subcutaneous toxicity (10%).
5.12.4 Head and Neck Cancer
Krempien et al. (2005) treated 14 patients with
unresectable, locally recurrent HNC with EBRT
(36 Gy at 1.8 Gy/F) given concurrently with cisplatin
and 5-FU, followed 3 weeks later by interstitial PDR-
BT, then additional chemotherapy starting 4 weeks
later. All recurrences were located near great vessels
or were nonpalpable due to fibrosis, so catheters were
placed using a frameless image-guided navigation
system, targeting the CTV with a 0.5 cm safety
margin. PDR-BT was delivered in 0.5 Gy hourly
pulses to a mean dose of 14.3 Gy (range 10–20 Gy),
and a mean volume of 76 cm3 (range 18–150 cm3).
At 2 years, the LC rate was 78% with 64% OS. One
patient developed soft tissue necrosis 6 weeks after
BT, which healed without surgical intervention. No
other severe late side effects were seen with a median
follow-up time of 21 months.
At the University Erlangen-Nuremberg, interstitial
PDR-BT has been used to treat patients with HNC in
a previously irradiated area (recurrent or second pri-
mary tumors) (Strnad et al. 2003; Geiger et al. 2002).
From 1999–2001, 15 patients were treated with a
combination of surgery if possible (n = 9), followed
by interstitial PDR-BT and one session of hyper-
thermia delivered via the same catheters, both con-
current with one cycle of cisplatin and continuous
infusion 5-FU. PDR-BT was prescribed according to
the Paris system in hourly pulses of 0.46–0.55 Gy, to
a median total dose of 55 Gy (range 34–60 Gy). The
median 85% isodose volume was 30.8 cm3 (mean
33.2 ± 13.7 cm3). Preliminarily (median follow-up
6 months) results show that this treatment was
well-tolerated with one acute grade 3 mucositis, one
late soft tissue ulceration, and no osteoradionecrosis.
455
The estimated 2-year LC rate was 68%, with 67%
2-year OS.
In a separate publication, Strnad et al. (2003)
reported the outcomes of 43 HNC patients who were
re-irradiated via PDR-BT at the University of Erlan-
gen-Nuremberg. The series included 31 recurrent
tumors and 12 s primary tumors, and nine of the
patients were implanted with palliative intent due to
tumor size [4 cm or KPS B50. The overall treatment
course also included surgical resection in 28 patients
(65%), EBRT to a median dose of 40 Gy in 13
patients (30%), interstitial hyperthermia in 20 patients
(47%), and concurrent chemotherapy in 16 patients
(37%). PDR-BT implants were performed according
to the Paris system, and a median of 0.52 Gy (range
0.4–0.7) was prescribed in continuous hourly pulses
to the 85% isodose. The total median PDR-BT dose
was 54 Gy (range 50–60 Gy) for patients treated
without EBRT, and 27 Gy (19.2–38.5 Gy) when
given with EBRT. At 2 years, the actuarial local
recurrence-free survival rate was 68% overall (80%
for patients treated with curative intent), DFS was
62% overall (77% with curative intent), and OS was
49% overall (66% with curative intent). Chemother-
apy and hyperthermia were not found to significantly
impact the results of treatment. No osteoradionecrosis
was noted, and soft tissue necrosis that resolved with
conservative management developed in only two
patients (4.7%). No other serious side effects occurred
over a median follow-up time of 24 months.
Investigators at the University Hospital Schle-
swig–Holstein Campus Kiel have developed an
interdisciplinary technique for treating locally recur-
rent skull base tumors, while striving to preserve
vision (Strege et al. 2005). Treatment includes R1–R2
resection with implantation of interstitial catheters for
PDR-BT, and EBRT. In a series of 18 patients with
paranasal sinus cancer, sarcoma, PNET, or parotid
gland carcinoma, there was no treatment-related
vision loss, and the median overall survival time was
16 months.
6 Ongoing Studies and Future
Directions
The European study on MRI-guided BT in locally
advanced cervical cancer (EMBRACE) opened in
2008 and aims to enroll over 600 patients. This
456
prospective, nonrandomized study has several goals,
including the systematic introduction of MRI-guided
BT (PDR or HDR) in a multicenter setting. Each
institution is to continue its own traditions in terms
of applicator type, dose prescription, and DVH
constraints, however contouring and reporting must
follow the GEC-ESTRO guidelines. Data will thus be
generated for future correlation of DVH parameters
with clinical outcome, as well as analysis of prog-
nostic and predictive factors.
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 Clinical Applications of High-Dose-Rate
Brachytherapy
Subir Nag and Granger R. Scruggs

Contents Abstract
Brachytherapy has the advantage of delivering a
1 Introduction.............................................................. 462 high dose to the tumor while sparing the
2 How to Design a New HDR Protocol.................... 462 surrounding normal tissues. With proper case
selection and delivery technique, high-dose-rate
3 Common Uses of HDR Brachytherapy................. 465
3.1 Carcinoma of the Cervix........................................... 465 (HDR) brachytherapy eliminates radiation expo-
3.2 Carcinoma of the Endometrium................................ 467 sure, allows short treatment times, and can be
3.3 Endobronchial Radiation ........................................... 469 performed on an outpatient basis. Additionally,
3.4 Cancer of the Esophagus........................................... 470 use of a single-stepping source allows optimiza-
3.5 Carcinoma of the Prostate......................................... 471
3.6 Head and Neck Cancers ............................................ 472 tion of dose distribution by varying the dwell
3.7 Soft Tissue Sarcomas ................................................ 473 time at each dwell position. However, when
3.8 Pediatric Tumors ....................................................... 474 HDR brachytherapy is used, the treatments must
3.9 Breast Cancer............................................................. 475 be executed carefully, because the short treat-
3.10 Skin Cancer................................................................ 476
ment times do not allow any time for correction
4 Discussion.................................................................. 477 of errors, and mistakes can result in harm to
References.......................................................................... 478 patients. Hence, it is very important that all
personnel involved in HDR brachytherapy be
well trained and constantly alert. The use of
HDR brachytherapy has expanded over the last
decade and will continue to do so with refine-
ments in the integration of imaging (computed
tomography, magnetic resonance imaging, intra-
operative ultrasonography) and optimization of
dose distribution. Better tumor localization and
normal tissue definition has led to more optimal
dose distribution to the tumor and reduction of
S. Nag (&) normal tissue exposure. It is anticipated that this
Northern California Kaiser Permanente, Santa Clara, will lead to better outcomes. The development of
CA 95070, USA
e-mail: Subir.nag@kp.org well-controlled randomized trials addressing
issues of efficacy, toxicity, quality of life, and
S. Nag
Stanford School of Medicine, Stanford, CA, USA costs versus benefits will ultimately define the
specific role of HDR brachytherapy in the
G. R. Scruggs
Department of Radiation Oncology, therapeutic armamentarium at different disease
Charles A. Sammons Cancer Center, sites.
Baylor University Medical Center–Dallas, Texas, USA

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 461
DOI: 10.1007/174_2011_332,  Springer-Verlag Berlin Heidelberg 2012
462
1 Introduction
Brachytherapy has the advantage of delivering a high
dose of radiation to the tumor while sparing the sur-
rounding normal tissues. Brachytherapy procedures
were initially performed by inserting the radioactive
material directly into the tumor (‘‘hot’’ loading),
thereby giving high radiation exposure to the physi-
cians performing the procedure. Manually afterloaded
techniques were introduced to increase accuracy and
reduce the radiation hazards. In afterloaded tech-
niques, hollow needles, catheters, or applicators are
first inserted into the tumor then loaded with radio-
active materials. The introduction of remote-con-
trolled insertion of sources eliminated radiation
exposure to visitors and medical personnel. In this
technique, the patient is housed in a shielded room,
and the radiation therapist controls the treatment from
outside the room. Hollow applicators, needles, or
catheters are inserted into the tumor and connected by
transfer tubes to the radioactive material, which is
stored in a shielded safe within the HDR afterloader.
The radiation source is driven through the transfer
tubes and into the tumor by remote control.
Remote controlled brachytherapy can be per-
formed using low-dose-rate (LDR), medium-
dose-rate (MDR), or HDR techniques. The usual
dose rate employed in current HDR brachytherapy
units is about 100–300 Gy/h. The use of remote-
controlled brachytherapy (whether it is LDR, MDR,
or HDR brachytherapy) eliminates the hazards of
radiation exposure. The use of HDR has the added
advantage of the treatments taking only a few
minutes, allowing them to be given on an outpatient
basis with minimal risk of applicator movement and
minimal patient discomfort. Additionally, use of a
single-stepping source, as used in most modern
HDR afterloaders, allows optimization of dose dis-
tribution by varying the dwell time at each dwell
position. However, it should be emphasized that
while optimization can improve the dose distribu-
tion, it should not be used to substitute for a poorly
placed implant. Nag and Samsami (2000) have
provided examples of inappropriate optimization
strategies, which can lead to suboptimal dosimetry
plans and clinical problems. The advantages and
disadvantages of HDR in comparison with LDR are
enumerated in Table 1.
S. Nag and G. R. Scruggs
The advantages listed above have led to increased
use of HDR worldwide; however, training and
expertise is required for proper administration of
these treatments. Scientific Societies, including the
American Brachytherapy Society (ABS), have
published guidelines and recommendations for the
use of HDR at various sites (Gaspar et al. 1997; Nag
et al. 2000a, b, 2001a, b, c, 2002, 2004a; Rodriguez
et al. 2001; Arthur et al. 2002, 2003). While this
chapter incorporates many of these recommendations,
the reader should refer to the original publications for
details.
2 How to Design a New HDR Protocol
Most radiation oncologists are familiar with LDR
brachytherapy. LDR (at 30–50 cGy/h) can be added
to external beam radiation therapy (EBRT) doses
(at 2 Gy/day) to obtain equivalent total doses. HDR
brachytherapy is a modality that is distinct from LDR
brachytherapy, and radiation oncologists who are
accustomed to LDR techniques must realize that
experience in LDR cannot be automatically translated
into expertise in HDR. It is important to review the
current literature and survey the experiences of
centers that have been performing HDR. When
converting from LDR to HDR, one must keep the
other parameters (chemotherapy, EBRT field/dose,
dose-specification point, applicators, patient popula-
tion, etc.) the same, changing only the LDR to HDR.
Fractionation schemes for HDR are widely vari-
able, and many radiation oncologists are not very
familiar with the resultant biological effects. Empiri-
cal methods such as the nominal standard dose, time–
dose factor, or a dose reduction factor of 0.6 have
been used in the past to convert HDR doses to LDR
equivalent doses. The linear-quadratic (LQ) equation
(Barendsen 1982) can be used to guide development
of HDR doses and fractionation schedules. However,
the LQ mathematical calculations are tedious and may
not be practical on a day-to-day basis. Hence, a
simplified computer program was developed by Nag
and Gupta (2000) to obtain the isoeffective doses for
HDR. The clinician needs only to enter the EBRT
total dose and dose/fraction, HDR dose, and the
number of HDR fractions. The computer program will
automatically calculate the isoeffective doses for
tumor and normal tissue effects. Isoeffective doses are
Clinical Applications of High-Dose-Rate Brachytherapy 463

Table 1 Advantages and disadvantages of high-dose-rate (HDR) compared with low-dose-rate (LDR) brachytherapy
Advantages Disadvantages
Radiation protection Radiobiological
HDR eliminates radiation exposure hazard for caregivers and The short treatment times do not allow for the repair of
visitors. Caregivers are able to provide optimal patient care sublethal damage in normal tissue, the redistribution of cells
without fear of radiation exposure within the cell cycle, or reoxygenation of the tumor cells;
hence, multiple treatments are required
HDR eliminates source preparation and transportation Limited experience
Since there is only one source, there is minimal risk of losing Few centers in the US have long-term ([20 years) experience
a radioactive source
Allows shorter treatment times Until recently, standardized treatment guidelines were not
available; however, the American Brachytherapy Society has
provided guidelines for HDR at various sites (Arthur et al.
2002; Nag et al. 2000a, b, 2001a, b, c; Rodriguez et al. 2001)
There is less patient discomfort, since prolonged bed rest is The economic disadvantage
eliminated
It is possible to treat patients who may not tolerate long The use of HDR brachytherapy, compared with manual
periods of isolation and those who are at high risk of afterloading techniques, requires a large initial capital
pulmonary embolism due to prolonged bed rest expenditure, since the remote afterloaders cost approximately
$400,000
There is less risk of applicator movement during therapy There are additional costs for a shielded room, and personnel
costs are higher, as the procedures are more labor intensive
There are reduced hospitalization costs, since outpatient Greater potential risks
therapy is possible
HDR may allow greater displacement of nearby normal Since a high activity source is used, there is greater potential
tissues (by packing or retraction), which could potentially harm if the machine malfunctions or if there is a calculation
reduce morbidity error. The short treatment times, compared with LDR, allow
much less time to detect and correct errors
It is possible to treat a larger number of patients in
institutions that have a high volume of brachytherapy patients
but insufficient in-patient facilities (e.g., in some developing
countries)
Allows intraoperative treatments, which are completed while
patient is still in the operating room
HDR sources are of smaller diameter than the Cesium sources
that are used for intracavitary LDR
This reduces the need for dilatation of the cervix and
therefore reduces the need for heavy sedation or general
anesthesia
High-risk patients who are unable to tolerate general
anesthesia can be more safely treated
HDR allows for interstitial, intraluminal and percutaneous
insertions
HDR makes treatment dose distribution optimization possible
Variations of the dwell times of a single stepping source
allow an almost infinite variation of the effective source
strengths, and the source positions allow for greater control of
the dose distribution and potentially less morbidity
464 S. Nag and G. R. Scruggs

Table 2 American Brachytherapy Society suggested doses of external beam radiation therapy (EBRT) and high-dose-rate (HDR)
brachytherapy to be used in treating early and advanced cervical cancer
Total EBRT No. of HDR Isoeffective Isoeffective dose Isoeffective dose Isoeffective dose
dose (Gy) @ HDR dose/ dose (Gy) for (Gy) for late effects (Gy) for late effects (Gy) for late effects
1.8 Gy/fraction fractions fraction tumor effects with DMF=0.6 with DMF=0.7 with DMF=0.9
(Gy)
Early cervical cancer
19.8 6 7.5 85.1 59.5 71.0 98.0
19.8 7 6.5 82.0 56.7 67.1 91.5
19.8 8 6.0 83.5 57.0 67.4 91.6
45 5 6.0 84.3 67.0 73.4 88.6
45 6 5.3 84.8 66.8 73.1 87.7
Advanced cervical cancer
45 5 6.5 88.9 70.1 77.6 95.0
45 6 5.8 90.1 70.3 77.6 94.7
50.4 4 7.0 89.2 72.6 79.4 95.3
50.4 5 6.0 89.6 72.1 78.6 93.7
50.4 6 5.3 90.1 72.0 78.3 92.9
The a/b ratio assumed for tumor equals ten. The a/b ratio assumed for normal tissue late effects equals three.
DMF = dose modifying factor

expressed in clinically familiar terms (as if given at
2 Gy/fraction) rather than as biologically equivalent
doses, which are unfamiliar to clinicians. Further-
more, a dose-modifying factor (DMF) is applied to
the normal tissues to account for the fact that doses to
normal tissues are different from the doses to the
tumor, thus providing a more realistic equivalent
normal tissue effect. This program can be used to
determine HDR doses that are isoeffective to radiation
therapy doses given at 2 Gy/day and used to treat
various cancers. Alternatively, the program may be
used to express the isoeffective dose of different HDR
dose-fractionation regimes, as shown for cervical
cancer in Table 2. It is remarkable that the isoeffec-
tive doses for tumor effects for the various fraction-
ation regimes used for early-stage cervical cancers are
so similar, ranging from 82 to 85 Gy, while those
used for advanced cancers are about 90 Gy (Table 2).
The isoeffective dose for normal tissue late effects
depends on the assumed DMF (0.6, 0.7, or 0.9). For
the fractionation scheme shown in Table 2, row 1, the
equivalent late effect on normal tissue (bladder or
rectum) would be 59.5, 71, or 98 Gy, respectively, if
the doses to normal tissues were 60, 70, or 90% of the
prescribed dose to point A.
Although the LQ biomathematical model can be
helpful in determining equivalent doses, it has many
limitations that must be kept in mind when using the
program. The L-Q model accounts for the repair of
sublethal damage and does not account for reoxy-
genation of hypoxic cells, reassortment within the cell
cycle, or repopulation of tumor cells. These factors
are generally small under normal circumstances.
However, large doses per fraction do not allow
reoxygenation of hypoxic tumor cells or reassortment
of tumors from radioresistant S-phase. Hence, a large
radiation dose will preferentially kill radiosensitive
cells, leaving a high number of hypoxic, radioresistant
cells. Therefore, the computer program will overes-
timate the tumor effect of a single large dose per
fraction (unless a resensitization factor is introduced).
The LQ equation does not take into account the
proliferation of tumor cells. This factor is small if the
treatments are performed over a short duration. How-
ever, if the treatments are highly protracted (e.g., there is
a long time interval between EBRT and HDR), or in
cases of tumors with high proliferation rates, the LQ
model will overestimate the actual tumor effect. It also
must be noted that individual a/b values are very vari-
able. The a/b values for early reactions vary from 6 to 13
Clinical Applications of High-Dose-Rate Brachytherapy
(the default in the program is set at 10); the a/b values for
late reactions vary from 1 to 7 (default being set at 3),
while a/b values for tumors vary from 0.4 to 13 (the
default being set at 10). However, a/b values for a par-
ticular patient are not known and may vary even within
the same tissue. The isoeffective doses obtained will,
therefore, depend on the a/b values used for that par-
ticular calculation. The LQ model assumes complete
repair between fractions. If the time interval between
fractions is too short (\6 h) or the half-time of repair is
very long, the repair of normal tissues will be incom-
plete, and the LQ formula will underestimate the bio-
logical effect. Hence, it is important to have a sufficient
time interval (at least 6 h) between treatment fractions.
The infinite variation of the dwell times that is
possible with HDR (or pulsed dose rate) allows better
optimization of the doses than can be achieved with
LDR. Better packing or retraction of normal tissues is
possible with HDR, due to the short treatment duration.
This factor is not usually taken into account in the LQ
model (unless the DMF is altered). Another difference
not accounted for in the LQ model is that the dose stated
in brachytherapy is generally the minimum tumor dose.
The doses within the tumor are much higher. Hence, the
effective dose for tumor control probability is much
higher for brachytherapy than for EBRT.
In view of the many limitations of the LQ model, it
must be stressed that, as with any mathematical
model, the LQ model should be used judiciously as a
guide only and should always be correlated with
clinical judgment and outcome results. Caution is
especially warranted whenever large fraction sizes are
used, since their clinical results have not been well
studied.
3 Common Uses of HDR
Brachytherapy
Although HDR brachytherapy has been used in
almost every site in the body, it is now most com-
monly used to treat cancers of the cervix, endome-
trium, prostate and breast. Less common treated sites
for HDR include the lung, esophagus, bile duct, rec-
tum, head and neck, skin, and soft tissues. HDR is
generally used as a component of a multi-modality
treatment that includes EBRT and/or chemotherapy
and surgery. A summary of the clinical uses of HDR
at various sites is included in this article.
465
3.1 Carcinoma of the Cervix
Brachytherapy is a necessary component in the
curative treatment of cervical cancers (Nag et al.
2000b). HDR has gained popularity in the US over the
last two decades due to the advantages alluded to
earlier, specifically the possibility of therapy on an
outpatient basis, avoidance of long-term bed rest, and
avoidance of cervical dilation. Additionally, greater
sparing of the rectum and bladder by temporary
retraction, dose optimization, and integration with
EBRT to the pelvis are possible. These advantages
must be counterbalanced with the greater number of
treatments required (typically five or six treatments
lasting approximately 10–15 min each). A recent
international survey revealed that 85% of centers
utlilize HDR brachytherapy (Viswanathan et al.
2011).
The ABS recommends keeping the total duration
of treatment (EBRT and HDR) to less than 8 weeks,
since prolongation adversely affects local control and
survival (Nag et al. 2000b). Because the overall
treatment duration would be unduly prolonged if
HDR treatments (generally five or six fractions given
once a week) were begun after completion of EBRT,
the HDR is commonly given concurrently during the
course of EBRT (but note that EBRT is not given on
the day of HDR brachytherapy).
Traditionally, the HDR dose was prescribed to an
arbitary applicator-based definition of point A (Nag
et al. 2000a). Unfortunately, Point A does not nec-
essarily reflect the dose to the tumor. Given this fact
and in conjunction with the proliferation of improved
imaging modalities as well as the advent of CT and
magnetic resonance imaging (MRI) compatible
applicators, there has been a shift toward image-based
treatment planning in brachytherapy for carcinoma of
the cervix. It is well established that (MRI) is superior
to other current imaging modalities in delineating
gross tumor involving the cervix and adjacent normal
tissues (Hricak and Yu 1996; Kim et al. 1990; Subak
et al. 1995). The use of MRI can lead to better
delineation of the target volume, which then could
translate to dose escalation for better tumor control
while simultaneously limiting dose to normal tissues.
A gynecological working group was formed by the
Groupe Europeen de Curietherapie and European
Society for Therapeutic Radiology and Oncology
(GEC-ESTRO) in 2000 to formulate and describe
466 S. Nag and G. R. Scruggs

Table 3 GEC-ESTRO image based planning volume definitions for cervical cancer
Volume Description
GTVD GTV at Diagnosis Macroscopic tumor extension at diagnosis as detected by clinical examination
and visualized on MRI
GTVB1,B2,B3… GTV at each BT procedure Macroscopic tumor extension at time of brachytherapy as detected by clinical
examination and as visualized on MRI
HR High Risk CTV at each BT Includes GTVB1,B2…,the whole cervix and presumed extracervical tumor
CTVB1,B2,B3… procedure extension at time of brachytherapy by means of clinical examination and by
MRI
IR Intermediate Risk CTV at Encompasses high risk CTV with a safety margin of 5–15 mm (Safety margin
CTVB1,B2,B3… each BT procedure is chosen according to tumor size and location, potential tumor spread, tumor
regression, and treatment strategy) *The IR CTV is never less than GTVD
GTV gross tumor volume, CTV clinical target volume, BT brachytherapy, MRI magnetic resonance imaging,
GEC-ESTRO Groupe Europeen de Curietherapie and European Society for Therapeutic Radiology and Oncology

new terminology regarding 3D image based treat-
ment planning in cervical cancer brachytherapy.
Their recommendations are summarized in Table 3
(Haie-Meder et al. 2005). In early 2006, the working
group released an update to their original recom-
mendations to include descriptions of dose volume
parameters for organs at risk and a step-wise proce-
dure for transition from the traditional dose pre-
scription to the 3D image-based volume prescription
(Potter et al. 2006). The reader is strongly encouraged
to refer to those publications to fully understand and
implement these recommendations.
The recommended combined EBRT and HDR
dose to at least 90% (D90) of the high risk clinical
target volume (HR-CTV—defined by GEC-ESTRO
as the volume including macroscopic tumor) is an
isoeffective dose of 75–90 Gy (Haie-Meder et al.
2005; Potter et al. 2006). The lower dose range can be
utilized for early stage disease defined as non bulky
stage I/II less than 4 cm in diameter and the higher
dose range is used for advanced stage disease defined
as stage I/II greater than 4 cm in diameter or stage
IIIB. The HDR dose is dependent on the stage of the
disease and the dose of EBRT. Most centers use a
schedule of approximately 6–8 Gy/fraction in four to
six fractions, although two or three fractions of
8–10 Gy have been used (a smaller number of frac-
tions is used by those using larger doses per fraction;
Orton et al. 1991; Petereit et al. 1999; Nag et al.
2000b; Sood et al. 2002; Nakano et al. 2005; Patel
et al. 2005; Souhami et al. 2005). While recognizing
that many efficacious HDR fractionation schedules
exist, the ABS suggestions and the isoeffective doses
are given in Table 2 as a guide. These doses, while
representing the traditional Point A doses, correspond
to the new HR-CTV D90. The ABS and GEC-ESTRO
guidelines suggest keeping the D2 cc dose to the
sigmoid to \75 Gy, D2 cc to the rectum to \75 Gy
and D2 cc to the bladder to \95–100 Gy.
In certain difficult clinical situations (e.g., a narrow
fibrotic vagina, bulky tumors, the inability to enter the
cervical os, extension to the lateral parametria or
pelvic side wall, lower vaginal extension and subop-
timal applicator placement), the normal tissue toler-
ance may be exceeded if the above doses are used. In
these situations, the HDR fraction size can be
decreased (which requires an increase in the fraction
number) or the EBRT dose increased while decreas-
ing the HDR total dose. Alternatively, an interstitial
implant (either LDR or HDR) may be used.
Although large, multi-institutional, randomized
trials are not available, the available data from single-
institution randomized trials, retrospective analyses
and meta-analyses suggest that survival, local control,
and morbidity of HDR treatments are equivalent to
that of LDR (Orton et al. 1991; Petereit et al. 1999;
Lorvidhaya et al. 2000; Hareyama et al. 2002; Lert-
sanguansinchai et al. 2004; Nakano et al. 2005; Patel
et al. 2005). A recent analysis utilizing the GEC-
ESTRO target volume and organs at risk parameters
demonstrated a local recurrence rate of 4% (mean
follow-up of 51 months) in those patients receiving at
least a D90 of 87 Gy (isoeffective dose) to the
HR-CTV (Dimopoulos et al. 2009 IJROBP).
Clinical Applications of High-Dose-Rate Brachytherapy 467

Table 4 American Brachytherapy Society suggested doses of been proven that the combination yields any superior
high-dose-rate (HDR) brachytherapy alone or in combination results. Others prefer ‘‘watchful waiting’’ and use
with external beam radiation therapy (EBRT) to be used for
adjuvant treatment of post-operative endometrial cancer salvage irradiation if there is a recurrence, since the
final survival rate is not compromised. However, in
EBRT (Gy) at No. of HDR dose/ Dose
1.8 Gy/ HDR fraction specification
cases of recurrence, a combination of pelvic EBRT
fraction fractions (Gy) point and brachytherapy is required.
00 3 07.0 0.5 cm depth The Post Operative Radiation Therapy in Endo-
metrial Cancer (PORTEC) II randomized trial was
00 4 05.5 0.5 cm depth
recently published and demonstrated equivalency in
00 5 04.7 0.5 cm depth
regards to vaginal cuff recurrence rates (1.6% vs.
00 3 10.5 Vaginal 1.8%) and survival (79.6% vs. 84.8%) between pelvic
surface
EBRT and vaginal brachytherapy alone for a specific
00 4 08.8 Vaginal
surface
population of endometrial patients (Nout et al. 2010).
Patients eligible for that trial included age [60 with
00 5 07.5 Vaginal
surface Stage IB Grade 3, Stage IC Grade 1–2, or any age
with Stage IIA Grade 1–2, Grade 3 if less than 50%
45 2 05.5 0.5 cm depth
myometrial invasion (FIGO 1988 Staging). While this
45 3 04.0 0.5 cm depth
trial has shed light on appropriate adjuvant treatment
45 2 08.0 Vaginal for this subset of patients, controversy remains for
surface
patients that fall outside of this group.
45 3 06.0 Vaginal
surface
If pelvic EBRT is used, the dose is usually
40–45 Gy in 20–25 treatments (Nag et al. 2000a).
A vaginal cylinder is commonly used to deliver
HDR brachytherapy. The largest diameter cylinder
3.2 Carcinoma of the Endometrium that comfortably fits the vagina should be used to
increase the depth dose. The length of vaginal vault
HDR brachytherapy is commonly used for adjuvant treated varies. Some treat the superior 3 cm or
treatment of the vaginal cuff after hysterectomy in 5 cm, while others treat the superior half or two-
patients at intermediate and high risk for vaginal thirds of the vagina (Sorbe and Smeds 1990; Nag
recurrence (high-grade, deep myometrial invasion, or et al. 2000a; Alektiar et al. 2002a, 2005; Rittenberg
advanced stage). Additionally, brachytherapy may be et al. 2003; Nout et al. 2010). For serous and clear
used for primary treatment in inoperable endometrial cell histologies, treatment of the entire vaginal
carcinoma and for treatment of recurrences after canal should be considered. The dose distribution
hysterectomy. should be optimized to follow the curvature of the
Patients at high risk for vaginal recurrences after dome of the cylinder to deliver the prescribed dose
hysterectomy (deep myometrial invasion, high histo- either at the vaginal surface or at 0.5 cm depth,
logical grade and stage, cervical or extra-uterine depending on the institutional policy. Regardless of
spread, squamous cell or papillary histology) should the prescription point, doses to both of these points
receive adjuvant radiation therapy. There is contro- should be reported (Nag et al. 2000a). The ABS
versy regarding the best method. Pelvic EBRT, vag- dose suggestions (Nag et al. 2000a) for HDR alone
inal vault brachytherapy or a combination can be used or in combination with 45 Gy EBRT are given in
depending on the extent of pelvic lymph node dis- Table 4. Since some institutions specify the dose to
section and whether chemotherapy will be added. the vaginal surface and others specify the dose at
EBRT has the advantage of irradiating the pelvic 0.5 cm depth, suggested HDR doses have been
lymph nodes but takes approximately 5 weeks to given for both specification methods.
perform and has some morbidity. Brachytherapy is The 5-year survival rates of HDR therapy vary
more convenient and has low morbidity, but does not from 72 to 97%, depending on the stage, grade,
treat the lymph nodes. Hence, some centers combine and depth of myometrial invasion (Sorbe and
both EBRT and brachytherapy, although it has not Smeds 1990; Alektiar et al. 2005; Jolly et al. 2005;
468
Table 5 American Brachytherapy Society suggested doses of
high-dose-rate (HDR) brachytherapy to be used in combination
with pelvic external beam radiation therapy (EBRT) for treating
vaginal cuff recurrences from endometrial cancer
EBRT (Gy) at No. of HDR dose/ Dose
1.8 Gy/ HDR fraction specification
fraction fractions (Gy) point
45 3 7.0 0.5 cm depth
45 4 6.0 0.5 cm depth
45 5 6.0 Vaginal
surface
45 4 7.0 Vaginal
surface
Chong and Hoskin 2008). The severe (grades III or
IV) late complication rate is usually less than 1% and
depends on the dose per fraction (Sorbe and Smeds
1990; Alektiar et al. 2005; Solhjem et al. 2005). The
incidence of vaginal shortening is also very much
dose dependent, reportedly as high as 70% when 9 Gy
per fraction was prescribed at 1 cm depth to 31%
when the dose was reduced to 4.5 Gy per fraction
(Sorbe and Smeds 1990). A randomized trial evalu-
ated two different fractionation schemes (2.5 Gy 9 6
vs. 5 Gy 9 6) and found no difference in locoregional
recurrence rates, but an increase in vaginal shorten-
ing, mucosal atrophy, and bleeding in the 5 Gy per
fraction arm (Sorbe et al. 2005). Other factors that
increase morbidity include the use of a small (2 cm)
diameter vaginal cylinder, the addition of pelvic
EBRT, and dose specification point beyond 0.5 cm
(Mandell et al. 1985).
A combination of pelvic EBRT and brachytherapy
is generally used to treat recurrences at the vaginal
cuff. With distal vaginal recurrences, the entire vagina
and medial inguinal nodes are included in the EBRT
field. Intracavitary vaginal brachytherapy should be
used only for non-bulky recurrences (thickness less
than 5 mm after the completion of EBRT) (Nag et al.
2000a). Interstitial brachytherapy is to be used for
bulky recurrences (thickness [5 mm after the com-
pletion of EBRT) and for previously irradiated
patients. The ABS suggested doses for HDR brachy-
therapy (in combination with 45 Gy EBRT) are pro-
vided in Table 5 (Nag et al. 2000a).
Patients with adenocarcinoma of the endometrium
who are not candidates for surgery because of severe
medical problems are treated with radiation therapy. A
combination of pelvic EBRT beam and brachytherapy
S. Nag and G. R. Scruggs
Table 6 American Brachytherapy Society suggested doses of
high-dose-rate (HDR) brachytherapy alone or in combination
with external beam radiation therapy (EBRT) for treatment of
inoperable primary endometrial cancer
EBRT (Gy) at No. of HDR HDR dose/
1.8 Gy/fraction fractions fraction (Gy)a
45 2 8.5
45 3 6.3
45 4 5.2
00 4 8.5
00 5 7.3
00 6 6.4
00 7 5.7
a
HDR doses are specified at 2 cm from the midpoint of the
intrauterine sources
is preferred whenever possible. However, many of the
conditions that do not allow surgery in these cases are
also relative contraindications for EBRT and for LDR
brachytherapy. These patients may be treated with
HDR alone.
Numerous applicators can be used for treatment of
primary endometrial cancer. A tandem and colpostat
is often used; however, this applicator will not irra-
diate the uterine surface homogeneously. Others have
used a curved tandem, turning it to the left and right in
alternate insertions. A ‘‘Y’’-shaped applicator irradi-
ates the fundus more evenly. Other possibilities
include modified Heyman capsules or multiple tan-
dems. The dose is commonly specified at 2.0 cm from
the source, although computed-tomography-based
treatment planning to ensure a more homogeneous
dose to the entire myometrium is preferred. The dose
per fraction has ranged from 5 to 12 Gy, and four to
six fractions are commonly employed (Sorbe and
Frankendal 1989; Rouanet et al. 1993; Nag 1996; Nag
et al. 2000a; Niazi et al. 2005). The dose and/or the
dose per fraction is reduced if EBRT is added. The
ABS-suggested doses for HDR brachytherapy alone
or in combination with 45 Gy EBRT are given in
Table 6 (Nag et al. 2000a). The survival at 5 years for
stage I is approximately 70–80%, which is slightly
lower than that obtained by surgery. A recent study
reported a 5 year cause specific survival of 87% for
patients treated with HDR twice daily with 35 Gy in 5
fractions without EBRT or with 20 Gy in five frac-
tions with EBRT (Coon et al. 2008). The toxicity is
Clinical Applications of High-Dose-Rate Brachytherapy
higher (about 7%) when patients are treated with high
doses per fraction (Sorbe and Frankendal 1989).
3.3 Endobronchial Radiation
The use of HDR brachytherapy is well established for
palliation of cough, dyspnea, pain, and hemoptysis in
patients with advanced or metastatic lung cancer. The
use of brachytherapy as a boost to EBRT in curative
cases should be restricted to a select group of patients
who have predominantly endobronchial disease, are
medically inoperable, or have small/occult carcino-
mas of the lung.
An initial bronchoscopy is performed to evaluate
the airway and locate the site of obstruction. While
the proximal site of obstruction is usually easily
visualized, the distal extent of the obstruction may
have to be estimated. Either a 5 or 6 French catheter
(inserted through the brush channel of the broncho-
scope) can be used to deliver the brachytherapy. The
catheter (with a radiopaque wire in the lumen) is
passed through the obstructed segment and lodged
into the distal bronchus. The bronchoscope is
removed, leaving the catheter in position. Fluoro-
scopic guidance helps catheter positioning and mini-
mizes inadvertent catheter dislodgment during
bronchoscopic removal. The length to be irradiated
usually includes the endobronchial tumor and
1.0–2.0 cm proximal and distal margins. If a single
catheter is used, and there is minimal curvature of the
catheter in the area to be irradiated, it is possible to
minimize the treatment planning time using pre-
planned dosimetry. For example, The Ohio State
University has pre-calculated treatment plans for 3, 5,
7, and 10 cm lengths to be irradiated to 5 or 7.5 Gy at
1 cm from the source using equal dwell times. This
allows the treatment to be performed without any
delay if standard lengths and doses are used. Indi-
vidualized image-based treatment planning must be
performed if multiple catheters are used.
Candidates for palliative endobronchial brachy-
therapy include (Mehta et al. 1992, 1997; Gaspar
1998; Speiser 1999; Nag et al. 2001a):
1. Patients with a significant endobronchial tumor
component that causes symptoms such as short-
ness of breath, hemoptysis, persistent cough, and
other signs of post-obstructive pneumonitis.
Tumors with a predominantly endobronchial
469
component are considered suitable, as opposed to
extrinsic tumors that compress the bronchus or the
trachea. Endobronchial brachytherapy can gener-
ally give quicker palliation of obstruction than
EBRT. Furthermore, brachytherapy can be more
convenient than 2–3 weeks of daily EBRT.
2. Patients who are unable to tolerate any EBRT
because of poor lung function.
3. Patients with previous EBRT of sufficient total
dose to preclude further EBRT.
A variety of doses have been successfully used by
various centers. Total doses ranging from 15 to 47 Gy
HDR in 1–5 fractions calculated at 1.0 cm have been
reported (Mehta et al. 1997; Gaspar 1998; Nag et al.
2001a). The ABS suggests using three weekly frac-
tions of 7.5 Gy each or two fractions of 10 Gy each or
four fractions of 6 Gy each prescribed at 1.0 cm when
HDR is used as the sole modality for palliation (Nag
et al. 2001a). These fractionation regimes have sim-
ilar radiobiological equivalence using the linear qua-
dratic model, and there is no evidence of superiority
for one regimen over the other. The benefits of fewer
bronchoscopic applications should be weighed against
the risks of a higher dose per fraction. Additional
treatments or doses higher than those suggested can
be considered for unirradiated patients or those who
have received limited radiation. When HDR is used as
a planned boost to supplement palliative EBRT of
30 Gy in 10–12 fractions, the ABS suggests using two
fractions of 7.5 Gy each or three fractions of 5 Gy
each or four fractions of 4 Gy each (prescribed at
1.0 cm) in patients with no previous history of tho-
racic irradiation (Nag et al. 2001a). The interval
between fractions is generally 1–2 weeks. The
brachytherapy dose should be reduced when aggres-
sive chemotherapy is given. Concomitant chemo-
therapy should be avoided during brachytherapy,
unless it is in the context of a clinical trial.
The results from various centers show clinical
improvement from 50 to 100% and bronchoscopy
response from 59 to 100% (Mehta et al. 1997; Gaspar
1998; Kelly et al. 2000; Nag et al. 2001a; Celebioglu
et al. 2002; Gejerman et al. 2002; Escobar-Sacristan
et al. 2004; Kubaszewska et al. 2008; Ozkok et al.
2008; Skowronek et al. 2009; Gaurnaschelli and Jose
2010; Dagnault et al. 2010; Hauswald et al. 2010).
Comparison of these results is difficult because of the
differences in patient populations and the variability
in dose and fractionation employed.
470
Complications include radiation bronchitis and
stenosis which may occur after endobronchial brach-
ytherapy, necessitating close follow-up (Speiser and
Spartling 1993a). Another more serious complication
is fatal hemoptysis. The hemoptysis could be a radi-
ation therapy complication resulting from the high
dose delivered to the area of the pulmonary artery, or
it could represent the failure of treatment due to the
progression of disease (Speiser and Spratling 1993b).
Multiple courses of brachytherapy, a high previous
EBRT dose, a left upper lobe location, or long-irra-
diated segments increase the rate of hemoptysis
(Khanavkar et al. 1991; Bedwinek et al. 1992). Inci-
dence of fatal hemoptysis varies from 0 to 50%, with
a median value of 8% (Mehta et al. 1997).
The standard, definitive therapy for unresectable
lung cancer is a combination of chemotherapy and
EBRT. Select patients with predominantly endo-
bronchial tumor may benefit from endobronchial
brachytherapy as a boost to EBRT (Aygun et al. 1992;
Mehta et al. 1992; Huber et al. 1997; Muto et al.
2000; Anacak et al. 2001). In cases of post-obstruc-
tive pneumonia or lung collapse, brachytherapy can
be used to open up the bronchus and aerate the lung,
which allows some sparing of normal lung from the
EBRT field. Endobronchial brachytherapy alone with
curative intent is indicated in patients with occult
carcinomas of the lung confined to the bronchus or
trachea who are medically inoperable because of
decreased pulmonary function, advanced age, or
refusal of surgery (Perol et al. 1997; Huber et al.
1997; Furuta et al. 1999; Marsiglia et al. 2000; Saito
et al. 2000; Hennequin et al. 2007). Marsiglia et al.
2000 reported a survival rate of 78% with a median
follow-up of 2 years in 34 patients treated with a
HDR dose of 30 Gy in six fractions (5 Gy fractions
given once a week).
Endobronchial brachytherapy can be used as
adjuvant treatment in cases with minimal residual
disease after surgical resection. Macha et al. (1995)
reported tumor-free survival up to 4 years in 19
patients with doses of 20.0 Gy delivered in four
fractions at 1 cm from the source axis.
The ABS suggests a HDR dose of three 5 Gy
fractions or two 7.5 Gy fractions as a boost to EBRT
(either 60 Gy in 30 fractions or 45 Gy in 15 fractions)
(Nag et al. 2001a). The HDR dose should be pre-
scribed at a distance of 1.0 cm from the central axis of
the catheter and given weekly. If endobronchial
S. Nag and G. R. Scruggs
brachytherapy is used alone (in previously unirradi-
ated patients), HDR doses of five 5 Gy fractions or
three 7.5 Gy fractions prescribed to 1 cm may be used
(Nag et al. 2001a).
Utilization of HDR brachtherapy in the lung in
other clinical situations or in conjunction with other
new treatments has recently been described. Follow-
ing sublobar resection for those patients with poor
pulmonary function not amenable to lobectomy, HDR
brachtherapy consisting of seven fractions of 350 cGy
each delivered twice daily has promising results
(McKenna et al. 2008). Additionally it has been used
following metallic stent placement in the endobron-
chial lumen for palliative purposes and has been used
in combination with photodynamic therapy or
Yttrium–aluminum-garnet laser (Allison et al. 2004;
Freitag et al. 2004; Chella et al. 2000).
3.4 Cancer of the Esophagus
Non-operable definitive treatment of esophageal
cancer has evolved over the last two decades to now
frequently include concurrent EBRT and chemother-
apy. HDR brachytherapy for palliative purposes has
been evaluated in a few randomized trials and is well
established but its role in conjunction with concurrent
EBRT and chemotherapy is less defined. HDR
brachytherapy can be used either alone or in combi-
nation with EBRT in the treatment of esophageal
cancer (Gaspar et al. 1997; Sur et al. 1998, 2002,
2004; Rosenblatt et al. 2010). Brachytherapy is rela-
tively simple to perform, since a single catheter is
used for the treatment. A nasogastric tube or a spe-
cially designed esophageal applicator is used to
deliver the treatments. The largest diameter applicator
that can be inserted easily (either intraorally or
intranasally) should be used to minimize the mucosal
dose relative to the dose at depth. The site to be
irradiated, which includes the tumor and a distal and
proximal margin of 2–5 cm, can be confirmed by
fluoroscopy or endoscopy. The ABS recommends a
HDR dose of 10 Gy in two fractions, prescribed at
1 cm from the source, to boost 50 Gy EBRT (Gaspar
et al. 1997). HDR brachytherapy can be given before,
concurrent with, or after EBRT. The advantage of
giving brachytherapy after EBRT is that a more uni-
form dose can be delivered to the residual tumor after
it has been reduced using EBRT. Brachytherapy given
Clinical Applications of High-Dose-Rate Brachytherapy 471

Table 7 Dose fractionation and isoeffective doses (as if given at 2 Gy/fraction) of combined external beam radiation therapy
(EBRT) and high-dose-rate (HDR) doses used for treating prostate cancer
EBRT No of Total HDR HDR dose/ No. of Isoeffective dose Isoeffective dose Isoeffective
dose EBRT dose (Gy) fraction HDR (Gy)* (a/b=1.5) (Gy)* (a/b=5) dose (Gy)*
(Gy) fractions (Gy) fractions (a/b=10)
35.75 13 17 8.5 2 92 72 64
36 20 22–24 5.5–6 4 80–87 69–74 64–68
45 25 18 6 3 81 72 68
45 25 19 9.5 2 102 83 75
46 23 17.5–23 8.75–11.5 2 97–131 80–100 73–87
50 25 20 10 2 116 93 83
50.4 28 18 9 2 102 85 78

initially provides rapid relief of dysphagia. HDR
brachytherapy at doses of 16 Gy in two treatments
have been used without additional EBRT to palliate
esophageal cancers (Sur et al. 1998, 2002).
Retrospective studies as well as prospective, ran-
domized clinical trials show that there is improved
local control, survival, and palliation with the com-
bination of HDR brachytherapy and EBRT but that
HDR brachytherapy alone can be used for palliation
of advanced esophageal cancers (Gaspar et al. 1997;
Sur et al. 1998, 2002, 2004; Rosenblatt et al. 2010).
Since a high dose is delivered to the esophageal
mucosa, side effects may include ulcerations, fistulae,
and esophageal strictures.
Recent studies have evaluated the use of HDR
brachytherapy as a boost to concurrent chemotherapy
and EBRT in the management of esophageal cancer
(Gasper et al. 2000, 2001; Vuong et al. 2005; Brunner
et al. 2008). Results have varied and thus caution
should be exercised with this approach.
3.5 Carcinoma of the Prostate
Currently, permanent implantation of iodine-125 or
palladium-103 seeds is the most common type of
prostate brachytherapy. However, several centers
have used HDR brachytherapy, usually as a boost to
EBRT for the treatment of prostate cancer, with
encouraging results (Galalae et al. 2004; Astrom et al.
2005; Demanes et al. 2005; Deger et al. 2005; Vargas
et al. 2006; Hoskin et al. 2007; Bachand et al. 2009;
Deutsch et al. 2010; Zwahlen et al. 2010; Kaprealian
et al. 2011; Neviani et al. 2011). One of the major
advantages of HDR is that the dose distribution can be
intraoperatively optimized by varying the dwell times
at various dwell positions, potentially allowing reli-
able and reproducible delivery of the prescribed dose
to the target volume while keeping the doses to nor-
mal structures, i.e., rectum, bladder, and urethra,
within acceptable limits (Kovacs et al. 2005). Another
potential advantage of HDR brachytherapy in prostate
cancer is the theoretical consideration that prostate
cancer cells behave more like late-reacting tissue with
a low alpha–beta ratio and they should, therefore,
respond more favorably to higher dose fractions
rather than to the lower dose rate delivered in LDR
brachytherapy (Duchesne and Peters 1999; Fowler
et al. 2001; Williams et al. 2007).
When HDR brachytherapy is used as a boost to
EBRT, it may be given concurrently with or within
two weeks before or after 36–50 Gy EBRT. The
minimum volume treated should include the entire
prostate and seminal vesicles with margin, with or
without pelvic lymph nodes. The HDR dose typically
is given in multiple fractions in one or two implant
procedures. A variety of dose and fractionation
schemes have been used for same-stage disease as
shown in Table 7 (Galalae et al. 2004; Astrom et al.
2005; Demanes et al. 2005; Deger et al. 2005; Vargas
et al. 2006; Hoskin et al. 2007; Kaprealian et al.
2011). The HDR fractions are generally given twice a
day with a minimum of 6 h between fractions. The
most commonly encountered acute genito-urinary
morbidities include urinary irritative symptoms,
hematuria, hematospermia, and/or urinary retention,
similar to LDR permanent implants.
HDR brachytherapy has also been used as
monotherapy, with early results showing equivalent
biochemical control compared to LDR permanent
472 S. Nag and G. R. Scruggs

Table 8 High-dose-rate (HDR) brachytherapy for head and neck cancers

Author Site EBRT dose Fraction size No. Isoeffective No. of LC
(Gy) (Gy) fractions dosea (Gy) patients (%)
Lau et al. (1996) Tongue 0 6.5 07 63 27 053
Inoue et al. ( 2001) Tongue 0 6 10 80 25 87
Leung et al. ( 2002) Tongue 0 4.5–6.3 10 54–86 19 95
Guinot et al. ( 2003) Lip 0 4.5–5.5 8–10 54–57 39 88
Levendag et al. Nasal 0 3–4 14 48.3 64 92
(2006) vestibule
Yu et al. (1996) Various 50 2.7 06 67 12 079
Dixit et al. (1997) Various 40–48 3 07 63–71 18 080
Nag et al. (2004a, b) Sinus 45–50 10–12.5 1 66–68 27 65
45–63 15–20 1 94–95 7
Lu et al. (2004) Nasopharynx 66 5 2 79 33 94
Nose et al. (2004) Oropharynx 0 6 8–9 64–72 14 82
14.4–66.6 6 3–6 62–90 68
Ng et al. (2005) Nasopharynx 43.2–70.4 2.5–3 2–7 65–79 38 96
Nag et al. (2005) Various 45–50 7.5–20 1 61–95 65 59
Leung et al. (2008) Nasopharynx 66 10–12 2 99–110 145 95.8b
Yeo et al. (2009) Nasopharynx 66 10 2 99 178 91.6
Martinez-Monge Oral cavity 45 4 4 63 8 86
et al. (2009) Oropharynx 4 6 72 31
Guinot et al. (2010) Tongue 0 4 11 51 17 79
50 3 6 63 33
LC local control, EBRT external beam radiation therapy
a
Isoeffective dose for tumor effects as if given at 2 Gy/day using the linear quadratic model with an a/b ratio of 10 (Nag and Gupta
2000)
b
5 yr local failure free survival

implant. However, overall patient numbers are low
and various risk categories were included in the lim-
ited available published series making adequate
comparison difficult. HDR doses of 38 Gy delivered
in four fractions (two times daily for 2 days), 54 Gy
in nine fractions given twice a day over 5 days, and
42 Gy in six fractions over two separate implants
have all been reported (Martin et al. 2004; Corner
et al. 2008; Yoshioka et al. 2011; Demanes et al.
2011). Finally, although again limited in patient
numbers, HDR brachytherapy has been effectively
used for salvage treatment (Niehoff et al. 2005; Lee
et al. 2007; Tharp et al. 2008).
3.6 Head and Neck Cancers
Brachytherapy, especially using manually afterloaded
iridium-192, has been widely used to treat head and
neck cancers. HDR brachytherapy has been used in
selected cases to reduce radiation exposure and permit
optimization as summarized in Table 8 (Lau et al.
1996; Yu et al. 1996; Dixit et al. 1997; Nag
et al. 2001a, 2001b, 2001c, 2001d, 2001e; Inoue et al.
2001; Leung et al. 2002; Guinot et al. 2003; Nag et al.
2004b; Lu et al. 2004; Nose et al. 2004; Ng et al.
2005; Nag et al. 2005; Levendag et al. 2006; Leung
et al. 2008; Yeo et al. 2009; Martinez-Monge et al.
2009; Guinot et al. 2010). However, these advantages
are offset by the need for multiple fractions, since the
head and neck area does not tolerate high doses per
fraction. Both the ABS and GEC-ESTRO have sepa-
rately published general recommendations for using
HDR brachytherapy in the various sites of head and
neck cancer (Nag et al. 2001e; Mazeron et al. 2009).
The nasopharynx is a site within the head and neck
area that is easily accessed by an intracavitary HDR
applicator (Levendag et al. 1997, 1998, 2002).
Clinical Applications of High-Dose-Rate Brachytherapy
Levendag et al. have extensive experience in treating
nasopharyngeal lesions with HDR brachytherapy.
They have shown that patients most suitable for a
HDR brachytherapy boost are those with T1 and T2
lesions following 60 (T1, T2a) to 70 Gy (T2b) of
EBRT. HDR doses of 18 Gy in six fractions are
delivered by a special nasopharynx applicator. T3 and
T4 lesions are better suited to be boosted with
intensity modulated radiation therapy or stereotactic
external beam techniques (Levendag et al. 2002).
The use of HDR brachytherapy catheters incor-
porated in removable dental molds allows repeated,
highly reproducible, fractionated outpatient brachy-
therapy of superficial (less than 0.5 cm thick) tumors
without requiring repeated catheter insertion into the
tumor (Jolly and Nag 1992). Suitable sites for mold
therapy include the scalp, face, pinna, lip, buccal
mucosa, maxillary antrum, hard palate, oral cavity,
external auditory canal, and the orbital cavity after
exenteration. HDR can be used as the sole modality or
in conjunction with EBRT. A total HDR dose
equivalent to approximately 60 Gy LDR (prescribed
at 0.5 cm depth) is recommended when used as the
sole modality (Nag et al. 2001e). The HDR can also
be used as a boost to 45–50 Gy EBRT, in which case,
the HDR doses are appropriately reduced to isoef-
fective doses of 15–30 Gy. The actual HDR dose per
fraction and number of fractions can be varied to suit
individual situations (including site and treatment
volume). Biomathematical (linear-quadratic) model-
ling can be used to assist in the conversion of LDR to
HDR (Nag and Gupta 2000).
Local regional recurrence remains the primary
pattern of failure in head and neck cancers despite
advancements in surgery and concurrent chemother-
apy and EBRT. Surgical salvage is generally the
preferred treatment, however, is not possible in all
cases. EBRT is effective as salvage treatment but
comes with high toxicity. HDR brachytherapy has
been used in a few limited series for recurrent disease
of previously irradiated patients. Various fraction-
ation schemes with or without EBRT or surgical
resection have been utilized. Initial results appear
comparable to other modalities (Leung et al. 2005;
Hepel et al. 2005; Martinez-Monge et al. 2006;
Narayana et al. 2007; Tselis et al. 2011).
Another innovative approach is the use of intra-
operative HDR brachytherapy, which permits normal
tissues to be retracted or shielded during
473
brachytherapy. Intraoperative HDR brachytherapy
can reach many sites in the head and neck area that
are difficult to treat or are inaccessible by either LDR
brachytherapy or intraoperative electron beam radia-
tion. The catheters are removed immediately after the
single dose of radiation, hence, minimizing inconve-
nience and permitting the use of brachytherapy in
areas such as the base of skull (Nag et al. 2004b; Nag
et al. 2005). Doses of 7.5–15.0 Gy are given when
EBRT of 45–50 Gy can be added. In recurrent tumors
where no further EBRT can be given, a single intra-
operative dose of 15–20 Gy can be given.
3.7 Soft Tissue Sarcomas
Excellent results are obtained with a combination of
wide excision of the tumor and adjuvant EBRT.
However, irradiation of large volumes after surgery
gives rise to morbidity, especially normal tissue
fibrosis. A few centers historically have used LDR
brachytherapy to minimize morbidity and improve
local control (Harrison et al. 1992; Alektiar et al.
2002a, b). More recently, a few centers have inves-
tigated the use of HDR brachytherapy for soft tissue
sarcomas (Alekhteyar et al. 1994; Crownover et al.
1997; Koizumi et al. 1999; Alektiar et al. 2000; Chun
et al. 2001; Kretzler et al. 2004; Mierza et al. 2007;
Pohar et al. 2007; Petera et al. 2010). HDR brachy-
therapy catheters are implanted approximately 1 cm
apart along the tumor bed, and radio-opaque clips
indicate the margins. A 2- to 5 cm margin proximally
and distally is used after gross excision of tumor.
Optimized treatment planning can be used to deliver a
more homogeneous dose. Doses of 40–50 Gy are
given in 12–15 fractions if the HDR is given alone. If
EBRT (45–50 Gy) is added, the brachytherapy dose is
limited to 18–25 Gy in 4–7 fractions. An alternative
technique not widely available is intraoperative HDR
brachytherapy (HDR-IORT) (Alektiar et al. 2000;
Rachbauer et al. 2003). A HDR-IORT dose of
12–15 Gy is given to the tumor bed in a single
fraction intraoperatively to boost EBRT doses of
45–50 Gy. Nerve tolerance to high dose per fraction
is poor, and HDR should be used with caution when
catheters have to be placed in contact with neuro-
vascular structures. The ABS suggests the following
interventions to minimize morbidity in soft tissue
sarcomas (Nag et al. 2001a, b, c, d, e):
474 S. Nag and G. R. Scruggs

Table 9 Results of HDR Brachytherapy used for treatment of pediatric tumors

Author/Reference No. of Brachytherapy HDR Dose EBRT Median Local Late
Patients (Gy) Dose Follow-up Control Toxicity
(Gy) (mo) (%) (%)
Nag et al. (2003a) 15 F-HDR 36 (3 Gy 9 12) 0 120 80 20
Martinez-Monge et al. 5 F-HDR 24 (4 Gy 9 6) 27–45 27 100 0
(2004)
Nakamura et al. (2005) 16 F-HDR 10 (5 Gy 9 2) 45–55 54 94 –
Viani et al. (2008) 18 F-HDR 18–24 21–40 30.6–50 79.5a 90 16.5a
0 100
Schuck et al. (1997) 20 IOHDR 10 45–55 24 65 40 (Post-op)
Nag et al. (2001d) 13 IOHDR 10–15 27–30 47 95 23
Goodman et al. (2003) 66 IOHDR 4–15 0–56 12 56 12
Nag et al. (2003b) 13 IOERT 10–15 0–50.4 42 72 31
EBRT external beam radiation therapy, F-HDR fractionated high dose rate (given twice a day), IOHDR intraoperative high dose
rate, IOERT intraoperative electron beam radiation therapy
a
Whole group

1. When brachytherapy is used as adjuvant mono-
therapy, the source loading should start no sooner
than 5–6 days after wound closure. However, the
radioactive sources may be loaded earlier (as soon
as 2–3 days after surgery) if doses of less than 20 Gy
are given with brachytherapy as a supplement to
EBRT.
2. Minimize dose to normal tissues (e.g., gonads,
breasts, thyroid, skin) whenever possible, espe-
cially in children and patients of childbearing age.
3. Limit the allowable skin dose—the 40 Gy isodose
line (LDR) to less than 25 cm2 and the 25 Gy
isodose line to less than 100 cm2.
A recent non-randomized study however has dem-
onstrated that intensity modulated radiation therapy
(IMRT) achieved better local control over brachy-
therapy in patients with high grade soft tissue sarcomas
of the extremity and thus has questioned the use of
brachytherapy in this patient population (Alektiar et al.
2011). Despite this, HDR brachytherapy still has a role
to play in the management of soft tissue sarcomas.
3.8 Pediatric Tumors
LDR brachytherapy has been used in children to
reduce the deleterious effects of EBRT (Merchant
et al. 2000; Blank et al. 2010). However, LDR
brachytherapy is difficult to perform in young
children and infants because they require prolonged
sedation and immobilization with close monitoring,
which increases the risk of radiation exposure to
nursing staff and parents. HDR is, therefore, very
appealing for infants and younger children and has
undergone various trials (Nag et al. 1995, 2003a, b;
Nag and Tippin 2003). The recommended dose for
HDR as monotherapy is 36 Gy in 12 fractions given
at 3 Gy (prescribed at 0.5 cm) twice a day (Nag et al.
2001c; Nag and Tippin 2003). The interval between
fractions is at least 6 h. There are no published dose
recommendations for HDR as a boost to EBRT. The
linear-quadratic model (Nag and Gupta 2000) can be
used to calculate a fractionation scheme equivalent to
that of a LDR implant boost-dose of 15–25 Gy (pre-
scribed at 0.5 cm). The recommended dose for
intraoperative HDR brachytherapy is 10–15 Gy
(prescribed at 0.5 cm), as a boost to 30–40 Gy EBRT,
depending on the extent of residual disease (Nag et al.
1998; Merchant et al. 1998; Nag et al. 2001c, d). The
results of HDR brachyterhapy in the treatment of
pediatric tumors are summarized in Table 9 (Nag
et al. 2003a, b; Martinez-Monge et al. 2004;
Nakamura et al. 2005; Viani et al. 2008; Schuck et al.
1997; Nag et al. 2001d; Goodman et al. 2003).
Although the long-term morbidity of HDR brachy-
therapy in young children is not fully known, one may
expect preservation of organ function similar to that
seen with LDR brachytherapy (Blank et al. 2010).
Clinical Applications of High-Dose-Rate Brachytherapy 475

Table 10 Indications for brachytherapy in the conservative management of breast cancer

Indications for brachytherapy as the sole modality Indications for brachytherapy as a
boost to EBRT
The patient lives a long distance from radiation oncology treatment facilities For patients with close, positive, or
unknown margins
The patient lacks transportation For patients with extensive intraductal
component
The patient is a professional whose schedule will not accommodate a six week course For younger patients
of therapy
The patient is elderly, frail, or in poor health and therefore unable to travel for a For deep tumor location in a large
prolonged course of daily treatment breast
The patient’s breasts are sufficiently large that they may have unacceptable toxicity For CTV of irregular thickness
with EBRT
EBRT external beam radiation therapy, CTV clinical target volume

Due to the complexities involved in pediatric HDR
brachytherapy, it is recommended that the use of
HDR brachytherapy in pediatric tumors be limited to
centers that have experience with pediatric implants
(Nag et al. 2001c).
3.9 Breast Cancer
EBRT is the standard radiation modality used after
lumpectomy in the conservative management of
breast cancer. Over the past decade there has been an
increase in use of brachytherapy as the sole modality
of treatment (Shah et al. 2004; Polgar et al. 2007;
Arthur et al. 2008; Polgar et al. 2010; Strnad et al.
2011; Vicini et al. 2011) to decrease the 6-week
treatment duration required for a course of EBRT to
approximately five days. Table 10 lists the patients in
whom an accelerated (4–5 days) brachytherapy
treatment course can be an attractive alternative to
6 weeks of EBRT (Keisch et al. 2007). The ABS
recommends a total dose of 34 Gy in ten fractions to
the clinical target volume when HDR brachytherapy
is used as the sole modality (Keisch et al. 2007). The
HDR treatments of 3.4 Gy are generally given at two
fractions per day separated by at least 6 h. This was
also the dose used in a Phase-II Radiation Therapy
Oncology Group trial (Arthur et al. 2008) and is the
dose used in the currently open Phase III National
surgical adjuvant breast and bowel project (NSABP)
B-39 Trial. Depending on the selection criteria, final
pathological assessment is necessary to completely
evaluate a patient for partial breast brachytherapy,
and, therefore, the ABS does not advocate intraoper-
ative treatment delivery at this time (Arthur et al.
2002). The use of a single-channel Mammosite
applicator has simplified the brachytherapy procedure
(Shah et al. 2004). Newer devices such as the SAVI
applicator and the Contura applicator are multi-
channeled and can allow improved dose shaping.
Various medical societies have published consensus
statement guidelines for the selection of appropriate
patients for breast brachytherapy as a sole modality
treatment with slight variations (Keisch et al. 2007;
Smith et al. 2009). Table 11 lists the guidelines
released by the American society of therapeutic
radiology and oncology (ASTRO). Thus far local
control and cosmeis are similar to whole breast EBRT
with one group quoting 12-year follow-up (Vicini
et al. 2011).
Brachytherapy has been used to boost the EBRT
dose in select high-risk patients (Manning et al. 2000;
Poortmans et al. 2004; Romestaing et al. 1997).
Because brachytherapy is an invasive procedure, it
should be used selectively as a boosting technique.
Situations in which brachytherapy may be advanta-
geous as a boost are listed in Table 10. The brachy-
therapy boost can be given before or after EBRT,
usually with a 1–2 week gap between EBRT and
brachytherapy. The ABS recommends a dose frac-
tionation scheme that yields early and late effects
approximately equivalent to those of 10–20 Gy LDR
following 45–50 Gy EBRT (Nag et al. 2001b).
Biomathematical models are often used to estimate
equivalent HDR regimens (Barendsen 1982; Nag and
Gupta 2000). For example, a HDR regimen of five
476 S. Nag and G. R. Scruggs

Table 11 Patient selection for partial breast radiation as a sole modality per ASTRO Consensus Statement
Suitable Cautionary Unsuitable
Age [60 50–59 \50
BRCA1/2 Not present – Present
mutation
Tumor size \2 cm 2.1–3.0 cm [ 3 cm
T stage T1 T0 or T2 T3–4
Margins Negative by at least 2 mm Close (\2 mm) Present
Grade Any – –
LVSI No Limited/focal Extensive
ER Status Positive Negative –
Multicentricity Absent – Present
Multifocality Clinically unifocal with total Clinically unifocal with total Clinically multifocal or microscopically
size \2.0 cm size 2.1–3.0 cm total size [3 cm
Histology Invasive ductal or favorable Invasive lobular –
subtypes
Pure DCIS None \3 cm [3 cm
EIC None \3 cm [3 cm
Associated Allowed – –
LCIS
N Stage pN0 – pN1-3
Nodal Surgery SN Bx or ALND – None performed
Neoadjuvant Not allowed – If used
therapy
LVSI lymph-vascular space invasion, ER estrogen receptor, DCIS ductal carcinoma in situ, EIC extensive intraductal component,
LCIS lobular carcinoma in situ, SN Bx sentinel lymph node biopsy, ALND axillary lymph node dissection
(Smith et al. 2009)

fractions of 310 cGy per fraction should approximate
the early and late effects of 20 Gy LDR delivered at
0.5 Gy/h. Although biomathematical models can be
used to estimate the appropriate dose, there is no
standardized HDR fractionation schedule that can be
recommended for the use of HDR as a boost. Controlled
clinical studies are required to further define the most
appropriate doses to be used for boost treatment.
3.10 Skin Cancer
The widespread availability of HDR remote after-
loading brachytherapy units allows the use of surface
molds as an alternative to electron beam and, for
cases where surface irregularity, proximity to bone, or
poor intrinsic tolerance of tissues do not allow for
satisfactory treatment using electron beam. Sites
where HDR has been used advantageously include the
scalp, pinna of ear, wrist and arm. For most cases, a
satisfactory mold can be made from 5 mm-thick
sheets of wax, or aquaplast with the HDR catheters
inserted parallel and 1 cm apart. A simpler alternative
is to use commercially available surface template
applicators (e.g., Freiburg flab from Nucletron
Corporation, Columbia, MD and HAM applicator
from Mick Radionuclear Instruments Inc, Bronx,
NY), which are used for intraoperative HDR brach-
ytherapy (Svoboda et al. 1995; Nag et al. 1999; Guix
et al. 2000).
In addition to melanoma and non-melanoma skin
cancers, Merkel cell lesions as well as benign keloids
have been treated with HDR brachytherapy. There is
a wide range of recommended doses and fractionation
schemes for treating skin cancer. Doses in the range
of 3500 cGy in five fractions to 5000 cGy in ten
fractions have been used with success in HDR molds.
Standard, more prolonged fractionation schemes with
Clinical Applications of High-Dose-Rate Brachytherapy 477

Table 12 Comparison of different brachytherapy techniques

LDR Ir-192 LDR remote MDR PDR HDR IOHDR
Dose rate Low Low Medium High High High
Duration of each treatment 2–6 days 2–4 days 1 day Min Min Min
Overall duration of treatment 2–6 days 2–4 days 1 day 2–4 days 3–5 weeks Min
Radiation hazards High Small Small Small Small Small
Availability (worldwide) ++ - - - + -
Ease of optimization - - - + + +
Dose as sole modality (Gy) 60 60 40 60 30–40 15–20
Dose as boost to EBRT (Gy) 20–40 20–40 20–30 20–40 20–30 10–15
LDR low-dose-rate brachytherapy, MDR medium-dose-rate brachytherapy, PDR pulsed dose rate, HDR high-dose-rate brachy-
therapy, IOHDR intraoperative high dose rate, EBRT external beam radiation therapy

180–200 cGy daily or twice daily fractions can
also be used. The linear quadratic radiobiological
model can be used to determine the total dose for a
given fractionation scheme (Nag and Gupta 2000).
Kuribayashi et al. recently reported 90% control rate
post-keloidectomy utilizing 20 Gy in four fractions or
15 Gy in three fractions based on the site of the keloid
(Kuribayashi et al. 2011).
4 Discussion
Brachytherapy has gradually evolved over the past
century. Initially, it was performed by inserting the
radioactive sources directly into the tumor (‘‘hot’’
loading), which exposed personnel to high doses of
radiation, and hence, brachytherapy did not gain much
popularity. Manual afterloaded procedures, in which
hollow catheters are initially inserted into the tumor
and then loaded with radioactive materials after proper
positioning, significantly reduced radiation exposure to
personnel. In remote afterloading, an operator outside
the room loaded the radioactive material into the
catheters using remote control. In HDR brachytherapy,
the elimination of radiation exposure and the short
treatment times allow for outpatient brachytherapy.
Intraoperative HDR brachytherapy allows a single dose
of radiation to be delivered during surgery. Doses of
10–20 Gy are usually given as a single fraction over
10–60 min. The advantages of intraoperative HDR
brachytherapy over perioperative brachytherapy or
electron beam IORT are listed in Table 12. Unfortu-
nately, the relative scarcity of shielded operating rooms
has currently limited its availability to just a few centers
(Merchant et al. 1998; Nag et al. 1999, 2004b; Nag and
Hu 2003).
One of the disadvantages of HDR brachytherapy is
that it requires a shielded room. A newer device, the
Axxent (Xoft Inc., Sunnyvale, CA), uses a mina-
turized X-ray source to deliver low energy X-rays
within a needle or catheter thereby mimicking HDR
brachytherapy. The reduced radiation protection
required for these devices due to limited penetration is
a great advantage since it allows brachytherapy to
be delivered in a non-shielded procedure room or a
regular (unshielded) hospital operating suite. Cur-
rently, the Xoft-Axxent system has only a single
channel and therefore has the limitation of being able
to treat only small volume tumor beds. It is being used
at a few centers in the US to treat breast cancer via a
balloon device similar to the Mammosite balloon,
the vaginal cuff with a single channel cylinder
applicator and skin cancers with a surface applicator.
(Schneider et al. 2009; Dickler et al. 2009).
Although brachytherapy is a very effective
modality, case selection and proper patient evaluation
are essential. If the tumor is very large or widely
metastatic, one is doomed to fail due to the physics of
dose distribution in the former case and due to the
biology of the tumor in the latter case. There are some
differences between the various brachytherapy
modalities (Table 12). These differences should be
kept in mind when selecting the brachytherapy
modality in a particular situation.
HDR has special relevance for developing coun-
tries, where resources may be scarce. In this regard,
the International Atomic Energy Agency issued rec-
ommendations for the use of HDR brachytherapy in
478
developing countries (Nag et al. 2002). A brief sum-
mary is given here; however, readers interested in the
details are referred to the original article. A HDR
treatment system should be purchased as a complete
unit that includes the 192Ir radioactive source, source
loading unit, applicators, treatment planning system,
and control console. Infrastructure support may
require additional or improved buildings and pro-
curement of or access to new imaging facilities.
A supportive budget is needed for quarterly source
replacement and the annual maintenance necessary
to keep the system operational. The radiation
oncologist, medical physicist, and technologist
should be specially trained before HDR can be
introduced. Training for the oncologist and medical
physicist is an ongoing process, as new techniques
or sites of treatment are introduced. Procedures for
quality assurance of patient treatment and the
planning system must be introduced. Emergency
procedures with adequate training of all associated
personnel must be in place. The decision to select
HDR in preference to alternate methods of brach-
ytherapy is influenced by the ability of the machine
to treat a wide variety of clinical sites. In depart-
ments with personnel and budgetary resources to
support this equipment appropriately, economic
advantage becomes evident only if large numbers of
patients are treated. With HDR, it is possible to
treat a large number of patients in institutions that
have a high volume of brachytherapy patients but
insufficient in-patient facilities for LDR brachy-
therapy or insufficient finances for the purchase of
iodine-125 or palladium seeds for permanent
implants. Intangible benefits of source safety, per-
sonnel safety, and easy adaptation to fluctuating
demand for treatments also require consideration
when evaluating the need to introduce this treat-
ment system.
When HDR brachytherapy is used, the treatments
must be executed carefully, because the short treat-
ment times do not allow any time for correction of
errors, and mistakes can result in harm to patients.
Hence, it is very important that all personnel involved
in HDR brachytherapy be well trained and be con-
stantly alert. However, with proper case selection and
delivery technique, HDR brachytherapy has great
promise and convenience, because it eliminates radi-
ation exposure, allows short treatment times, and can
be performed on an outpatient basis.
S. Nag and G. R. Scruggs
It is expected that the use of HDR brachytherapy
will continue to expand over the coming years and
that refinements in the integration of imaging
(computed tomography, magnetic resonance imag-
ing, intraoperative ultrasonography) and optimiza-
tion of dose distribution will foster this expansion
(Li et al. 2003; Nag et al. 2004a). Better tumor
localization and normal tissue definition has led to
more optimal dose distribution to the tumor and
reduction of normal tissue exposure (Nag et al.
2004a). It is anticipated that this will lead to better
outcomes. The development of well-controlled ran-
domized trials addressing issues of efficacy, toxic-
ity, quality of life, and costs versus benefits will
ultimately define the role of HDR brachytherapy in
the therapeutic armamentarium.
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 Quality Management and Safety
in Radiation Oncology
James A. Purdy, Eric E. Klein, Philip Poortmans, and Coen Hurkmans

Contents 9 Treatment-Planning System QA............................ 514

10 Treatment-Planning QA ......................................... 517
1 Introduction.............................................................. 486 10.1 Patient Positioning, Immobilization and Data
Acquisition................................................................. 518
2 Goals and Structure of a QM Program ............... 488 10.2 Tumor, Target Volume, and Organ at Risk
2.1 Physics Staffing ......................................................... 488 Delineation................................................................. 518
2.2 Training and Qualifications....................................... 490 10.3 Designing Beams....................................................... 520
2.3 Structure of a QM Program ...................................... 490 10.4 Dose Calculation and Computation of Monitor Units 520
10.5 Plan Evaluation.......................................................... 521
3 Dosimetry Instrumentation QA ............................. 491
10.6 Treatment Plan Review ............................................. 521
4 Medical Linear Accelerator QA ............................ 494 10.7 Plan Implementation and Verification...................... 521
4.1 Linac Daily, Weekly, and Monthly QC/QA Tests... 497
11 Clinical Aspects of QA............................................ 522
4.2 Linac Annual QA Tests ............................................ 501
11.1 Planning Conference ................................................. 522
4.3 LINAC Computer-Control Systems QA................... 502
11.2 Chart Review ............................................................. 522
4.4 Asymmetric Jaws (Independent Collimation) QC/
11.3 Port Film/Image Verification Review ...................... 523
QA.............................................................................. 506
11.4 Review of Incidents in the Radiation Therapy
4.5 Dynamic Wedge QC/QA Tests................................. 507
Department................................................................. 524
4.6 Multileaf Collimation: Non-IMRT QC/QA.............. 508
12 Summary................................................................... 524
5 Intensity Modulated Radiation Therapy QA ....... 508
13 Conclusion ................................................................ 525
6 In-Room Imaging..................................................... 512
References.......................................................................... 525
7 Treatment Machine Maintenance ......................... 513
8 Simulator QA ........................................................... 514
Abstract
Today’s treatment planning and delivery processes
J. A. Purdy (&)
Department of Radiation Oncology,
have become much more complex and much less
University of California Davis Medical Center, intuitive. These complexities, coupled with the
Sacramento, CA 95817, USA inadequate informatics infrastructure typically
e-mail: james.purdy@ucdmc.ucdavis.edu found in radiation oncology department and
E. E. Klein outdated national QM guidelines, have created
Department of Radiation Oncology, enormous QM challenges for modern radiation
Washington University School of Medicine,
St. Louis, Missouri 63110, USA
therapy. Communication among the planning team,
including physician, resident, simulation therapist,
P. Poortmans
Department of Radiation Oncology,
dosimetrist, physicist, and treating therapist, is often
Institute Verbeeten, Tilburg, The Netherlands cryptic and complicated by the hybrid charting
C. Hurkmans
systems (electronic and paper medical records) now
Department of Radiation Oncology, commonly used. Multiple imaging modalities are
Catharina Hospital, Eindhoven, The Netherlands

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 485
DOI: 10.1007/174_2011_328,  Springer-Verlag Berlin Heidelberg 2012
486
often used to define target volumes, and 4-D
imaging is now emerging in routine practice, all
complicating the information processing further.
In a typical U.S. clinic, over 40% of patients are now
managed with IMRT plans using computer-assisted
optimization software. Plan data, transferred over a
network to the verify and record system and
computer controlled linac systems, carry complex
specifications for treatment including precise,
accurate positioning of MLC leafs, variable
dose rates, gantry angles, and, in some instances, a
moving treatment table. In many cases, different
vendor software systems are utilized, and interop-
erability is not always robust. With such complex
technology and even newer advanced treatment
modalities continuing to be implemented, e.g. volume
modulated arc therapy (VMAT), updated national
QM guidelines/approaches, and development of an
efficient and robust treatment delivery verification
system must be given higher priority by the profes-
sion. This greater complexity found in today’s
radiation therapy requires a far stronger teamwork
approach, since no individual has all of the skills
necessary to insure its maximum quality. Continued
assessment and updating of QM methodologies and
procedures are urgently needed. This chapter will
address all these issues focusing primarily on the
United States and European QM experience.
1 Introduction
It has long been accepted that the accuracy and precision
in radiation therapy (RT) absorbed dose delivery must be
on the order of ±5%, based upon the fact that certain
tumors and normal tissues exhibit steep dose-response
curves (Herring and Compton 1971), leaving only a
small ‘‘therapeutic window’’ in which tumorcidal effects
are more important than undesired side effects. Delivery
of radiation with this criterion places great demands on
the entire process, although such a level has been
believed to be required and achievable since the 1970s
(ICRU 1976). Today, with the increasing availability of
Monte-Carlo dose calculations, improved dosimetry
protocols, and more tissue equivalent dosimeters, the
recommended accuracy/precision criteria may eventu-
ally be made even more stringent (ICRU 2010).
J. A. Purdy et al.
Uncertainties in treatment are due to many factors
including: (a) dose calibration at a point in a phantom;
(b) patient-specific data used for treatment planning,
including delineation of target volumes and organs at
risk; (c) dose calculation in the patient; (d) transfer
of the treatment plan to the RT machine; and (e)
day-to-day variations in patient positioning, organ and
target deformation, and internal motion of tumor
volume and organs at risk. The uncertainties may
be separated into systematic and random. Random
uncertainties vary in magnitude and sign and cannot be
totally controlled; for example, the position of the
radiation field on the patient may vary from day to day
by a few millimeters. Moreover, the degree with which
treatments can be reproduced will differ between
institutions. Systematic uncertainties maintain their
magnitude and direction over a period of time. For
example, the use of an incorrect factor in the calibration
of a treatment unit would have the same effect on the
dose delivered to all patients for a number of fractions
until the error is corrected. Systematic errors, in prin-
ciple, should be more controllable than random errors:
for example, periodic external audit of beam calibra-
tion. However, many systematic errors remain—for
example the approximations used in the treatment-
planning system’s dose calculation algorithm.
Before proceeding further, it is imperative to
understand the distinctions between the various
‘‘quality’’ terms used such as quality management
(QM), quality assurance (QA), quality control (QC),
and Continuous Quality Improvement (CQI). The
following definitions are taken directly from the
handbook ‘‘Juran’s Quality Handbook, 5th edition’’, a
classic text that has shaped the quality field over the
last several decades (Juran and Godfrey 2000). QM is
a term used to cover all of the activities directed
toward achieving the quality desired; (note QA and
QC are a part of QM). QA refers to all the planned and
systematic activities implemented within the QM
program that are designed to provide adequate con-
fidence that an entity will fulfill the quality require-
ments. QC refers to operational techniques and
activities that are used to fulfill requirements for
quality. Clearly, QC and QA have much in common.
In RT, QC constitutes the actual tests performed to
maintain and improve the quality of the treatment
while QA can be thought of as the set of policies and
procedures including additional tests instituted to
ensure the proper and safe delivery of the prescribed
Quality Management and Safety in Radiation Oncology
dose to the patient. Finally, CQI is a methodology that
seeks to continually improve the quality of a process
or program by controlled alteration of the process
workflow itself or its associated QC/QA components.
A common CQI approach often used by RT facilities
is the Deming ‘‘Plan-Do-Check-Act (PDCA)’’ cycle
shown in Fig. 1 (Deming 1986).
It is also important to realize that a radiation
oncology QM program is an interdisciplinary effort
involving radiation oncologists, radiation physicists,
dosimetrists, radiation therapists,1 clinical engineers
and IT specialists. Although some team members
such as medical physicists and radiation therapists are
more involved in the technical aspects of the QM
program, and others such as radiation oncologists
more in the medical aspects, the efforts of each
member’s group often overlap substantially.
RT in general has a long history of QA, perhaps
most notably by the adoption of a comprehensive QA
program in the early 1990s as put forth by the
American Association of Physicists in Medicine
(AAPM) Task Group 40 Report (Kutcher et al. 1994).
This approach relies heavily on prescriptive QA tests,
tolerances, and frequencies as provided by consensus
expert groups from national professional organiza-
tions and/or international bodies.
A major QA Symposium sponsored by the
American Society for Radiation Oncology (ASTRO)
and AAPM was held in 2007 to assess physical
QA issues in modern day RT and found that this
methodology remains valid for many of the proce-
dures, devices, and software systems used in modern
RT, although for some technologies, e.g. image
guidance, it is incomplete, or out of date, and is likely
inadequate by itself in the more advanced modalities
used today (Williamson et al. 2008).
For example, consider today’s imaged-guided
treatment-planning and delivery processes which
have become much more complex and much less
intuitive. These complexities, coupled with the inad-
equate informatics infrastructure and outdated
national QA guidelines, have created enormous QA
challenges for our department. Communication
among the planning team, including physician,
1
There is significant variation in the title and the function used
for this position, especially from one country to another: in the
US radiation therapist is used, in Europe the name radiotherapy
technologist (RTT) is more common.
487
Fig. 1 Schematic diagram of the PDCA cycle [adapted from
Deming (1986)]
resident, simulation therapist, dosimetrist, physicist,
and treating therapist, is often rushed, cryptic, and
complicated by the lack of integration of the radiation
oncology electronic medical record (EMR), e.g.
Elekta-IMPAC MOSAIQ, with the hospital’s elec-
tronic health record (EHR), e.g. EPIC, Verona, WI.
In fact, in most cases, one must resort to a hybrid
charting system (ad hoc combinations of EMR, EHR
and paper charts), which is a dangerous situation. In
addition, multiple imaging modalities are often used
to define target volumes, and now 4D imaging is
being implemented clinically, all complicating the
information processing. IMRT plan data, transferred
over a network to the verify-and-record system and
computer-controlled linac systems, carry complex
specifications for treatment including positioning of
Multileaf collimators (MLC) leafs, variable dose
rates, collimator rotation, gantry angles, and, in some
instances, a moving treatment table. In some cases,
different vendor software systems are utilized, and
interoperability is not always robust. This continuing
increasing complexity of devices and systems is
clearly problematic for a totally prescriptive QA
approach as it results in increased time demands on
staff and groups where there are already shortages.
Thus, while the prescriptive QA approach remains
valid and valuable for much of the technology and
procedures currently in place, new and different
approaches need to be developed in parallel for
488
advancing technology (Ford et al. 2009; Pawlicki and
Mundt 2007). These must be risk-/evidence-based, and
process-oriented rather than device-and procedure-
oriented; they likely need to be multi-disciplinary in
nature, resource and risk optimized and flexible enough
to cope with current and anticipated changes in tech-
nology. Such process-oriented QA includes risk-based
analysis, process mapping, application of failure modes
and effects analysis (FMEA), and fault tree analysis
(FTA), including analyses of human actions and
responses (Rath 2008).
While the 2007 QA Symposium identified major
changes needed and made strong recommendations;
little progress has been made in the ensuing 3 years to
address the issues raised. Now, and mainly as a result
of recent New York Times articles (Bogdanovitch
2010), national organizations are slowly beginning to
move forward to improve the QM situation in RT
(ASTRO 2010, 2011; Klein et al. 2009). It is imper-
ative that this focus be given even higher priority as
the profession continues because with newer
advanced treatment modalities continuing to be
implemented, e.g. volumetric modulated arc therapy
(VMAT) and adaptive radiation therapy (ART), the
need for updated national (and international) QC/QA
guidelines, new approaches to QM, and development
of more efficient and robust treatment delivery veri-
fication systems becomes even greater.
A series of publications known as the ‘‘Blue
Book’’, published over the period 1968–1991, pro-
vided a strong rational for the development, purpose,
and need for QA in radiation oncology in the pre-3
Dimensional conformal radiation therapy (3DCRT)
era (ISCRO 1991). The following statement taken
from the 1991 version rings even truer today:
The purpose of a QA Program is the objective, systematic
monitoring of the quality and appropriateness of patient
care. Such a program is essential for all activities in
Radiation Oncology. The QA Program should be related
to structure, process and outcome, all of which can be
measured. Structure includes the staff, equipment and
facility. Process covers the pre- and post-treatment eval-
uations and the actual treatment application. Outcome is
documented by the frequency of accomplishing stated
objectives, usually tumor control, and by the frequency
and seriousness of treatment-induced sequelae.
The greater complexity of RT today requires a far
stronger teamwork approach, since no individual has
all of the skills necessary to ensure its maximum
quality. Unfortunately, the profession is gradually
J. A. Purdy et al.
losing control over important quality aspects of
radiation oncology to hospital and financial adminis-
trators who may not fully understand the complexity
of RT and focus on cost-cutting efficiencies. The
authors strongly believe that ASTRO and the AAPM
should return to the ‘‘Blue Book’’ concept and publish
an updated document that emphasizes the needs for
(1) metrics for determining proper staffing (numbers
and expertise) for clinics that provide IMRT, image-
guided radiation therapy (IGRT), stereotactic body
radiation therapy (SBRT), stereotactic radiosurgery
(SRS), brachytherapy, and other advanced modalities,
(2) continuing education and focused efforts in error
prevention, and (3) continued assessment and updat-
ing of QA methodologies and procedures.
Organizations from other countries, such as the
European Society for Therapeutic Radiology and
Oncology (ESTRO), should also address this need
and if needed develop similar guidance documents
appropriate for their country’s RT programs. Such a
document would be a powerful tool in negotiating
with hospital administrators or government agencies
for the funding needed to adequately support the
required QM programs.
2 Goals and Structure of a QM
Program
It is essential that the pertinent senior administrator
responsible for radiation oncology department fund-
ing understands the need for a robust radiation
oncology QM program and works with the radiation
oncology team to ensure adequate funding is available
to support such a program, particularly in regard to
staffing and QC/QA equipment. For a QM program to
be effective, all of the faculty and staff involved with
providing RT to patients must be strongly committed
to the program.
2.1 Physics Staffing
Appropriate physics staffing is an essential component
of the radiation oncology QM program. The staffing
guidelines promulgated in the previously mentioned
‘‘Blue Book’’ were based only on patient load and
treatment equipment (ISCRO 1991). These outdated
recommendations called for at least one clinical
Quality Management and Safety in Radiation Oncology
physicist for up to 400 patients treated annually. Note
recommendation was for clinical duties only and
additional medical physicists would be required for
any training, classroom teaching, research, and
administration duties. In addition, those staffing
numbers did not take into account the complexity of
treatments being performed in the clinic today such as
IMRT, SRS, SBRT, and brachytherapy; and the fact
that such procedures are much more medical physics
intensive, often requiring the physicist to be present
at the treatment machine throughout the patient’s
treatment.
The most detailed information currently available
regarding medical physics work effort is found in the
reports by Abt_Associates (1995, 2003). These
reports were the result of the American College of
Medical Physics (ACMP) and the AAPM engaging
Abt Associates Inc. to conduct a study that measured
what was termed Qualified Medical Physicist (QMP)
work for medical physics services and to develop a
relative work value scale depicting the relative
amount of QMP work required for each medical
physics service. The results of that effort were pub-
lished in 1995 and updated in 2003 (Abt_Associates
1995, 2003). Herman et al. used the data from the first
Abt report along with a manpower study conducted
by the ACMP and AAPM, accounting for IMRT and
other special procedures to show that current reim-
bursement models do not adequately support the
needed physics QA effort (Herman et al. 2003).
Herman et al. (2005) making use of the Abt II study
and the afore referenced work survey data, deter-
mined medical physics FTE recommendations for a
modern day clinic as a function of number and types
of procedures, including IMRT, SRS, HDR, and
prostate seed implants. Their analysis showed a
much larger physics FTE number needed than the
number determined using the old Blue Book recom-
mendations. In 2010, Klein used the Abt data to
develop a staffing justification grid to equate the
clinical needs to the number of physics FTEs and the
expertise quality required (Klein 2010). In this study,
comparison was made to the staffing level suggestions
provided by the American College of Radiology
(ACR) accreditation program for radiation oncology
(ACR 2008). Again, this analysis showed a larger
physics FTE number needed than that predicted by
the ACR suggested values. It should be pointed out
that the ACR accreditation program is now a joint
489
Table 1 Staffing level recommendations/suggestions pub-
lished for US radiation oncology clinics located at academic
cancer centers
Number of Bluebook ACR ACR/ASTRO
patients/FTE 1991 2009 2011
Radiation 200–250 213 213
oncologists
Clinical 400 333 196
physicists
program with the ASTRO and their staffing level
survey data have recently been updated (see Table 1)
showing a much more realistic value of 196 for the
ratio of new patients per physicist for an academic
center and a value of 213 for the ratio of new patients
per radiation oncologist.
The European Organization for Research and
Treatment of Cancer (EORTC) published recom-
mendations on minimum staffing levels for radiation
oncologists, medical physicists, and radiation thera-
pists in 1993 (Horiot et al. 1993). These recommen-
dations were updated in 2008 based on a survey of
actual staffing levels using a questionnaire completed
online by 98 active EORTC ROG member institutions
from 19 countries, between December 2005 and
October 2007 (Budiharto et al. 2008). It should also
be noted that in 2005, ESTRO also published their
recommendations regarding staffing levels (Slotman
et al. 2005). Both EORTC and ESTRO guidelines
were derived based on good clinical practice and
expert consensus. As shown in Table 2, the recom-
mended number of FTEs does not differ much
between these European guidelines, although a large
spread in the survey data was noted. The table also
shows staffing recommendations for the Netherlands
(Hurkmans et al. 2008). It should be pointed out that
the survey showed that the number of required
physicists was greatly influenced by the number of
radiation therapists and physics assistants in a
department and their skill level/assigned duties
(Hurkmans et al. 2008). Considerable variance was
seen especially along a north–south direction with a
higher number of dedicated radiotherapy technolo-
gists in the north of Europe. For example, in the
Netherlands treatment planning and imaging verifi-
cation is performed by well-trained therapists, leading
to a higher number of patients per physicist ratio
recommendation (Hurkmans et al. 2008).
490
Table 2 Actual and recommended staffing levels from ESTRO, EORTC, and the Netherlands [modified from Hurkmans et al.
(2008)]
Number of Survey EORTC Survey Dutch
patients/FTE 2007 2007
Radiation 258 282
oncologists
Clinical physicists 426 682
2.2 Training and Qualifications
The education and training of the radiation oncology
team and their continuing education are of critical
importance to a QM program. In the past, clinical
physics training and dosimetrists’ training have been
one of the weakest links, as the training programs
lacked organized clinical training beyond individual
apprenticeships or self-training on the job. This was
probably adequate in the early days of physics
involvement in radiation oncology. However, as
radiation oncology has become increasingly more
sophisticated and complex, this strategy is no longer
acceptable. The practice of hiring inadequately
trained medical physicists who perform patient-
related tasks simply must not be allowed.
The AAPM Report Number 36, ‘‘Essentials and
Guidelines for Hospital-Based Medical Physics
Residency Training Programs’’ was the first to set down
the educational and administrative requirements for a
hospital-based physics residency training program
(AAPM 1990); later updated as AAPM Report 90
(AAPM 2006). Two years of formal clinical physics
residency training beyond a M.Sc. or Ph.D. degree in
physics or a closely-related field is recommended. As of
early 2011, there are nearly 50 radiation oncology
physics residency programs in the United States accred-
ited by the Commission on Accreditation of Medical
Physics Education Program (CAMPEP), with several
more programs waiting to undergo the review process.
The AAPM and other pertinent national organi-
zations have reached consensus that board certifica-
tion is a means documenting qualification in radiation
oncology physics. Specifically, in the US a radiation
oncology physicist is considered qualified if he/she
has an M.Sc. or Ph.D. degree in medical physics,
physics, or a closely-related hard-science field and is
certified by the American Board of Radiology, the
American Board of Medical Physics, or an equivalent
certification board.
J. A. Purdy et al.
Guidelines ESTRO Guidelines Dutch Guidelines EORTC
2005 2007 2008
200–250 217 250
450–500 565 500
This issue was addressed in Europe as documented
by European Federation of Organisations for Medical
Physics (EFOMP) Policy Statement No. 9 (EFOMP
1999), which is the EFOMP’s response to the European
Union’s Directive concerning medical exposures
(European Commission 1997). It defined two levels
of medical physics expertise: the qualified medical
physicist (QMP) and specialized medical physicist or
Medical Physics Expert (SMP). For an individual to be a
QMP, he/she must have a M.Sc. in physics or equivalent
study plus 2 years of on-the-job training in a hospital.
Registration as an SMP requires another 5 years of
experience and continuous training. The joint ESTRO-
EFOMP core curriculum for education and training of
medical physicists in RT was first published in March
2003 (Eudaldo et al. 2004); it is currently being updated
and should be published by the end of 2011. The content
of the curriculum is aimed at bringing trainees up to a
level of competence so as to be able to practice inde-
pendently in the field of RT physics.
2.3 Structure of a QM Program
Central to the RT QM program is an oversight com-
mittee having representation from all of groups that
make up the RT team. The need for such a committee
is documented in reports by several United States
radiation oncology organizations including the ACR
(ACR 2010) and the AAPM (Kutcher et al. 1994), and
international organizations such as the World Health
Organization (WHO 1988). To properly function, the
QM Committee should report directly to the radiation
oncology chairman and the hospital administration.
Its function is to design, implement, and maintain a
multi-disciplinary QC/QA/CQI program whose goal
is to improve the quality of patient care. The com-
mittee should meet regularly, preferably on a monthly
basis to review the ongoing QM program and
facilitate good communication between the various
Quality Management and Safety in Radiation Oncology
Fig. 2 Structure of a quality
management committee
illustrating typical areas
addressed
groups, and these deliberations should be reported to
the Department Chairman in writing. It is important
that the committee has the full support of the
departmental chairman and the entire faculty and
staff; otherwise maintaining quality and implementing
improvements in care will prove extremely difficult.
The makeup of a typical QM Committee is shown
schematically in Fig. 2. As indicated previously, the
committee’s work encompasses numerous areas, and
needs the participation of many individuals, including
the committee chairman (preferably a radiation
oncologist or medical physicist), radiation oncolo-
gists, radiation therapists, dosimetrists, nurses, and
physicists involved in treatment preparation, treat-
ment delivery, and radiation safety. The number of
committee members varies and in smaller depart-
ments, the committee might be comprised of only
three individuals: a radiation oncologist, a medical
physicist, and a radiation therapist.
Depending on the institution, the responsibilities of
the committee members will differ. Moreover, there
are many gray zones in responsibilities in the radia-
tion oncology practice. In fact, one of the essential
roles of the committee is to define the lines of
demarcation between tasks so that some important
functions are not overlooked or neglected. Table 3
provides a list of guiding principles to help a
department prioritize QM efforts for improving
patient safety and quality of both well-established and
also emerging advanced technology RT modalities.
This list is a compilation of the key recommendations
491
for QM by several national and international groups
(ACR 2010; Hendee and Herman 2011; IAEA 2000b,
2007; Klein et al. 2009; Kutcher et al. 1994; RCR
et al. 2008) In addition, Table 4 provides a updated
list of safety recommendations taken from the AAPM
Task Group 35 report for a modern day radiation
oncology accelerator facility (Purdy et al. 1993). Most
importantly, an external audit should be performed on
an annual basis to help ensure that radiation treat-
ments are delivered as intended.
3 Dosimetry Instrumentation QA
A list of the type of equipment typically considered
most useful in a QA program for treatment machines
is given in Table 5 and several are shown in Fig. 3.
All of these QA devices for treatment machines are
now commercially available ranging from ion cham-
ber dosimetry systems and water phantoms used for
basic beam calibration and treatment machine com-
missioning to devices designed specifically for peri-
odic checking of beam alignment, field symmetry,
flatness, and energy, and the linac’s beam output.
Accurate data acquisition with automated beam
data scanning systems and scanning film densitome-
ters requires that the systems be subjected to a sys-
tematic performance test prior to use and also undergo
periodic QA tests thereafter. Details of acceptance
testing and QA of such devices have been reported in
the literature (Mellenberg et al. 1990).
492 J. A. Purdy et al.

Table 3 Guiding principles for radiation oncology quality management program

1. Establish a safety-conscious culture within the department and ensure that the processes for safe delivery of radiotherapy are in
place and appropriately resourced. To that end,
a. Establish a formal covenant and commitment to safety. The radiation therapy team should work under a radiation safety
covenant, and each member of the team should pledge a commitment to protect the safety of each and every patient
b. Make sure it is clear that each member of the treatment team has the right and the responsibility to declare a ‘‘time out’’ if he/
she has concerns or questions about the plan or course of treatment for a patient
c. Make sure that QM program is properly resourced
2. Seek practice accreditation by the appropriate national body, e.g. American College of Radiology (ACR)/American Society for
Radiation Oncology (ASTRO)
3. Participate in external dosimetric audits such as provided by the Radiological Physics Center (RPC) annual ERDA (External
Reference Dosimetry Audit)
4. Expand the use of checklists in treatment planning and treatment delivery
5. Implement a formal policy that ensures that policy and procedures (P&Ps), including checklists, are in place and are regularly
updated and reviewed on an annual basis (require documentation that this is actually done)
6. Conduct periodic reviews of staffing levels to ensure that the staffing and skills mix are appropriate for the numbers of patients
treated and the complexity of treatments delivered
7. Implement a clinical operations committee (COC), with supervisor representatives from each group, to address any
problematic issues in the clinic and to help ensure good communications exists between all groups involved in the treatment
process
8. Conduct Town Hall meetings (with QM program being a major focus) with department faculty/staff at least quarterly to help
ensure good communications exists between all groups involved in the treatment process
9. Maintain training records for all staff involved in radiation therapy. They should be detailed and specific to particular
procedures, i.e., an internal form of credentialing
10. Maintain funding to support training and continuing education, particularly when new techniques are introduced
11. Introduction of new techniques always needs to be carefully planned with thorough risk assessment, review of staffing levels
and skills required, and development of pertinent P&Ps. All staff involved in the process should undergo specific training in the
new treatment technique or process prior to clinical use
12. Working environment, particularly in two areas (a) treatment machine console and (b) treatment planning, needs to be
conducive to safety and designed such that it ensures that staff can work without inappropriate interruptions
13. Prescriptive QC/QA program should be in place, but continually evaluated to ensure that each specific test adds value and
eliminates those that do not add the required value
14. Perform systematic risk analysis and improvement using industrial engineering-based tools such as process mapping, failure
modes and effects analysis (FMEA), and fault tree analysis (FTA) for all advanced treatment modalities
15. Implement a treatment table registration system (CT-simulator and treatment machines) so that all patients’/immobilization
devices’ position on the table can be registered
16. Make use of treatment planning/delivery systems tolerance tables for specific procedures and monitor setup variability (i.e.,
any therapist overrides of treatment couch, gantry, collimator position,… settings in order to treat patient)
17. Perform on-treatment verification imaging as needed, but be mindful of imaging dose and look for ways to become more
efficient
18. Perform in vivo dosimetry (e.g. diode checks) at the beginning of treatment for all non-IMRT patients when physically
possible
19. Conduct peer-review chart rounds (review prescription, verification images, dose distribution, and other pertinent
documentation, e.g. signed consent, pathology,…) at least weekly
20. Implement treatment-planning workflow monitoring software system
21. Implement a software system for reporting and analyzing errors and near-misses, with feedback to the staff at Town Hall
meetings
22. Strive to have the right balance between both accountability and openness in the department’s incident reporting culture
23. The department should strongly endorse a national/international incident reporting system for RT incidents
Quality Management and Safety in Radiation Oncology 493

Table 4 Model quality assurance and safety program for medical accelerator facilities (modified from AAPM TG 35 report)
1. Use of the Medical Accelerator
• Unit should be operated only by authorized personnel who are trained in the safe operation of the unit; this typically includes
radiation therapists, qualified medical physicists, dosimetrists, physics residents, and machine maintenance personnel
• Instructions on how the unit is to be operated should be maintained at the console
2. Safety Devices
• Console and room radiation warning lights and door interlock should be checked daily by the radiation therapist. Their status
should be recorded in the unit’s daily log
• All ancillary equipment, including but not limited to that for patient aural and visual communication, should be in good
working order and regularly tested at appropriate intervals as part of a continuing quality assurance (QA) program. Treatment
should not proceed if specific ancillary equipment essential to treatment is inoperative
• All computer-controlled treatment machines with the associated ancillary high-technology devices (MLC, dynamic wedge,
etc.) should be equipped with a verify-and-record (V&R) system
3. Personnel Dosimetry
• Appropriate personnel monitors (e.g. film badges) should be provided by the institution’s radiation safety office
• Personnel monitors should be supplied with a specified frequency, e.g. monthly
• Personnel dose reports should be reviewed by radiation safety office staff and reported values exceeding the investigative levels
of the institution’s ALARA program should be referred to the ALARA investigator for timely review. Monthly personnel reports
should be posted conveniently for ready access by involved personnel
4. Procedures for Securing the Medical Accelerator
• Treatment room should be secured during non-working hours and when left unattended
5. Instrument Calibration and Checks
• Radiation survey meters should be calibrated annually. A description of the sources calibration frequency and equipment
procedures should be documented
• Dosimetry system used for full calibration should be calibrated every two years by an AAPM Accredited Dosimetry Calibration
Laboratory (ADCL)
• Dosimetry system(s) used for periodic QA checks should be calibrated on a yearly basis by a qualified medical physicist (QMP)
by intercomparison with a dosimetry system calibrated by an ADCL
6. Acceptance Testing and Full Calibration of Medical Accelerator
• Testing and full calibration should be performed prior to clinical use by a qualified medical physicist following the procedures
given in the AAPM TG 40, 45, and 142 reports, and the AAPM TG 51 protocol
7. Software Quality Assurance and Testing (See Purdy et al. 1993)
• Acceptance testing procedures for new software and/or new computer-control features should be designed specifically to test
the software and control aspects of the system. All safety interlocks and new functionality should be tested rigorously after
review of all vendor documentation and testing information which is available
• Routine updates of software for a computer-controlled machine should be treated as if it includes the possibility of major
changes in system operation. All vendor information supplied with the update should be studied carefully, and then a detailed
software/control system test plan created. All safety interlocks and dosimetry features should be carefully tested, regardless of the
scope of the changes implied by the update documentation
8. Periodic QC/QA measurements of Medical Accelerator
• QC/QA measurements should be performed following procedures and frequencies recommended by the AAPM TG 40 and 142
reports
• Results of the spot check measurements should be reviewed (and signed/initialed) by the qualified medical physicist if not
measured by QMP
• Participate in external dosimetric audits such as provided by the Radiological Physics Center (RPC) annual ERDA (External
Reference Dosimetry Audit)
9. Servicing and Inspection of the Medical Accelerator
(continued)
494 J. A. Purdy et al.

Table 4 (continued)
• Only persons or firms specifically authorized by the QMP in charge at the institution should perform any maintenance or repair
of the unit
• Appropriate dosimetry measurements should be performed after any maintenance or service is performed. The person
responsible for releasing the accelerator to clinical service after maintenance is the qualified medical physicist
• A full inspection of the medical accelerator should be made by the manufacturer at intervals not to exceed three years
10. Radiation survey
• A radiation survey should be performed by a QMP before initial use and whenever any changes are made in the shielding,
location, or use of the unit that could affect radiation levels in surrounding areas.
11. Emergency procedures
• Emergency procedures should be posted at the medical accelerator control console
• All new treatment personnel should be trained in emergency procedures as soon as they report to duty. Practice drills in
emergency procedures should be conducted by the QMP or his designee with all appropriate personnel at least once a year
12. Procedure for notifying the proper person in the event of an accident or an unusual occurrence
• In case of an accelerator malfunction, individuals listed on facility’s ‘‘emergency procedures’’ should be notified immediately
• For suspected treatment misadministration, follow guidelines listed in Sect. 4 of AAPM TG-35 Report
13. Radiation therapist training
• Before a therapist starts operating a treatment machine, he/she should be given extensive training on (a) the normal operation of
the machine, (b) the meanings of the various interlocks and fault lights, as well as the appropriate response to their occurrence,
(c) any unusual aspects of the machine that could be important during routine treatments, and (d) QC/QA tests
• Continuing education should be provided at regular intervals on subjects pertinent to machine operation, QC/QA, and safety to
supplement previous training
14. Record keeping
• Copies of the following records should be maintained by the institution: (a) results of safety device checks; (b) records of
personnel dose monitoring; (c) survey instrument calibration reports; (d) calibration report for dosimetry system used for full
calibration measurements; (e) calibration or intercomparison report for dosimetry system(s) used for periodic QA measurements;
(f) acceptance test and full calibration reports; (g) periodic QC/QA test results; (h) training and experience credentials of the
qualified medical physicist; (i) training of new personnel and annual refresher training of personnel; (j) full inspection and all
maintenance work performed; (k) radiation survey(s) reports; and (l) copies of applicable regulatory statutes

Film is often used for assessing beam symmetry
and flatness, but one must be cautious if it is used to
measure dose (Williamson et al. 1981). For example,
for some types of radiographic film, the dose is not a
linear function of optical density so that it is necessary
to calibrate the film; appropriate corrections can then
be made to the densitometer readings when used for
dosimetry purposes. It is also important to make sure
that processing conditions are maintained so that the
measurements are reproducible. Another issue with
use of radiographic film as a dosimeter is that the
results of measurements are not immediately known,
i.e., after exposing the film, it must be developed and
then read on a densitometer. This is becoming less of
a problem as radiographic film dosimetry is rapidly
becoming obsolete with the advent of self-developing
radio-chromic film and high-resolution laser and
optical scanners that have greatly improved the film
data acquisition and analysis process (Niroomand-Rad
et al. 1998).
Radiation QA devices consisting of a matrix of
ionization chambers or diodes positioned in a plastic
phantom are now in widespread use and in many
cases replacing film dosimetry. An example of such a
device along with the data analysis output display is
shown in Fig. 4.
4 Medical Linear Accelerator QA
As indicated previously, significant technical devel-
opments for improving dose delivery have occurred
over the last two decades including the development
of 3DCRT and IMRT (Purdy 2007). These develop-
ments are primarily based on advances made in
computer technology and imaging and include image-
Quality Management and Safety in Radiation Oncology 495

Table 5 Typical QA instrumentation/equipment needed for a modern radiation oncology clinic

Instrumentation/equipment
Secondary standard ion chamber dosimetry system
Field use ion chamber dosimetry system(s)
Parallel plate ion chamber
Daily treatment machine array check device
Standard and field use barometers, thermometers, timers
Plastic phantom for treatment machine output calibration constancy checks
Small sealed water phantom for treatment machine output calibration constancy checks
Small water phantom with movable fixed ion chamber holder
Plastic, solid water, substitute tissue heterogeneity stack phantoms
Anthropomorphic phantom
Specialized imaging phantoms and instrumentation for simulator, CT-simulator, and linac on-board imaging systems
Specialized phantoms and instrumentation for treatment-planning systems
2D array detector (diodes/ion chambers) device(s)
Film densitometer system
Beam data scanning system
In vivo dosimetry system (Diodes, MOSFETs, and/or TLD)
Radiation survey meter
MU/Dose calculator software for independent chart checks
QA Software-Database

Fig. 3 Examples of QA devices for treatment machines that scanning water phantom system; bottom row: sealed small
are now commercially available—starting in upper left hand water phantom, electrometer/ion chamber system, daily multi-
corner top row: small water phantom, solid water phantom, detector array check device, diode in vivo dosimetry system

based 3D treatment-planning systems (3DTPS), imaging devices including MV electronic portal

computer-controlled treatment machines, dynamic imaging devices (EPIDs), and MV and kV planar, and
wedge, MLCs, beam intensity modulation, X-ray cone-beam CT (CBCT) for treatment verification.
496
Fig. 4 Example of an array
detector (MapCHECKTM, sun
nuclear corporation,
Melbourne, FL) and display
comparing treatment plan and
measured data for a head and
neck cancer patient treated
with IMRT
In addition, novel designs of treatment-planning/
delivery systems such as the TomoTherapy HI-ART
(TomoTherapy Inc., Madison, WI, USA), Accuray
CyberKnife (Accuray, Inc., Sunnyvale, CA), and
Brainlab VERO (Brainlab AG, Feldkirchen,
Germany) are rapidly coming to the market place,
presenting huge QA challenges to practicing medical
physicists. Both HI-ART and VERO systems include
daily megavoltage CT localization, followed by
helical treatment delivery by a rotating linac source
mounted to a CT gantry with synchronized binary
collimator leaf movements and table motion. While
the HI-ART model has been in clinical use for over a
decade, the AAPM only recently provided compre-
hensive QA recommendations (Langen et al. 2010).
A more recent challenge for QA is set by the modified
design of a medical linear accelerator such that it is
flattening filter free (FFF), one example of which is
the Varian TrueBeam (Varian Medical Systems, Inc.,
Palo Alto, CA, USA).
No doubt, advanced technologies provide for RT
techniques that will likely improve therapeutic ratios
through the use of conformal physical dose distribu-
tions that cannot be achieved using older 2D plan-
ning, delivery, and verification methods. However,
the point being made is that ensuring that the RT
process is safe and accurate when these advanced
technologies are used is much more difficult than
ensuring the 2D process that uses a treatment machine
J. A. Purdy et al.
with simple electromechanical controls, 2D planning
systems, standard treatment aid devices (alloy blocks,
physical wedges, etc), and weekly port film treatment
verification (Kutcher et al. 1994; Nath et al. 1994).
In many cases, the complexity of interactions
between hardware and software in a near real-time
environment makes it virtually impossible to dem-
onstrate with certainty that the operation of the
advanced technology system is correct and that all
possible failure modes have been eliminated.
Exhaustive testing of all possible combinations of
inputs, in all possible sequences, and from all possible
sources, cannot be realistically accomplished. There-
fore it is essential that the decision to purchase and
implement a modern RT linear accelerator for clinical
use carries with it a commitment to a well-planned
and rigorous QM approach including ensuring there is
adequate staffing, test equipment/instrumentation, and
allotted time to make sure the system is performing
according to specifications and that the latest safety
procedures are practiced when these advanced tech-
nologies are implemented in the clinic (RCR et al.
2008).
An effective QC/QA program for treatment
machines establishes criteria for optimum machine
performance, monitors adherence to those predefined
criteria, ensures the accuracy of the dose delivered,
minimizes treatment machine downtime, and enhances
communication between the individuals that make up
Quality Management and Safety in Radiation Oncology
the RT team. The importance of this last point cannot be
overemphasized in that a treatment machine QC/QA
program is very much a team effort and will at some
stage call on the expertise of the physicist, dosimetrist,
therapist, clinical engineer, IT specialist, and radiation
oncologist. Other key points for a QC/QA program to
be successful include: (a) a commitment by the staff to
the program; (b) participation of radiation, electronic,
mechanical, and IT specialists; (c) active radiation
therapists participation; (d) regularly scheduled
QC/QA tests and preventive maintenance inspec-
tions(PMIs) of the linac; (e) agreement on machine
performance tests and acceptance criteria; (f) adequate
test instrumentation; (g) accurate and complete docu-
mentation of the linac; and (h) commitment to proper
maintenance and radiation calibration record keeping
(bound archival records and/or computer database).
The prescribed dose planned and the dose deliv-
ered by a linear accelerator is dependent on several
parameters including the dose calibration, percentage
depth-dose ratios used in calculating the dose distri-
bution and machine monitor unit settings, off-axis
beam characteristics, wedge and block factors, MLC
calibration, etc. All parameters must be carefully
determined when the therapy machine is installed
during machine commissioning. Periodic QA proce-
dures at different levels and different frequencies must
then be implemented to ensure the accuracy and
reproducibility of the dose delivered by the linear
accelerator over time. These typically include: (a)
daily checks, performed each morning by the radia-
tion therapists who normally operates the machine;
(b) weekly/monthly checks performed by a physicist,
dosimetrist, therapist, or a physics resident; (c) PMIs
performed by a radiation oncology clinical engineer;
(d) annual full calibration performed by a qualified
medical physicist, and most importantly; and (e)
checks after changes/repairs as human errors in the
implementation of these changes cannot be ruled out
(Kutcher et al. 1994).
As previously stated, the responsibility of per-
forming the various tasks can be divided among
physicists, physics residents, therapists, dosimetrists,
engineers, and IT specialists. It is essential that each
individual competently performs and records the
results of their tests on a regular basis, and that the
overall responsibility for a treatment machine QA
program be assigned to one individual, generally a
senior medical physicist.
497
All calibration/test measurements should be
recorded chronologically in bound notebooks or in a
computer database. Such records and the data con-
tained therein are a valuable resource in maintaining
the treatment machine. All parties involved should
have access to the periodic tests reports and mainte-
nance/repair logs.
An acceptance criterion must be established for
each of the QC/QA checks performed. The frequency
of each check procedure to be performed depends
primarily on the stability of the parameter tested,
based on one’s own experience. For some tests, only a
very quick ‘‘qualitative’’ type test is required. For
example, a weekly ‘‘light-radiation field congruence’’
test result can be analyzed by simply looking at a
radiograph showing the light field and radiation field
edges and observing whether or not the agreement
appears reasonable and similar to the last week’s test.
Other tests require a more careful quantitative anal-
ysis. For example, a baseline quantitative ‘‘light-
radiation field congruence’’ test would require that the
film be analyzed using a film densitometer and that
the results be carefully plotted on graph paper in order
to determine the edge agreement precisely.
The QC tests should be designed to be quick and
reproducible checks on key parameters, if they are to be
accepted and performed faithfully. The discussion
provided in the following sections is for general guid-
ance and the actual QC/QA tests required at a particular
institution are the responsibility of that institution. For
guidance purpose, the daily, monthly, and annual tests
recommended for linacs and their tolerance values are
taken from AAPM TG 40 (Kutcher et al. 1994) and
AAPM TG 142 (Klein et al. 2009).
4.1 Linac Daily, Weekly, and Monthly
QC/QA Tests
Specific daily checks that are generally recommended
are listed in Table 6. They are separated into safety,
mechanical, and dosimetry checks. However, it
should be clearly understood that it is important to
first follow the manufacturer’s instructions for
machine start-up and operation of the accelerator.
Initial readings of the various meters, dials, and
gauges recommended for monitoring should be
recorded. The daily readings should be maintained in
a logbook or computer database. These data provide
498 J. A. Purdy et al.

Table 6 Daily QC/QA tests with recommended tolerances for

medical linear accelerators (modified from AAPM TG 40 and
TG 142 reports)
Procedure Machine type tolerance
non-IMRT IMRT (SRS/
SBRT)
Safety
Door interlock (beam off) Functional
Door closing safety Functional
Audiovisual monitor(s) Functional
Stereotactic interlocks NA NA Functional
(lockout)
Radiation area monitor Functional Fig. 5 Plastic photon output calibration constancy phantom
(if used) used at UC Davis for daily output checks (valiant instruments,
Beam on indicator Functional St. Louis, MO)
Mechanical
Laser localization 2 mm 1.5 mm 1 mm
ionization chamber, and which attaches to the accel-
erator at the standard SSD (Fig. 5). A cylindrical
Distance indicator 2 mm 2 mm 2 mm
(ODI)@ iso ionization chamber (e.g. Farmer type) or other type of
ionization chamber can be used for the test. The
Collimator size indicator 2 mm 2 mm 1 mm
ionization chamber reading should be corrected for
Dosimetry
temperature and pressure and converted to dose using
X-ray output constancy 3% predetermined factors so that the output value can be
(all energies)
compared to the value established at the time of the
Electron output constancy
(Weekly, except for
last full calibration. The previously described multi-
machines with unique detector devices can also be used for this daily review
e-monitoring requiring check of output, but does not replace the need to have
daily) available a robust ion chamber dosimetry system
assigned for daily use by the therapists.
The electron beam radiation output calibration
constancy for each of the electron energies used for
performance trends for a particular component and the reference geometry applicator (e.g. 14 9 14 cm)
are helpful in isolating faults and may even alert one should be checked at least weekly, depending on
to a developing problem before full component failure machine type. However, some accelerators (e.g.
occurs. Siemens) possess a unique internal monitor chamber
Daily treatment room checks include testing the system for electrons, and require daily checks. This
functionality of the treatment room door, door beam can be accomplished efficiently using a plastic stack
off interlock, intercom and closed circuit monitor phantom and ion chamber dosimetry system as shown
system, and radiation warning lights. Linac checks Fig. 6 or with a multi-detector device designed for
include the accuracy of the optical distance indicator this check.
(ODI), alignment of the laser localization lights, and The constancy phantom used for the photon beam
the collimator size indicator. output check is also convenient for the daily check of
The photon beam radiation output calibration the ODI and the laser localization lights. A visual
constancy for each of the photon energies used should inspection of where the ODI indicator image strikes
be checked daily for the reference geometry (e.g. 10 the output constancy phantom surface generally suf-
9 10 cm, 100 cm SSD or SAD). This can be fices as a daily check. Tests using a mechanical front
accomplished efficiently using an ionization chamber pointer can be performed when a more quantitative
in a simple plastic phantom which contains a fitted test is needed. The vertical and sagittal lines of the
hole at a standard depth from the top surface for the laser localization lights should pass through the
Quality Management and Safety in Radiation Oncology
Fig. 6 Plastic electron output calibration constancy phantom
used at UC Davis for daily output checks (valiant instruments,
St. Louis, MO)
central axis of the beam. This may also be checked
using marks on the top surface of the plastic con-
stancy phantom and observing the intersection of the
laser lines with the image of the light field’s cross-
hair.
Recommended monthly checks are listed in
Table 7 (Klein et al. 2009; Kutcher et al. 1994). The
checks are separated into safety, mechanical, dosim-
etry, and respiratory gating checks. The light-field-
radiation congruence test can be performed by
exposing a film placed perpendicular to the central
axis of the beam (Fig. 7). The film is aligned with
metal markers placed on the edges of the light field
(or alternatively pressure marks from a sharp device
or pin-prick) to mark the position of the light field.
A plastic sheet of adequate thickness to provide
electronic buildup is placed over the film. In some
cases, this may need to be checked more often
depending on utility. The developed film can be
analyzed visually for the weekly test and with a film
densitometer for a monthly quantitative check.
Gantry and collimator angle indicators along with
treatment couch position indicators should also be
checked monthly as well as the mechanical distance
indicator. Using a simple level and rotating the gan-
try, the gantry angle indicators can be checked at the
vertical and horizontal positions. The collimator angle
indicators and the field size indicators at selected field
sizes can be checked using graph paper placed on the
treatment couch at the reference distance. Collimator
rotation can be quickly checked by observing the
movement of the image of the cross-hair as the col-
limator is rotated +90o and -90o.
499
The alignment of the intersection of the cross-hairs
with the center of the light and radiation field should
be checked. This is easily accomplished by placing a
film at the isocenter perpendicular to the beam and
marking (e.g. pin-prick) the intersection of the cross-
hairs on the film. The relative motion of the cross-
hairs around the pin-prick should be observed as the
collimator is rotated ±90o. The center of the radiation
field can be determined from the exposed film and
compared to the position of the pin-prick.
Additional mechanical checks include examining
accessories such as wedge filters, electron beam
applicators, physical IMRT compensators, and
blocking tray assemblies—including the mounting
slots and micro-switches—for any cracks, potential
malfunctions, and latching.
Beam profile constancy can be checked using a
multi-detector device (usually four or five detectors)
and compared to the values obtained at the last full
calibration. Profile constancy can also be checked
with a film in a plastic phantom placed perpendic-
ular to the beam central axis for a large field.
It should be noted that for ‘‘bent-beam’’ linear
accelerators, where the electron scattering foil and
the photon flattening filter are moved in and out of
position, checks more frequent than monthly may
need to be performed.
Photon beam energy can be checked by measuring
the beam profile constancy in a plastic phantom at a
specified depth or by use of the multi-detector system.
For electrons, the relative ionization measured at two
depths is usually a sufficient check.
In addition, the constancy of the radiation output
calibration (cGy/MU) should be checked using a
different dosimetry system than that used for the daily
output constancy check. This check is in fact a
redundancy check on both the treatment machine
monitor chamber calibration and the daily dosimetry
system used to check the output calibration constancy.
It should be noted that if respiratory gating is
performed, the monthly checks should include beam
output consistency (in gating mode), phase and
amplitude beam control, and gating interlock checks
(Klein et al. 2009).
Additional monthly checks for the linac are listed
in Table 8 (for Dynamic Wedge), Table 9 (for
MLCs), and Table 10 (for imaging systems) and will
be discussed in later sections for these newer
technologies.
500 J. A. Purdy et al.

Table 7 Monthly QC/QA tests with recommended tolerances for medical linear accelerators (modified from AAPM TG 40 and
TG 142 reports)
Procedure Machine type tolerance
non- IMRT (SRS/SBRT)
IMRT
Safety
Laser guard—interlock test Functional
Mechanical
Light/radiation field coincidencea 2 mm or 1% on a side
a
Light/radiation field coincidence (asymmetric) 1 mm or 1% on a side
Distance check device for lasers compared with front 1 mm
pointer
Gantry/collimator angle indicators (@ cardinal angles) 1.0 deg
(Digital only)
Accessory trays (i.e., Port film graticule tray) 2 mm
b
Jaw position indicators (Symmetric) 2 mm
Jaw position indicators (Asymmetric)c 1 mm
Cross-hair centering (walk-out) 1 mm
Treatment couch position indicatorsd 2 mm/ 2 mm/1 deg 1 mm/0.5 deg
1 deg
Wedge placement accuracy 2 mm
e
Compensator placement accuracy 1 mmf
f
Latching of wedges, blocking tray Functionale
Localizing lasers ±2 mm ±1 mm \±1 mm
Dosimetry
X-ray output constancy 2%
Electron output constancy
Backup monitor chamber constancy
Typical dose rateg output constancy NA 2% (@ IMRT dose 2% (@ stereo dose rate,
rate) MU)
Photon beam profile constancy 1%
Electron beam profile constancy
Electron beam energy constancy 2%/2 mm
Respiratory gating
Beam output constancy 2%
Phase, amplitude beam control Functional
In-room respiratory monitoring system Functional
Gating interlock Functional
a
Light/Radiation field coincidence only needs to be checked monthly if light field is used for clinical setups
b
Tolerance is summation of total for each width or length
c
Asymmetric Jaws should be checked at settings of 0.0 and 10.0
d
Lateral, longitudinal, and rotational
e
Compensator-based IMRT (solid compensators) require a quantitative value for tray position (wedge or blocking tray slot) set at
a maximum deviation of 1.0 mm from the center of the compensator tray mount and the cross-hairs
f
Check at Collimator/Gantry angle combination that places the latch toward the floor
g
Dose monitoring as a function of dose rate
Quality Management and Safety in Radiation Oncology
Fig. 7 Radiographic film showing check of light-field-radia-
tion field congruence
Finally, the monthly check should include a quick
review of the preventative maintenance logs/schedule
as these include regular safety checks for electrical and
mechanical interlocks. Also, check that an up-to-date
machine operator’s manual is located at the treatment
machine console and that detailed, unambiguous
written procedural instructions are maintained at the
control console. One should also check that the posting
of radiation warning signs and emergency instructions
have not been removed. For non-English speaking
countries, all manuals should be translated in the native
spoken language of the country of the radiation
oncology department, to avoid errors induced by
insufficient knowledge of the English language.
However, even then, care must be taken to avoid
introduction of ambiguous instructions due to the
translation being performed by people not sufficiently
knowledgeable in the complex processes of RT.
The monthly checks may take several hours
depending upon the number of tests performed and
the number of modes and energies available. These
times clearly show that a QA program for treatment
machines designed to help ensure the delivery of dose
can be implemented in any size RT clinic at an
acceptable cost in terms of time, staff, and equipment.
When such a program is neglected and problems are
not fixed as they arise, the treatment machines
will inevitably deteriorate and the quality of patient
treatments will be compromised.
501
4.2 Linac Annual QA Tests
A full calibration of the treatment machine should be
performed annually. Suggested tests (with tolerances)
for this annual calibration categorized under safety,
mechanical, dosimetry, and respiratory gating are
listed in Table 11. Additional annual tests for some of
the newer technologies are also listed in Table 8 (for
Dynamic Wedge), Table 9 (for MLCs), and Table 10
(for imaging systems) and are discussed in later
sections.
Various mechanical alignment checks include the
mechanical isocenter. Gantry rotation isocenter can
be checked by observing the position of the front
pointer tip in relation to a 2 mm diameter rod as the
gantry is rotated through 360. Similar tests should
be performed for the collimator rotation. A ‘‘star
pattern’’ is sometimes produced to check coinci-
dence of radiation isocenter and mechanical isocen-
ter, i.e., a film is placed parallel to the radiation
beam and one set of collimator jaws is closed to a
narrow slit and exposures are made at different
gantry angles (Fig. 8). All couch movements
including rotation and table top sag (under typical
patient load condition) should also be checked. If
special procedures, such as TBI, TSET, or SRS/
SBRT are performed requiring a different opera-
tional mode of the accelerator, additional annual
checks should be performed.
The X-ray and electron output calibration should
be performed in a water phantom using an ion
chamber according to an appropriate protocol such as
the AAPM TG-51 protocol (Almond et al. 1999) or
the IAEA TRS 398 protocol (IAEA 2000a). The sta-
bility of the dose per monitor unit and the beam
symmetry should be checked at different gantry
angles. Verification of the output factors and central
axis depth dose should be done for several different
field sizes. In addition, current values for OAFs,
monitor linearity, and monitor end effect should be
checked. All attenuation factors including wedge
factors, tray factors, bolus compensating filter, and
couch inserts should be checked.
If respiratory gating has been implemented, the
annual checks on the linac should include beam
energy constancy, temporal accuracy of phase/
amplitude gate-on, calibration of surrogate used for
respiratory phase/amplitude, and gating interlock
checks.
502 J. A. Purdy et al.

Table 8 Dynamic/Universal/Virtual wedge QC/QA tests with recommended tolerances for medical linear accelerators (modified
from AAPM TG 142 report)
Dynamic-incl. EDW (varian), virtual (siemens), universal (Elekta) wedge quality assurance
Frequency Procedure Tolerance
Dynamic Universal Virtual
Daily Morning check-out run for 1 angle Functional
Monthly Wedge factor for all energies C.A. Axis 45 or 60 C.A. Axis 45 or 60 5% from unity,
WF (within 2%)a WF (within 2%)a otherwise 2%
Annual Check of wedge angle for 60, full field and Check of Off-Center Ratios @ 80% field width @ 10 cm to be
spot check for intermediate angle, field size within 2%
a
Recommendation to check 458 if angles other than 608 are used

Table 9 Multi-leaf collimation QC/QA tests with recommended tolerances for medical linear accelerators (modified from AAPM
TG 142 report)
Multileaf collimation quality assurance (with differentiation of IMRT vs. non-IMRT machines)
Frequency Procedure Tolerance
Weekly Qualitative test (i.e., matched segments, Visual inspection for discernable deviations such as an increase in
(IMRT aka, ‘‘picket fence’’) interleaf transmission
machines)
Monthly Setting vs. radiation field for two 2 mm
patterns (non-IMRT)
Backup diaphragm settings (Elekta 2 mm
only)
Travel speed (IMRT) Loss of leaf speed [0.5 cm/sec
Leaf position accuracy (IMRT) 1 mm for leaf positions of an IMRT field for 4 cardinal gantry
angles. (Picket fence test may be used, test depends on clinical
planning—segment size)
Annually MLC transmission (average of leaf and ±0.5% from baseline
interleaf transmission), all energies
Leaf position repeatability ±1.0 mm
MLC spoke shot B1.0 mm radius
Coincidence of light field and X-ray ±2.0 mm
field (all energies)

Continuing education lectures on the machine
operation, safety and QA should be presented to the
staff on an annual basis. It is important that emer-
gency procedures be reviewed with the staff to ensure
proper interpretation and understanding. A thorough
‘‘hands on’’ training period for all therapists is
essential following instruction about the operation of
the equipment and prior to assuming treatment
responsibilities. Written instructions should be pro-
vided to guide therapists as to a safe response when
equipment malfunctions or exhibits unexpected
behavior or after any component has been changed or
readjusted.
Special procedures, such as TBI, TSET, or
SRS/SBRT require more in-depth training for the
therapists and a credentialing system should be put in
place to ensure that therapists participating in these
procedures have the training/competence required.
4.3 LINAC Computer-Control Systems
QA
Modern day medical linear accelerators utilize com-
puter-control systems. Incidents in the past have
shown that such accelerators have the potential for
Quality Management and Safety in Radiation Oncology 503

Table 10 Imaging systems QC/QA tests with recommended tolerances for medical linear accelerators (modified from AAPM TG
142 report)
Procedure Application type tolerance
non-SRS/SBRT SRS/SBRT
Dailya
Planar kV and MV (EPID) imaging
Collision interlocks Functional Functional
Positioning/repositioning B2 mm B1 mm
Imaging and treat. coordinate coincidence (single gantry angle) B2 mm B1 mm
Cone-beam CT (kV & MV)
Collision interlocks Functional Functional
Imaging and treat. coordinate coincidence B2 mm B1 mm
Positioning/repositioning B1 mm B1 mm
Monthly
Planar MV Imaging (EPID)
Imaging and treat. coordinate coincidence (4 cardinal angles) B2 mm B1 mm
Scalingb B2 mm B2 mm
Spatial resolution Baselinec Baseline
Contrast Baseline Baseline
Uniformity and noise Baseline Baseline
Planar kV Imagingd
Imaging and treat. coordinate coincidence (4 cardinal angles) B2 mm B1 mm
Scaling B2 mm B1 mm
Spatial resolution Baseline Baseline
Contrast Baseline Baseline
Uniformity and noise Baseline Baseline
Cone-beam CT (kV & MV)
Geometric distortion B2 mm B1 mm
Spatial resolution Baseline Baseline
Contrast Baseline Baseline
HU constancy Baseline Baseline
Uniformity and noise Baseline Baseline
Annual (A)
Planar MV Imaging (EPID)
Full range of travel SDD ±5 mm ±5 mm
Imaging dosee Baseline Baseline
Planar kV imaging
Beam quality/energy Baseline Baseline
Imaging dose Baseline Baseline
Cone-beam CT (kV & MV)
Imaging dose Baseline Baseline
a
Or at a minimum when devices are to be used during treatment day
b
Scaling measured at SSD typically used for imaging
c
Baseline means that the measured data is consistent with or better than ATP data
d
kV imaging refers to both 2D fluoroscopic and radiographic imaging
e
Imaging dose to be reported as effective dose for measured doses per TG 7579
504 J. A. Purdy et al.

Table 11 Annual QC/QA tests with recommended tolerances for medical linear accelerators (modified from AAPM TG 40 and
TG 142 reports)
Procedure Machine type tolerance
non-IMRT IMRT (SRS/SBRT)
Safety
Follow manufacturers test procedures Functional
Mechanical
Collimator rotation isocenter ±1 mm from baseline
Gantry rotation isocenter ±1 mm from baseline
Couch rotation isocenter ±1 mm from baseline
Electron applicator interlocks Functional
Coincidence—radiation and mechanical ±2 mm from ±2 mm from ±1 mm from baseline
isocenter baseline baseline
Table top sag 2 mm from baseline
Table angle 1 degree
Table travel max. range movement (in all ±2 mm
directions)
Stereotactic accessories, lockouts, etc. NA Functional
Dosimetry
X-ray flatness change from baseline 1%
X-ray symmetry change from baseline ±1%
Electron flatness change from baseline 1%
Electron symmetry change from baseline ±1%
SRS arc rotation mode (range: 0.5–10 MU/deg) NA NA Monitor units set vs. delivered: 1.0
MU or 2% (whichever is greater)
Gantry arc set vs. delivered: 1.0 deg
or 2% (whichever is greater)
X-ray/electron output calibration (TG-51) ±1%(absolute)
Spot check of field size dependent output factors 2% for field size \4 9 4 cm2, 1% C4 9 4 cm2
for X-ray (2 or more FS)
Output factors for electron applicators (spot ±2% from baseline
check of 1 applicator/energy)
X-ray beam quality (PDD10 or TMR1020) ±1% from baseline
Electron beam quality (R50) ±1 mm
Physical wedge transmission factor constancy ±2%
X-ray MU linearity [output constancy] ±2% C5MU ±5% (2–4 MU), ±5% (2–4), ±2% C5MU
±2% C5MU
Electron MU linearity [output constancy] ±2% C5MU
X-ray output constancy vs dose rate ±2% from baseline
X-ray output constancy vs gantry angle ±1% from baseline
Electron output constancy vs gantry angle ±1% from baseline
Electron and X-ray Off-Axis Factor constancy vs ±1% from baseline
gantry angle
Arc mode (expected MU, degrees) ±1% from baseline
Quality Management and Safety in Radiation Oncology
Table 11 (continued)
Procedure
TBI/TSET Mode
PDD or TMR and OAF constancy
TBI/TSET output calibration
TBI/TSET accessories
Respiratory gating
Beam energy constancy
Temporal accuracy of phase/amplitude gate-on
Calibration of surrogate for respiratory
phase/amplitude
Interlock testing
Fig. 8 Radiographic films showing ‘‘star pattern’’ check of radiation isocenter. a Gantry rotation. b Collimator rotation. c Couch
rotation
massive overdoses to the patient as a result of soft-
ware flaws (Joyce 1986; Karzmark 1987; Leveson
1995). This poses a major problem for the RT com-
munity since standard QA tests on accelerators are not
designed to catch software flaws. We caution the
physicist to scrutinize carefully the computer opera-
tion of the linac during the acceptance testing period,
paying particular attention to verifying what happens
when beam setup parameters are edited.
The AAPM TG35 report (even though somewhat
dated) remains a relevant resource for addressing this
issue (Purdy et al. 1993). It provides an in-depth
discussion of the safety considerations stemming from
the increased use of computer logic and micropro-
cessors in the control systems of treatment units.
It suggests how procedures and operator responses
505
Machine type tolerance
non-IMRT IMRT (SRS/SBRT)
Functional
1% (TBI) or 1 mm PDD shift (TSET) from baseline
2% from baseline
2% from baseline
2%
100 ms of expected
100 ms of expected
Functional
can be improved to reduce or avoid risks associated
with hardware and software failures in RT equipment.
Acceptance testing procedures for new software
updates and/or new computer-control features should
be designed specifically to test the software and control
aspects of the system. Safety interlocks and new
functionality should be tested rigorously after review of
all vendor documentation and testing information
provided by the vendor (Leveson 1995; Weinhous et al.
1990). One should also note that while it is much easier
to test safety interlocks in non-clinical mode, such tests
do not necessarily properly predict the accelerator’s
behavior in clinical mode. Therefore, to ensure safe
operation, it is important that machine operation/
interlocks be tested in the clinical modes used to treat
patients. Computer-assisted setup features should be
506
verified. If possible, return of the machine to a safe
condition in the event of a computer or computer-
related hardware failure should be verified. One
must also pay special attention to all supplementary
options (and especially to their mutual communi-
cation interface) that may be installed to accom-
modate the use of the machine according to the
department’s site-specific procedures and protocols.
Often, these computer-assisted mechanical add-ons
may be manufactured by a separate vendor, making
communication links crucial.
Routine updates of software for a computer-
controlled machine should be treated as if it includes
the possibility of major changes in system operation.
All vendor information supplied with the update
should be studied carefully, and a detailed software/
control system test plan created. All safety interlocks
and dosimetry features should be carefully tested,
regardless of the scope of the changes implied by
the update documentation. All tests suggested by the
manufacturer to confirm correct operation of the
new software should be performed. Treatment beam
parameters which may be affected by the software
changes should be verified. Also, even though the
software may have passed testing without demon-
strable errors, latent bugs may appear as the hardware
changes with age. Therefore, constant vigilance is
necessary. Near full acceptance testing may be nec-
essary depending on the nature and extent of the
changes. As this can become very labor intensive, a
carefully thought-out test plan is essential. Decisions
on what to test and what not to test should be based
on: (1) details of the modifications made, (2) details
of planned or expected operational changes following
installation of the update, (3) revised design specifi-
cations, support documentation, and/or operations
manuals, and (4) results of beta tests and if available,
results from tests at other institutions.
Safety interlocks may also have to be tested fol-
lowing non-trivial repairs. Because software and
hardware are intimately linked in a computer-con-
trolled machine, even minor changes in hardware can
produce aberrations in the operation of the machine
if there is a flaw in the software design or imple-
mentation. Integrity of software and data should be
verified using appropriate tools supplied by the
manufacturer. If repairs are extensive or involve
critical components, near full acceptance testing may
again be necessary to ensure proper operation.
J. A. Purdy et al.
Despite extensive in-house and field testing by the
manufacturer, new problems are frequently discov-
ered by users in the field. Manufacturers should pro-
vide clear procedures for reporting such problems.
Manufacturers should respond to problem reports
with a written acknowledgment, followed by a timely
response evaluating the severity of the problem, a
recommended temporary solution or a recommenda-
tion to suspend treatments, and a proposed permanent
solution with time schedule for implementation.
Dissemination of significant problem reports to all
users should be done in a timely manner.
4.4 Asymmetric Jaws (Independent
Collimation) QC/QA
All modern medical accelerators have collimator jaws
that move independently, (and in most occasions
beyond isocenter). Independent jaw capability allows
the isocenter to be maintained at a location other
than the treatment field center. This flexibility allows
simplified patient positioning and improved safety
by avoiding overlapping field abutments without
the necessity of using heavy beam-splitting blocks.
For example, breast irradiation techniques now
commonly use the independent jaw feature (Klein
et al. 1994).
Monitor unit calculations are only slightly more
complex for independent jaws than for symmetric
jaws (Gibbons 2000; Slessinger et al. 1993). An off-
axis correction factor can be used that depends only
on the distance from the machine’s central axis to the
center of the independently collimated open field.
However, the influence of backscattered photons into
the monitor chamber may influence the output for
very elongated symmetric fields (Palta et al. 1988).
The dose distributions of asymmetric fields defined by
jaws are quite similar to those defined by alloy blocks.
Only slight differences are seen at the field edges due
to the distance between the patient and the jaws.
Treatment record forms that denote each jaw setting
(Y1, Y2, X1, X2) should be used. We also recommend
that the four jaws be identified by labels placed on the
treatment machine, simulator collimator, and the block
trays when alloy blocks are used. This is especially
useful when treatment techniques call for collimator
rotation or involve the use of multileaf collimation or
dynamic wedge, which are oriented in a particular
Quality Management and Safety in Radiation Oncology
Fig. 9 Radiographic film showing independent jaw QA test;
each quadrant of the field is irradiated separately and super-
imposed using a single film
direction along an independent jaw set (i.e., MLC-X1 or
X2, dynamic wedge Y1 or Y2).
Monthly QC/QA checks of each independent
jaw can be performed by comparing jaw setting
versus the light field position versus 50% radiation
value (edge) for fields designed as quadrants (two
non-divergent edges). We recommend specifying
the jaw position accuracy to an accuracy of 1 mm
for setting versus light field at all positions, and a
specification of 1 mm or 1o for light versus radia-
tion field per TG-142. An effective QC/QA test is
to irradiate a film superimposing each quadrant of
the field separately (Fig. 9). Ideally the composite
film should exhibit no distinct regions of overlaps
or gaps.
Annually, all off-axis factors (OAFs) used for
asymmetric jaw monitor unit calculations should be
checked during beam profile assessment to ensure
agreement is within 0.5% of the tabulated OAFs. The
output at dmax off-axis when the Y-jaw is 10.0 cm
beyond isocenter should also be checked annually to
ensure that backscattering to the monitor chamber that
can cause an eventual decrease in output is not
occurring. This measurement (at the respective dmax
depths) is compared to calculations using the appro-
priate OAF.
507
4.5 Dynamic Wedge QC/QA Tests
Dynamic wedge technology takes advantage of
asymmetric jaw technology in conjunction with con-
trol of the dose rate over the course of one treatment
(Kijewski et al. 1978; Leavitt et al. 1990). An initial
field is set along with a desired isodose angle (wedge
angle) with a particular wedge direction (heel-toe).
After a specific number of monitor units have been
delivered, the designated collimator jaw begins to
move with a varying speed while the dose rate is
varied simultaneously. This type of technology has
generally replaced physical wedges in modern day RT
and is available on all vendors’ modern linacs. For
discussion purposes, we will focus on the Varian
system called ‘‘Enhanced Dynamic Wedge’’ (Varian
Medical Systems, Inc., Palo Alto, CA). The variations
in jaw position and dose rate are driven by computer
files called segmented treatment tables (STTs), which
are unique for each energy, wedge angle, and field
size. This customization of each dynamic wedge
angle for each field size yields excellent wedged
isodose distributions when compared to physical
wedges. A similar technology exists for Siemens
accelerators, called ‘‘Virtual Wedge’’ (Siemens
Oncology Systems, Concord, CA) and for Elekta,
referred to as the ‘‘OmniWedge’’ (Elekta AB (Publ),
Stockholm, Sweden). It should be noted that Elekta also
provides a 60o mechanical wedge, referred to as Uni-
versal Wedge, permanently mounted in the treatment
head and which can automatically be moved into place
for a designated portion of treatment to produce dose
distributions for wedge angles ranging from 1–60o.
Table 8 lists recommended daily, monthly, and
annual QC/QA checks (with tolerances) for the
Varian, Elekta, and Siemens modern wedge technol-
ogies. These include checking of 45 or 60o wedge
factors for all energies on a monthly basis. More
details regarding the QA of Dynamic, Universal, and
Virtual wedges are given in the AAPM TG 142 report
(Klein et al. 2009).
Patient-specific checks when this technology is
used include a diode placed on the patient skin surface
for each beam (if practical) for the first treatment
fraction. A dual diode system works best, with one
placed at the central axis on the patient’s skin surface
and the other at an off-axis point toward an anatom-
ically noted direction that corresponds to the ‘‘heel or
toe’’ of the wedge. For best results, the diode
508
electrometer reading should be corrected by factors
that depend on SSD, field size, and diode response for
that day. The corrected reading corresponds to the
dose at dmax and deviations up to 5% are considered
acceptable due to the diode’s systematic limitations in
terms of spatial resolution, sensitivity to temperature
changes, and placement by the therapists. A second
reading and investigation should be performed for
larger deviations (Klein et al. 2005).
Therapists should also confirm the display of the
moving jaw is as expected when this technology is
used in treatment. A verification and record (V&R)
system provides a direct check of the dynamic wedge
angle and orientation. However, there must be an
independent check confirming the V&R entry of the
wedge angle and direction before the first fraction.
4.6 Multileaf Collimation: Non-IMRT
QC/QA
MLCs have now become the state-of-the-art method for
generating irregularly shaped fields for photon beam RT.
AAPM TG-50 (Boyer et al. 2001) provided early rec-
ommendations on MLC QA, but only as a block aperture
replacement; as it did not address MLC use for IMRT.
More recently, AAPM TG Report 142 updated MLC
QC/QA test recommendations and took into account
whether or not the MLC system is used for IMRT (Klein
et al. 2009). Table 9 provides a summary of the updated
recommendations for MLCs (non-IMRT). Note that the
additional recommended tests for MLCs that are used
for IMRT will be discussed in Sect. 5.
When first clinically implemented, all MLC fields
should be checked visually (light field vs skin marks)
and imaged using film or via EPID on a weekly basis to
compare with DRRs. Other QC/QA tests performed
include the daily running sample of field during the
morning checkout of the accelerator. In addition,
AAPM TG Report 142 recommends the following
periodic checks: (1) testing of MLC settings vs light
field vs radiation field for selected gantry and colli-
mator angles; (2) leaf speed; (3) leaf transmission; and
(4) interlock checks (Klein et al. 2009).
Recommended annual MLC checks of linacs
include the above listed monthly MLC tests and also
film scans to review abutted leaf transmission, pen-
umbra dependence on leaf position, and a review of
procedures with clinical staff.
J. A. Purdy et al.
5 Intensity Modulated Radiation
Therapy QA
Increased vigilance is required for IMRT and the users
of this technology must accept an even greater
responsibility with regard to patient safety. The accu-
rate delivery of IMRT dose distributions depends on
robust linac QA programs as discussed in the previous
sections plus additional tests that will be discussed
in this section. In addition, the reader is referred
to ‘‘Linac-Based Image Guided Intensity
Modulated Radiation Therapy’’ in this textbook for
more details on IMRT. Also, there have been several
consensus documents published regarding the use of
IMRT (Ezzell et al. 2009; Galvin et al. 2004; Holmes
et al. 2009; IMRT CWG 2001).
The accurate localization of the accelerator iso-
center relative to the patient alignment markers is
critical for external beam RT, and even more so for
IMRT. If the lasers are not correctly aligned, the
localization of the dose distribution within the patient
will suffer. For IMRT treatment planning and deliv-
ery, dose distributions are generated using fluence
distributions incident on the patient from a series of
directions. The superposition of the fluence distribu-
tions generates the planned dose distribution, and the
planning system assumes that the orientation and
position of each beam angle is accurate. Dose-deliv-
ery errors can occur due to excessive gantry sag and
gantry and collimator angle misalignments. Periodic
QC/QA tests must be in place to ensure radiation
beam and mechanical isocenter alignment is main-
tained. Consequently, the accuracy of the patient
positioning and immobilization system is critical for
accurate dose delivery. Thus periodic testing of
patient indexing system accuracy should be con-
ducted. Studies evaluating the implications of incor-
rect treatment setup have shown that variations in the
delivered-dose distribution can arise when the gantry,
collimator, or couch angle are incorrectly set (Hong
et al. 2005; Siebers et al. 2005).
The impact of leaf positioning accuracy and
interleaf or abutted leaf transmission on the accuracy
of delivered IMRT fields has been well documented
(Klein and Low 2001; LoSasso 2008; LoSasso et al.
1998; Sharpe et al. 2000). Therefore, additional tests
of MLCs that are used for IMRT (see Table 9) are
recommended along with any vendor-specific
Quality Management and Safety in Radiation Oncology 509

Fig. 10 Radiographic film used to verify MLC relative leaf position and gap width accuracy with the so-called ‘‘picket fence’’ test.
Top row shows results for leafs out of calibration tolerance and bottom row shows test results after corrections were made in leaf setting

recommended tests. Specifically, AAPM TG-142
report recommends that the ‘‘picket fence’’ test
(LoSasso 2008) be performed weekly with a careful
examination of the image acquired by static film (see
Fig. 10) or on-line portal image, and on a monthly
basis, perform a leaf position accuracy test that can
account for gantry rotation, which may affect leaf
motion due to gravitational effects imposed on the leaf
carriage system (Klein et al. 2009). Also, a monthly test
to ensure that leaf travel speed is maintained (loss must
be less than 0.5 cm/sec from baseline data to avoid
increased beam holds or gap width errors) is recom-
mended. Finally, the physicist must be much more
cognizant of PMIs and repairs/replacement of MLC
parts such as leaf motors and make sure robust post-
testing relevant to IMRT is performed.
For those clinics using physical compensators to
modulate beam fluences, it should be noted that
QC/QA checks must be in place to ensure the correct
position of the custom made compensating filter in
relation to the patient during treatment is maintained,
as any misalignment can result in a serious error.
More details on this subject can also be found in the
AAPM TG-142 report (Klein et al. 2009).
The IMRT treatment-planning system provides the
number of MUs for each field. In the US the MU
calculations for every single patient must be verified
by direct measurement prior to treatment using either
510
Fig. 11 Example of individual IMRT QA results for a patient
referred for stereotactic lung radiotherapy. Upper left panel:
calculated dose in coronal plane through isocenter. Lower left:
a point detector (e.g. ion chamber) and film or a
sufficiently fine-grid array detector system (Fig. 11).
In addition, many clinics also perform independent
MU calculations as an additional check (Yang et al.
2005). General consensus is that for the generated
IMRT plans, point dose measurements should agree
with the calculated dose to within 3% of the pre-
scription dose or satisfy a 3 mm distance to agree-
ment criterion. Palta et al. (2003) have proposed
values of the planning confidence limit and action
levels for different regions in an IMRT plan, which
are summarized in Table 12. What is still not so clear
is the acceptable tolerance rate for the number of
points needing to meet the 3%/3 mm criterion. Most
try to hold to a 90% pass rate, but in some cases
clinical judgment is still required to evaluate just
where the majority of points are failing. It should
be noted that the AAPM TG-119 report provides
quantitative baseline confidence limits for IMRT
J. A. Purdy et al.
corresponding measured dose. Upper right panel: calculated (red)
and measured (green) dose profiles along the vertical lines as shown
in the other panels. Lower left panel: 3%/3 mm gamma map
commissioning based on measurements at a number
of institutions (Ezzell et al. 2009). These values can
be used for comparison to locally derived confidence
limits and if substantial differences are seen, it may
indicate the need for improved IMRT commissioning.
A critical clinical issue is the impact on patient or
target volume motion during IMRT treatments. For
3DCRT in which a uniform dose distribution is the
norm, the motion of the patient during treatment will
result only in minor dose variations within the plan-
ning target volume (PTV) assuming proper margins
are used. In IMRT, the dose distribution is created by
a delivery sequence of incident fluences, each with a
potentially large lateral fluence gradient. Yu et al.
(1998) showed that the fluence delivery error can be
as high as a factor of two when dynamic-MLC
delivery is coupled with breathing motion; however,
Bortfeld et al. (2004, 2002) showed that with typical
fractionation schedules the dose-delivery error is
Quality Management and Safety in Radiation Oncology
Table 12 Proposed values of the confidence limits and action levels for IMRT treatments (modified from Palta et al. 2003)
Region
High-dose, low-dose gradient
High-dose, high-dose gradient
Low-dose, low-dose gradient
Dose fall off (d90–50%)
a
Confidence limit is defined as the sum of the average deviation and 1.96 SD. The average deviation used in the calculation
of confidence limit for all regions is expressed as a percentage of the prescribed dose according to the formula:
100% 9 (Dcalc-Dmeas/Dprescribed)
significantly less and averages out over the multiple
fractions. However, when SBRT techniques or other
hypo-fractionation schedules are used, this issue is
likely to be more problematic. Thus, clinicians are
cautioned that when using IMRT for tumors that
move due to breathing, one should provide good
immobilization techniques for the patient and target
volume (Engelsman et al. 2005).
One consequence of IMRT, similar to some modern
3DCRT techniques, is the lack of a convenient open
portal for image-based patient position and treatment
verification. Most clinics today, verify patient position
using orthogonal EPIs using fixed open fields and
comparing against digitally reconstructed radiographs
(DRRs) or simulator films, or via CBCT images com-
pared to the reference planning CT.
In vivo dosimeters (TLD, diodes, and MOSFET)
have been used with IMRT (Higgins et al. 2003). The
dosimetry system must have negligible dose rate
effects or time dependence, but even then readings are
likely to have more uncertainty due to the large gra-
dients typically found with IMRT.
Another important issue is the potential that IMRT
may actually result in an increased rate of secondary
malignancies (Followill et al. 1997; Hall 2006).
Looking closely at a typical IMRT dose distribution,
one sees that in general, there is an increase in radi-
ation dose to both the tumor and a limited amount of
normal tissue, and an overall reduction in the volume
of normal tissues receiving a high dose. However, a
larger volume of normal tissue within the irradiated
volume now receives lower radiation doses, as com-
pared to 3DCRT. In addition, dose to the patient
outside the irradiated volume is increased with beam
modulation systems because the number of MUs
required to deliver a specific dose to the patient is
substantially increased resulting in increased scattered
511
Confidence limita Action level
±3% ±5%
10% or 2 mm DTA 15% or 3 mm DTA
4% 7%
2 mm DTA 3 mm DTA
and leakage radiation from the accelerator. The
amount varies depending on the distance from the
edge of the treatment field and the X-ray energy used.
Since the out-of-field dose is much smaller than the
therapeutic dose, it is generally not recorded in the
patient’s radiotherapy dose documentation. Similarly,
the additional radiation dose outside the field due to
IGRT procedures is also typically not documented. It
should be noted, however, that in some centers, the
MU needed for EPID images is incorporated in the
total treatment plan.
It should be noted that the unwanted radiation
leakage and scatter dose could be decreased by manu-
facturers’ redesign of treatment units, including adding
increased shielding in the primary collimator, treat-
ment head, and removal of the flattening filter (which is
already being done in several RT treatment machines)
(Purdy 2008). Newer techniques such as volumetric
modulated arc therapy (VMAT), in which the number
of MUs needed to deliver a given prescribed dose is
lowered significantly compared to ‘‘conventional’’
IMRT also decreases the leakage dose. In addition, it is
also possible to limit unwanted dose to especially ra-
diocarcinogenic tissues, such as thyroid and breast,
inside irradiated volumes via the IMRT optimization
processes. It will be important for clinical trial QA
centers to capture the whole-body dose data for patients
enrolled in advanced technology clinical trials (Purdy
2008) for the eventual correlation of acute and late-
radiotherapy effects with administered organ doses.
In summary, QA for IMRT techniques is still
evolving. The AAPM TG119 report (Ezzell et al.
2009) provides good insight into IMRT treatment-
planning and dosimetry comparisons. AAPM TG148
report (Langen et al. 2010) provides the practicing
clinical medical physicist the necessary information
to establish an independent and comprehensive QA
512
program for a helical tomotherapy unit, including
examples of tests that can be performed. AAPM TG
142 recommends specific checks of the MLC if IMRT
is performed. In Europe, extensive recommendations
for the QA of IMRT treatments are given in ESTRO
Booklet 9 (Alber et al. 2008).
6 In-Room Imaging
In the past (2D era), portal imaging was focused on
verifying the initial patient set-up, portal aperture
checks, and thereafter weekly check of patient set-up.
Today, with the advent of 3DCRT and IMRT, and
advanced on-board imaging technologies, there is
much more emphasis on daily image guidance for more
accurate treatment delivery. A wide variety of in-room
imaging methods have been developed over the last
decade to ensure more accurate patient setup and target
localization and to facilitate margin reduction as
reported in the AAPM TG 104 Report (AAPM 2009).
It is beyond the scope of this chapter to review all such
systems; hence we will focus on only: (a) megavoltage
(MV) EPID with its own flat-panel image detector and
(b) kilovoltage X-ray system in which a conventional
X-ray tube is mounted on the gantry with an opposing
flat-panel image detector, which provides planar
imaging as well as cone-beam computed tomography
(CBCT) capability for patient positioning. QA
issues for these systems can be separated into the fol-
lowing categories: (1) physical operation and safety,
(2) geometric accuracy (agreement of megavoltage
and kilovoltage beam isocenters), (3) image quality,
(4) image processing and storage, (5) reference image
acquisition, (6) image registration and correction
accuracy, and (7) dose to patient and system stability.
Specific QA requirements for initial and continuing
clinical use of EPID systems are provided by the
AAPM TG 58 report (Herman et al. 2001); specific QA
requirements for initial and continuing clinical use of
kV and MV CBCT systems are provided by articles by
early adopters and by the AAPM TG 104 and TG-142
reports (AAPM 2009; Lehmann et al. 2007; Klein et al.
2009; Jaffray 2002; Pouliot 2005). In addition, ASTRO
and the ACR have jointly published practice guidelines
for IGRT that include QC and QI recommendations
(Potters et al. 2010). A summary of the AAPM TG 142
recommended QA checks for planar and CBCT imag-
ing systems for both non-SRS/SBRT and SRS/SBRT
J. A. Purdy et al.
procedures are listed in Table 10 and several of the tests
are discussed briefly below.
Physical operation and safety checks consider the
physical motions of the imaging system, as well as
patient and operator safety considerations. Interlocks
and bypasses that prevent collisions should be tested
for functionality both during commissioning and
periodically for correct operation.
For the CBCT system, alignment of the isocenters
of the kV imaging beam and the MV treatment beam
is crucial for accurate patient positioning. For
example, in the Elekta Synergy system any possible
flexing that occurs in mechanical components of the
imaging system arms and the accelerator beam arm
at various gantry angles is accounted for using so-
called ‘‘flex maps.’’ The flex maps are lookup tables
used to correct the images of the kV system for
small deviations between the isocenters of the kV
and MV systems, depending on gantry angle. These
maps are initially created after installation of the
system, and they are checked periodically during
scheduled preventive maintenance. A daily QA
procedure to check kV-MV isocenter congruence
and image registration is recommended (Sharpe
et al. 2006); commercial phantoms are available to
maximize efficiency for these checks (see Fig. 12).
In addition, quantitative monthly check of the
agreement of the isocenters is performed using a
ball-bearing phantom supplied by the vendor and
discussed by Lehmann et al. (2007). Figure 13
shows the result of such a test in which a steel ball
aligned to the MV isocenter is re-imaged by the kV
system at all four cardinal angles; based on these
four images, the maximum deviation of the kV
isocenter from the megavoltage isocenter can be
determined.
Image quality checks can be performed using
commercially available phantoms such as the Catphan
phantom (The Phantom Laboratory, Salem, NY) in
which specific cylindrical sections (modules), can be
used for testing both resolution and low-contrast.
Finally, one must be vigilant to potential data
corruption due to problems with transfer of the
reference image from the planning system or CT-
simulator and/or as a result of any storage and
retrieval problems. For example, corruption of simple
‘‘header’’ information such as the patient orientation
(head first/supine or feet first/prone, etc.) could be
disastrous.
Quality Management and Safety in Radiation Oncology
Fig. 12 Penta-guide phantom used for daily check of Elekta synergy IGRT (kV cone beam CT) system
Finally, it should be noted that there are several
non-radiographic imaging systems employed for
localization and monitoring, e.g. a wireless electro-
magnetic localization system (Calypso 4D Locali-
zation System, Calypso Medical, Seattle, WA) used
for localizing the prostate (Balter et al. 2005). While
QA programs for such systems are still evolving,
published reports are beginning to appear and the
reader is referred to the article by Santanam et al.
(2009).
7 Treatment Machine Maintenance
The division of labor between clinical engineering
(CE), IT specialist, and the physics group can be
problematic in a busy RT clinic. An effective QA
program must coordinate all preventive maintenance/
repairs and computer hardware/software upgrades of
the treatment machines and it must be clearly
513
understood that the release of the treatment machine
following any changes bears the final responsibility of
the medical physicist.
CE should absolutely avoid by-passing interlocks
and document clearly any changes made to the unit.
Often unnecessary tweaking (fine tuning) of the
accelerator is done which can put the system into
marginally unstable or erratic operation. This can
cause unnecessary service calls, confusion and delay
in restoring a system to proper operation.
It is important that all groups be kept updated to
new developments and system changes. It is also
imperative that good documentation of testing and
repair, including vendor support, and operator and
staff training is maintained.
The contribution from the vendors to machine
maintenance and repair varies considerably from
country to country, and even from one department to
another within a specific country. It is quite under-
standable that a small department with two treatment
514
Fig. 13 a Ball-bearing phantom consists of a steel ball
(diameter: 8 mm) located at the tip of a long plastic tube,
which is connected to a base plate locked to the Elekta synergy
couch with a set of vernier adjustments that allow 0.01 mm
adjustments in the position of the steel ball. b Kilovoltage
image of the ball-bearing phantom. Steel ball (diameter:
machines of varying age and from different vendors
might very well prefer a different service contract
with the vendors compared to a large department that
can afford the increased staffing of physics, IT, and
CE staff needed to maintain a large number of similar
machines. Apart from the guidelines and manuals
from the vendors, several (inter)national QA/QC
procedures have to be handled with as well.
8 Simulator QA
In modern day RT, CT-simulators have become the
norm and many clinics no longer utilize conventional
X-ray simulators. The AAPM TG 66 report (Mutic
et al. 2003) provides recommendations and guidance
for establishment of a comprehensive QA program for
CT-simulation, including the CT scanner, associated
software, and the CT-simulation process. A list of
recommended tests by this report, frequency of test,
and tolerance criteria is given in Table 13 (Mutic
et al. 2003). For completeness, Table 14 (adapted
from the AAPM’s TG-40 report) lists the recom-
mended QA tests with frequency and tolerance
criteria for conventional X-ray simulators (Kutcher
et al. 1994).
J. A. Purdy et al.
8 mm), which had previously been aligned with the center of
megavoltage beam, is shown relative to the center of a kV
image taken at one of the cardinal angles. Based on four such
images (taken at all four cardinal angles), the maximum
deviation of the kilovoltage isocenter from the megavoltage
isocenter is determined
9 Treatment-Planning System QA
The complexity of treatment-planning systems (TPSs)
continues to increase to facilitate the accurate deliv-
ery of image-based conformal therapy. In a number of
instances, the treatment machine is configured with a
dedicated TPS, often introducing the clinical use of
more than one TPS in the RT department. Rigorous
acceptance and commissioning of the TPS is essential
to ensure it is functioning accurately before it is used
clinically. The TPS, in this respect, is no different
than other medical devices. There are multiple pub-
lications providing detailed information for the com-
missioning and periodic QC/QA testing of TPS,
several of which are referenced here (Bruinvis et al.
2006; Ezzell et al. 2009; Fraass et al. 1998; IAEA
2004; Jacky and White 1990; Mijnheer et al. 2004;
Van Dyk 2008; Van Dyk et al. 1993).
One class of tests consists of a comparison of
treatment plans calculated for standard phantoms to
dose measurements for the same phantoms. Such tests
are recommended because they check the dose
delivered under treatment conditions, but they are
time consuming because of the large number of var-
iable parameters. However, these comparisons will
Quality Management and Safety in Radiation Oncology 515

Table 13 QC/QA tests for CT-simulators (modified from AAPM TG-66)

Frequency/procedure Tolerance limits
Daily
Alignment of gantry lasers with the center of imaging plane ±2 mm
CT number accuracy for water 0 ± 5 HU
Image noise Manufacturer specifications
In plane spatial integrity (x or y direction) ±1 mm
Monthly
Orientation of gantry lasers with respect to imaging plane (or after ±2 mm over the length of laser projection
laser adjustments)
Spacing of lateral wall lasers with respect to lateral gantry lasers and ±2 mm
scan plane (or after laser adjustments)
Orientation of gantry lasers with respect to imaging plane (or after ±2 mm over the length of laser projection
laser adjustments)
Orientation of wall lasers with respect to imaging plane ±2 mm over the length of laser projection
Orientation of the ceiling laser with respect to imaging plane ±2 mm over the length of laser projection
Orientation of CT-scanner tabletop with respect to imaging plane ±2 mm over the length and width of tabletop
Table vertical and longitudinal motion ±1 mm over range of table motion
CT number accuracy for 4–5 different materials ±5 HU
In plane spatial integrity (both x or y direction) ±1 mm
Field uniformity (most commonly used kVp) within ±5 HU
Annually
Table indexing and position ±1 mm over the scan range
Gantry tilt accuracy ±1o over the gantry tilt range
Gantry tilt position accuracy ±1o or ±1 mm from nominal position
Scan localization ±1 mm over the scan range
CT number accuracy (use electron density phantom) ±5 HU
Field uniformity (other used kVp setting) within ±5 HU
Electron density to CT number conversion (or after scanner Consistent with commissioning results and test
calibration) phantom manufacturer specifications
Spatial resolution Manufacturer specifications
Contrast resolution Manufacturer specifications
Patient dose from CT-scan, CTDI (or after major CT-scanner ±20% of manufacturer specifications
component replacement)
X-ray generator tests (kVp, HVL, mAs linearity, mAs reproducibility Manufacturer specifications
time accuracy)
Depending on the goals and prior clinical experience of a particular CT-simulation program, these tests, frequencies, and toler-
ances may be modified by the medical physicist

not only test the system, but will also deepen the users
understanding of the computation models. Further-
more, it may reveal errors in coding of the algorithms
that cannot be obtained directly from dosimetric
measurements. Knöös et al. provide results of tests for
both standard and more advanced calculation algo-
rithms (Knöös et al. 2006).
However, it should be appreciated that all possi-
bilities can never be fully tested, nor can the man-
ufacturer assure the user of a ‘‘bug free’’ system.
Rather, the system should be tested over a range of
parameters which would be typical of those used in
the clinic, with the following items being checked:
(a) consistency of I/O data, (b) monitor units (time)
516 J. A. Purdy et al.

Table 14 QC/QA tests for conventional simulators (modified Tests should always be repeated on the system after
from AAPM TG-40) software version updates. The tests should include a set
Frequency/procedure Tolerance of typical treatment-planning examples which can be
limits compared to the initial acceptance/commissioning test
Daily results. The user should test the operation of the treat-
Localizing lasers 2 mm ment-planning system as a whole, even if only one
Distance indicator (ODI) 2 mm module is modified since changes in one part of the
Monthly code can lead to unexpected results elsewhere. How-
Field size indicator 2 mm
ever, as the complexity and extent of the software has
grown extensively over the last years, testing all aspects
Gantry/collimator angle indicators 1 deg
again might not always be feasible. Therefore, minor
Cross-hair centering 2 mm
software updates, releases, or bug fixes might some-
diameter
times allow less extensive testing. Such tests could be
Focal spot-axis indicator 2 mm
based on release notes and experience of other users
Fluoroscopic image quality Baseline which have performed similar upgrades. In the period
Emergency/collision avoidance Functional immediately following software modifications, clinical
Light/radiation field coincidence 2 mm or physicists should always be extra alert to possible
1% unexpected results.
Film processor sensitometry Baseline Periodic QA tests should be performed on a regular
Annually basis. For example, daily tests of the consistency of I/
Mechanical checks O should be confirmed. Testing of DICOM data
Collimator rotation isocenter 2 mm transfer should be made as part of ‘‘end-to-end’’ tests
diameter between the various systems (e.g. CT, TPS, treatment
Gantry rotation isocenter 2 mm machine, R&V,…). This procedure will often reveal
diameter any nonlinearities and other errors in digitizers and
Couch rotation isocenter 2 mm display systems. In addition, an annual test should be
diameter performed in standard geometries with the beam
Coincidence of collimator, gantry, couch axes 2 mm arrangements used during acceptance tests. These
and isocenter diameter procedures may reveal changes in the way the system
Table top sag 2 mm is used and inadvertent modifications in the treatment-
Vertical travel of couch 2 mm planning programs or beam library.
Radiographic checks The manufacturer should provides full documen-
Exposure rate Baseline tation needed to operate and understand the hardware
Table top exposure with fluoroscopy Baseline
and software components of the system. This
documentation includes, but is not limited to, the
Kvp and mAs calibration Baseline
following: (a) beam data library, (b) description of the
High-and low-contrast resolution Baseline
dose calculation models, (c) procedures for entering
The tolerances mean that the parameter must exceed the tab- patient data and machine parameters into the system,
ulated value (e.g., the measured isocenter under gantry rotation
exceeds 2 mm diameter)
and (d) system test procedures.
The user must have the ability to produce and have
access to the beam data library. The format of this
library, and how to produce and edit it, should be
calculations, (c) relative dose distributions, (d) clearly documented. If beam data are provided by the
graphical data including BEV display and field treatment-planning system manufacturer, the source
apertures, and (e) output data including isodose of the data should be fully documented and carefully
curves, DVHs, and DRRs. The test procedures and checked by independent measurements.
results should be fully documented. They will pro- It is important that the manufacturer provides a
vide basic test data to which further tests can be complete description of the dose calculation models
compared. used in the planning system. The documentation should
Quality Management and Safety in Radiation Oncology
include a description of the expected accuracy of the
dosimetric calculations for various treatment planning
conditions and a discussion of the limitations of the dose
calculation models. Furthermore, it should include a
description of geometry calculations used in the system.
There should be complete documentation on pro-
cedures for entering patient data and machine param-
eters into the system. Equally important is a description
of the definition of the output parameters, such as field
size, and gantry angle. If the coordinate system of the
TPS differs from the treatment system, proper corre-
lation and transformation of coordinate systems should
be established, tested, and documented in written pro-
cedures. In addition, if shifts from the image data center
point of reference to the treatment isocenter are
required, the translations should be clearly defined, and
independently checked before the patient is treated.
The manufacturer should also provide examples
illustrating the use of the system. For example, it should
be clear to the user how the different normalization and
weighting procedures operate. Also important is to
clearly understand and document whether wedge
transmission factors are internally used during the dose
computation process or externally applied by the user
as illustrated by an incident that occurred in a French
radiation oncology department (Peiffert et al. 2007).
Finally, the manufacturer should make available
documentation on their software testing of the treat-
ment-planning system and provide detailed informa-
tion on the error rate discovered in their testing and by
users reporting. The schedule for software upgrading
should also be clearly documented. Furthermore, the
manufacturers should specify their procedures for
documenting and correcting software bugs discovered
in the field.
10 Treatment-Planning QA
When considering QA procedures in treatment plan-
ning one must consider the method of planning being
utilized in their clinic. For convenience, the type of
planning is categorized as follows: (a) Non-graphical
planning, often used for single or parallel-opposed
fields; in this approach, the number of monitor units
(or treatment time for cobalt units) for the prescribed
dose to a point on the central axis is usually calculated
using central axis depth dose or TMR’s and calibra-
tion tables. Furthermore, the apertures for the
517
treatment beams, which define the treatment volume,
are usually determined during (traditional or virtual)
simulation; (b) Traditional 2D graphical planning is
used for many patients; a target volume is defined
from CT or orthogonal simulation films, the patient’s
contour is obtained either mechanically or by using
the CT images, field arrangements including beam
apertures are designed, the dose is prescribed to a
point or an isodose curve, and dose distributions
calculated on a limited number of axial cross sections;
(c) 3D planning where the treating physician (assisted
often by a resident or dosimetrist) defines target vol-
umes, organs at risk volumes, and surface contours
directly on images obtained with CT or MR scans.
The field apertures are defined using beams-eye-view
(BEV) techniques (virtual simulation). Moreover, 3D
TPSs produce DRRs using the CT data set, which are
useful in patient set-up and patient QA conferences.
Doses are evaluated volumetrically using 2D isodose
planes, 3D isodose surfaces, dose-volume histograms
(DVHs), equivalent uniform doses (EUDs), tumor
control probabilities (TCPs), and normal tissue com-
plication probabilities (NTCPs). 3D planning systems
are often used for an advanced form of external beam
RT called ‘‘three-dimensional conformal radiation
therapy (3DCRT)’’ in which the high-dose treated
volume is planned to encompass the PTV, while at the
same time minimizing the dose to the surrounding
organs at risk. It is typically accomplished with a set
of fixed radiation beams, which are shaped using the
projection of the target. The radiation beams typically
have a uniform intensity across the field, or, where
appropriate, have the beam intensity modified by
simple beam modifying devices like wedges or
compensating filters. This type of planning is some-
times referred to as ‘‘forward planning’’ since the
planner defines the beam directions and shapes, beam
weights, wedges, blocks, margins, etc., followed by
dose calculation and then display and evaluation of
the dose distribution. Iteration through the process is
performed manually to reach an optimal (or at least
acceptable) plan; and (d) IMRT planning is an advanced
form of conformal therapy planning in which con-
touring and plan evaluation are similar to the 3D
planning, but uses non-uniform radiation beam inten-
sities incident on the patient that have been determined
using a computer-based optimization technique. This
type of planning is sometimes referred to as ‘‘inverse
planning’’ in that the clinical (i.e., dose-volume
518
constraints) objectives are specified at the beginning of
planning and a computer optimization algorithm is
used to automatically determine beam fluence that will
lead to the desired dose distribution.
Treatment planning should be considered as a
process that begins with patient data acquisition
and continues through graphical planning, plan
implementation/execution, and treatment verification.
It entails interactions between the treatment planners,
radiation oncologists, medical physicists, residents,
and radiation therapists (subsequently referred to
as the treatment-planning team), and uses a large
number of software programs and hardware devices.
Each step of the complex treatment-planning process
consists of a number of issues relevant to QA.
10.1 Patient Positioning, Immobilization
and Data Acquisition
It is important to position the patient such that patient
set-up uncertainties are minimized. Typically this
requires some type of immobilization to ensure
position reproducibility for daily treatment and to
ensure maintaining the patient in a fixed position
during the course of imaging and treatment. A num-
ber of techniques may be used for immobilization;
these vary from taping the patient’s head to the couch
to applying complex body molds.
Conventional simulators, CT, MRI, and ultrasound
are used for acquiring patient external contours and
target and normal organ volumes. There are a number
of additional QA demands placed on imaging units
which are specific to treatment planning (Mutic et al.
2003). Since the patient needs to be repositioned
reproducibly, special couch attachments simulating the
particularities of the treatment machines are necessary.
Immobilizing devices should be constructed so that
they can be attached similar to the CT, MR, or PET
imaging system couches used in obtaining the planning
imaging data as to the couch of the treatment machine
itself. These devices should not only attach and lock to
all couches, but they should also do so in a configurable
method to allow indexing of the devices to the treat-
ment couches for daily reproducibility. In some
instances the composition of these devices is important,
for example, low-atomic number materials are neces-
sary for CT scanners. In addition, patient motion can
distort MRI and CT images and can cause changes in
J. A. Purdy et al.
the linear attenuation coefficients derived from CT.
Furthermore, the position of the patient in the CT
scanning ring can lead to errors in the CT numbers
which are used to derive the linear attenuation coeffi-
cients of the patient. One of the solutions toward
improving reproducibility between the imaging sys-
tems and the treatment machines is to install the same
table top and immobilization devices to all tables in the
department used for planning and treatment delivery.
As previously indicated, CT-simulation has now
become the standard methodology to obtain patient
data (Mutic et al. 2003). However, other imaging
modalities are used in conjunction with CT, particu-
larly MRI, PET, and US. Geometrical accuracy of all
imaging modalities used for this purpose must be
checked. This can be accomplished by imaging suitably
designed phantoms on the various machines and com-
paring the results with the known values. Special care
should be given to MRI units which may suffer from
appreciable spatial distortions. For a number of indi-
cations, this can be solved by simply using only part of
the MRI image set for co-registration with the planning
CT-scan. In addition, for CT, it is necessary to obtain or
confirm the relationship between CT number and
electron density. If a PET-CT is installed, special
attention should be paid to the physical alignment of the
table couch and both imaging rings, as correcting for
deviations with dedicated software always remains
suboptimal compared to optimal physical adjustment.
The transfer of image data routinely occurs directly
via a computer network. Data transfer routines should
be designed to check the integrity of the transfer. Sys-
tematic errors can also occur: for example, an error in
the specification of a scan diameter can lead to geo-
metric distortions of the image. Computer data transfer
systems should be checked on a regular basis. If images
from CT, MR, and/or PET are registered and fused, a
QC/QA program must be implemented to ensure that
the inherent algorithm is used and departmental pro-
cedures are able to produce accurate composite images
for planning (Lavely et al. 2004; Mutic et al. 2001).
10.2 Tumor, Target Volume, and Organ
at Risk Delineation
Many uncertainties in the target volume are clearly
related to uncertainties in the size of the tumor mass
and the extent of the microscopic spread of the
Quality Management and Safety in Radiation Oncology 519

Fig. 14 Inter-observer study of prostatic fossa CTV delineation in clinical practice. CTV delineation performed by five physicians
on the same CT-scan, with the EORTC guidelines clearly mentioned in the study protocol

disease. Therefore, high-quality imaging on treatment

simulators and other imaging devices is essential.
With CT for example, the window level setting can
greatly affect the size of the target volume. The gross
tumor volume including a margin for suspected
microscopic spread constitutes the clinical target
volume (CTV), after which an additional margin
should be included to account for internal motion,
patient motion, and setup uncertainty to obtain the
PTV (ICRU 1993, 1999, 2010). The size of this
margin should be dependent on local experience but is
often based on data from the literature.
Most specialists involved in the process of RT
consider target volume delineation as being currently
the weakest link in the entire chain from treatment
prescription to follow up of the patient after treatment.
A high variation has been seen in all studies evaluating
consistency of delineation of target volumes and organs
at risk among physicians (Gregoire et al. 2000, 2003;
Matzinger et al. 2009; Poortmans et al. 2007; Symon
et al. 2011; van Mourik et al. 2010). It is clear that this
can seriously undermine the precision of conformal RT
planning. To improve this, a number of initiatives have
been undertaken, after which it has been demonstrated
that training as well as the availability of clearly written
guidelines decreases inter- as well as intra-observer
variability. The EORTC Radiation Oncology Group
demonstrated the contouring variability using the
VODCA platform (Medical Software Solutions
http://www.vodca.ch/) for QA in the dummy run
preceding an ongoing trial in post-operative RT for
prostate cancer; (see Figs. 14, 15, 16). ESTRO has put
high priority to offer more online educational and
Fig. 15 Inter-observer study of prostatic fossa CTV delinea-
tion in clinical practice. Superposition of the dummy run
treatment planning from 12 submitting departments on the
consensus PTV. A high variation in the slope of the DVHs can
be seen with the treatment plan submitted by four departments
clearly underdosing the consensus PTV
professional services. Within this perspective, a
multi-functional platform for contouring and delinea-
tion was created. This will also be used to facilitate the
organization of teaching courses and the writing of
internationally accepted guidelines.
Jiang et al. (2008) provides guidance for the
challenges presented by motion-adaptive radiation
therapy including gating, breath holding, and 4D-CT.
Hurkmans et al. reports on the 4D-CT experience in a
multi-institutional trial for SBRT in the treatment of
early-stage non-small-cell lung cancer (Hurkmans
et al. 2011). Notable differences were seen in the 4D-
CT imaging protocols among the centers. However,
the observed deviations in target volumes were
520
Fig. 16 Inter-observer study of prostatic fossa CTV delineation in clinical practice. Outer rectal wall delineation performed by
five physicians on the same CT-scan
generally small, but the report did conclude that steps
to optimize and standardize 4D-CT scanning proto-
cols for SBRT are desirable.
When using a classical simulator, normal organs
are sometimes difficult to localize on plane films.
Procedures should be in place to assure that contrast
agents are used to localize critical organs. For
example, if the small bowel is imaged, pelvic fields
can be individually designed to minimize small
bowel toxicity. Although most internal organs are
imaged on CT with sufficient contrast, it is possible
to improperly define normal organs due to faulty or
incomplete CT procedures. For example, the base of
the brain may be better defined if sagittal recon-
structions are also available. If contrast is used,
density over-rides may be needed before treatment
planning is performed to avoid the erroneous effects
of the high-Z media. Related to this is when high-Z
materials like hip prosthesis are found within the
patient and density over-rides are required to account
for artifacts.
10.3 Designing Beams
In 2D treatment planning, beam apertures are
defined most often using the simulator and simula-
tion radiographs; therefore accurate specification of
the magnification factors is critical. 3D treatment-
planning systems are more complex in that apertures
are defined interactively using BEV computer dis-
plays. In this approach all volumes of interest are
projected onto a plane (usually passing through the
J. A. Purdy et al.
isocenter) along ray lines that originate the source.
Block apertures or MLC leaf settings can be entered
to encompass the projected target. BEV accuracy as
a function of gantry angle, collimator angle, field
size, and isocenter distance must be confirmed
prior to clinical use and checked after any software
modification.
10.4 Dose Calculation and Computation
of Monitor Units
As indicated previously, the accuracy of dose calcu-
lations must be thoroughly examined during the TPS
commissioning process. Periodic checks of calcula-
tions vs measured dose are essential due to possible
data corruptions in the TPS and the accuracy with
which treatment machine parameters such as flatness
and symmetry are maintained. Also, beam normali-
zation points (normally at isocenter) can be prob-
lematic if near non-tissue medium, or under, or near a
MLC leaf edge, and hence, should be moved to a
more suitable location.
The number of monitor units to realize the dose
prescription is typically obtained directly from the
TPS. These values must be independently checked
either by ‘‘hand calculations’’ or by independent
computer calculations. Obviously, any MU check
system must be tested prior to clinical use, and fol-
lowing any change or software upgrade. The AAPM
Task Group 114 report provides valuable information
on the verification of MU calculations for non-IMRT
radiotherapy treatments (Stern et al. 2011).
Quality Management and Safety in Radiation Oncology
10.5 Plan Evaluation
Treatment plan evaluation includes review of the dose
distribution and DVHs. The fidelity of the TPS output
(i.e., display, hard copy, and/or data input into the EMR)
depends upon many factors in addition to just the
accuracy of the dose calculation algorithm. For exam-
ple, non-linearities in the graphical display and/or
plotting systems can lead to distortions in the displayed
patient anatomy and the overlaying dose distributions.
Hence, it is good practice to have fixed length scales
displayed/printed in order to be able to check the geo-
metrical accuracy of the plan output. Furthermore, the
dose distribution calculations can be sensitive to the grid
size, and DVHs can additionally be sensitive to the dose
bin size (Henriquez and Castrillon 2010). All output
data, including those presented in graphical format,
should be regularly checked. As mentioned earlier, plan
evaluation is becoming more cumbersome as treatment
techniques are becoming more complex. This loss of
direct ‘‘clinical feeling’’ of the adequacy of a treatment
plan is being solved by newer means of plan evaluation
including the use of DVHs, Rooms-Eye-Views of dose
surfaces, and the compliance to a list of dose-volume
constraints for target volumes and organs at risk.
10.6 Treatment Plan Review
All treatment plans should be reviewed, signed, and
dated by the treatment planner. The treating physician
should of course also review, approve, and sign the
treatment plan. In addition, all plans should be inde-
pendently checked by an individual who was not
involved directly in the production of the plan prior to
initiation of RT. It should be noted that in some
countries, e.g. the Netherlands, approval of treatment
plans needs to be traceable to a medical physicist, in
addition to the treating physician. The independent
plan check should assure that set-up instructions have
been properly recorded, e.g. field size and gantry
angle. In addition, planning errors may be revealed if
the dose at one point in the plan (preferably at the
isocenter or at the center of the tumor) is indepen-
dently calculated. The dose at the specified point
should be calculated for each field using the pre-
scribed MUs, tabulated TMRs, inverse square factor,
and any other relevant factors. An action level should
be established based upon the accuracy of the
521
computer algorithm and independent dose calculation
procedure. As previously indicated, IMRT plans
require additional checks including review of; opti-
mization parameters, minimum gap size, minimum
MU/segment, and maximum doses in and outside of
the target. In addition, in the US the patient’s plan
must undergo phantom measurement checks on the
intended treatment machine to verify both point dose
and spatial dose distribution agreement.
10.7 Plan Implementation
and Verification
It is important to check that all treatment plan parame-
ters are properly implemented. This can be best
accomplished by having the treatment-planning team
available (or on call) during the first day set-up so that
any detected ambiguities or problems can be addressed
immediately. Localization (portal) images should be
reviewed by the radiation oncologist or the radiation
therapist and, when necessary, in conjunction with a
treatment planner. Special care should be taken to
ensure that all beam modifying devices are correctly
positioned. Although errors in MLC settings, or
block fabrication/mounting should be observed when
reviewing the portal images, wedge or compensator
misalignment is much more problematic, and may only
be revealed by careful observation during patient set-up.
A V&R system should be used to assure that the same
parameters (within tolerance limits) are used each
day. Such systems are valuable for the verification
and recording of at least the following parameters: (a)
monitor units, (b) energy, (c) mode, (d) collimator
settings (including independent jaws and multileaf col-
limator), (e) collimator angle, (f) gantry angle, (g) table
position, and (h) wedge number and orientation.
However, V&R systems must be used with care since
they can give the user a false sense of security. For
example, if a set-up error is made on the first day and the
machine geometry parameters are captured, the system
will faithfully verify this erroneous setting from day to
day. To reduce the chance of this occurring, the patient
should be carefully set-up according to the treatment
plan (best if there is a direct electronic transfer of plan
parameters to the V&R system); a robust P&P for
approval of patient treatment position should be in place
(e.g. several of the authors require a double-check ver-
ification of this critical step); upon approval the
522
parameters are captured with the V&R system. One
report by Patton et al showed propagation of errors
where pretreatment checks of the V&R data entry were
not performed (Patton et al. 2003). Another study by
Klein et al. examined the frequency, longevity, and
dosimetric impact of errors in a process where V&R
entries were checked pre-treatment (Klein et al. 2005).
Today, as vendor implementation of DICOM data
exchange has matured significantly, the direct transfer of
data from the TPS to the V&R system has undoubtedly
reduced such errors; however a careful check of patient
position is still recommended.
Thermoluminescent dosimeters (TLD), diodes, and
MOSFET detectors are often used for in vivo dosimetry
because they are small and relatively easy to calibrate;
diodes, unlike TLD, have instantaneous read-out
(AAPM 2005). This is useful, since if an error is
observed, the treatment can be immediately discontin-
ued and the source of the error traced. However, diodes
are more difficult to calibrate than TLDs since their
readings depend upon dose rate, beam direction, beam
energy, and temperature. In vivo dosimetry is usually
used in the United States for checking the dose for
unusual treatment conditions or for critical structures in
or near the treatment volume. However, Leunens has
used in vivo dosimetry on a more systematic basis and
has demonstrated that systematic errors in treatment
techniques can be identified with a carefully controlled
in vivo diode dosimetry system (Leunens et al. 1990).
More recently, exit portal dosimetry using EPIDs has
been demonstrated to provide full-field information,
even for IMRT fields (Kruse 2010; Mans et al. 2010).
And finally, implantable dosimeters are now being used
for real-time dosimetry (Black et al. 2005).
11 Clinical Aspects of QA
The clinical aspects of QA refer here to new patient
planning, EMR or paper chart review, portal image
review and reporting, analyzing and discussing of
incidents in the RT departments.
11.1 Planning Conference
One of the most important components of a QA
program is the establishment of a Planning Confer-
ence that is attended by radiation oncologists, medical
J. A. Purdy et al.
physicists, radiation therapists, and dosimetrists.
During a patient planning conference, the pertinent
medical history, physical, pathology, and diagnostic-
imaging findings along with the tumor staging and
proposed plan of treatment, including the prescrip-
tion, should be presented by the attending radiation
oncologists or residents. Ideally, all patients seen in
consultation should be discussed, although this may
not always be practical. The background information
presented in a planning conference is important for
the treatment planner since significant medical prob-
lems or prior radiotherapy in the past as well as
intended surgery or chemotherapy will all have an
influence on the design of the treatment plan. In
addition, this information is important for the radia-
tion therapist, since it may influence scheduling, and
the requirements for set-up and treatment.
11.2 Chart Review
The items recorded in the radiation oncology
chart/EMR (Table 15) are reviewed by a number of
individuals at different times during the patient’s
treatment. For example, the radiation therapist usually
refers to the chart (paper and/or electronic) on a daily
basis, and errors are not infrequently discovered by
the therapist during this daily routine. Furthermore,
radiation oncologists refer to the chart on a frequent
basis, especially during medical examinations during
the course of treatment. Given the complexity of
modern day radiotherapy, and the great differences in
functioning of various departments, it is not possible to
define when and where each item in a chart should be
reviewed. However, it is necessary for each depart-
ment’s QMC to recommend and implement a program
which clearly and unambiguously defines: (a) which
items are to be reviewed; (b) who is to review them; (c)
when they are to be reviewed; and (d) what actions are
to be taken in the event of an error.
The frequency of these checks varies between
institutions, but charts should probably be reviewed
on a weekly basis by the medical physicist and
the radiation oncologist. In some departments a
review of this type occurs during weekly port
film conference, in others during special chart
review sessions. Many centers have automated the
port film match and set-up correction procedure
using well-established set-up correction protocols
Quality Management and Safety in Radiation Oncology
Table 15 Suggested components of RT patient treatment
record/electron medical record
Suggested items to include
Patient name, ID number, photograph
Consent form
Medical background (diagnosis (pathology report), stage,
etc.)
Physician orders (ongoing medical tests during treatment)
Nursing reports
Simulation request form (patient setup parameters)
Prescription (total dose, dose per fraction)
Treatment plan
Treatment field documentation (field photographs, portal
films/images)
Monitor unit (time) calculations check
Total cumulative dose (PTV and organs at risk)
Medical progress notes
Treatment verification films/images
Special quality assurance documentation (e.g. In vivo
dosimetry reports and pacemaker evaluation)
(de Boer and Heijmen 2001, 2007), making port
film conferences obsolete. The extent of a weekly
check depends, in part, on the functioning of the
department and the rate and extent of other reviews
and checks of the treatment chart. If information
resides in both the paper and the electronic charts,
they both should be reviewed simultaneously for
consistency and accuracy. If a clinic relies primarily
or exclusively on an electronic record, it is imper-
ative that a backup plan be in place in the event
that the server or the network puts the electronic
environment in a non-functioning mode. During this
weekly review, typical treatment plan items that
should also be reviewed are listed in Table 16.
11.3 Port Film/Image Verification Review
In general, two types of portal imaging techniques
were commonly used to assess radiation field
position and target volume coverage, namely, (sin-
gle or double exposure) verification images taken
prior to treatment or continuous during the entire
delivery of a given field. With the first option,
imaging mostly assesses the position of the patient
523
Table 16 Suggested treatment plan review
Items to check
Data consistency (e.g. prescribed dose is same as dose used to
calculate monitor units)
Integrity of acquired images
Graphical treatment plan
Monitor unit (time) calculation
Treatment record (e.g. monitor units and graphical plan
parameters are properly transferred to chart and record and
verify system)
Digitally reconstructed radiographs noting isocenter
Shift information, if applicable
Critical doses (e.g. the cord dose is correctly calculated and
recorded)
Matching fields (e.g. field gaps are correctly calculated and
implemented)
Potential overdoses (e.g. prior treatment of the areas currently
irradiated)
Cumulative tumor and other specified doses
over a time interval much shorter than the treat-
ment, and therefore does not assess the effect of
patient motion during treatment. Another difficulty
is that, although the dose per portal field is low
(less than 5 cGy), it represents an additional dose to
the patient, particularly if a significant number of
images are needed. In such case, the additional dose
should be accounted for in the treatment plan. To
enhance the interpretation, a double exposure tech-
nique can be used in which an image of the treat-
ment field is superimposed on a larger image that
contains more anatomical structures for appropriate
comparison with the simulator X-ray. Verification
images that image the entire radiation delivery for
each field are a record of what occurred during
treatment, including motion of the patient and the
presence of radiation field modifiers. However, it is
generally more difficult to analyze these films due
to less inherent contrast, patient motion, field
modifiers, and the limited view of the anatomy.
On-line EPIDs have now become common place
and provide improved patient imaging before and
during treatment (Herman et al. 2001). Results are
now available on a video monitor within seconds,
making review of the radiation fields more expedi-
tious. This makes it possible to obtain images of the
patient on a more frequent basis. Furthermore, these
524
devices are capable of enhancing images and
improving bony landmark contrast.
With the continuing implementation of even
more advanced on-board imaging and other data
localization systems (i.e., ultrasound, video surfacing,
static kV imaging, kV cone-beam CT, MV helical
CT, and MV cone-beam CT) and the progressive use
of (implanted) markers for image guidance, clinical
workflow processes must be clearly established with
emphasis on a quality streamline review process.
Clear Policy and Procedures (P&Ps) should be in
place as to: (a) localization procedures, (b) therapists
instructions and tolerance criteria to move (or not
move) a patient, (c) whether post imaging is required
when a move is made, (d) subsequent reviews by
physicians, and (e) the process for peer review of
verification images.
11.4 Review of Incidents in the Radiation
Therapy Department
Several models do exist for safe reporting of incidents
related to patient care. The incidents can vary sub-
stantially in type and severity ranging from giving a
wrong appointment time to the patient to an error in
dose calculation or machine malfunctioning. Locally,
the QMC discussed earlier (involving at least one
member of each of the groups that make up the RT
team) regularly evaluates and classifies the reported
events. Based on the QMC review, suggestions for
improvement are made. In case of a (possibly) serious
event, immediate measures are always required.
In the US reporting of RT incidents outside the
institution is primarily through state and federal regu-
latory agencies such as the Nuclear Regulatory
Commission (www.nrc.gov) although there is growing
interest in the anonymous voluntary reporting of mis-
takes and equipment failures (Hendee and Herman
2011; Williamson et al. 2008). Several authors have
pointed out the value of incident reporting that includes
near-misses (Clark et al. 2010; Mutic et al. 2010).
Internationally, much more progress in this area has
already been made. In 2001, a voluntary web-based
safety information database for RT called ROSIS
(Radiation Oncology Safety Information System) was
established under the auspices of ESTRO, and has
successfully established an international voluntary
incident and near-incident reporting system, a
J. A. Purdy et al.
supporting website (http://www.rosis.info/index.php),
and an annual teaching course on patient safety in
radiation oncology. In addition, in the Netherlands, the
PRISMA-RT (Prevention, Recovery and Information
System for Monitoring and Analysis in RadioTherapy)
model (http://www.prisma-rt.nl/index.htm) is used by
the majority of the RT departments, after which it can
be used for mutual exchange of experiences and
benchmarking.
12 Summary
It should be clear from the previous sections that radi-
ation oncology is facing a new set of QC/QA challenges
as computer-controlled machines and related high-tech
ancillary devices are now the standard of care. To meet
these challenges, first and foremost it is essential that
radiation oncology departments strive toward estab-
lishing a safety-conscious culture and do all that they
can to ensure that processes for safe planning and
delivery of RT are in place and appropriately resourced.
To that end, Hendee and Herman recommend that the
RT team work under a radiation safety covenant, and
that each member of the team pledge a commitment to
protect the safety of each and every patient (Hendee and
Herman 2011). Key to such a safety culture is the
understanding that any member of the RT team has the
responsibility to declare a ‘‘time out’’ if he/she has
concerns or questions about the plan or course of
treatment for a patient.
The increased time demands and continuing chan-
ges in workflow caused by the new technologies
require that staffing levels be adjusted to ensure that the
staffing levels and skills mix are appropriate for the
numbers of patients treated and the complexity of
treatments delivered, particularly in physics and treat-
ment planning. This does require considerable effort in
educating hospital administrators regarding the new
treatment complexities and their need for increased
staff and QC/QA equipment; similarly referring phy-
sicians need education about the increased time needed
to start a patient’s radiotherapy treatment. No doubt
rushing the plan and/or attempting short-cuts/work-
arounds increases the potential for serious error.
Making sure that departments are adequately resourced
has given new credence to requiring departments to be
accredited (e.g. accreditation by the ACR/ASTRO in
the US or by NIAZ in the Netherlands and Belgium).
Quality Management and Safety in Radiation Oncology
The introduction of new techniques needs to be
carefully planned with thorough risk assessment,
along with review of staffing levels and skills
required. All staff involved in the process should
undergo specific training in the new treatment tech-
nique or process prior to clinical use. Training records
should be created and maintained for all staff involved
in RT. They should be detailed and specific to par-
ticular procedures, i.e., credentialing. Funding to
support training and continuing should be available,
particularly when new techniques are introduced.
Other key areas include participation in periodic
audits of the treatment machine calibrations by an inde-
pendent source. This is even more important when new
modalities such as SBRT are implemented. Equally
important is the commitment to ensure that all P&Ps
including pertinent checklists be reviewed and updated as
needed, and periodically not less than annually. The
usefulness of checklists in a medical environment has
once again been pointed out in the recent book by
Gawande (2009); similarly, the editors of this textbook
strongly recommend their use in RT, particularly with
advanced modalities such as SRS, SBRT, TBI, and HDR.
Because of the complexity of RT and the large
number of hand-offs and interdependent tasks, it is
essential that the department facilitates and strengthens
the communication between team members. Suggested
methods to accomplish this include daily morning
meetings with representatives from all groups to review
new patient CT-simulations and status of new patients’
treatment planning. Such meetings are supplemented
with weekly Chart Rounds dedicated to peer-review QA,
and weekly Treatment-Planning conferences in which
completed plans are presented for teaching purposes and
peer-review QA. Lastly, the authors recommend holding
periodic departmental-wide ‘‘Town Hall’’ type meetings
focusing on the quality and safety programs and the need
for optimum teamwork. All such efforts to improve
communications will help achieve the right balance
between both accountability and openness in the
department’s safety culture for reporting of incidents.
While the past prescriptive QC/QA programs have
been effective in RT, they can no longer keep up with the
pace and complexity of the new technology implemen-
tation. Hence, these programs should be continually
evaluated to ensure that each specific QC/QA test adds
value and those that do not should be eliminated. The
prescriptive QC/QA program should be complemented
with systematic risk analysis and improvement efforts
525
using industrial engineering-based tools such as process
mapping, FMEA, and FTA for all advanced treatment
modalities (Ford et al. 2009; Huq et al. 2008; Pawlicki
et al. 2011; Pawlicki and Mundt 2007).
Vendors can help address the new QA challenges
by improving the design of the interfaces between the
user and the planning and treatment machine con-
soles. This holds particularly true for the treatment
machine, where the interfaces are typically an add-on
of new features requiring the therapist to interact with
multiple workstations and keyboards. Lack of stan-
dard nomenclature is also an issue to some degree.
Departments must ensure that the working environ-
ment is such that staff can work without inappropriate
interruptions and any clutter is minimized.
13 Conclusion
There is no doubt that the use of computer-controlled
medical linear accelerators and the associated high-
tech planning and ancillary devices are advancing the
state-of-the-art in RT by providing the opportunity
for more sophisticated treatments. However, it must
be stressed that the radiation oncology team must be
constantly vigilant because no computer system can
fully compensate for a team member’s error in judg-
ment, misunderstanding of physical concepts or
technological limitations, or for unsatisfactory plan-
ning and delivery of RT.
The department must maintain a strong commit-
ment to a culture of quality and safety and require the
active participation of physicians, medical physicists,
dosimetrists, radiation therapists, IT specialists and
electronic and mechanical maintenance specialists in
the QM program. Most importantly, the administra-
tion must have a strong commitment to adequate
staffing, continuing education, and the implementa-
tion of any needed safety and QA devices.
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 Quality Assurance for Multi-Institutional
Clinical Trials
James A. Purdy and Philip M. Poortmans

Contents
1 Introduction.............................................................. 532
2 Clinical Trial Radiation Therapy Quality
Assurance Organizations ........................................ 532
3 Requirements for Exchange of Digital Data ........ 533
4 QA Centers: Informatics Infrastructure
Requirements............................................................ 534
5 Credentialing ............................................................ 536
5.1 General Credentialing................................................ 537
5.2 Advanced Credentialing ............................................ 539
6 Individual Case Review .......................................... 542
7 Data Analysis............................................................ 543
8 Considerations for the Future................................ 544
References.......................................................................... 546
J. A. Purdy (&)
Department of Radiation Oncology,
University of California Davis Medical Center,
Sacramento, CA 95817, USA
e-mail: james.purdy@ucdmc.ucdavis.edu
P. M. Poortmans
Department of Radiation Oncology,
Institute Verbeeten, Tilburg, The Netherlands
Abstract
The need for specific quality assurance (QA)
activities in the framework of clinical trials is
continually increasing as the technical require-
ments needed for optimal radiation oncology
continue to evolve and to become more demand-
ing as new technologies continue to be devel-
oped and implemented at a progressively higher
rate. The need for exchange of digital data
allowing the evaluation of volume delineation
and dose-volume parameters and enabling the
linking of these QA parameters to the clinical
outcome has led to the development of dedicated
technical platforms and software for clinical
trials QA. All of these developments present
credentialing and QA challenges for cooperative
groups and clinical trial QA centers. The level of
appropriate QA in clinical trials is highly
dependent on the complexity of the trial. It
should be evidence based; by doing this, efficient
QA in clinical trials will improve the overall
quality of treatment for most patients at an
acceptable cost. It is also apparent that clinical
trials are becoming much more multicenter,
multidisciplinary and international, thereby not
only giving additional relevance to the already
stringent demands for QA but also putting
forward the critically important issue of harmo-
nization of clinical trials credentialing and QA
procedures. This chapter will address all these
issues focusing primarily on the United States
and European clinical trial QA experience.

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 531
DOI: 10.1007/174_2011_324,  Springer-Verlag Berlin Heidelberg 2012
532
1 Introduction
Radiation therapy treatment planning and delivery
processes have changed dramatically since the intro-
duction of three-dimensional treatment planning in
the 1980s and continue to change in response to
the implementation of new technologies (Purdy
1996, 2007). CT-simulation and image-based three-
dimensional radiation treatment planning systems
(3DTPS) provide the tools for carrying out three-
dimensional conformal radiation therapy (3DCRT),
which is now routinely used in clinical trials as well
as in daily practice. Intensity modulated radiation
therapy (IMRT) (Webb 2000) techniques provide
highly conformal target volume coverage for even the
most complex shapes, and conformal avoidance of
specific sensitive normal structures and its use in
clinical trials is ever increasing. Daily execution of
these complex beam set-ups is facilitated by the
development of semi-automated sequential delivery
of the numerous beams typically required for these
advanced treatment modalities. The introduction of
these complex and sensitive procedures into daily
clinical use requires a new approach towards quality
assurance (QA) in the clinic and in the conduct of
clinical trials QA (Purdy 2008; Purdy et al. 2011;
Williamson et al. 1981). In 2004, National Cancer
Institute (NCI) guidelines for use of IMRT in clinical
trials were developed (Palta et al. 2004).
The increasingly conformal doses provided by
IMRT and stereotactic body radiation therapy (SBRT)
and the introduction of smaller safety margins to limit
the dose to the surrounding organs at risk have
focused attention on the need to better account for
both intrafraction and interfraction variation in patient
positioning and in the change of the shape and posi-
tion of the tumor and internal organs. This has helped
spark the development of treatment machines with
integrated planar and volumetric imaging capabilities
as well as tracking devices for accurate real-time
position verification of the implanted volume (Jaffray
et al. 2002; Shchory et al. 2010; Willoughby et al.
2006). Technological advances continue to occur at a
rapid rate and are pushing radiation oncology towards
a new era of highly focused image-guided RT (IGRT)
and eventually adaptive RT (ART) (Bortfeld et al.
2006; Martinez et al. 2001).
J. A. Purdy and P. M. Poortmans
All these techniques show the potential for signifi-
cantly improving the ability to optimize the radiation
dose received by the tumor and target tissues while
minimizing the dose (and possibilities of toxicity) to
nearby normal tissues, and thus have been rapidly and
widely integrated into clinical trials. However, as
previously stated, these advanced technologies present
significant QA challenges for clinical trial groups and
their associated QA centers. In addition, many modern
clinical trials are becoming much more multicenter,
multidisciplinary, and international, thereby adding
even more layers to the already beleaguered clinical
trial RTQA process.
Such developments are focusing attention on the
critically important issue of harmonization of QA
procedures of clinical trials worldwide. In this regard,
discussions are underway between the cooperative
group QA centers listed in Table 1 (and discussed in
detail in the following section) regarding credential-
ing requirements and processes for the exchange and
evaluation of the digital data needed to evaluate
volume delineation and dose–volume parameters.
Agreement on these harmonization issues is urgently
needed for some clinical trial studies in order to
achieve sufficient patient accrual for the required
statistical power in a timely manner.
2 Clinical Trial Radiation Therapy
Quality Assurance Organizations
Publications describing the radiation therapy quality
assurance (RTQA) programs for clinical trials are
available (FitzGerald et al. 2008a; Ibbott et al. 2008;
Poortmans et al. 2005; Purdy 2008). For the purpose
of this book, we will focus mostly on the clinical trial
organizations and RTQA centers listed in Table 1
which include: (1) Image-guided Therapy QA Center
(ITC) located at Washington University in St. Louis
(WUSTL); (2) Radiological Physics Center (RPC)
administered through the M.D. Anderson Cancer
Center (MDACC); (3) Quality Assurance Review
Center (QARC) administered through the University
of Massachusetts; (4) Radiation Therapy Oncology
Group (RTOG)-RTQA section located in Philadel-
phia, and (5) European Organization for Research and
Treatment of Cancer Radiation Oncology Group
(EORTC-ROG).
QA of Clinical Trials
Table 1 Clinical trials quality assurance centers/groups
Cooperative group quality assurance centers Year
established
Radiological Physics Center (RPC) 1968
Radiation Therapy Oncology Group (RTOG)– 1971
RTQA Group
Quality Assurance Review Center (QARC) 1980
European Organization for Research and 1982
Treatment of Cancer-Radiation Oncology Group
(EORTC-ROG)
Image-guided Therapy QA Center (ITC); 1994
Originally called RTOG 3DQA Center
Advanced Technology Consortium for Clinical 1999
Trials QA (ATC)
EqualEstro 2004
From a historical viewpoint, it should also be
mentioned that EqualEstro was founded in 2004 thanks
to an EU grant to the European Society for Therapeutic
Radiology and Oncology (ESTRO). Its mission is to
provide QA solutions for all existing radiation therapy
techniques. It was reorganised later as an independent
provider for QA for clinical trials in radiation oncology
(http://www.equalestro.org). Currently, it is support-
ing a number of clinical trials in Europe and the US and
will not be discussed further in this chapter.
These QA programs have helped to ensure that
institutions participating in clinical trials deliver the
prescribed radiation doses that are clinically compa-
rable and consistent. Specifically, they have helped to
improve compliance with protocols, reduced minor
and major deviations, identified misunderstanding and
misinterpretation in protocols, and detected system-
atic errors in the participating institution’s clinical
practice. While most believe that these endeavors
have benefited clinical trials, there is relatively little
evidence in the published literature supporting the
533
Current mission
Assure NCI and the cooperative groups that institutions
participating in clinical trials deliver prescribed radiation
doses that are clinically comparable and consistent
Provides QA for member institutions’ participation in
RTOG clinical trials
Provides services to multiple cooperative groups in support
of cancer clinical trials to improve the standards of care in
the management of cancer by improving the quality of
clinical trials medicine
Provides QA for member centers of the EORTC
Provides software tools and data management services to
multiple cooperative groups in support of QA for advanced-
technology radiation oncology clinical trials
Serves as the administrative core of the NCI-sponsored ATC
A consortium of US QA Centers that include the ITC,
RTOG, RPC, and QARC, and which capitalizes on the
existing infrastructure and strengths of these national QA
programs
Facilitate and support NCI-sponsored advanced technology
clinical trials, particularly those requiring digital data
submission
Provides customers with a full range of services and
products in quality control within the specific field of
radiation oncology
value of trial specific QAs (Bentzen et al. 2000;
Pettersen et al. 2008; Poortmans et al. 2001). Often
under-appreciated though is the indirect improvement
in the quality of patient care at participating institu-
tions via the training and education of personnel in
safe implementation of new methodologies and
techniques in radiation therapy that comes with par-
ticipation in clinical trials.
3 Requirements for Exchange
of Digital Data
Institutions planning to participate in advanced tech-
nology clinical trials utilizing 3DCRT, IMRT, SBRT,
SRS, brachytherapy, and particle beams should be
able to submit the volumetric treatment planning and
verification data electronically to an RTQA center.
Films and other forms of hardcopy data are simply not
adequate for evaluating target volumes and 3D-dose
distributions. In addition, DVH data alone are not
534 J. A. Purdy and P. M. Poortmans

Fig. 1 Schematic depicting

of the ITC informatics
Data Secondary
infrastructure referred to as Analysis
Submission
the QuASA2R system, which Participating St. Louis
Data Integrity
has been in use since the Institution ITC QA Tools Researcher
mid-1990s and provides an 1
RTOG/
environment in which Treatment DICOM
Treatment Data
institutions can submit, Planning Planning Exchange Researcher
System System Export 2
and ITC can receive, Files
share, review, and analyze RTOG /
DICOM /
CERR
protocol-specific volumetric DICOM SFTP (Matlab)
CERR
multimodality ITPV digital Data
(SSH2) Secure
RTOG/ Format
NBIA /
FTP caBIG TB
data (Courtesy of Image- Submission DICOM RRT TPS Conv.
Workstation Server Web Citrix
guided therapy QA center) Medi Data
Server Server
SFTP Client/ a Import CERR
DICOMpiler HTTPS HTTPS (Matlab)

External QA
Review
Study Chairs,
QA Centers
Commercial
RRT TPS CERR

sufficient as there is no spatial information provided
and the dose fractionation information is lost. Clearly,
variation in dose distributions throughout an organ
may lead to different expectations of toxicity for some
organs. In addition, the volumetric treatment planning
database resulting from a digital data submission
process (that can be linked to clinical outcomes) will
be a significant resource for secondary analyses and
further development of robust dose-response models
(Purdy et al. 1998).
Today, digital data exchange has become almost a
non-issue for conducting clinical trials as the RTOG
data exchange (RDE) (Bosch et al. 1997; Harms Sr
et al. 1997) and digital imaging and communications
in medicine (DICOM)-RT export features have been
implemented on most treatment planning systems
(DICOM 2000). A current list of treatment planning
systems that are both RDE and DICOM compliant
with the ATC members per modality is given on the
ATC website (http://atc.wustl.edu/credentialing/atc_
compliant_tps.html).
Progress will continue to be made toward
improved interoperability by DICOM WG-7 and by
the Integrating the Healthcare Enterprise-Radiation
Oncology (IHE-RO) initiative shared by healthcare
professionals and the industry to improve the
way computer systems in healthcare share informa-
tion (http://www.ihe.net/). This effort promotes the
use of established standards such as DICOM and HL7
to address specific clinical needs in support of optimal
patient care. Systems developed in accordance with
IHE communicate with one another better, are easier
to implement, and enable care providers to use
information more effectively. The IHE-RO interop-
erability profiles in the 2007 (RT objects) and 2008
(image registration) technical frameworks are helping
make DICOM exports from commercial TP systems
more consistent and eventually facilitate the use of
more commercial softwares for clinical QA trials.
4 QA Centers: Informatics
Infrastructure Requirements
There are several computer software (or multi-
component) systems developed and in use by RTQA
centers that can receive and process imaging and RT
digital data objects for protocol patients and allow for
remote individual case reviews. They will be briefly
discussed in the following paragraph. The authors
stress that without such software systems, it is not
possible to perform case RTQA at an international
acceptable level.
The ITC informatics infrastructure was the first
such system developed for clinical trial RTQA that
required digital data submission and is referred to as
the quality assurance submission, archive, analysis,
and review (QuASA2R) system (Fig. 1). It provides an
environment in which institutions can submit, and ITC
can receive, archive, and review/analyze protocol-
QA of Clinical Trials 535

Fig. 2 a QuASA2R WWW-based RRT that allows desig- dose–volume histograms, including dose–volume statistics;
nated individual to review target volume and organs-at-risk b RRT’s interactive dose–volume histogram evaluation display
contours, selected isodoses overlaid on axial CT images, and (Courtesy of Image-guided therapy QA center)

Fig. 3 Commercial software

packages including treatment
planning systems are
available for protocol
reviewers via QuASA2R
Citrix server and provide
additional QA review tools
including image registration.
Shown is a MIMvista display
of a head and neck cancer
data set (PET fused to
planning CT with dose
displayed) (Courtesy of
image-guided therapy QA
center)

specific volumetric multimodality imaging/treatment
planning/verification (ITPV) digital data (Bosch et al.
2000, 2006, 2007; Purdy et al. 1996, 1998, 2006). The
system is fully RDE and DICOM compliant and sup-
ports data submission that includes CT images, RT
structures, beam geometry, 3D-dose distributions,
DVHs, digital reconstructed radiographs (DRRs), and
verification images. Moreover, it provides fully
remote review via QuASA2R’s web-based Remote
Review Tool (RRT) as shown in Fig. 2a, b. and if
needed using commercial planning/review systems via
its QuASA2R’s Citrix server (Fig. 3).
Another software system developed at WUSTL
called Computational Environment for Radiation
Therapy Research (CERR, Deasy et al. 2003), has been
integrated into the QuASA2R system (Fig. 4) as well
as QARC’s clinical trials workflow and database sys-
tem, referred to as MAX (FitzGerald et al. 2008b).
CERR provides multi-axis review of images and many
other features that enhance the case review process.
536 J. A. Purdy and P. M. Poortmans

Fig. 4 Display of CERR

software system (CERR,
Deasy et al. 2003), which has
been integrated into the
QuASA2R system to support a
gynecological trial that
requires review of patient’s
contours from two different
fused CT imaging studies
(one with bladder full and one
with bladder empty). System
allows simultaneous remote
review by two different
reviewers located at different
centers (Courtesy of Image-
guided Therapy QA center)

More recently, the RTOG has created a core lab
(http://www.rtog.org/CoreLab.aspx) so that digital
data can flow directly to them, rather than through the
ITC, if so desired using the ACR developed TRIAD-
QA system. Details on that system are available at the
ACR webpage (https://triad.acr.org/index.htm).
EORTC Headquarters has implemented the visu-
alization and organization of data for cancer analysis
(VODCA) system developed by Stefano Gianolini
and Daniele Henggeler. The VODCA system was
first used in the framework of a number of UK trials and
is now available commercially from Medical Software
Solutions, Switzerland (http://www.vodca.ch). It pro-
vides review features similar to the QuASA2R system
discussed above.
More recently, an EORTC Imaging Platform has
also been set up in conjunction with VODCA to allow
exchange and central review of diagnostic images
coming from patients treated in EORTC clinical tri-
als. The platform uses the standard internet transfer
and tools in order to bypass firewall issues in hospitals
and avoid the need for installing software in an
uncontrolled IT environment, and various levels of
access rights can be implemented.
The informatics infrastructure of the QART plat-
form of the EORTC-ROG is depicted in Fig. 5a, b, c.
The data flow used for the QA evaluation using this
system is shown in Fig. 6. Images are automatically
available to designated reviewers, and reviewing tools
are available to process the images from various
modalities. The patient’s clinical data is available to
the reviewer within the same environment as the
image. The reviewer is able to report the result of his
reading on a central reading form, and his conclusions
are stored with the clinical data. The EORTC imaging
and radiation oncology groups plan to cooperate on
imaging in radiotherapy.
For completeness, one other clinical trial QA sys-
tem (called the SWAN system) should be referenced.
It was developed by Martin Ebert and colleagues and
is used to support Trans–Tasman radiation oncology
group (TROG) clinical trials (Ebert et al. 2008).
5 Credentialing
Prior to participation in any RT clinical trial utilizing
advanced technologies, certain credentialing require-
ments must be met by the institution. The creden-
tialing can be broken down into two levels: (a)
general credentialing typically used for all RT clinical
trials, and (b) a trial specific credentialing process
used for more complex trials utilizing advanced
technologies.
QA of Clinical Trials
Fig. 5 The 2010 structure of the QART platform of the
EORTC-ROG. a General overview, b intermediate detailed
plan, c in-depth detailed structure (Courtesy of Akos Gulyban,
EORTC QA manager 2009–2010)
5.1 General Credentialing
The general credentialing mainly aims to ensure that
basic RT quality is available at a participating insti-
tution. It consists of: (1) facility questionnaire (FQ)
that provides detailed information about equipment
and human resources available at the institution, and
(2) a check of output measurements under reference
537
Fig. 6 Data flow of the QA evaluation performed at the
EORTC HQ (Courtesy of Akos Gulyban, EORTC QA manager
2009–2010)
conditions that provide reassurance that beam cali-
bration is within the internationally accepted stan-
dards. This is now referred to as an external reference
dosimetry audit (ERDA).
5.1.1 Facility Questionnaire
The most basic credentialing requirement is to
complete and submit a FQ to the protocol’s associ-
ated QA center. The information contained in the
questionnaire typically includes: (a) staffing infor-
mation and contact information for the responsible
individuals (physician, physicist, dosimetrist/radia-
tion technologist, and data manager) who will be
working on the clinical trial to enable RTQA center
personnel to contact the appropriate individual as
needed in the credentialing and trial participation
review process, (b) a list of the therapy machines to
be used for the treatment of patients enrolled in the
study, (c) documentation of the infrastructure avail-
able for data acquisition/imaging for treatment
preparation, the image-based planning system, and
other pertinent information depending on the proto-
col and modality used such as patient motion
management systems.
Currently, each clinical trial group/QA center has
developed its own FQ with little regard for the
repetitive effort thrust on an institution participating
in multiple trial groups. In the US, FQ harmonization
is already underway through ATC efforts, but the
process is very slow. When possible, international
harmonization is recommended by the authors. It
should also be noted that for some inter-group trials,
538
Table 2 Summary of actual and proposed new requirements on infrastructure, staffing, and workload for the EORTC. (From
Budiharto et al. 2008)
Human resources: workload
Number of FTE radiation oncologists per department
Number of patients treated per year/FTE radiation oncologist
Number of FTE qualified radiation physicists per department
Number of patients treated per year/FTE radiation physicist
Number of radiation technologists per treatment unit
Equipment: numbers
Simulator (classical and/or CT-scanner)
Megavoltage treatment units (preferably \10 years old)
Equipment: workload (based on normal working hours)
Patients per year/megavoltage unit
Patients per year/conventional simulator
Patients per year/CT (simulator) unit
mutual recognition of the FQ from the various par-
ticipating clinical trial groups (or a shortened trial-
dedicated FQ) has been agreed upon.
It should be noted that both in the US and Europe,
there have been publications addressing minimal
requirements for RT staffing and equipment, in terms
of quantity as well as expertise. In the US, these
publications were known as the ‘‘blue book’’, and
provided guidance and a strong rationale to help
ensure that adequate staffing, equipment, and facili-
ties were available in radiation therapy departments
participating in clinical trials (ISCRO 1991).
Unfortunately, the document is now out-of-date and
national organizations such as the American Society
for Radiation Oncology (ASTRO) and the American
Association of Physics in Medicine (AAPM) have
not produced a replacement guidance document
till date.
In Europe, surveys/reports in the 1980s docu-
menting the profile of radiotherapy departments
participating in clinical trials of the EORTC-ROG,
showed that large variations in equipment, staffing,
and workload existed. Based on these results,
repeated recommendations were made in the form
of minimum requirements for participation in clin-
ical trials within the framework of the EORTC
(Bernier et al. 1996; Budiharto et al. 2008;
Horiot et al. 1986). A summary of the actual and
proposed requirements on infrastructure, staffing,
J. A. Purdy and P. M. Poortmans
Actual requirements Proposed new requirements
Minimum 2.5 Minimum 3
Maximum 300 Maximum 250
Minimum 1.3 Minimum 2
Maximum 500 Maximum 500
Minimum 2 Minimum 2
Minimum 1 Minimum 1 including access
to a CT-scanner
Minimum 2 Minimum 2
Maximum 700 Maximum 600
Maximum 1500 Maximum 1200
– Maximum 2400
and workload for the EORTC is presented in
Table 2. Hopefully ASTRO and AAPM will revive
the blue book and develop similar infrastructure
guidance recommendations.
5.1.2 External Reference Dosimetry Audit
There is strong consensus among US QA centers and
the EORTC-ROG that each institution must pass a
dosimetry audit by an expert center which has direct
links to a primary dosimetry laboratory (which also
has links to primary laboratories throughout the
world) prior to entering patients on a clinical trial.
This credentialing test has become known as ERDA.
However, the process by which this is accomplished
varies between the US and Europe at two major
points, namely the provider and the frequency of
subsequent audits.
The RPC initiated a mailed thermoluminescent
dosimetry (TLD) program for machine output checks
for photon beams in 1977 and electron beams in 1982
(Kirby et al. 1986, 1992). More recently, monitoring
of proton beams began in 2007. For a significant
period, institutions participating in NCI-sponsored
clinical trials underwent the RPC-ERDA (mailed
TLD check), every six months. This ERDA frequency
was eventually changed to an annual check, but
unfortunately, there are no subsequent peer-reviewed
published reports analyzing the RPC data to validate
either the biannual or annual ERDA requirement.
QA of Clinical Trials
The EORTC-ROG has implemented a two-year
ERDA frequency requirement based on the following
peer-reviewed studies. In 1982, the EORTC-ROG
initiated a mailed TLD program for machine output
check. This revealed a few large deviations ([7%)
between the dose measured and the dose stated by the
centers (Hansson and Johansson 1991; Hansson et al.
1993). Based on this, corrections were made by the
participating centers. Subsequent mailings resulted in
a decrease in the measured deviations and in the
standard deviation. Correlating information from the
TLD measurements with the on-site visits led to a
further decrease in the beam output deviations
(Hansson et al. 1993). In 1993, a report on the mailed
TLD results of radiation therapy centers in Europe
showed that the large majority of the beams (23/25)
with deviations [3% were from centers that had not
participated in external audits in the 5 years preceding
the audit (Dutreix et al. 1993). Based on these studies,
a report listing minimum requirements for QA in
radiation therapy departments was published in 1993
(Horiot et al. 1993).
Bentzen reported on the possible clinical impact of
QA programs focusing on dosimetry using radiobio-
logical modeling of data obtained from 140 mailed
TLD measurements of the EORTC from 1993 to 1996
for 26 Cobalt machines and 114 linear accelerators
from 35 centers (Bentzen et al. 2000). The study
pointed out that theoretically, the 10% most ‘‘under-
dosed’’ beams would result in an estimated 7–8% loss
in tumor control probability (TCP), whereas the 10%
most ‘‘overdosed’’ beams leads to a 19–22% increase
in G1-2 complication rate and a 4–5% increase in
G3-4 complication rate.
The mailed TLD dosimetry program of the
EORTC-ROG was later taken over by ESTRO
(Derreumaux et al. 1995; Ferreira et al. 2000). After
funding ended for this program, it is now available
through EqualEstro for a fee. In 2006, ERDA was
made mandatory for all EORTC members prior to
participation in RT trials. Based on the previously
referenced reports, an ERDA is required to be per-
formed only on a 2-year basis, for both photons and
electrons (if applicable for the trials in which centers
participate). The ERDA can be performed by any
provider, as long as the primary standard is traceable.
To summarize, the requirement for an annual
ERDA by the US against the EORTC requirement of
at least every two years is one of the major differences
539
in the clinical trial QA programs between the US and
Europe. Both agree that the institution must complete
a successful ERDA prior to their participation in a
clinical RT trial.
It should be noted that a study to compare the
appropriateness of the one- versus two-year frequency
is currently underway among the RPC, RTOG, and
EORTC in the framework of the phase III RTOG
0848 trial in pancreatic head cancer, which includes
participation by member institutions of SWOG,
NCIC, and EORTC.
5.2 Advanced Credentialing
5.2.1 Dry-Run/Dummy Run
Some protocols may require additional credentialing
tests beyond the FQ and the ERDA. For example, in
the US some protocols require each institution to
successfully complete a dry run (DR) test (Purdy et al.
1998); EORTC calls this test a dummy run,
(van Tienhoven et al. 1991). The DR test is intended
to demonstrate that an institution preparing for par-
ticipation in a particular clinical trial has both the
technical capability and an appropriate understanding
of the requirements of the protocol (tumor and target
volumes, organs-at-risk, and dose prescription/heter-
ogeneity requirements). Each DR test is typically
specific for a particular study.
The DR credentialing test has become more
important as trials are increasingly making use of
treatment planning based on modern imaging tech-
niques including CT, MRI, and PET-CT. This has
introduced a new level of uncertainty and variation in
target volume and organ at risk delineation. In the
distant past, radiation therapy fields were often based
on bony landmarks, without added blocking to make
the beam more conformal to the target volume.
Whereas these beams were large enough to cover the
actual target, this approach limited the dose that could
be prescribed due to normal tissue constraints and
toxicity, and when it was attempted to make the
radiation therapy beams more conformal, part of the
target volume was often missed (Pilepich et al. 1982).
With the broad introduction of 3D-treatment planning
and the use of imaging for 3D-volume delineation in
the 1990s, several new RTQA challenges were
introduced. For example, for many disease sites, the
definition of the actual target volume to be treated is
540
uncertain and the treating physician is faced with
multiple issues, including:
• What imaging technique should be used for a spe-
cific target volume.
• What margins are needed from GTV to CTV to
account for microscopic tumor spread.
• What margins are needed from CTV to PTV that
takes into account setup uncertainties. Internal
organ movement/shape change from day-to-day,
and internal organ movement during a treatment
session.
Multiple reports have confirmed the fear of many
that the variance in target volume delineation has
become the largest remaining source of variation in
clinical radiation therapy (Wu et al. 2005). Both the
US and European groups have made a serious effort
to assist in minimizing this source of uncertainty and
variance by authoring a number of papers dedicated
to the subject of delineation of the target volumes as
well as of the organs at risk (Boehmer et al. 2006;
Hall et al. 2008; Lawton et al. 2009a, b; Michalski
et al. 2009, 2010; Poortmans et al. 2007). These
reports are, in general, related to clinical trials either
active or under preparation so that later participants
can be given a tool to decrease inter-observer vari-
ability. However, this does not obviate the need for
sustained training and QA due to differences in
interpretation (Girinsky et al. 2008; van Mourik
et al. 2010). Moreover, improved tumor and normal
organ definition using combined anatomical and
functional imaging such as PET-CT and MRI, has as
indicated previously introduced yet other possible
sources of errors and variations and thereby new
challenges for QA (Devic et al. 2010; Geets et al.
2007; Piroth et al. 2009; Schinagl et al. 2006;
Villeirs et al. 2005).
It should be noted that in most recent EORTC
trials a DR is used first to perform volume delineation
per protocol specification, which is then compared to
a consensus volume determined by a number of
experts; if acceptable the institution then performs
treatment planning to demonstrate understanding of
the protocol dose prescription/heterogeneity require-
ments. As indicated previously, each DR test is typ-
ically specific for a particular study. In addition, in
several RTOG trials, the DR credentialing test has
transitioned into the case review arena by which a
‘‘rapid review’’ approach is used. In such protocols,
the treatment of the first patient registered is not
J. A. Purdy and P. M. Poortmans
allowed until the study chair reviews and approves the
submitted volumes. Also, training sessions are now
routinely organized and the results presented and
discussed at the various cooperative group meetings.
Finally, the actual margin from CTV to PTV that
should be used is related to both GTV/CTV delinea-
tion and setup variations and might therefore very
well be different from one participating institution to
another. This issue is not being addressed robustly in
current clinical trials and how to take this into account
in future trials is yet another challenge for future
clinical trial QA.
5.2.2 Phantom/Benchmark Credentialing
In addition to the DR test (or rapid review require-
ment), some protocols may require additional cre-
dentialing tests such as a phantom dosimetry check
for IMRT protocols, or an IGRT test for SBRT pro-
tocols. This is particularly true for protocols utilizing
new treatment modalities where there is essentially no
experience in the multi-group setting.
In this regard, the RPC has developed a series of
postal anthropomorphic phantoms that contain
dosimeters (film and TLD) which are intended to
provide a comprehensive test of an institution’s
ability to image, plan, and treat a patient using IMRT
or SBRT techniques (Molineu et al. 2005). This type
of credentialing test is depicted in Fig. 7 for an
EORTC head and neck cancer clinical trial. Several
years of use with this phantom shows that approxi-
mately 30% of institutions fail to deliver a dose dis-
tribution to the RPC H and N phantom that agrees
with the institution’s submitted treatment plan to
within 7% or 4 mm on their first try (Ibbott 2009;
Ibbott et al. 2008). Somewhat higher pass rates have
been seen with the other RPC phantoms (Ibbott et al.
2008). Unfortunately, it is not clear in the publications
what exactly caused the failure. These phantom test
results clearly point to the need for careful planning of
phantom credentialing tests, so that the exact cause of
failure can always be explicitly determined in each
and every case.
QARC has taken a different approach for coop-
erative group clinical trial credentialing. Rather than
using postal phantoms, they have developed a series
of treatment planning/delivery benchmarks that use
the institution’s own phantoms, dosimetry systems,
and treatment planning systems. For example, they
developed the IMRT benchmark, which was reported
QA of Clinical Trials
Fig. 7 Schedule of the pretest performed by RPC for the new
H and N EORTC clinical trial. a Test demonstrating the ability
to dis- and re-assemble the phantom while remaining within the
RPC criteria of acceptance. Thereby, sequential phantom
irradiation at several institutions in several countries proved
by ATC and does not require the use of a postal
phantom (Palta et al. 2004).
Bridier et al. (2000) published a comparative
description of several multipurpose phantoms (MPPs)
541
feasible, b graphical presentation of the results of the phantom
check in the three main axes, c table presentation of the results
of the phantom check (Courtesy of Akos Gulyban, EORTC QA
manager 2009–2010 and RPC)
for external audits of photon beams in European
institutions. To date such MPPs have seen relatively
little use in clinical trial credentialing in Europe.
Swinnen et al. (2002), did report on the use of an MPP
542
called operational phantom for European radiation
therapy audits (OPERA), which was designed to
check the dosimetric aspects of complex treatments
by comparing the planned versus the measured dose
distribution as well as the on-line treatment portal
imaging verification. OPERA was adapted for IMRT
and used in five key centers in Europe to establish the
principle and functionality for IMRT credentialing.
However, the estimated cost of such complex
dosimetry was found to be high. It is therefore
expected that participating centers may have to bear
at least part of the costs involved, unless sufficient
funding can be found from other sources, or less
costly credentialing tests are developed.
It should also be understood that in the US, the
RTOG now requires an institution to re-credential for
IMRT when important elements of an institution’s
planning/delivery process change, e.g., changing from
standard multileaf collimator IMRT dose delivery to
tomotherapy or volumetric modulated arc therapy
IMRT (VMAT or RapidArc).
Finally, it should be noted that a series of pub-
lished exchanges between Back et al. (2008) and
Williams et al. (2007, 2008) clearly point out that
those involved in carrying out credentialing of clinical
trials need to tread cautiously. Although the aim is to
ensure the quality and integrity of the scientific data,
achieving that aim may require consideration of fac-
tors that go beyond the science, and is very much
dependent on healthy collaborations between the
RTQA centers and the participating institutions
(Williams et al. 2008). Bridier et al. (2000) pointed
out that this is particularly problematic for postal
phantoms used for external audits, and that a number
of special precautions have to be taken. Relevant
information must be gathered in a small number of
easily performed setups and appropriate dosimeters
must be used. It is essential to make instructions as
clear as possible and keep the necessary contribution
by the institution’s staff to plan, set up, and irradiate
the phantom, as time efficient as possible. If these cri-
teria cannot be met, a large number of failures may be
seen that are in fact ‘‘false positives,’’ i.e., they do not
reflect the ability of the institution to plan and deliver
the required dose to the protocol patient, but rather
reflect the ability to pass a flawed credentialing test
design. Such tests will clearly have a negative impact
on protocol case accrual and may even turn off insti-
tutions’ willingness to participate in clinical trials.
J. A. Purdy and P. M. Poortmans
An important development in this matter is the
EORTC-ROG project about to start that will perform
a comparison and analysis of physical and digital
phantom methodologies and outcomes. In order to
arrive at a digital phantom to be used for IMRT cre-
dentialing, the RPC physical phantom is being com-
pared with several institutions’ own physical
phantoms. New IMRT credentialing guidelines based
on a fully digital phantom procedure, in which a
digital DICOM data set will be the basis for the
dosimetry check, have been agreed upon by the
RTQA Strategy Committee. The study should get
underway in late 2011.
6 Individual Case Review
While a DR is based on a fictitious patient and can be
done before actual patient accrual, an individual case
review (ICR) refers to the evaluation of submitted data
for a patient actually entered into a study (Bolla et al.
1995). In some circumstances, patient-, tumor-, and
(non-radiation) treatment-related data must be evalu-
ated to check the eligibility of the randomized patients
and to compare the data reported on the case report
forms (CRF) with the ones in the actual patient file. For
many cooperative groups, both in the US and Europe,
this kind of evaluation used to be typically performed
on the occasion of the group’s meeting where partici-
pants were invited to bring the required data with them.
Alternatively, hard copies were sent after removing the
identified information to the RTQA office for evalua-
tion and comparison with the CRF. Nowadays, in trials
involving radiation therapy, the focus is placed on RT
information for which digital data submission is
required, alongside which patient- and tumor- related
data might be uploaded digitally as well.
To ensure a maximal effect of the ICR, it should be
performed as early as possible during patient accrual.
A predefined number of patient data sets are typically
evaluated, ranging from a low percentage to even all
of the randomized patients. As indicated previously,
in some specific trials, data on treatment planning are
sent to the RTQA office for rapid evaluation, with
treatment execution allowed only after acceptance
and––if necessary––corrections made.
The modern ICR review process pioneered by the
RTOG and ITC is now clearly divided between a
digital data integrity QA (DDIQA) review and a
QA of Clinical Trials
protocol compliance QA (PCQA) review (Purdy
et al. 2006; Straube et al. 2006). The DDIQA process
involves the processing and review of the submitted
data for completeness and consistency (i.e., com-
pleteness of protocol required elements, format of
data, possible data corruption, and uniformity in
OAR/TV contour names) Also, recalculation of each
submitted DVH is performed. Experience has shown
that submitted DVH lack consistency due to algo-
rithmic differences among TPS (Straube et al. 2005).
The ITC DDIQA experience in accepting, process-
ing, and reviewing digital data submissions for
support (QA and analysis) of advanced technology
protocols for the past 15 years has shown that
approximately 25–30% of the cases require inter-
vention, often requiring iterative communications
with personnel at the submitting institution (Purdy
et al. 2006). The ITC has implemented software
tools to increase the efficiency of the DDIQA pro-
cess, but experience has shown that completely
automated data DDIQA is not yet realistic in the
foreseeable future.
The PCQA process includes review of target vol-
ume and organ at risk contouring as well as protocol
dose prescription and dose heterogeneity compliance.
PCQA is typically performed by the study chair using
a review system such as QuASA2R’s web-based RRT
discussed earlier.
As indicated, the EORTC employs a similar pro-
cess. All CRF data submitted to the EORTC Head-
quarters are verified using a double data entry
procedure and, more recently, by direct data capture
through an internet access. After verification for
consistency and completeness, queries are sent to the
participating centers to check, correct, and complete if
needed. For the most recent EORTC protocols, the
paper reviewing procedures are now completely
replaced by digital submission and review, either in
collaboration with other organizations (including
ATC) or using the VODCA platform. The review is
coordinated by the tumor site-specific RTQA team
members and can involve other reviewers as well.
7 Data Analysis
Currently, there is a lack of robustness in the coop-
erative group/RTQA centers’ informatics infrastruc-
tures for querying and retrieval of data from disparate
543
data objects that may be hosted by different entities
involved in the clinical trial. The data may include
non-anonymized computed tomography images,
radiation therapy treatment plan objects, pre- and
post-therapy imaging studies, clinical assessment data
associated with the imaging and treatment planning
data (including demographics, initial assessment,
follow-up forms….), genomic/proteomic data, and
outcomes data. In the US there is a strong drive to
involve more imaging expertise in RT clinical trials,
particularly at the RTQA centers. Similarly, the
EORTC Imaging and Radiation Oncology groups are
collaborating to improve the exchange of data by
linking the imaging and VODCA platforms. The
development of this ‘‘backend data mining’’ capabil-
ity will be an important area of research for radiation
oncology moving forward.
It is obvious that the credentialing and ICR
processes have become more comprehensive and
labor intensive and concomitantly it has become
more burdensome for institutions to participate in
modern day clinical trials. Although intuitively the
credentialing and ICR programs are seen as bene-
ficial, there is relatively limited hard evidence
supporting their value (Bentzen et al. 2000; Peters
et al. 2010; Pettersen et al. 2008; Poortmans et al.
2001).
Perhaps the best evidence is provided by Peters
et al. (2010) who reported the critical impact of
radiotherapy protocol compliance and quality in the
treatment of advanced head and neck cancer in a
phase three randomized intergroup trial lead by
TROG. With the support of QARC, all plans and
radiotherapy-related data underwent post-treatment
review. Factors associated with poor protocol com-
pliance were studied, and outcome data were ana-
lyzed in relation to protocol compliance and
radiotherapy quality. Major deficiencies were highly
correlated with the number of patients enrolled by the
participating center. In patients who received at least
60 Gy, those with major deficiencies in their treat-
ment plans had a markedly inferior outcome com-
pared with those whose treatment was initially
protocol compliant: 2 years overall survival, 50 ver-
sus 70%; P \ 0.001; and 2 years freedom from loco
regional failure, 54 versus 78%; P \ 0.001, respec-
tively (Figs. 8, 9, 10). It is possible that in this large
trial designed with 90% power to detect a 10%
improvement in OS at 2 years, the deleterious effect
544 J. A. Purdy and P. M. Poortmans

Fig. 8 CONSORT flowchart

showing sequence of reviews
and analyses. QARC, Trial
Management Committee
(TMC), TCP, radiotherapy
(RT). Reproduced with
permission from (Peters et al.
2010)

of poor radiotherapy itself leads to non-significant

difference in the outcome of the experimental arm
(Peters et al. 2010).
A second study by Dühmke et al. (2001) demon-
strated in a prospective randomized trial from the
German Hodgkin Study Group evaluating the radia-
tion dose in the treatment of favorable risk early stage
Hodgkin lymphoma that radiation therapy protocol
violations were associated with significantly poorer
relapse free survival (Fig. 11).
8 Considerations for the Future
New technologies continue to be developed and
implemented in radiation oncology at a progressively
higher rate. As the use of these new technologies
makes their way into clinical trials, they pose new
challenges for cooperative groups and RTQA centers.
Current challenges for clinical trials RTQA include
the following: (1) image management including
QA of Clinical Trials
Fig. 9 Time to locoregional failure by deviation status. The
four cohorts are (1) compliant from the outset (n = 502),
(2) made compliant following a review by the QARC (n = 86),
(3) noncompliant but without predicted major adverse impact
on tumor control (n = 105), and (4) noncompliant with
predicted major adverse impact on tumor control (n = 87).
Overall P \ 0.001. TCP, RT. Reproduced with permission
from (Peters et al. 2010)
Fig. 10 Overall survival by deviation status: (1) compliant
from the outset (n = 502), (2) made compliant following a
review by the QARC (n = 86), (3) noncompliant but without
predicted major adverse impact on tumor control (n = 105),
and (4) noncompliant with predicted major adverse impact
on tumor control (n = 87). Overall P \ 0.001. TCP, RT.
Reproduced with permission from (Peters et al. 2010)
association of trial metadata with images and RT
objects, de-identification of images and associated
metadata, coordinated single-reviewer and multi-
reviewer central review, multi-modality pre- and
545
Fig. 11 Relapse-free survival according to presence
(n = 127) or absence (n = 242) of a relevant RT PV. (RT,
PV––protocol violation). Reproduced with permission from
(Dühmke et al. 2001)
post- therapy imaging (including but not limited to
PET, MRI, MRS); (2) IGRT data submission/cre-
dentialing QA including EPID, MV and kV cone
beam CT, helical tomotherapy MV CT, US,…); (3)
agreement on nomenclature to be used for target
volumes and OAR; (4) credentialing of the institu-
tion’s motion management methodology; (5) hetero-
geneous dose calculations including QA evaluation
criteria; (6) proton beam therapy; (7) compliant data
export for stereotactic specialized treatment systems
(e.g., Elekta Gamma Knife and Accuray CyberKnife);
(8) new processes such as adaptive radiation therapy
(need deformable registration QA tools); (9) harmo-
nization of credentialing and ICR among groups in
US and Europe (particularly the frequency of ERDA
and non-phantom IMRT credentialing); and (10)
consistent/proper delineation of volumes for treatment
planning, which is the largest remaining variance in
current radiation therapy. It is essential that radiation
oncologists and medical physicists interested in clinical
trials monitor the progress (and help contribute to the
solution) in solving the credentialing and QA review
issues associated with new technologies.
The level of appropriate credentialing and ICR in
clinical trials is highly dependent on the complexity
of the trial. It should be adequate and its effects
should also extend to the treatment of all patients, but
it must be evidence based. By doing this, efficient
quality assurance in clinical trials will improve the
overall quality of treatment for most patients at an
acceptable cost.
546
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 Promises and Pitfalls of Health Technology
Assessment
Yolande Lievens, Peter Dunscombe, and Andre Konski

Contents Abstract
Over the last decades, a continuous rise in health
1 Introduction.............................................................. 549 care expenditure has been observed in all Western
2 Health Technology Assessment .............................. 550 countries, partly, at least, due to the rapid diffusion
of novel treatments and technologies. This growth
3 Economic Evaluations in Health Care.................. 551
3.1 Types of Economic Evaluations ............................... 551 in health care costs is not sustainable in the long run
3.2 How to Perform a Sound Economic Evaluation? .... 552 and hence strategies are being developed to set
priorities about which interventions to fund and
4 Outcomes .................................................................. 553
4.1 Dosimetric Outcomes ................................................ 553 implement. Although radiotherapy is commonly
4.2 Clinical Trial Based Outcomes ................................. 553 accepted to be a very cost-effective treatment
4.3 Model Based Outcomes ............................................ 554 strategy, it is not immune from this general
5 Costs .......................................................................... 555 tendency toward cost-consciousness and cost-
5.1 Whose Perspective?................................................... 555 containment. This chapter will guide the interested
5.2 Cost Categories.......................................................... 555 radiation oncology professional through some the-
5.3 Global Cost Estimates ............................................... 556
5.4 Reimbursement Based Costs..................................... 557 oretical aspects of health technology assessment,
5.5 Model Based Costs.................................................... 558 economic evaluation and cost accounting. In order
6 Potential Pitfalls in the Interpretation
to illustrate the concepts, recent examples from the
of Economic Evaluations ........................................ 559 economics literature on radiotherapy treatments are
discussed. Additionally, this chapter will review
7 Conclusion: Challenges and Opportunities .......... 560
some diverging results and conclusions from eco-
References.......................................................................... 561 nomic analyses of similar interventions and hence
highlight potential pitfalls in the interpretation of
health economic data. The chapter concludes by
discussing which strategies could be pursued to
Y. Lievens (&)
Radiation Oncology Department, support the economic future of our specialty.
Universitaire Ziekenhuizen Leuven,
3000 Leuven, Belgium
e-mail: yolande.lievens@uzleuven.be
P. Dunscombe 1 Introduction
Department of Oncology,
University of Calgary, Calgary, Over the past several decades, developed countries
AB T2N 1N4, Canada
have been devoting an ever-growing proportion of
A. Konski their Gross Domestic Product (GDP) to health care.
Department of Radiation Oncology,
According to the 2008 report of the Organisation for
Wayne State University School of Medicine,
Karmanos Cancer Center, Detroit, MI 48201, USA Economic Co-operation and Development (OECD),

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 549
DOI: 10.1007/174_2011_248,  Springer-Verlag Berlin Heidelberg 2012
550
the average annual growth rate in health care spend-
ing between 2000 and 2006 ranged between 1.4% in
Germany and 10.7% in Korea. With health expendi-
ture of US$ 6,714 per person per year, the United
States largely outspent the other countries surveyed
(OECD 2008). Obviously, such cost increases are not,
in the long run, sustainable and priorities will have to
be set regarding both the share of society’s resources
to devote to health care and, within that share, which
interventions to implement and fund, taking cost and
effectiveness into consideration.
Among the many reasons that have been put for-
ward to explain the continuous rise in health care costs,
the rapid diffusion of new technologies has been
proposed as a major contributing factor (Bodenheimer
2005). Radiation oncology, a highly technological
discipline, is obviously highly susceptible to this
particular cause of rising costs. Increasingly sophisti-
cated radiotherapy (RT) equipment, alongside
expanding imaging and information-communication
applications, has resulted in more accurate but more
resource intensive treatment strategies. Many of these
strategies, including intensity-modulated (IMRT),
image guided (IGRT) and stereotactic RT (SRT)—to
name only a few—have rapidly gained acceptance and
established their place in daily practice. The intro-
duction of others, such as heavy ion therapy, has
provoked much discussion, especially related to the
question of whether or not the expected benefit justifies
the much higher capital and operating costs. Although
some attempts have been made to analyze the impact of
new treatment strategies, the overall cost consequences
of technological and clinical process evolution in RT
have so far remained largely unexplored.
In spite of these resource-intensive advances, it is,
however, widely accepted that radiation therapy’s
budget share remains very modest in comparison with
both the total health care 1.7% of Medicare’s payment
in 2009 (Medicare data 2009) and oncology approx-
imately 5% of total cancer care costs (Norlund 2003)
budgets. This point can be emphasized by considering
the high incidence rate of cancer in an aging popu-
lation and the large proportion of cancer patients for
whom radiation is considered beneficial (Delaney
et al. 2005). However, in this era of financial
restrictions and tightening budgets, it is imperative
that radiation oncologists, and their colleagues in the
clinical team, not only develop an interest in, but also
become partners in health care management,
Y. Lievens et al.
decision-making and budgeting in cooperation with
governmental and insurance parties.
We continue this chapter, with discussions of the
principles of both Health Technology Assessment and
Economic Evaluation with the focus on the latter. As we
shall see, economic evaluations require estimates of
outcome and costs and we outline common approaches
to obtaining these estimates. The outcome component of
an economic evaluation may be difficult to measure but
can be relatively unambiguously specified. In contrast
the estimation of costs has been handled very differently
by different researchers. A considerable portion of this
chapter is devoted to describing and distinguishing
between the different possible approaches to cost esti-
mation. We include, throughout, reviews of recent
publications to demonstrate the principles discussed and
to shed light on the large variability in published results,
which are related to differences in the methodologies
used and perspectives adopted.
It is hoped that this elucidation will assist the
interested reader to better interpret the economic
literature.
2 Health Technology Assessment
Health Technology Assessment (HTA) plays an
essential role in modern health care by supporting
evidence based decision-making in policy and prac-
tice. HTA involves addressing five different questions
(Detsky and Naglie 1990):
(1) Can a health care intervention achieve its
expected goal when used in optimal circum-
stances? (Efficacy)
(2) Does the intervention do more good than harm
when used in routine practice? (Effectiveness)
(3) What is the balance between the health outcome
obtained and the resources required to deliver the
intervention? (Efficiency or Cost-Effectiveness)
(4) Is the supply of services matched to locations
where they are accessible to persons that need
them? (Availability)
(5) Who gains and who loses by choosing to allocate
resources to one health care program instead of
another? (Distribution).
A statistically valid answer to the first question can
be obtained through a clinical trial of appropriate
level. The second question considers the specificities
of daily clinical practice, such as the variability in
Promises and Pitfalls of Health Technology Assessment
Table 1 Levels of economic evaluation
Are both costs and outcome examined?
No
Costs only
Is there a comparison between two No Cost
alternatives? description
Yes Cost analysis
a
Cost-minimization, cost-effectiveness, cost-utility or cost-benefit analysis
patient characteristics and compliance with the clinical
protocol, as well as potential geographic differences in
available resources and treatment techniques. Fairly
rigorous analytical methodologies can be brought to
bear on the third question addressing efficiency or cost-
effectiveness. Such methodologies are grouped under
the heading of economic evaluations (EE) and are
described in detail in the next section. The final two
questions regarding where to introduce a new treatment
and how to allocate funding among different treatment
strategies by society entail ethical, jurisdictional, and
social considerations besides purely medical, opera-
tional, economic and budgetary issues.
3 Economic Evaluations in Health
Care
In the past, choices about which new interventions to
introduce and reimburse in daily practice were solely
based on safety and efficacy, i.e. on the basis of data
related to the two first HTA questions. More
recently, due to the growing awareness of resource
limitations and tightening budgets, treatment cost
has played a more conspicuous role in decision-
making. The weighing of costs and outcome is
typically performed within the context of an EE and
this has now become an integral part of the resource
allocation process in many countries, with the UK
and Canada having pioneered research in this area.
EE are frequently required prior to the introduction
of new drugs. In the adoption of other health care
interventions, such as new surgical procedures and
RT techniques, EE seems to have played a lesser
role so far. However, this is changing for our spe-
cialty with the question of cost-effectiveness being
more frequently raised when reimbursement and
global budgeting are discussed.
551
Yes
Effects only
Outcome description Cost-outcome
description
Efficacy or effectiveness Full economic
evaluation evaluationa
3.1 Types of Economic Evaluations
Various levels of sophistication of EE have been
described and discussed in detail in the comprehen-
sive text by Drummond et al. (2005) (Table 1, adap-
ted from Drummond et al. 2005).
A full EE typically involves the quantitative
examination of both costs and outcomes, or conse-
quences, of competing interventions possibly includ-
ing no intervention. An appropriately performed EE is
incremental, i.e. it measures the extra cost incurred in
order to obtain the incremental improvement in
outcome.
Drummond et al. identify different types of full EE,
based on the denominator chosen.
The most widely used approach, referred to as
cost-effectiveness analysis (CEA), compares the
incremental costs of a new technology or interven-
tion to the incremental gain or loss of clinical out-
come of the new intervention, ideally measured in
life years gained (LYG). Other potential denomina-
tors in a CEA are disease-free survival or number of
cancers prevented or detected, but the use of such
intermediary outcome measures hampers comparison
among different CEA’s and should therefore be
discouraged. The evaluation will result in a ratio of
the cost/outcome, e.g. cost/life year gained ($/LYG,
€/LYG), called the iCER (incremental cost-effec-
tiveness ratio).
In the situation where the outcome of the evaluated
interventions is expected to be the same, the EE will be
limited to a cost-comparison, called cost-minimization
analysis (CMA).
Assuming a well-defined comparison of two RT
approaches and a sufficiently long follow-up, pro-
longation of life, life years gained, can be measured
but it can be questioned whether this is the metric that
has most relevance to patients. Would, for example,
552
2 years spent in serious pain be regarded as a better
outcome than 1 year in good health?
This brings us to the third type of full EE, the cost-
utility analysis (CUA). CUA acknowledges quality of
life following an intervention by weighting the LYG
with a ‘utility factor’ typically ranging from 0 (death)
to 1 (perfect health). For example, if a patient had a
utility or preference for a health state of 0.5 and he
survived in that state for 1 year, then he would have
had a quality-adjusted survival of 6 months. A CUA
employs quality-adjusted life years (QALYs) as the
denominator with the result expressed as cost/QALY.
Utilities or patient preferences for a certain health
outcome can be measured with instruments such as
the Health Utilities Index III (Feeny et al. 1995) and
EuroQol (EuroQol Group 1990) or tests such as Time-
Trade Off or Standard Gamble (Drummond et al.
2005). CUA are helpful in trying to compare
non-similar health interventions, such as a prostate
cancer-screening program with a child immunization
program, for example. When analyzing such dissimilar
programs with a cost-effectiveness analysis it would be
argued that it is impossible to compare a year of life of
a child to that of an adult. This sort of discussion can be
avoided by using a cost-utility analysis because the use
of QALY, at least in principle, implicitly corrects for
the above-mentioned disparities.
The last type of full EE is cost-benefit analysis
(CBA). In a CBA, both cost and outcome are valued
in terms of currency. In theory, this approach has the
advantage of allowing a direct comparison between
input costs and savings: any alternative where the
benefit, in monetary units, is greater than the cost is
considered worthwhile. Putting a dollar value on the
quantity and quality of a life is however a highly
specialized and quite controversial area. As a
consequence, a CBA—although one of the most
overused phrases in health care economics—is rarely
performed.
As can be imagined, full EE in RT, requiring as
they do detailed input on short- and long-term costs
and outcomes, can turn out to be difficult to perform.
Fortunately, we can make some progress in under-
standing the implications of current and new tech-
nology and processes using more limited approaches.
One such approach addresses costs and outcomes
separately and leads to cost and outcome descriptions,
respectively (Drummond et al. 2005). However, there
are dangers with separating costs and outcomes in this
Y. Lievens et al.
way and one has to be cautious that the information so
generated will not be misused. The most useful
descriptions of outcome of a new treatment strategy,
particularly from the patient’s perspective, result from
the conduct of clinical trials. Fully randomized and
controlled Phase 3 trials (Randomized Controlled
Trials, RCT) have been categorized as efficacy or
effectiveness evaluations (Drummond et al. 2005).
It can be argued, however, that such comparisons may
indirectly lead to the increased cost of health care as
funders come under pressure to broadly adopt new
interventions with only marginal clinical benefit and
no consideration of the opportunity cost.
A pure cost-comparison, in contrast, entails the
opposite risk. If the tendency to reduce health care
spending is strong, this might result in the simple
choice of the cheapest approach, which may, in turn,
result in reduced quality, hence inferior outcome.
Provided that there is sufficient evidence that the
outcome of interest for the experimental treatment or
intervention does not differ from the standard treat-
ment, a CMA is undertaken (discussed above), i.e. a
mere cost-comparison with the intervention resulting
in the lower cost being the favored one from a health
economics’ perspective.
The above discussion illustrates some of the
complexity of estimating both costs and outcomes, i.e.
of performing full EE, of a service. There are different
methodological approaches possible to collect the
cost and outcome data of alternative interventions and
we will discuss some of these later in this article.
3.2 How to Perform a Sound Economic
Evaluation?
Drummond et al. (2005) outlined the different ele-
ments which should be acknowledged in an accurate
economic analysis. We repeat them here as a
checklist:
(a) Is there a well-described question, from a
clearly defined perspective (societal, payer,
institutional,…)?
(b) Is the evaluated intervention compared to the
relevant competing alternative(s) and are the
alternatives described in a comprehensive way?
(c) Are all important and relevant costs and conse-
quences for each alternative identified and
included?
Promises and Pitfalls of Health Technology Assessment
(d) Is the outcome (e.g. survival, quality-adjusted
survival, number of complications prevented) of
the competing treatments or technologies avail-
able and correctly assessed?
(e) Are all costs appropriately measured and defined
from the perspective of the analysis?
(f) Are all costs credibly valued, i.e. based on pre-
vailing prices for similar services; is valuation of
the benefits performed in a reasonable way?
(g) Is adjustment made for differential timing of
costs and consequences?
(h) Does the economic analysis correctly determine
the incremental cost and extra benefit of the new
treatment or technology compared with existing
treatments or technologies?
(i) Is a sensitivity analysis performed to determine
the robustness of the overall result to assump-
tions made in the analysis?
(j) Are all issues or concerns to the users included in
the economic analysis and are the judgments
made in performing the analysis made explicit?
(k) Are the limitations of the economic analysis
defined and discussed?
Some of the terms used in this checklist may not be
familiar to the reader and are discussed in sections to
follow.
4 Outcomes
4.1 Dosimetric Outcomes
In the development phase of new interventions or
techniques in radiation therapy, dosimetric quantities
related to Dose Volume Histograms are quite often
used as outcome measures. For example, in the early
days of IMRT there was a wealth of literature
describing the improved dose distribution and organ
sparing that was (in principle) achievable with IMRT
as compared to three dimensional RT (3D-CRT).
Such intermediate outcome measures are useful in the
prospective evaluation of a new technique which is
being considered for implementation but for which
there is no substantial clinical experience as might be
gained through a randomized clinical trial (Ploquin
and Dunscombe 2009). However, they do suffer from
the obvious shortcoming that we do not understand, in
more than a general way, the relationship between
dosimetric outcomes and actual clinical consequences
553
for the patient. Hence, EE based on such intermediate
outcomes do not allow comparison across different
diseases and are, as such, of limited value in sup-
porting economical decision making from a broad
societal perspective. Nevertheless, they may play a
role in a more limited (e.g. departmental) context by
distinguishing between strategies which are the same
in terms of intended clinical outcome but may have
quite different costs.
4.2 Clinical Trial Based Outcomes
RCTs offer the best option for comparing one or more
treatments because the care is standardized within
each treatment arm of the trial. It may therefore seem
obvious to evaluate cost-effectiveness alongside such
clinical trials, collecting cost data in parallel with the
effectiveness data. Such an approach is referred to as
a piggy-back analysis.
A major practical problem, however, is that many
health care interventions have never been formally
evaluated in RCTs. In the context of RT, for example,
we can easily refer to the unsolved question regarding
the place of RT versus surgery as the primary local
treatment of prostate cancer, or to the ongoing dis-
cussion regarding the need for an RCT of proton-
beam therapy.
Apart from this, methodological problems may
arise. Clinical trials are generally designed to show a
difference in clinical endpoints and not economic
endpoints (Willan and Brien 1999). The statistics of
costs and effects being different, a statistical differ-
ence in the incremental cost-effectiveness ratio may
not occur if small differences in cost or outcomes
resulted. It may therefore become necessary to enter
more patients into a clinical trial to show statistically
significant differences in cost-effectiveness. On top of
that, it may be necessary to continue to follow-up on a
study longer than requested for the effectiveness data,
in order to collect sufficiently valid costs data as these
could include subsequent care resulting from the
intervention.
Furthermore, external validity may also be difficult
to ascertain: do costs consumed according to the
recommendations of a trial correctly represent those
of clinical practice outside the context of a trial? A
further difficulty is translating the cost-effectiveness
computed within one country to another country
554
where the economical environment, and therefore the
costs, might be quite different. Similar issues are
encountered in generating outcome data: is the highly
selected patient population of a trial a correct proxy
for daily care? Does the trial provide long enough
clinical follow-up, and was it measured in terms of
survival? What about the measurement of quality of
life (QOL) and the expected impact of treatment
toxicity on long-term QOL?
4.3 Model Based Outcomes
Due to its capacity to overcome the afore mentioned
problems of acquiring correct cost and outcome data
in the context of a clinical trial, the model based
approach has become the favored methodology to
perform EE in health care.
Decision analysis allows health services researchers
to disaggregate complex problems into smaller more
readily comprehended sections. Decision trees visually
represent treatment options and outcomes while Markov
models are more advanced forms of decision analysis
(Naimark et al. 1997). Using a Markov model as opposed
to decision trees allows us to evaluate problems with
ongoing risk over time, such as the ongoing risk of
cancer recurrence or development of a complication.
The model assumes that patients spend a cycle of time, a
month or year depending on the disease, in a health state
before moving to the next state or staying in the same
health state according to the definitions (transition
probabilities) specified in the model. Before performing
the analysis, modelers must determine the possible
health states and the possible transitions between states.
In order to clarify the terminology associated with
Markov modeling, Fig. 1 shows a Markov model
constructed with a commercially available software
program (TreeAge Pro, Williamstown, MA) for
patients with bone metastases treated with a single
fraction or with a fractionated course of RT (Konski
et al. 2009). In the treatment arm shown, the patient
would start out in the box marked ‘Single Fraction RT’
and would then progress through the arms based on the
probabilities in each of the branches of the model. For
example, if ‘‘Alive’’, he would either have ‘‘Pain’’ or
‘‘No Pain’’, based on the transition probabilities. If in
‘‘Pain’’, he would receive ‘‘Retreatment’’ but if in ‘‘No
Pain’’ he would progress to the health state ‘‘No Pain’’.
Patients spend a length of time in each health state
Y. Lievens et al.
Fig. 1 Markov transitions for patients with bone metastases
treated with a single fraction. SRT = single fraction radiotherapy
Pain Meds = pain medications
before either staying in the same health state, if
allowed, or transitioning to another allowed health
state. Cycle length is dependent on the acuity of the
disease with rapidly progressing conditions having
shorter cycle lengths whereas diseases such as prostate
cancer would have longer cycle lengths. In this exam-
ple on bone metastases, patients cycle through the
model 36 times with each cycle having a period of one
month, which means they are followed for a total period
of 3 years. The analysis could however be terminated at
any time point with the termination condition, or
stopping point, tested in a sensitivity analysis. Each
model has an absorbing state that accumulates patients.
Death, for example, was the absorbing state in this
model (Fig. 1). Markov models as described here are
informed both with transition probabilities as well as
costs for the various treatments and utility values for
each health state. Total cost and quality-adjusted sur-
vival can then be summed for each period and a cost-
effectiveness ratio calculated.
In a Monte Carlo simulation of a Markov Model, a
simulated patient progresses through the model with
transition probabilities varying per patient according to
a prespecified distribution. Patients progress until they
are in the absorbing state or have completed the
model as determined by the termination condition.
Promises and Pitfalls of Health Technology Assessment
Fig. 2 Incremental cost-util-
ity ratio’s (cost/QALY) of
adjuvant radiotherapy for
breast cancer. breast-conserv-
ing, invasive carcinoma D,
breast-conserving, in situ can-
cer , post-mastectomy ,
internal mammary and medial
supraclavicular lymph node
irradiation
Another patient would then progress through the model
until the predetermined termination condition is
encountered or the patient ended in the absorbing state.
The readers are referred to the literature for a full
and complete description of Markov Models and
Monte Carlo simulation of Markov Models (Naimark
et al. 1997).
5 Costs
5.1 Whose Perspective?
As mentioned in Sect. 3.2, the perspective of an EE
needs to be defined unambiguously, as it will deter-
mine which costs are included in the analysis.
Society, the patient and the payer all have different
perspectives on the delivery of health care.
5.1.1 Society
A societal perspective for an EE would include all
costs affecting society in general. Therefore, treat-
ment and medical care costs, patient’s time
including lost productivity, caregiver costs, trans-
portation, and other non-medical costs would be
included in the analysis. The costs in an EE
adopting a societal perspective are the largest of all
the perspectives.
5.1.2 Patient
Depending on a patient’s insurance coverage, costs in
an analysis using a patient perspective could be the
lowest. The only costs that are included in this anal-
ysis are all patient out-of pocket expenses including
555
opportunity costs (lost wages) of patient time for
treatments. The overall result of this type of analysis
could be very misleading if there are little or no out-
of-pocket expenses including costs for travel to and
from treatment, a situation that varies hugely from
one country to another.
5.1.3 Payer
A payer perspective is the most frequent perspective
used in EE of health care interventions. Costs may be
covered in part or in whole by government agencies or
by private insurance companies, e.g. health mainte-
nance organizations. Costs paid by insurance compa-
nies are often used as a proxy for cost of health care
products and services, although, in reality, there may be
large discrepancies between reimbursement levels and
actual resource costs. Costs in a payer’s perspective are
all costs paid by the payer. Costs not paid by the payer,
such as patient out-of-pocket expenses or travel costs
for treatment, are not included in the analysis. This
perspective could underestimate costs for treatments
requiring frequent physician visits, treatments with
considerable out-of-pocket expenses, or treatment at a
distance from a patient’s place of residence. True costs
could also be overestimated if the re-imbursement
structure is such that billing codes generate higher
revenue for the facility than the actual costs incurred.
5.2 Cost Categories
In order to make an EE meaningful, different types of
costs have to be acknowledged and either taken into
consideration or specifically excluded.
556
5.2.1 Costs During Treatment
Direct medical costs include the value of all the
goods, services, and other resources consumed in
the provision of an intervention or dealing with the
side effects of treatment. These costs include the
consumption of all capital and human resources such
as professional time, diagnostics, treatment, and
medications. It is relatively straightforward to calcu-
late the total salary costs within a radiation treatment
program. However, many of us interested in such
analyses work in academic centers and have respon-
sibilities beyond purely clinical activities. These other
activities are not necessarily costed out from the
salary budget but are not direct medical care costs.
Such ambiguities can confound economic analyses.
Direct costs are included in the numerator of the
cost-effectiveness ratio.
Direct non-medical costs include all costs made as
a consequence of undergoing a treatment but not
related to the treatment itself. Examples are the cost
of child care or of transportation while patients are
receiving treatment. Such costs are generally borne by
the patient although in countries such as the Nether-
lands and Belgium a reimbursement is foreseen to
cover costs of transportation.
Other costs that are sometimes included in EE are
changes in use of informal caregiver time (including
the cost of family or other providers to provide health
care in the home, chronic nursing care for disabled
individuals, or care for a sick child), and patient time
costs (referring to the time patients spend receiving
care, including the value of the time consumed in
receiving the treatment as well as travel and waiting
time). This latter cost can be understandably variable.
The time cost for a CEO of a Fortune 500 company
would be significantly higher than that for a homeless
person. Intangible costs, lastly, are costs that are
related to the pain and suffering of an individual
undergoing a medical treatment of intervention. Just
as patient time costs, these are very difficult to esti-
mate and are therefore often accounted for in the
numerator by a change in outcome (utility).
5.2.2 Costs After Treatment
Indirect medical costs include all costs that are made
in the time after the treatment has been terminated
and include costs of (late) toxicity or related diseases
occurring in later patient life. In RT, these costs can
differ quite substantially between different approaches
Y. Lievens et al.
if the side effects are very different or if one of the
interventions has a higher curative potential. Typi-
cally, however, these costs will occur many years
after termination of the treatment. While such costs
are generally borne by the payer, these subsequent
costs may accrue to a different payer, or section of the
payer, than those identified during the estimate of
direct medical costs while under the initial treatment.
Indirect non-medical costs refer to costs that are
important for society in that they measure loss of
productivity due to long-term disability or premature
death.
From the above it immediately appears that cost
descriptions, although based as they are on the metric
of monetary units, are not easier to develop than
outcome descriptions. Moreover, apart from the
problems related to the identification of direct non-
medical costs and indirect costs, residual ambiguity
may exist when defining the costs related to treatment
itself. For example, are capital costs properly included
and how is depreciation handled? Do the costs used
truly represent actual resource consumption? Are
overhead costs included and if so which and how are
they apportioned?
5.3 Global Cost Estimates
Global estimates of the cost of RT are the aggregate
costs of the human and capital resources consumed in
the delivery of a RT service. Thus they do not contain
the fine detail required when comparing, say, one RT
protocol with another. However, they can have
value as a background to allocating national health
care budgets between different classes of medical
intervention.
As mentioned above, the cost of RT is often per-
ceived as being high due to its technological envi-
ronment requiring significant upfront investment in
treatment machines and buildings. Interestingly,
however, available data have shown that even in
countries with optimal infrastructure, the budget
consumed by RT comprises roughly only 5% of the
total amount spent on cancer care (Norlund 2003). In
the early 1990s, the European Union estimated the
average cost per course of RT at about 3,000€,
compared to roughly 7,000€ and 17,000€ for surgical
and chemotherapy treatments respectively. However,
in spite of the perception of high capital costs, it is the
Promises and Pitfalls of Health Technology Assessment
personnel cost that dominates the cost of the provision
of the service with capital investment typically repre-
senting less than 30% of the total RT budget (Lievens
et al. 2003; Norlund 2003; Perez et al. 1993). Although
analysts broadly agree on the division of costs between
infrastructure and process (Ploquin and Dunscombe
2008), many details are still missing. For example, how
do we account for the fact that specific equipment, such
as electronic portal imaging, may be used more or less
intensively depending on the complexity of the treat-
ment? And how does the initial purchase cost of dif-
ferent pieces of equipment translate into the final
treatment cost of each individual treatment? We will
suggest below that these issues can be addressed
through Activity Based Costing.
For the more general point of view, two reports
give us some hint of RT cost evolution over the last
decades. The Swedish Council on Technology
Assessment in Health Care (SBU) computed an
inflation-corrected 16% increase in the total cost of
external RT in Sweden between 1991 and 2000. Due
to increased automation and computerization,
however, the number of fractions increased even
more, rendering external RT delivery more efficient
overall (Norlund 2003). More recently based on an
analysis of the limited costing literature from high
income countries—the real, inflation-corrected,
annual increase in RT cost per patient was estimated
at 5.5% over the last 15 years (Ploquin and
Dunscombe 2008). The improved efficiency apparent
from the Swedish study was not reflected in this lit-
erature analysis. Intuitively one can easily understand
that RT costs will evolve with time, in parallel with
the technical evolution of our treatments. It is
important to note, however, that the cost estimates
presented in the two publications discussed above
were made well before the recent and widespread
introduction of more sophisticated treatment tech-
niques such as IMRT, IGRT, and SRT.
Even after correcting for the time factor, the con-
siderable variation between the computed costs in
different studies is significant. This variation can, in
part, be attributed to the different salary and cost
structures of the countries of origin of the studies,
making the interpretation of the computed treatment
costs across country borders a delicate exercise. On
top of that, the lack of a standardized costing
methodology—institutional vs. societal perspective,
cost per patient vs. cost per fraction, the inclusion of
557
different cost components, and RT activities—renders
the comparison between the analyses extremely hard
to do. In order to arrive at solid cost data for current
and new RT techniques and strategies, the choice of
an appropriate evaluation methodology is clearly
crucial.
5.4 Reimbursement Based Costs
Whereas EE theoretically advocates for the use of
cost figures that reflect the actual resource consump-
tion, this is frequently not achievable and charges are
then used as a proxy. It should, however, be realized
that large discrepancies may exist between the reim-
bursement of treatments and their costs in terms of
resources consumed while delivering a treatment.
In many European countries, due to the fact that
reimbursement often lags behind the introduction of
novel technologies, there is a tendency for high-tech
treatments to be under reimbursed and the financial
coverage of less demanding treatments to reflect,
more realistically, the true resource consumption.
The inverse seems to hold for the US, where the
reimbursement is likely to be higher for new tech-
nologies but decreases with time.
Besides the observed numerical differences
between costs and charges, other, more practical and
theoretical problems may arise when utilizing reim-
bursement figures for EE. This was observed by the
Radiation Therapy Oncology Group (RTOG) when
performing an EE based on combining clinical trial
data with cost data obtained from Medicare for each
patient (Konski 2011).
The first problem arising was that Medicare-man-
aged care products do not have individual claims as
managed care companies receive capitated payments
and may therefore not record and/or report individual
claims to Medicare. A more accurate estimation of
costs would result from using administrative claims
data to calculate costs, provided that they contain all
claims of care a patient received. This type of anal-
ysis, however, would then be from the payer’s per-
spective. Another potential problem is that an
underestimation of costs could occur if codes with
only a cancer diagnosis were used, thus neglecting
costs related to treatment toxicity or indirect medical
costs occurring in the further follow-up of the patient.
It may also be difficult to generalize the results of an
558
analysis based on Medicare patients older than 65 to
the general population. Lastly, it is apparent that
obtaining administrative claims data from Medicare
can be a costly procedure in itself.
As a result of all these considerations, it can be
concluded that the results of EE of clinical trials using
actual claims data should be interpreted with caution.
5.5 Model Based Costs
A technique that is very useful in evaluating the bud-
getary impact of new technologies and strategies in
radiation therapy is Activity Based Costing (ABC)
(Baker 1998). ABC finds its primary use in the
estimation of direct medical costs as described in
Sect. 5.2. of this chapter. It was developed with the aim
of capturing the economic consequences of product
complexity. In this approach the course of treatment
that a patient receives is made up of a basket of services
(activities) each of which is costed, most frequently on
the basis of time consumption. Thus, the cost of a
course of treatment will depend on whether or not
image guidance is included, for example.
Besides a more accurate calculation of the treat-
ment costs, the use of ABC provides a better insight
into the (cost-) structure of the treatment and of the
RT department as a whole, which makes it suitable
for evaluating the budgetary impact of new technol-
ogies and process changes. The major advantage of
ABC is indeed found in the fact that it allows inclu-
sion or exclusion of particular steps in the process,
such as IMRT or portal verification, for which the
financial impact can then be studied. An ABC model
could also be used to quantify the financial impact of
the increased QA efforts resulting from the current
emphasis on patient safety.
Similarly, different fractionation schedules can be
modeled without relying on the very poor approxi-
mation that treatment cost scales linearly with the
number of fractions, as is assumed in more simple
spreadsheet models.
An example of an ABC cost-calculation model is
the one developed in the Leuven RT department
(Lievens et al. 2003). As it was felt that current RT
protocols, with a shift towards more complex treat-
ment planning and delivery techniques and more
thorough QA procedures, were no longer accurately
captured within the original model, a novel version
Y. Lievens et al.
has recently been developed (Van de Werf et al.
2011). As an example of the financial impact of
evolving technology over the last decade, it was
found that the introduction of IMRT instead of
3D-CRT translated into an almost doubling of the
costs. The use of ABC allowed the authors to trace
exactly where these extra costs were incurred. In their
example, it was shown that the cost increase was not
the consequence of the IMRT technique as such, but
of the combined effect of IMRT delivering higher
fraction numbers and the introduction of more
important, often daily, online imaging for position
verification. If, however, new techniques such as
IMRT or gated radiotherapy delivery make it possible
to reduce the number of fractions using simultaneous
integrated boosts or accelerated hypofractionation,
then the resulting costs may come down again
(Lievens 2010).
Another example of ABC is the analysis of Ploquin
and Dunscombe (2009) in which cost outcome esti-
mates of image guided patient repositioning for
prostate cancer patients have been made in the con-
text of different correction protocols. Similarly to the
Leuven study, ABC allowed the inclusion or exclu-
sion of certain activities, in this case specifically
related to image guidance.
An advantage of ABC, already mentioned above,
is that it allows the analyst to separate out the impact
of preparatory activities from the actual RT delivery
and its QA. In an era with revived interest for hypo-
fractionated schedules, this feature is valuable. The
difference in approach can be demonstrated by two
articles focusing on the cost of particle therapy. The
article of Perrier et al. devoted to the cost of carbon
ion therapy, used an ABC-approach similar to the
examples discussed above. In this way, it allowed an
in-depth definition of the cost of treatment preparation
and the actual irradiation depending on various
parameters such as actual treatment time and patient
set-up time (Perrier et al. 2007). The approach of
Peeters et al. conversely, was more aggregate using a
spreadsheet model which assumes that treatment costs
scale linearly with the number of fractions (Peeters
et al. 2010). This, obviously, is a somewhat simple
approximation of reality which results in less accurate
estimates than the ones described earlier.
Whether the more refined—but in itself also more
time-consuming and thus costly—ABC-approach is
required will have to be judged depending on the
Promises and Pitfalls of Health Technology Assessment
specific situation. Nevertheless, the examples pre-
sented above demonstrate that ABC is particularly
well suited for the study of incremental costs, and
savings, of process and technology changes.
6 Potential Pitfalls
in the Interpretation of Economic
Evaluations
To illustrate some of the challenges with performing
and interpreting EE we use, as examples, two cost-
effectiveness analyses comparing proton therapy for
prostate cancer to IMRT. These illustrate how dif-
ferent input variables can lead to completely different
conclusions. Although proton-beam therapy is being
increasingly used in the treatment of a number of
malignancies, especially in the United States, a lively
discussion continues on whether the expected long-
term benefits are worth the important extra invest-
ments. The long natural history of prostate cancer
would make it very difficult to show a survival
advantage of using proton-beam therapy compared
with IMRT, and the reimbursement in the US has
encouraged a swift uptake of the technology making
formal comparison between the two alternatives
practically impossible. Hence the interest in per-
forming an EE.
Two studies were published on the subject. The
first, a Swedish analysis, computed an iCER of
€26,800/QALY and concluded that proton RT for
prostate cancer may be cost-effective, provided there
was an appropriate patient selection (Lundkvist et al.
2005). The second, performed in the US, calculated
an iCER between US$63,578/QALY and US$55,726/
QALY and came to the conclusion that even assum-
ing a potential of 10-Gy dose escalation, proton-beam
therapy is not cost-effective for most patients with
prostate cancer compared to the IMRT standard
(Konski et al. 2007).
The difference in result (and interpretation) can be
appreciated when looking at the details of the studies.
Although both used a Markov modeling approach, the
structure of the model was quite different with
inclusion of the (cost and outcome) consequences of
systemic treatment at disease progression in the US
model, whereas the Swedish model merely focused on
survival and toxicity issues. The latter analyzed a
younger cohort (65-year old prostate cancer patients),
559
whereas the American study modeled a somewhat
older (70-year-old patients) cohort with intermediate-
risk adenocarcinoma of the prostate. Most impor-
tantly, large differences were seen in the cost and
outcome estimates. The Swedish analysis, based on a
costing study, calculated an incremental cost of pro-
ton therapy of only €7,953; the American analysis
used US reimbursement figures resulting in an
incremental cost as high as US$32,765. Finally, the
expected improvement in outcome was estimated
more modestly in the American study, i.e. 10%
increase in freedom from biological failure at
10 years without impact on QOL, compared to an
assumed 20% reduction in overall prostate cancer
mortality along with a 20% reduction in the risk of
adverse events in the Swedish analysis.
It does not seem surprising that combining all
these various parameters into different models can
only but translate into a different result. All in all it is
not a question of which model is right, but whether
the assumptions made in the models are correctly
reflecting the actual treatment standards in the eco-
nomic environments in which these models may be
used for supporting financial decisions.
A further contributing factor to the discrepancy
between these two studies is the different time hori-
zons used. The American analysis was stopped after
running the model for 10 years, whereas the Swedish
cohort of patients was allowed to evolve between time
of diagnosis until death or 100 years of age.
When performing EE in RT, the importance of the
choice of a sufficiently long time horizon cannot be
overemphasized, as it is probably the single most
important factor influencing the final outcome of the
analysis. The reason for this time dependency is that
in the context of primary or adjuvant RT, the costs are
made immediately, whereas the outcome—be it
improved local control or survival and/or decreased
late toxicity—will only become apparent with time.
If the analysis is terminated too early, these outcomes,
as well as the related cost saving, will be missed
and the analysis may incorrectly result in very high
iCERs.
To illustrate this issue we consider adjuvant RT for
breast cancer, another common disease with a slow
natural history and many treatment possibilities
available at relapse. Figure 2 compiles the iCERs
reported in the literature on post-operative RT for
breast cancer, be it post-mastectomy (squares), breast
560
conserving for invasive (triangles) and in situ cancer
(circle), or internal mammary and medial supracla-
vicular lymph node (IM-MS) irradiation (star).
Making abstraction from the large diversity in other
parameters included in these studies, there is a clear
trend toward lower iCERs with increasing time. As a
matter of fact, the longer patients are allowed to
evolve within a model (in parallel with the survival
curves in the clinical studies on which the EE are
based), the more the difference in absolute relapse
rate between patients receiving adjuvant RT and those
who do not becomes apparent. Along with the accu-
mulating relapses, the costs start to separate. As such,
all studies evaluating the economic effect of adjuvant
RT after more than 10 years have proven cost-effec-
tive, with the IM-MS analysis being at the extreme.
It not only resulted in a greater effectiveness but also
in a lower cost; the additional upfront RT cost being
limited, it was easily compensated for by the pre-
vention of later relapse and its associated costs, even
if only in a small proportion of the patients. This was
so if a time horizon of 20 years was adopted in the
model. However, using progressively shorter time
intervals, the costs per outcome slowly changed and
suddenly rose to a dramatically high level at 5 years
(Lievens 2008). This is logical with the difference in
survival being negligible shortly after adjuvant RT for
breast cancer and only becoming apparent after many
years. A comparable time-dependent observation was
made in the analyses of Liljegren et al. (1997) and of
Dunscombe et al. (2000).
7 Conclusion: Challenges
and Opportunities
Availability of the necessary resources for radiation
therapy, by and large based on correct financing,
remains the precondition to safeguard accessibility,
quality, and technological evolution of our special-
ization. However, to obtain reimbursement for new
treatment strategies and technologies, quantitative
data confirming that the novel treatment delivers
value for money are nowadays frequently demanded.
In contrast to other medical disciplines—especially
those supported by the pharmaceutical industry,
which introduced the methodology of EE in their field
decades ago—the radiation oncology community has
so far not felt the urgent need to be concerned about
Y. Lievens et al.
cost-effectiveness. But if we want to maintain and
further improve the service we provide to RT patients
in a societal and economically responsible manner in
an era of cost-consciousness and tightening budgets,
we need to improve our understanding of the
costs and benefits of new technologies and treatment
strategies.
The amount of money that a society is willing to
pay for, let us say, an extra QALY resulting from a
new treatment is highly variable among countries. By
examining the costs and outcomes of those interven-
tions which have been implemented and those which
have not, it appears that one QALY is worth between
US$50,000 and more than US$100,000 in the United
States (Weinstein 2008; Braitwaithe et al. 2008),
£20,000–£30,000 in the UK (NICE 2004), €80,000 in
other European countries such as the Netherlands
(Raad voor de Volksgezondheid en Zorg et al.
2006), and CAN$20,000–CAN$100,000 in Canada
(Laupacis et al. 1992). This wide range in accepted
iCERs among and within different countries can, in
part, be explained by differences in economic struc-
ture and political climate, both of which determine the
accepted share of health care in the national budget.
Similar factors may also influence issues related to
resource availability and accessibility of care.
On top of that, the methodological diversity in
health economic studies, discussed extensively in this
chapter, may further blur the picture. In order to
support the evaluation of health economic aspects of
radiation treatment at the national level and to
benchmark between countries, it therefore seems
wise to develop a standardized health economic
framework.
It is in this context that the European Society of
Therapeutic Radiology and Oncology (ESTRO) is
launching the HERO-project (Health Economics in
Radiation Oncology). Its overall aim is to develop a
knowledge base and a model for health economic
evaluation of radiation treatment at the European
level. To accomplish these objectives, the HERO-
project will address five different dimensions.
The need for RT will be assessed by defining the
optimum RT uptake in Europe derived from evi-
dence-based guidelines and by describing the
resources required to deliver this defined optimum
level of care. Provision and accessibility will be
addressed by surveying national recommendations on
infrastructure and staffing levels, compared with the
Promises and Pitfalls of Health Technology Assessment
available infrastructure, machines, and staffing in
European countries. In addition, the actual RT treat-
ment mix delivered within the different countries
will be documented. Based on the former data, a
cost-accounting program for RT in Europe will be
developed, using ABC methodology. These cost data
will, in a subsequent phase, be used in economic
evaluations, performed with Markov models. As a
final step in the HERO-project, the identified key
figures and generated data will be used for profiling
RT in the cancer management spectrum, to help
countries prioritize the most cost-effective approaches
and to define optimal reimbursement strategies in
order to tackle the potential discrepancies between the
evidenced-based need for RT and the resources
available in different countries.
It is only by investing in this kind of research
that the RT community will be able to demonstrate
that RT truly delivers value for money and that the
radiation treatment team can become partners in
healthcare management, decision-making and bud-
geting in cooperation with governmental and
insurance parties.
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 Part II

Clinical Applications
 Central Nervous System Tumors
William A. Hall and Walter J. Curran
Contents
1 Introduction.............................................................. 566
2 Natural History ........................................................ 566
2.1 Anatomy of the Brain ............................................... 566
2.2 Epidemiology............................................................. 567
3 Workup and Staging ............................................... 570
4 General Management ..............................................
4.1 Medical Management ................................................
4.2 Surgical Management ................................................
4.3 Radiation Therapy .....................................................
5 General Concepts of Modern Radiation
Therapy Technique..................................................
5.1 Principles of Imaging-Based Treatment Planning....
5.2 Target Volumes and Organs at Risk
Specifications.............................................................
5.3 Dose Reporting ..........................................................
5.4 Intensity-Modulated Radiation Therapy ...................
5.5 The Role of Image-Guided Radiation Therapy
in the Central Nervous System .................................
6 Simulation Procedures ............................................
6.1 General Concepts of Positioning, Immobilization,
and Simulation...........................................................
6.2 Specific Examples of Treatment Techniques...........
6.3 Spinal Radiosurgery ..................................................
6.4 The Use of Heavy Charged Particles in Central
Nervous System Radiotherapy ..................................
6.5 Brachytherapy and Radiocolloid Solutions
in the Central Nervous System .................................
7 Simulation Films and Portal Films ....................... 591
7.1 Image Guided Radio Therapy, General Principles ... 591
W. A. Hall (&)  W. J. Curran
Department of Radiation Oncology,
Winship Cancer Institute, Emory University,
Atlanta, GA, USA
e-mail: whall4@emory.edu
S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_280, Ó Springer-Verlag Berlin Heidelberg 2012
8 Dose Prescriptions ................................................... 592
8.1 Primary Central Nervous System Tumors................ 592
8.2 Metastatic Central Nervous System Tumors............ 592
8.3 Stereotactic Radiosurgical Dose for Metastatic
Central Nervous System Lesions .............................. 593
8.4 The Role of Sterotactic Radiosurgery Versus
Whole Brain Radiation Therapy for Metastatic
Central Nervous System Tumors .............................. 593
8.5 The Use of Invasive Head Frame Immobilization
Techniques Versus Non-Invasive Immobilization
571 for Stereotactic Radiosurgery.................................... 593
571
572 9 The Role of Chemotherapeutic Agents in Central
573 Nervous System Tumors ......................................... 594
10 Future Directions..................................................... 594
573
References.......................................................................... 594
573
577
579 Abstract
579 Tumors of the central nervous system account for a
substantial amount of morbidity and mortality annu-
581
ally. Radiation therapy (RT) has played an increas-
581 ingly larger role in the treatment of CNS tumors as
technology has advanced and radiation delivery has
581
583 become more accurate and conformal. In the modern
587 era of radiation therapy normal structures can be
delineated and avoided with extreme precision and
588
accuracy, maximizing the delivery of RT to the tumor
588 and minimizing the RT to normal structures.
For patients with tumors not amenable to surgical
resection radiotherapy often plays a definitive role in
the management of these malignancies. Additionally
the ability of radiotherapy to control brain tumors is
increasing in the era of modern day chemotherapy
which can frequently be used to increase the
sensitivity of various malignancies to radiotherapy.
As RT technology advances the role of RT in the
565
566
management of CNS malignancies will likely con-
tinue to increase over the coming years. The future of
radiation delivery in the CNS is exciting and rapidly
changing. The following chapter servers as a general
overview to the management and treatment of a
variety of CNS tumors, and presents some exciting
advances in radiation therapy that may play a larger
role in the future.
1 Introduction
The central nervous system (CNS) comprises the
brain and spinal cord and their coverings and may be
affected by either a primary or a metastatic tumor.
The outcomes of treatment are highly variable, being
dependent on diagnosis. Patients with benign diseases
may be able to live out their natural life span, while
those with malignant tumors may have a life expec-
tancy measured in weeks or months. The clinician
should use an appropriate treatment technique for any
patient with a CNS tumor in order to minimize the
chance of significant acute toxicities (or late toxicities
in survivors) and maximize the therapeutic benefit.
2 Natural History
2.1 Anatomy of the Brain
Knowledge of the basic topographical and functional
anatomy of the brain and spinal cord is critical for
accurate delineation of tumor location within the CNS
as well as defining areas of functional eloquence that
need to be considered when planning any therapy.
Generally, the brain is considered to have three major
divisions: the cerebrum, cerebellum, and brain stem.
Consideration of tumor location often leads to dis-
tinguish between supratentorial (cerebral hemispheres
and midline structures) and infratentorial (cerebellum,
lower brain stem) locations.
The longitudinal cerebral fissure divides the cere-
brum into the left and right hemispheres, with each
hemisphere separated by major sulci into four lobes:
frontal, parietal, occipital, and temporal. There are
also two midline lobes known as the central and
limbic lobes (Fig. 1).
The prominent central sulcus (of Rolando) sep-
arates the frontal lobe from the parietal lobe. The
W. A. Hall and W. J. Curran
parietal–occipital fissure separates parietal lobe from
occipital lobe. The lateral fissure (of Sylvius) defines
the temporal lobe boundaries. The cerebral hemi-
spheres are connected by the corpus callosum, beneath
which are the midline structures (third ventricle, pineal
body, and midbrain) and the deep paramedian struc-
tures (lateral ventricles, caudate nucleus, lentiform
nucleus, thalamus, and hypothalamus).
A basic understanding of the functional anatomy of
the cerebral hemispheres can be approached in three
ways. The first is a regional or ‘‘lobe-by-lobe’’ con-
sideration of function. The occipital lobe is primarily
involved with vision and its dependent functions. The
temporal lobe processes sound, vestibular sensations,
sights, smells, and other perceptions into complex
‘‘experiences’’ important for memory. Wernicke’s
area is located on the posterior portion of the superior
temporal gyrus and plays a critical role in receptive
speech. The parietal lobe, specifically the postcentral
gyrus, is critically involved in somatosensory func-
tion. Sensory integration (body image) and Gnostic
(perceptive) functions also reside within the parietal
lobe. The frontal lobe is associated with higher level
cognitive functions such as reasoning and judgement.
The frontal lobe also contains the primary motor
cortex (precentral gyrus) and Broca’s area (inferior
third of the frontal gyrus), important in expressive
speech. The limbic lobe mediates memories, drives,
and stimuli. It affects visceral functions central to
emotional expression, such as sexual drive. Finally,
the central lobe (insula) is important in visceral sen-
sation and motility.
The second approach to functional neuroanatomy
is the schema of Brodmann, which numbers the
areas of structural specialization (Brodmann 1908a, b).
These numbered areas, in some cases, correspond to
the functional location of important primary, sensory,
and motor areas. The 52 numbered areas provide both
an anatomical and functional ‘‘road map’’ of the brain
by which tumor location can be described (Fig. 2).
The final and most eloquent method to describe
functional neuroanatomy is through various tech-
niques of functional mapping (Fig. 3).
While classic mapping utilizes microelectrode
stimulation of the cortical surface directly, new
non-invasive techniques such as functional magnetic
resonance imaging (fMRI), positron emission tomog-
raphy (PET), and magnetoencephalography (MEG) are
increasingly being integrated into clinical practice
Central Nervous System Tumors
Fig. 1 a Lateral surface of the brain including cerebral
hemisphere, cerebellum, and brainstem. The major sulci divide
the cerebral cortex into four lateral lobes: frontal, parietal,
Fig. 2 Location of the major motor, sensory, and speech areas
of the cerebral cortex with reference to Brodmann’s area
numbers
(Babiloni et al. 2004; Barnes et al. 1997; Choi et al.
2005). These procedures allow for precise mapping of
function in an individual and can accurately predict
deficits related to injury of a given area by tumor or
therapy.
In its most basic form Functional Magnetic Reso-
nance Imaging is a type of specialized MRI scan that
measures the hemodynamic response of neuronal
activity in the brain or spinal cord (Di Salle et al.
2003) (Fig. 4). The principle of fMRI is based on the
limited neuronal reserve of glucose. As the neuronal
activity increases this requires more glucose and
oxygen to be delivered through the blood stream to
the neuronal tissue. This increase in blood flow results
in a surplus of oxyhemoglobin in the area of active
neural tissue. The presence of oxyhemoglobin chan-
ges the magnetic resonance of blood when compared
to deoxyhemoglobin. fMRI uses this difference to
acquire an image of the function brain tissue (Ogawa
567
occipital, and temporal. b Medial surface of the left brain
demonstrating midline structures of the central and limbic lobes
et al. 1990). Its validity in a variety of arenas con-
tinues to be studied.
Other new functional brain imaging techniques
such as single-photon emission computed tomography
(SPECT), specifically Thallium-201 (201Tl), are
gaining increased importance in clinical tumor
response assessment. The utility of Thallium-201
SPECT comes from its ability to selectively uptake in
tumor cells. This is caused by the Thallium-201
(201Tl) SPECT cell-specific tracer uptake in malignant
cells. Normal brain tissues and non-tumor tissues
(radiation necrosis) do not uptake the Thallium-201.
This has a variety of clinical applicabilities discussed
in the subsequent sections of this chapter.
2.2 Epidemiology
2.2.1 Primary Central Nervous System
Tumors
The incidence rate of all primary non-malignant and
malignant (including pilocytic astrocytomas) brain
and CNS tumors is 14.1 cases/100,000 person years
(6.8/100,000 person years for benign and borderline
tumors and 7.3/100,000 person years for malignant
tumors). The overall incidence rates increased from
13.5/100,000 person years in 1997 to 14.7/100,000
person years in 2001 (CBTRUS 2004). The rate is
higher in females (14.3/100,000 person years) than
males (13.9/100,000 person years). An estimated
41,130 new cases of primary non-malignant and
malignant brain and CNS tumors were expected to be
diagnosed in 2004 (CBTRUS 2004). The worldwide
568
Fig. 3 Cortical surface electrode mapping of the speech area
in a patient undergoing resection of recurrent glioma.
a Exposed cortical surface. b Mapping array in place.
c Resection cavity with electrode number 5 demarcating
speech area. Patient had normal speech postoperatively
incidence rate of primary malignant brain and CNS
tumors, age-adjusted using the world standard popula-
tion, is 3.6/100,000 person years in males and 2.5/
100,000 person years in females. The incidence rates are
higher in more developed countries (males 5.9/100,000
person years; females 4.1/100,000 person years) than in
W. A. Hall and W. J. Curran
less developed countries (males 2.8/100,000 per-
son years; females 2.0/100,000 person years) (Ferlay
et al. 2001). The incidence rate of childhood primary
non-malignant and malignant brain and CNS tumors
is 4.0 cases/100,000 person years. The rate is higher
in males (4.2/100,000 person years) than females
(3.8/100,000 person years) (CBTRUS 2004). An
estimated 18,500 deaths in 2005 will be attributed to
primary malignant brain and CNS tumors (American
Cancer Society 2005).
The majority of primary CNS tumors (31%) are
located within the frontal, temporal, parietal, and
occipital lobes of the brain. Tumors in other locations in
the cerebrum, ventricle, cerebellum, and brainstem
account for 3, 2, 4, and 2% of all tumors, respectively.
Other tumors of the brain account for 16% of all tumors.
Tumors of the meninges represent 24% of all tumors.
The cranial nerves and the spinal cord/cauda equina
account for 6 and 4% of all tumors, respectively. The
pituitary and pineal glands account for about 7% of
tumors. Olfactory tumors of the nasal cavity and other
CNS tumors, NOS (not otherwise specified), each
account for less than 1% of tumors (CBTRUS 2004).
The overall incidence of primary spinal cord tumors
is approximately 10–19% that of all primary brain
tumors (Connoly 1982). The incidence ratio of intra-
cranial to intraspinal tumors is up to four times higher in
pediatric patients than in adults, the frequency of specific
spinal cord tumors being quite different from that of their
brain tumor counterparts. The incidence ratios of intra-
cranial to intraspinal astrocytomas, ependymomas and
meningiomas are approximately 10:1, 3:1, and 18:1,
respectively (Sasanelli et al. 1983). Schwannoma and
meningioma account for approximately 60% of primary
spinal tumors, with schwannoma being slightly more
frequent; both types occur primarily in adults. Regional
differences are also noted. Gliomas constitute 46% of
primary intracranial tumors but only 23% of spinal
tumors. Most primary spinal gliomas are ependymomas
with a predilection for the cauda equina.
In 2007, the World Health Organization (WHO)
updated their comprehensive classification of primary
CNS neoplasms. This was based on the concensus of
an international working group of 25 pathologists,
geneticists, and 70 international experts. The classifi-
cation contains several new entities, including
angiocentric glioma, papillary glioneuronal tumor,
rosette-forming glioneuronal tumor of the fourth ven-
tricle, papillary tumor of the pineal region, pituicytoma
Central Nervous System Tumors 569

Table 1 Grading of astrocytic tumors

WHO WHO Kernohan St. Anne/Mayo St. Anne/Mayo grade criteria
designation grade grade grade
Pilocytic I I (excluded) (n/a)
astrocytoma
Astrocytoma II I, II 1 0 criteria presenta
2 1 criterion present: usually nuclear atypia
Anaplastic III II, III 3 2 criteria present: usually nuclear atypia and mitosis
astrocytoma
Glioblastoma IV III, IV 4 3–4 criteria present: usually the above and/or endothelial
multiforme proliferation and/or necrosis
A given tumor may not fall under the same designation in all three systems (Daumas-Duport et al. 1988; Huntington et al. 1965;
International Agency for Research on Cancer 2000)
a
Criteria include nuclear atypia, mitosis, endothelial proliferation and necrosis

and spindle cell oncocytoma of the adenohypophysis
(Louis et al. 2007). The most frequently reported his-
tology is a predominately benign tumor, meningioma,
which accounts for over 29% of all tumors, followed
closely by glioblastomas and astrocytomas. The pre-
dominately benign nerve sheath tumors and pituitary
tumors account for 8 and 6% of all tumors, respec-
tively. Acoustic neuromas account for 54% of all
nerve sheath tumors. Gliomas are tumors that arise
from glial cells, and include astrocytomas, glioblasto-
mas, oligodendrocytomas, ependymomas, mixed glio-
mas, malignant gliomas NOS, and neuroepithelial
tumors. The broad category glioma represents 42% of
all tumors (CBTRUS 2004). Of gliomas, 61% occur in
the frontal, temporal, parietal, and occipital lobes of the
brain. Glioblastomas account for the majority of glio-
mas, while astrocytomas and glioblastomas account for
three-quarters of gliomas (CBTRUS 2004). Table 1
shows a comparison of different grading systems
that have been used to classify the malignant gliomas.
The most common spinal cord intramedullary tumors
are those that are derived from glial precursors
(astrocytes, ependymocytes, and oligodendrocytes)
(Preston-Martin 1990).
2.2.2 Tumors Metastatic to the Central
Nervous System
The most common intracranial neoplasms in adults are
metastasis from extracranial malignancies, and they
constitute a significant cause of morbidity and mortal-
ity. The estimate of the incidence rate of metastatic
brain tumors varies from 8.3 to 11/100,000 (Percy et al.
1972; Walker et al. 1985). In two cohorts of patients
who were diagnosed with colorectal, lung, breast, or
kidney carcinoma or melanoma, brain metastases were
diagnosed in 8.5–9.6% of patients (Barnholtz-Sloan
et al. 2004; Schouten et al. 2002). The cumulative
incidence was estimated at 16.3–19.9% in patients
with lung carcinoma, 6.5–9.8% in patients with renal
carcinoma, 6.9–7.4% in patients with melanoma,
5.0–5.1% in patients with breast carcinoma, and
1.2–1.8% in patients with colorectal carcinoma.
The spinal boney elements are the most common
site of bony metastases overall, with a reported inci-
dence in cancer patients as high as 40% (Byrne 1992).
Malignant spinal cord compression (MSCC) from
epidural metastases occurs in 5–10% of cancer patients
and in up to 40% of patients with preexisting nonspinal
bone metastases (Bilsky et al. 1999; Byrne 1992;
Healey and Brown 2000; Wong et al. 1990). In patients
with bony spinal disease, 10–20% develop sympto-
matic spinal cord compression. This results in between
14,100 and 28,200 cases/year (Gerszten and Welch
2000; Loblaw et al. 2003; Schaberg and Gainor 1985).
The overall incidence of MSCC within 5 years of
death from cancer is 2.5% (Loblaw et al. 2003).
Symptoms depend on location of the compression and
can involve the spinal cord at any level. The most
common initial presenting symptom of MSCC is back
pain, and new onset back pain in any patient with a
history of malignancy requires serious attention and
evaluation. Common initial presenting symptoms in
addition to back pain consist of urinary incontinence,
fecal incontinence, or neurologic symptoms corre-
sponding to the level of compression. The incidence of
570
MSCC by vertebral level is 10–16% cervical, 35–40%
in T1-6, 44–55% in T7-12, and 20% lumbar (Gilbert
et al. 1978; Patchell et al. 2003; Pigott et al. 1994).
Metastatic lesions present initially at multiple, non-
contiguous levels in 10–38% of cases (Gilbert et al.
1978; O’Rourke et al. 1986; Ruff and Lanska 1989).
The histology of MSCC follows the incidence
patterns of malignant disease, with the most common
histological diagnoses (breast, lung, and prostate)
accounting for approximately half of all cases
(American Cancer Society 2005; Byrne 1992).
Approximately, 25% of all patients with MSCC have
breast cancer, 15% lung cancer, and 10% prostate
carcinomas. Overall, 5.5% of breast cancer patients,
2.6% of lung cancer patients, 7.2% of prostate cancer
patients, and 0.8% of colorectal cancer patients
experience an MSCC (Loblaw et al. 2003). Other
commonly reported histological diagnoses in adults
include, by order of cumulative incidence, multiple
myeloma, nasopharynx, renal cell, melanoma, small-
cell lung, lymphoma, and cervix (Byrne 1992;
Loblaw et al. 2003; Schiff et al. 1998).
3 Workup and Staging
For CNS tumors, both benign and malignant, MRI
with and without contrast remains the gold standard
for imaging (Ricci and Dungan 2001). The preferred
slice thickness of MRI is 5 mm or less with a 2.5 mm
or lower slice sampling. T1-weighted images with
contrast allow excellent visualization of contrast-
enhancing tumors such as meningiomas, glioblastoma
multiforme, and brain metastases. T2-weighted
images demonstrate areas of edema that reflect
involvement by infiltrative low- or high-grade glio-
mas T1-weighted FLAIR images are also useful in
this regard. MRI fusion or registration with the
treatment planning computed tomography (CT) scan
should be utilized for target definition; this is descri-
bed in the section Principles of Imaging-Based
Treatment Planning (MRI-CT fusion Fig. 4). Other
imaging studies such as MRI spectroscopy, fMRI,
PET scans, and single photon emission tomography
(SPECT) scans better reflect the biological charac-
teristics of CNS tumors, such as tumor metabolism,
proliferation, oxygenation and blood flow, and func-
tion of surrounding normal brain (fMRI tongue
movement Fig. 4). Functional and biological imaging
W. A. Hall and W. J. Curran
data are currently incorporated into decisions as to
whether ablative procedures such as surgery, radio-
surgery, or brachytherapy can be safely considered.
Also, PET scans and MRI spectroscopy may allow for
differentiating active tumor versus radionecrosis after
radiation therapy. The integration of MR spectros-
copy and PET imaging into radiation therapy treat-
ment planning is a current topic of research by a
variety of groups (Munley et al. 2002; Nuutinen et al.
2000; Pirzkall et al. 2000; Kovacs et al. 2010).
CNS tumors rarely metastasize outside the CNS
but may spread within it. For example, medulloblas-
tomas, primitive neuroectodermal tumors, anaplastic
ependymomas, choroids plexus carcinomas, pineobl-
astomas, germ cell tumors, and lymphomas may
involve the cerebrospinal fluid (CSF), leptomeninges
(i.e., coverings of the brain), or spinal cord. Studies
that stage the extent of these tumors include MRI of
the entire neural axis and CSF cytology. For patients
who cannot receive MRI-based imaging secondary to
metallic components in their body a CT myelogram
can be used in addition to a contrast enchanced CT
scan to evaluate the neuronal axis for compression.
In patients who present emergently, CT can be
obtained rapidly, and provide information about
ventricular obstruction, hemorrhage, or edema,
although imaging of the parenchyma is inferior to
MRI. Lumbar puncture should be avoided if possible
until intracranial pressure has normalized, due to the
risk of herniation and death. The most important
modality in the workup of suspected MSCC is gad-
olinium-enhanced MRI of the entire spinal axis. This
imaging should be performed in any situation where
spinal cord compression is suspected as focal. Imag-
ing based on clinic symptoms can miss other occult
locations of spinal metastatic disease. With the
exception of a primary paraspinal or neuraxis tumor,
MSCC occurs most often in the setting of dissemi-
nated disease from a distant primary tumor site. As
previously mentioned, a potential pitfall in the initial
evaluation of a patient with suspected spinal cord
compression is imaging only the symptomatic area of
the spine. Frequently, patients with lower body or
extremity symptoms, and/or radicular pain in the
lumbar distribution present for evaluation and man-
agement with only partial spine imaging. It is
important to consider that 25% of patients have spinal
cord compression verified at multiple levels by MRI,
and approximately two-thirds of these have
Central Nervous System Tumors
Fig. 4 Example of fMRI with tongue activation, this imaging is utilized when evaluating a patient for surgical intervention of a
CNS tumor
involvement of different regions of the spine
(Husband et al. 2001). When a sensory level is present
on patient evaluation, it may be two or more segments
different from the actual lesion on MRI in 28% of
patients, and four or more levels distant from the
lesion in 21% of patients (Husband et al. 2001).
4 General Management
Multimodality therapy for CNS tumors routinely
takes the form of medical treatment followed by
surgical resection for durable decompression and to
obtain a tissue diagnosis. Patients who are medically
inoperable, refuse surgery, or have multiple and/or
unresectable lesions often receive whole brain radia-
tion therapy (WBRT) for palliation of their symp-
toms. Essential in the management of all patients with
CNS malignancy is a multidisciplinary effort involv-
ing a neurosurgeon, a medical oncologist and a radi-
ation oncologist.
4.1 Medical Management
Medical treatment generally consists of steroids with
or without mannitol (Sarin and Murthy 2003). Both
571
drugs have previously been shown to decrease perit-
umoral brain edema by different mechanisms of
action (Bell et al. 1987). Mannitol is used in steroid
refractory patients. A common regimen of mannitol is
20–25% solution given intravenously (i.v.) over
approximately 30 min dosed at 0.5–2.0 g/kg (Quinn
and DeAngelis 2000). Patients who present emergent
symptoms from intracranial malignancy are typically
treated with dexamethasone. Response to therapy is
usually noted within 12–18 h of administration, and
over 80% of patients show dramatic improvement by
3–4 days after initiation of therapy (French 1966;
Long et al. 1966). A common regimen in patients
receiving radiation therapy is high-dose dexametha-
sone (10–25 mg i.v.) followed by maintenance on
oral steroids (4–6 mg p.o. every 6 h), with tapering
initiated at the clinician’s discretion, usually over
1–2 months following the completion of radiation
therapy (Sarin and Murthy 2003; Vecht et al. 1994;
Wolfson et al. 1994). Important attention should be
paid to consoling patients regarding the possible side
effects of long-term steroid use. Common physical
changes associated with steroid use should be
discussed with the patient at the time they are started
and documented and reviewed with the patient at the
time of follow up. In the setting of MSCC from solid
tumors, dexamethasone has been shown to improve
572
rates of surviving with intact gait function (Kalkanis
et al. 2003; Sorensen et al. 1994).
Given the concerns over the incidence of steroid-
induced toxicity with steroid dosing longer than
21 days in duration, higher doses and longer tapering
schedules should be based on the physician’s assess-
ment of symptom severity and response (Heimdal
et al. 1992; Sorensen et al. 1994; Weissman et al.
1991). Side effects of intermediate- to long-term ste-
roid use include: hyperglycemia; insomnia; emotional
lability; thrush; gastric irritation, ulceration and pos-
sibly perforation; proximal muscle wasting; weight
gain and adiposity (moon facies, buffalo hump, cen-
tripetal obesity), osteoporotic compression fractures;
and aseptic necrosis of the hip joints (Bilsky and
Posner 1993). As previously mentioned, these side
effects should be discussed with the patient prior to
steroid initial to prevent an alarming reaction from the
patient if they develop these symptoms. Select
patients with MSCC may not require steroids during
treatment (Maranzano et al. 1996). This management
strategy may be considered reasonable if a patient is
at high risk of complication from steroids due to
underlying medical comorbidities such as peptic ulcer
disease, uncontrolled diabetes, or other medical
problems that may cause severe or life-threatening
problems if steroids are initiated.
Stabilization of the patient in status epilepticus in
order to perform imaging and make management
decisions is critical (Working Group on Status Epi-
lepticus and Epilepsy Foundation of America 1993).
After securing the airway and stabilizing the patient,
seizure activity must be terminated as rapidly as
possible. Phenytoin and rapid onset/short-acting
benzodiazepines are commonly used to quickly con-
trol seizure activity. Recommended initial regimens
include 0.1 mg/kg at 2 mg/min lorazepam or 0.2 mg/
kg diazepam at 5 mg/min. Phenytoin infusion of
15–20 mg/kg at 50 mg/min or less in adults is indi-
cated for seizure activity refractory to benzodiaze-
pines or after truncation of seizures with diazepam
(Working Group on Status Epilepticus and Epilepsy
Foundation of America 1993). Failure to control sei-
zures can potentially lead to physical injuries, airway
compromise and secondary brain hypoxia/injury, or
coma (Epilepsy Foundation of America 1993; Quinn
and DeAngelis 2000). However, there is no evidence
to support routine use of prophylactic anticonvulsants
W. A. Hall and W. J. Curran
for patients diagnosed with a brain tumor (Forsyth
et al. 2003; Glantz et al. 1996).
4.2 Surgical Management
Surgical resection and/or placement of a shunt is often
required for emergent management of brain tumors
causing life-threatening hydrocephalus, mass effect,
or profound neurological impairment. Surgical inter-
vention may relieve symptoms enough so that other
treatment modalities may be considered as alternate
or adjunctive management strategies. Symptoms are
usually related to mass effect, so resection or debul-
king are often the only logical choice if medical
therapy fails to provide improvement in neurological
symptoms. Rapid surgical decompression is the
treatment of choice for such problems when surgery
can be safely performed based on patient performance
status or tumor location. If no neurosurgical team is
available, transfer of the patient should be initiated
while medical measures are undertaken to stabilize
the patient.
Laminectomy has historically been the standard
surgery for MSCC, with most series in the literature
showing no benefit to laminectomy-treated patients
over patients managed with radiation therapy (Byrne
1992; Gilbert et al. 1978; Loblaw and Laperriere
1998; Young et al. 1980). In reality, many patients
with spinal cord compression are not surgical candi-
dates and are best treated with steroids and radiation
therapy as their primary modality. Even patients with
very poor initial performance or mobility/continence
status can be helped by receiving emergent radiation
therapy. A randomized trial examining the benefit of
adding surgical decompression to the radiotherapeutic
management of symptomatic metastatic spinal cord
compression showed that patients who underwent
decompressive surgery had a significantly improved
median time of gait retention and ability to regain gait
function (Patchell et al. 2005). The overall survival
was not significantly different. These data indicate
that all patients presenting MSCC of short duration
should be evaluated by a neurosurgeon for emergent
decompression prior to initiating radiation therapy. If
the patient is deemed a poor surgical candidate by a
full neurosurgical evaluation, then they should be
started on radiotherapy immediately.
Central Nervous System Tumors
4.3 Radiation Therapy
4.3.1 Definitive Radiation Therapy
Radiation therapy is a mainstay of the management of
most malignant and a significant number of benign
primary CNS tumors. Increasingly, the standard of
care is becoming Intensity-Modulated Radiotherapy
(IMRT). Table 2 provides an overview of the most
common primary CNS tumors and literature-based
guidelines for treatment. For tumors treated with a
‘‘shrinking-field’’ technique, ICRU (International
Commission on Radiation Unit) definitions of treat-
ment volumes for both the initial and boost fields are
given, together with general dosing guidelines.
Selected outcome endpoints are provided along with
the appropriate references. A more detailed descrip-
tion of the treatment techniques is provided for
selected tumors later in the chapter.
4.3.2 Palliative Radiation Therapy
Upwards of 60–70% of patients who present with
brain metastases have multiple lesions. This makes
radiotherapy the primary modality for palliation in the
majority of cases (Hazuka et al. 1993; Patchell 2003).
Many patients will respond dramatically to medical
therapy and radiation in the emergent setting with an
improvement in their performance status, particularly
if their symptoms are largely caused by edema. With
this in mind, radiation therapy dosing schedules for
the treatment of emergent patients can be tailored to
patient parameters such as initial response to steroids,
extent of extracranial disease, primary site, and pur-
ported response of primary to systemic therapy. The
overall performance status of the patient and ability to
tolerate prolonged daily therapy should also be taken
into account when deciding on the fractionation
schedule for a course of palliative radiation therapy.
Two randomized trials comparing radiotherapy with
or without surgical resection in the management of a
solitary brain metastasis have documented a survival
advantage with the addition of surgery over radiation
alone (Patchell et al. 1990; Vecht et al. 1993). A third
randomized trial was negative (Mintz et al. 1996).
There is no level-I evidence demonstrating any sur-
vival benefit from operating on patients with multiple
metastases. However, patients with multiple lesions
and severe neurological symptoms from a dominant
metastasis that is unresponsive to medical therapy
may benefit from a craniotomy for reasons described
573
above. An improvement in the patient’s performance
status may then allow further aggressive therapy with
external beam radiation therapy and/or radiosurgery.
Leukemic brain infiltration causing acute mental sta-
tus changes and/or impending herniation is a rare
entity treated with whole brain radiation therapy.
Patients with malignant glioma who require emer-
gent treatment are typically treated with regimens
similar to those used for brain metastases. Surgical
debulking is the mainstay of emergent treatment, as is
the initiation of steroid therapy. Patients who are
unable to undergo surgical debulking may be treated
with a short course of whole brain radiation similar to
that used for brain metastases.
Although no randomized trials exist comparing
radiotherapy over best supportive care or medical
therapy alone, every published series for MSCC has
shown efficacy of radiation therapy in helping patients
relieve pain and retain/regain lost function. Morbidity
is generally low and well tolerated even by patients
with a poor performance status. Approximately 89%
of patients who are ambulatory prior to radiation
therapy can expect to retain gait function, while an
average of 39% of paretic patients and only 10% of
paraplegic patients will remain ambulatory (Loblaw
et al. 2003).
5 General Concepts of Modern
Radiation Therapy Technique
5.1 Principles of Imaging-Based
Treatment Planning
The current standard of care for radiation therapy of
primary CNS tumors is to use CT- and MRI-based
three-dimensional (3D) treatment planning. CT sim-
ulation is still necessary, since most commercial
treatment planning systems perform dose calculations
from CT data sets. Fusion of an MRI scan data set
(Fig. 5) with the treatment planning CT scan allows
for optimum definition of the extension of the tumor
and accurate delineation of surrounding structures of
interest including the optic apparatus. MRI scans are
essential to define treatment planning volumes based
on the reports of the ICRU 50 (International Com-
mission on Radiation Units and Measurements I
1993) and ICRU 62 (International Commission on
Radiation Units and Measurements I 1999), which are
Table 2 Suggested definitions of ICRU volumes by diagnosis, based on magnetic resonance imaging and dose ranges (in Gray; Gy) delivered to these volumes
574

Diagnosis Definition of Usual dose Definition Usual dose to Dose to MS DFS5 OS1 OS5 LC5 Selected
initial treatment to CTV of final GTV (Gy) craniospinal axis references
field (CTV) field (to (if indicated)
GTV)
WHO grade-I (n/a) (n/a) Enhancing 45–50.4 (n/a) 95% 95% Brown et al.
glioma tumor (2004)
(T1 ? C);
1-cm
margin
WHO grade-II Enhancing tumor 45 Gy Enhancing 50.4–54 (n/a) 37–50% 58–73% Karim et al.
glioma (T1 ? C); Edema tumor (1996,
(T2/FLAIR) 2-cm (T1 ? C); 2002); Shaw
margin 2-cm et al. (2002)
margin
WHO grade-III Enhancing tumor 45–50.4 Gy Enhancing 59.4 Leptomeningeal 17.5–58.6 months 38% Prados et al.
glioma (T1 ? C); edema tumor spread on MRI: (2004);
(T2/FLAIR); 2-cm (T1 ? C); 30–39.6 Gy. Bulky Scott et al.
margin 2-cm disease: (1998);
margin 55.8–59.4 Gy Tortosa et al.
(2003)
WHO grade-IV Enhancing tumor 45–50.4 Gy Enhancing 59.4–64.8 Leptomeningeal 17.5–17.1 months 28–70% 0–14% Shaw et al.
glioma (T1 ? C); edema tumor spread on MRI: (2003)
(T2/FLAIR); 2-cm (T1 ? C); 30–39.6 Gy. Bulky
margin 2-cm disease:
margin 55.8–59.4 Gy
Meningioma, (n/a) (n/a) Enhancing 52.2–64.8 (n/a) 48–89% 58–85% Condra et al.
benign/atypical tumor (1997);
(T1 ? C); Goldsmith
1-cm et al. (1994);
margin Stafford
et al. (1998)
Meningioma, Enhancing tumor 45–50.4 Gy Enhancing 55.8–59.4 (n/a) 1.5 years Perry et al.
malignant (T1 ? C); edema tumor (1999)
(T2/FLAIR); 2-cm (T1 ? C);
margin 2-cm
margin
Pituitary (n/a) (n/a) Enhancing 45–50.4 (n/a) 90–95% Stieber and
adenoma tumor (non- (33–95% de Guzman
(T1 ? C); functioning); biochemical (2003)
0.7–1-cm 45–54 control)
margin (functioning)
(continued)
W. A. Hall and W. J. Curran
Table 2 (continued)
Diagnosis Definition of Usual dose Definition Usual dose to Dose to MS DFS5 OS1 OS5 LC5 Selected
initial treatment to CTV of final GTV (Gy) craniospinal axis references
field (CTV) field (to (if indicated)
GTV)
Ependymoma Enhancing tumor 45 Gy Enhancing 50.4–55.8 Negative CSF: 67–100% 95–100% Stieber et al.
(T1 ? C); edema tumor CSI not indicated. (2005)
(T2/FLAIR); 2-cm (T1 ? C); Positive CSF: 36 Gy.
margin 2-cm Gross
margin leptomeningeal
spread on MRI:
39.6 Gy. Bulky
Central Nervous System Tumors

disease: 54 Gy
Chordoma, Enhancing tumor 50.4 Gy Enhancing 59.4–70.2 (n/a) 36–72% 75–80% 40–75% Stieber et al.
chondrosarcoma (T1 ? C); tumor tumor (2005)
bed; 2-cm margin (T1 ? C);
2-cm
margin
Central (n/a) (n/a) FLAIR 50.4–55.8 (n/a) 98% 98% Rades et al.
neurocytoma changes; (2003b,
1-cm 2005)
margin
Vertebral Enhancing vascular (n/a) (n/a) 36–45 (n/a) 82% Rades et al.
hemangioma lesion (2003a)
Entire involved
vertebral body C 1-
cm margin
Brain Whole brain 30–37.5 Gy (n/a) (n/a) (n/a) 3.8–7.1 months 12–32% Gaspar et al.
metastases (adjuvant (1997, 2000)
40–50.4 Gy)
Spinal cord Enhancing tumor 30–37.5 Gy (n/a) (n/a) (n/a) 3.3–4.2 months Patchell
metastasis (T1 ? C); tumor et al. (2003)
bed; surgical track,
including scar; One
vertebral body
above and below
Leukemic brain Whole brain 24–30 Gy in (n/a) (n/a) 18 Gy 9 months Sanders
infiltration 1.8–3.0 Gy et al. (2004)
fractions
GTV gross tumor volume, CTV clinical target volume, GTV gross tumor volume, +C with contrast, MS median survival, DFS disease-free survival, OS overall survival, LC local control. The numbers in subscript
denote years
575
576
Fig. 5 CT-MR registration
Fig. 6 Conformal spinal
radiosurgical plan for solitary
spine metastasis
described in detail in the section on target volume
definition, below (Table 2). Imaging of tumor biology
or physiology may provide additional information for
radiation therapy treatment planning. Functional MRI
scans that image cerebral blood flow can show
regions of normal brain function, e.g., motor strip,
expressive, and receptive language areas (Ricci and
Dungan 2001) (Fig. 4). With 3D MR spectroscopy,
the choline-to-N-acetylaspartate ratio or index (CNI)
appears to be both sensitive and specific at differen-
tiating tumor from normal tissue when the proper
threshold is selected (McKnight et al. 2002). Choline
generally represents a marker of increased cellularity
and cellular integrity with creatine marking cellular
energy, the ratio of these two values that most closely
corresponds to a malignancy is increased creatine to
choline. In addition lactate may be reported on in MR
spec, this is frequently a marker of anaerobic
metabolism and can be seen in radiation necrosis.
[11C]-Methionine PET imaging also shows promise in
improving the anatomical delineation of low-grade
gliomas (Nuutinen et al. 2000). Currently, the main
W. A. Hall and W. J. Curran
utility of these functional and metabolic imaging
studies is to better define the anatomical extent of the
tumor for radiation therapy treatment planning. Bio-
logical or physiological data are becoming more
important in clinical practice and advances in these
techniques are playing a greater role in treatment
planning and radiation response assessment.
The applicability of advanced CNS imaging tech-
niques such as fMRI and FDG-PET in radiation
therapy is increasing. In a recent study by Hahn and
colleagues a prospective evaluation in a small cohort
was performed looking at the dose- dependent effects
of radiation on cerebral blood flow, metabolism, and
neurocognitive dysfunction. A dose dependent
response was observed in the CNS tissue detected
with the FDG-PET. Additionally, the response seen in
the brain tissue correlated with decreased perfor-
mance on neuropsychological tests for problem
solving, cognitive flexibility, and global measures of
psychopathology (Hahn et al. 2009). Future directions
with FDG-PET in the CNS may consist of a stratifi-
cation of patients based on the CNS response as
Central Nervous System Tumors 577

Table 3 Normal tissue tolerance of intracranial organs at risk

Organ TD5/5 (volume) TD50/5 (volume) Endpoint
1/3 2/3 3/3 1/3 2/3 3/3
Brain 6,000 5,000 4,500 7,500 6,500 6,000 Necrosis, infarction
Brainstem 6,000 5,300 5,000 6,500 Necrosis, infarction
Optic nerve 6,000 Blindness
Optic chiasm 5,400 Blindness
Eye (lens) 1,000 Cataracts
Eye (retina) 4,500 Blindness
Lacrimal gland 3,000 Dry eye syndrome
Ear (mid/external) 3,000 3,000 5,500 4,000 4,000 4,000 Acute serous otitis
5,500 5,500 5,500 6,500 6,500 6,500 Chronic serous otitis
Pituitary \4,500 6,000 Panhypopituitarism
All doses are in cGy at conventional fractionation (Emami et al. 1991)

assessed by FDG-PET to therapy. This could enable
selection of patients at risk for having a poor response
with respect to cognitive outcomes. The clinical
utility of this technology in this setting needs further
evaluation.
The ability to directly measure the metabolic
activity of brain tissues with advanced functional
imaging techniques such as Thallium-201 single-
photon emission computed tomography (201Tl-
SPECT) is gaining increased clinical importance.
Thallium-201 which accumulates in viable tumor
cells and hardly accumulates in normal brain tissue or
non-tumor tissue (radiation necrosis) has been applied
as a tool to assess for the presence or absence of
radiation necrosis (Schwartz et al. 1991). Recent
studies have shown that the maximal tumor intensity
as seen on 201Tl-SPECT was the strongest predictor of
survival in recurrent glioma and was inversely related
to overall survival of the percentage of patients alive
and progression-free at 6 months (Vos et al. 2003,
2006). Future directions for the use of this advanced
CNS SPECT imaging continues to undergo
investigation.
All diagnostic information, but particularly MRI
scans (including T2 and FLAIR images) and CT
scans, as well as clinical and surgical findings, should
be combined to define the tumor volume and critical
structures. Depending on diagnosis, some patients
may have survival measured in years rather than in
months, so it is especially critical to respect dose-
tolerances of normal structures in order to limit late
toxicities. Normal tissues to be contoured include, at a
minimum, the eyes (including lacrimal glands and
lenses), optic nerves, optic chiasm, pituitary gland,
brainstem, and temporal lobes. Using dose–volume
histograms (DVHs), dose to the tumor can be maxi-
mized and normal tissue dose minimized by analyzing
competing treatment plans. The importance of IMRT
in the treatment of CNS lesions is increasing sec-
ondary to its ability to decrease dose to many of these
critical normal structures.
Table 3 shows the normal tissue tolerance of
critical normal intracranial structures to radiation
therapy. Comparison of dose tolerances to the doses
required to control disease demonstrated clearly that
at the ‘‘standard’’ treatment doses of 54–60 Gy the
probability of causing serious toxicity is quite low
as long as care is taken with planning. Beam
energies of no less than 6 MV should be used in
order to spare surrounding structures, most notably
the temporal lobes. A very good balance between
depth dose and penumbra width is provided by
10 MV photons.
5.2 Target Volumes and Organs at Risk
Specifications
Treatment planning is based on the 3D volumes of
interest described by the international commission on
radiation units and measurements (ICRU) (Interna-
tional Commission on Radiation Units and Measure-
ments I 1993, 1999). Figure 7 shows a graphical
representation of these volumes as described below.
578
Fig. 7 Diagrammatic representation of ICRU 50 and 62
volumes. Abbreviations are defined in the text. Solid arrows
expansion of one volume to define another. The gross tumor
Based on the ICRU 50 and 62 reports, gross tumor
volume (GTV) represents the grossly visible disease
burden (International Commission on Radiation Units
and Measurements I 1993, 1999). For grade-IV
astrocytoma (glioblastoma multiforme) this is a T1-
enhancing abnormality on MRI. If there is no residual
abnormality after a surgical resection, the tumor
resection cavity is defined to be the GTV. It is
important to note that surrounding edema is not
considered part of the GTV. The clinical target vol-
ume (CTV) is subclinical microscopic malignant
disease, often seen as T2 or FLAIR abnormality
(which does include edema) on MRI (International
Commission on Radiation Units and Measurements I
1993). Suggested definitions of and doses to be
delivered to GTV and CTV are given in Table 2 by
histological diagnosis.
The planning target volume (PTV) is also referred to
as ‘‘dosimetric margin’’. The dosimetric margin of the
PTV takes two additional margins into consideration
(International Commission on Radiation Units and
Measurements I 1999). The PTV1 is the CTV plus a
dosimetric margin; the smaller PTV2 is the GTV also
plus dosimetric margin.The internal margin is defined
so as to take into account variations in size, shape, and
position of the CTV in relation to anatomical reference
points. The set-up margin is added to take into account
uncertainties in patient–beam positioning, these
uncertainties are machine and immobilization device
dependent. Segregating the internal margin and the
W. A. Hall and W. J. Curran
volume (GTV; orange) expands to the planning target volume
(PTV)2 (red). The clinical target volume (CTV; blue) expands
to the PTV1 (green)
set-up margin reflects the differences in the source of
uncertainties. The internal margin is due mainly to
physiological variations that are difficult or impossible
to control, such as (potential) fluctuations in the mass
effect from cerebral edema which may occur over the
course of treatment. In contrast, the set-up margin is
added because of uncertainties related mainly to tech-
nical factors that can be reduced by more accurate
positioning and immobilization of the patient (such as
stereotactic positioning), as well as improved
mechanical stability of the machine. The addition of
uniform margins that take into account all types of
uncertainties would generally lead to an excessively
large PTV, which could result in exceeding normal
tissue tolerances. Thus, the balance between disease
control and risk of complications may require an
evaluation based on the experience and judgment of the
clinician in order to avoid serious treatment-related
complications. The PTV may therefore be reduced in
areas near critical structures. Dosimetric margins as
low as 3–5 mm may be acceptable with appropriate
immobilization devices. The target is usually consid-
ered to be appropriately treated if the PTV is enclosed
within the 95–105% isodose line. For plans empha-
sizing homogeneous dose delivery, typically no more
than 20% of the PTV should exceed 110% of the pre-
scription dose. The topic of margin adjustment is
addressed further in the IMRT (Sect. 5.4).
Organs at risk (OARs) are critical normal struc-
tures that are at risk for significant toxicity in the
Central Nervous System Tumors
judgment of the treating physician. Such OARs are
normal tissues, of which the radiation sensitivity and
proximity to the CTV may significantly influence the
prescribed dose and the treatment planning strategy.
When possible to do so without compromising the
dose to the GTV, attempts should be made to limit the
dose to any part of the following normal structures as
follows: optic chiasm (54 Gy); optic nerves (55 Gy);
optic globes including retina (50 Gy); brainstem to
include mid-brain, pons, and medulla (54 Gy); pitui-
tary gland (50 Gy); and spinal cord (45 Gy). In
pediatric patients, doses as low as 18 Gy have been
implicated in neurocognitive deficits (Silber et al.
1992; Jankovic et al. 1994). A more detailed guideline
to dose tolerances is provided in Table 3. It is esti-
mated that, with conventionally fractionated irradia-
tion (1.8–2.0 Gy/fraction, five fractions per week), at
5 years the incidence of myelopathy is 5% for doses
in the range of 57–61 Gy (tolerance dose TD5/5) and
50% for doses of 68–73 Gy (TD50/5) (Schultheiss
et al. 1995). There is no convincing evidence that the
cervical and thoracic cords differ in their radiosensi-
tivity, and there appears to be little change in toler-
ance with variations in the length of cord irradiated
(Schultheiss et al. 1995). A dose of 45–50.4 Gy in
25–28 fractions over 5–5.5 weeks is usually consid-
ered to be safe, the risk of myelopathy being less than
1%, well below the steep portion of the dose–response
curve (Marcus and Million 1990; Schultheiss et al.
1995).
The ICRU Report 62 also describes the concept of
the planning organ at risk volume (PRV) (Interna-
tional Commission on Radiation Units and Measure-
ments I 1999). The relationship between a PRV and
the OAR for a given structure is analogous to the PTV
and the CTV for a given target. For reporting, the
description of the PRV (like that of the PTV) should
include the extent of the margins in all directions. The
PTV and the PRV may overlap, and often do so,
which requires a compromise as discussed above
when determining the allowable dose. For each OAR,
when part of the organ or the whole organ is irradiated
above the accepted tolerance level, the maximum
dose should be reported (International Commission on
Radiation Units and Measurements I 1993). The
volume receiving more than the maximum allowable
dose should be evaluated using the corresponding
DVH.
579
5.3 Dose Reporting
Recommendations contained in ICRU Report 50 for
dose specification reporting are maintained in ICRU
Report 62 (International Commission on Radiation
Units and Measurements I 1999). First, the absorbed
dose at the ICRU reference point should be reported.
Second, the maximum and the minimum doses to the
PTV should be reported. Furthermore, any additional
relevant information should be given when available,
for example, DVHs. The absorbed doses to the OARs
should also be given. When reporting doses in a series
of patients, the treatment prescription or protocol
should be described in detail, including the volumes,
absorbed dose levels, and fractionation. The treatments
should be reported following the above recommenda-
tions, and the deviations from the prescription should
be stated. In particular, the proportion of patients in
whom the dose variation is less than ±5, ±5–10, and
more than ±10% of the prescribed dose at the ICRU
reference point should be reported.
5.4 Intensity-Modulated Radiation
Therapy
Intensity-modulated radiation therapy (IMRT) is a
treatment delivery method that may be used to further
optimize the dose distribution. The NCI defines IMRT
as ‘‘a dose plan and treatment delivery that is opti-
mized using inverse or forward planning techniques
for modulated beam delivery, using either a binary
collimator, or with a conventional MLC system using
either ‘‘sliding window’’ (DMLC) or ‘‘step and shoot’’
(SMLC) modes; note that this definition also includes
techniques with compensators designed by inverse
planning techniques, to create a highly conformal
dose distribution. The IMRT plan includes dose
planning objectives and constraints, criteria for target
and critical structure expansions, 3D dose distribu-
tions, DVH analysis for targets and critical structures,
and plan verification.’’ (Deye et al. 2005).
There are several aspects of treatment that may ben-
efit from the use of IMRT. First, since multiple critical,
sensitive organs are located near the CNS, one may
reason that improved dose distribution should allow the
dose to these structures to be minimized. Second, since
most primary CNS tumors typically recur locally, IMRT
580
should allow the exploration of anatomical/biological
treatment planning and delivery in order to optimize
different doses to different cell populations within het-
erogeneous volumes (Stieber and Munley 2004). The
benefits of IMRT in the CNS are currently under
investigation at multiple institutions.
IMRT should be used often to improve dose
delivery to target volumes. In situations where tumor
biology is known to consist of a homogeneous cell
population, such as is the case with a WHO grade-I
meningioma, IMRT may allow for more homoge-
neous dose delivery with decreased dose to normal
surrounding tissues. This improvement in homoge-
neous dose delivery is especially true with irregularly
shaped lesions. Conversely, WHO grade-IV gliomas
typically comprising heterogeneous cell populations,
and dose escalation with increased dose per fraction
to the GTV compared with the CTV are quite feasible
using IMRT techniques and again allow for improved
sparing of normal tissues. In general, the goal is to use
IMRT to more conformally treat irregularly shaped
tumors, and enable improved dose homogeneity.
Furthermore, when treating patients with craniospinal
axis irradiation, IMRT may improve homogeneous
dose delivery to the contents of the spinal canal and
allow improved conformality of any boost volumes.
IMRT should be ideally suited to sparing of normal
organs. There are numerous dose-limiting structures
of interest within the cranium which include the optic
chiasm, right and left optic nerves, both globes, the
brain stem, the right and left inner ear, the area pos-
trema, and uninvolved normal brain, especially optic
cortex and right and left temporal lobes (Miller and
Leslie 1994). Reducing the dose to the area postrema
may reduce the incidence of treatment-related nausea
(Miller and Leslie 1994). In addition, current trials are
underway evaluating the ability to spare structures
essential for memory, specifically the hippocampus
(Marsh et al. 2010). An indication to use IMRT to
treat patients should involve an assessment of which
dose-limiting structures are uninvolved by tumor and
therefore do not need to receive a clinically signifi-
cant dose. This decision should include an honest
assessment as to the patient’s expected life span, as
many late toxicities will not manifest until after six
months from the time of treatment. Patients with poor
performance status, for example, are unlikely to sur-
vive long enough to benefit from such organ-sparing
approaches (Gaspar et al. 2000; Shaw et al. 2003).
W. A. Hall and W. J. Curran
Based on the anatomical location of the treatment
volumes, one may imagine several examples where
IMRT could be of marked benefit. One such example
is a patient with a concave or otherwise irregularly
shaped target in a frontal lobe who may require IMRT
in order to spare the adjacent globe and any unin-
volved optic apparatus. In patients with well-lateral-
ized tumors involving the brain parenchyma, maximal
sparing of the contralateral hemisphere is a desirable
goal. Patients with infiltrative gliomas traditionally
have large margins placed around the treatment vol-
umes, and these may often encompass uninvolved
critical normal structures (usually the optic chiasm
and the brain stem); in these cases, IMRT allows
non-uniform reduction of the treatment volume
around these structures. Patients with large, well-
circumscribed lesions near the base of the skull (e.g.,
meningiomas, acoustic neuromas, chordomas, and
chondrosarcomas) should be also considered for
IMRT in order to minimize the dose to the brain stem,
inner ear, and posterior fossa. In the setting of
retreatment (e.g., previous whole brain radiation
therapy for metastases) an IMRT approach may be
considered if the clinical situation suggests that
these patients may be long-term survivors with
aggressive treatment.
With the increasing use of intensity modulation in
the radiotherapy of the CNS the questions of margin
use for a variety of tumors has come into question.
One such example that has been the focus of much
research has been malignant gliomas. An advantage to
smaller margins for gliomas that enables decreased
dose to the normal tissues in the brain, however, runs
the risk of marginal miss caused by microscopic
disease falling outside of the area of high- dose
radiation. The traditional margins used for high-grade
gliomas in the CNS were 2.0–3.0 cm. This was based
on an earlier clinical and anatomical research (Liang
et al. 1991; Hochberg et al. 1980). With the rise in
prevalence of accurate intensity modulation use in the
CNS the necessity of these large margins has come
into question.
The successful implementation of margin reduc-
tion has recently been demonstrated in a retrospective
series by and colleagues. Patients with glioblastoma
were analyzed who received smaller than the standard
margin of 2.0 cm. Median margins of 0.7 cm to create
a CTV were used on the T2 enhancing volume with
an additional margin of 0.3–0.5 cm to create a PTV
Central Nervous System Tumors
with a total expansion of 1–1.2 cm from the initial
GTV. Of the patients analyzed 92% had a margin of
1 cm or less. Of the patients who had available
imaging at a follow up of 12 months 93% of these
patients had central or in field failure. The major
conclusions of this retrospective analysis were that
reduced margins for glioblastomas did not appear to
increase the risk of marginal or distant failures
(McDonald et al. 2011).
5.5 The Role of Image-Guided Radiation
Therapy in the Central Nervous
System
The accuracy of radiotherapy delivery has increased
significantly over the past decade. Much of the
improved accuracy of radiotherapy delivery has come
from an increase in the amount of image guided
radiotherapy (IGRT) use. IGRT has been defined by
the RTOG IGRT committee report as ‘‘radiotherapy
delivery using an array of modern imaging techniques
including CT, MRI, PET, and Ultrasound’’ (Michalski
et al. 2001). This method of radiotherapy delivery is
playing an important role in a variety of disease sites,
notwithstanding the CNS. A common method of
IGRT delivery is performed by obtaining kv images
onboard the treatment machine; these are then regis-
tered to the digitally reconstructed radiographs
(DRRs) that are generated by the treatment planning
system. A recent analysis by Ali and colleagues has
shown that even with the use of a BrainLAB stereo-
tactic head immobilization mask without the use of kv
onboard imaging system daily setup errors could be as
much as 2 mm in the anterior– posterior, right to left,
and superior– inferior directions (Ali et al. 2010). The
importance of image guidance in the CNS has also
been confirmed by Hong and colleagues who showed
that daily onboard kv imaging plays a particularly
important role in fractionated radiotherapy delivery. It
was demonstrated that with the suggested shifts of the
kv images, when compared to the DRRs, they were
out of the tolerance of 3 mm in 31 of the 309 patients
that were set up (Hong et al. 2009). Given these
demonstrations of the important amounts of setup
deviations that would occur without the use of
onboard image guided therapy, it is likely that over
the years to come we will see an increase in the use of
image guidance in the CNS.
581
6 Simulation Procedures
6.1 General Concepts of Positioning,
Immobilization, and Simulation
The first step in the treatment process is the decision of
how to position a patient for simulation and treatment.
While the positioning of patients for CNS radiotherapy is
not as complex as other treatment sites, several factors
must be taken into account. Historically, an important
consideration was whether to have the patient lie supine
or prone; with the current use of IMRT in the CNS the
vast majority of patients will be simulated supine. A
second important consideration is whether to have the
head and neck in a neutral, flexed, or extended position.
In general, the supine position with a neutral head
position is the most stable and most frequently used
when treating the majority of brain tumors and with the
use of IMRT enables effective targeting of lesions in a
variety of locations in the CNS. Historically, with two-
dimensional (2D) treatment planning, a neutral position
was often not optimal for brain tumors in certain loca-
tions; for example, anteroposterior (AP) or posteroan-
terior (PA) beams would enter or exit through the eyes
when treating a centrally located target such as a pitui-
tary tumor. Flexion of the head would rotate the eyes
inferiorly relative to the target, thus allowing utilization
of AP and PA beams. When treating brain tumors
located in the posterior fossa, such as pontine gliomas,
the supine position with neck extension allowed a PA
beam to be utilized, since the eyes were rotated superi-
orly and out of the exit of the beam. These old conven-
tions are mostly items of historical significance alone. In
the modern era, 3D radiation treatment planning (3D
RTP) and IMRT allow for neutral head and neck posi-
tions in most situations as non-coplanar beams can be
used to avoid entry and exit doses to critical structures.
Lastly, positioning of the head, neck, and body should be
such that the anterior and lateral setup marks are in
locatable and reproducible positions. Marks on steeply
sloping surfaces, ears, nose, lips, and chin should be
avoided whenever possible.
Once positioned, the patient must be immobilized.
There are a variety of commercially available custom-
made head immobilization devices, most of which
utilize thermoplastic or other materials such as
expandable foam or plastic beads in a vacuum bag.
They are adaptable for flexion or extension when the
582
patient is in the supine position. Variability of setup
should be no more than 2 or 3 mm with contemporary
immobilization such as a thermoplastic mask. When
more accurate and/or rigid head positioning and
immobilization is desired, such as for fractionated
stereotactic radiation therapy or radiosurgery, a modi-
fied stereotactic head frame with non-invasive multi-
ple-point head fixation could be used. Additionally, for
extracranial spinal radiosurgery full body immobili-
zation devices could be used such as a medical intelli-
gence immobilization device.
Invasive head-frame immobilization devices used
during radiosurgery can often be associated with mor-
bidity and discomfort for the patient. An alternative to
invasive immobilization devices gaining popularity in
the setting of CNS radiosurgery is the use of tracking
devices in conjunction with a non-invasive immobili-
zation mask. One such example of patient positioning
and track tracking is optical- based tracking systems
that have been gaining popularity in a variety of body
sites including the CNS. Essentially, optical tracking
involves the use of infrared light-emitting diodes that
are placed on the patient and located in 3D space with
infrared detecting cameras. The position of the patient
can be verified by the infrared camera system and any
displacement of the patient from the isocenter can be
reported during patient setup. This has been shown to
improve the accuracy of focal stereotactic radiotherapy
delivery, and may have implications for the necessity of
invasive frame- based radiosurgery. This is discussed
in further detail in Sect. 8.5.
Once the patient is placed in the positioning device,
they are scanned, typically with radio-opaque reference
markers placed at the setup isocenter. The isocenter
may be placed at a standard location on every patient
with a planned isocenter shift taking place after simu-
lation; alternatively, the clinician may decide a priori at
the time of simulation, where the isocenter should be
placed. If multi-leaf collimation will be employed,
isocenter verification films still need to be taken on the
simulator. Portal films must be periodically obtained to
verify the accuracy of the treatment setup.
Generally, special immobilization devices are not
used for patients with spinal cord tumors when the
radiotherapy is delivered as a fractioned treatment
although custom devices made of thermoplastic,
expandable foam or of plastic beads in vacuum bags are
available. The exception is in the arena of spinal radi-
osurgery, where very complex devices such as the
W. A. Hall and W. J. Curran
Elekta stereotactic body frame may be utilized. The
importance of patient immobilization is paramount
when patients are treated with radiosurgical dosing, this
is expanded upon in the Sect. 6.3 on spinal radiosur-
gery (Fig. 12). Regardless of the immobilization device
chosen, it must be designed to fit the physical dimen-
sions of the CT or MRI scanner and constructed of
materials that are compatible with the imaging
modalities to prevent image artifact or distortion.
For CT simulation involving the brain, the patient
is placed in a positioning device and scanned with
three radio-opaque reference markers placed on the
thermoplastic mask. Patients are usually treated in the
supine position with a neutral head position. All plans
in this section assume that patients are simulated in
the supine position using 3D CT-based planning;
exceptions will be clearly indicated. Prone setup may
be considered for posterior fossa tumors, however,
this is rarely required with IMRT use. If intracranial
disease is limited in scope whole brain radiotherapy is
typically not the best treatment modality and IMRT is
frequently used to spare normal brain tissue. When
IMRT is used, a practical approach is to utilize the
beam arrangement from an optimum non-coplanar 3D
plan and then invoke the treatment planning system’s
IMRT module. This can significantly shorten the
treatment planning effort and allows for greater
freedom of optimization than a coplanar IMRT plan,
which is conceptually 2D.
Beam arrangements suggested in the text are
described by a commonly used 3D naming system
resulting in a unique name for each field (Jasper et al.
2004). The importance of beam arrangements is
becoming less as IMRT treatment is emerging as a
new standard of care for CNS disease, they are
mentioned here more for their historical significance.
The primary body planes are transverse, sagittal, and
coronal, with body axes anterior, posterior, right, left,
superior, and inferior. Isocentric treatment machines
rotate 360° around a transverse plane of the patient’s
body, and treating in a coronal or sagittal plane
requires the treatment couch to be rotated. Whether a
patient lies in a supine or prone position, beams
entering the patient’s body are always named relative
to the patient’s anatomy. In this 3D naming system, a
beam is named based on the plane and the axis closest
to its entry and angle of deviation, which are rules and
steps 1 and 2. Rule 3 states that the angle of deviation
used to describe the beam will never exceed 45°.
Central Nervous System Tumors
Table 4 Naming rules for 3D beam arrangements (Jasper et al.
2004)
Rule Step Description
1 1 Identify the closest primary axis relative to
the beam’s entry
2 2 Describe the angle of deviation toward the
next closest axis
3 The angle of deviation shall be less than or
equal to 45°
4 3 Describe the angle of deviation in the third
axis
5 The beam’s name should be listed with
gantry angle first, followed by any couch
angle
A beam lying in a primary plane will only be
described by three descriptive parameters. To name a
non-axial beam, distinguished by the entry of the
central axis between three axes in two planes, one
additional step is necessary, with a total of two
additional rules. Thus, each field name defines the
beam’s direction and relation to the patient, literally
spelling out the correct gantry and couch positions to
be used for treatment. These rules are summarized in
Table 4. Differential weighting of beams and the use
of wedges or compensators are assumed and will not
be described in detail, due to considerable variability
from patient to patient. Most lesions can be treated
well with 6 MV photons; for some deeper seated
targets, 10 MV photons may provide slightly better
dose distribution with respect to normal tissues,
although with small targets penumbra issues may
dominate. For very lateralized tumors, 10 MV pho-
tons may be used for contralateral beams.
6.2 Specific Examples of Treatment
Techniques
6.2.1 Pituitary Region
6.2.1.1 Simulation
In the simulation of tumors of the Pituitary Region the
size of the region and the proximity of critical normal
structures makes accurate and reproducible patient
setup essential to minimize the PTV. Fusion of an MRI
scan both pre and post contrast with the contrasted
treatment CT scan allows for optimum definition of the
suprasellar optic apparatus and extension of the tumor.
583
The treatment volume should be slightly larger to
include a margin for error in estimating tumor volume
and for variation in day-to-day setup. (Table 2 for
dosing and margins) With invasive tumors, such as
those involving the sphenoid or cavernous sinuses or
other intracranial structures, there is greater uncer-
tainty, which must be considered in determining the
volume to be included in the CTV and PTV.
The GTV is the pituitary adenoma as defined on the
contrast enhanced MRI, including any of its extensions
into adjacent anatomical regions. Generally, the entire
contents of the sella and, if appropriate, the entire cav-
ernous sinus are included in the CTV. Since pituitary
adenomas are non-infiltrating tumors, a CTV expansion
of 0.5 cm, i.e., 1.0 to 1.5 cm margin to block edge may
be adequate to determine the PTV. With fractionated
stereotactic treatment setups, block edge margins in the
order of 7 mm can provide excellent dose distribution
with minimal dose to surrounding tissues. OARs to be
contoured include the eyes (lenses), optic nerves, optic
chiasm, brainstem, and temporal lobes. An essential
structure to be contoured accurately is the optic appa-
ratus and chiasm. These contours should be based on
MRI and CT registered images and the defined structure
should be evaluated in both the coronal, sagital, and axial
planes for correct positioning.
Pituitary adenomas can also be treated with stereo-
tactic radiosurgery and have been successfully treated
with this technique for decades. In order to be a good
candidate for SRS patients should have at least 3–4 mm
between the pituitary tumor edge and the optic appa-
ratus, ideally there should be a separation of 5 mm. An
important consideration in radiosurgery is the dose to
the optic apparatus, the most conservative of dose tol-
erance reports to the optic apparatus is approximately
8–10 Gy. Simulation in the case of the radiosurgical
patient is done with the appropriate immobilization
devices as required by the radiosurgery device that will
be used. This may consist of either a rigid head frame or
thermoplastic mask with optical tracking device (see
Sect. 6.1). Radiosurgical doses for pituitary tumors can
range from 14 to 25 Gy to the tumor margin, and typ-
ically results in very high rates of tumor control ranging
in most series from 92 to 100% (Sheehan et al. 2005).
6.2.2 Whole Brain Irradiation
There are several techniques that can be utilized for
whole brain irradiation. Typically, patients are treated
with two opposed lateral fields. A clinical setup
584
places a rectangular treatment field over the cranial
vault with the collimator angled so as to place the
inferior border 1–2 cm below a line drawn from the
medial canthus to the mastoid tips. The superior,
anterior, and posterior borders are simply set up with
a light border flashing over the skull. A small block is
carefully placed to shield the globes while still
allowing adequate coverage of the anterior–inferior
extent of the cranial contents.
More commonly, the field will be shaped with
custom designed MLCs that follow the contours of
the base of the brain with a 1–2 cm margin. When
drawing the custom block, one should take care to
correctly identify the floor of the anterior cranial fossa
including the cribriform plate, middle cranial fossa,
posterior fossa, and skull base including the foramina
through which the cranial nerves exit. The cribriform
plate is often misidentified and hence underdosed
(Gripp et al. 2004; Weiss et al. 2001) The dosing to
the cribriform plate is critical when treating the cra-
niospinal axis, for tumors that seed the subarachnoid
space and for whole brain treatment of leukemia or
lymphoma as misses in these areas can result in
recurrences that are difficult to treat. The patient
should be simulated in the supine position with the
head immobilized, usually with a thermoplastic cast.
Radio-opaque markers should be placed on each lat-
eral canthus to document the eye position with respect
to the radiation field. If the isocenter is chosen to be
centrally located in the cranium, the canthus markers
will not be aligned due to beam divergence. The
lenses of the eyes should be contour and dose to these
structures should be kept as low as possible. The
opposite eye will receive dose from each lateral beam
unless this divergence is corrected. One may calculate
the number of degrees to compensate for beam
divergence using the formula:
 
1 0:5  L
h ¼ tan ð1Þ
SAD
where L = the length of the field (assuming a sym-
metrical field), so (0.5 9 L) equals the distance from
the isocenter to the canthus and the source-axis dis-
tance (SAD). One should verify this calculation by
rotating the gantry until the canthus markers are
superimposed and verifying the correct angle. Alter-
natively, one may place the beam axis along the
canthi: if the patient has been set up straight, the
canthi should then be superimposed and there will be
W. A. Hall and W. J. Curran
Fig. 8 Example of whole brain
no beam divergence into the contralateral eye at the
central axis (Fig. 8).
The selection of beam energy must be taken into
consideration for whole brain irradiation. With photon
energies above 10 MV, the peripheral tissues of the
brain (e.g., the temporal lobes) and the meninges may
be underdosed, depending on the thickness of the
scalp and skull. Conversely, due to the curvature of
the skull, there will be a relatively high- dose region
toward the ‘‘Mohawk’’ of the skull. This inhomoge-
neity is increased with lower energies. When treating
whole brain fields, the clinically relevant issue is to
provide a set minimum dose to the entirety of the
cranial contents. Therefore, a photon energy of 6 MV
is usually recommended. If desired, a compensator
can be manufactured or wedges employed to improve
the dose distribution.
6.2.3 Craniospinal Irradiation
Certain neoplasms, such as medulloblastomas and
other primitive neuroectodermal tumors, high-grade
ependymomas, some germ cell tumors, pineoblasto-
mas, and some CNS lymphomas require treatment to
the entire craniospinal axis. This technique can also
be used for patients with craniospinal leptomeningeal
carcinomatosis or gliomatosis. Several modifications
of this approach are used in clinical practice (Shiu
et al. 2003). Patients may be treated either in the
supine or prone position, often in an immobilization
cast to ensure daily positional reproducibility. The
neck should be slightly flexed so as to avoid unnec-
essary exit dose to the mandible, maxilla, and oral
Central Nervous System Tumors 585

cavity. The fleshy canthi are visualized by radio-

opaque skin markers. The intracranial contents,
including the upper one or two segments of the cer-
vical cord, are treated through opposed lateral fields,
usually positioned so that the isocenter is at midline
with the beam axes passing through the lateral canthi
to minimize divergence into the contralateral eye.
Customized blocks protect the normal head and neck
tissues from the primary radiation beam; as men-
tioned above, care must be taken not to underdose the
cribriform plate. The inferior border of the short field
is placed around C2–3, leaving adequate room for
subsequent shifts in the match with the upper spine
field (see below). This is commonly referred to as
‘‘feathering the gap’’.
The spine is treated through one or two posterior
fields, this decision depends on the length of the
spine. It is customary to maximize the field length of
the upper spinal field (40 cm at 100 cm source-to-
skin distance) and minimize the length of the lower
spinal field, as this simplifies planning for junction
shifts (see below). If 40 cm or less of length covers
the spine, inclusive of the end of the thecal sac (as
defined by MRI, typically near the level of S3), a
lower spine field is not necessary. All fields’ central
axes remain fixed; it is only the fields’ lengths that are
changed. Therefore, the caudal border of the lower
PA spine field should be set inferior to S3 by a length
equal to the two field shifts, then blocked back to S3
Fig. 9 a Lateral view of the treatment fields used for
using asymmetric collimators or custom blocking. craniospinal axis irradiation. The collimator of the lateral brain
Matching the upper border of the spine field to the fields must be rotated by the angles shown to match the
lower border of the cranial field requires strict atten- divergence of the upper spine field. b Posteroanterior view of
the match between the lateral brain fields and the upper spine
tion to accuracy, since overlap (i.e., overdosing) in the
field. Note the areas of overlap and gap between the inferior
upper cervical cord may have catastrophic outcomes border of the brain fields and the superior border of the upper
for the patient. In one method, the collimator for the spine field
lateral cranial fields is angled to match the divergence
of the upper border of the adjacent spinal field, and
the treatment couch is angled so that the inferior Alternatively, one may dispense with couch rota-
border of the cranial field is perpendicular to the tion by calculating appropriate skin gaps (the colli-
superior edge of the spinal field (‘‘exact-match’’ mator should still be rotated for accurate alignment).
technique). Both the rotation of the collimator and The gap is calculated so that the 50% isodose lines
degree of couch rotation are calculated from Eq. 1, meet at the level of the anterior spinal cord (‘‘Gap-
and typically range from 9° to 11°. The drawback to Match’’ technique).
this technique is that the couch rotation displaces the 1=2ðCL1 þ CL2 Þ  d
contralateral eye cephalad so that it cannot be blocked G¼ ð2Þ
SAD
without blocking frontal brain tissue (Figs. 9, 10,
Craniospinal Fields). where CL is the field length from isocenter to the field
This technique may also result in underdosing of edge to be matched, d is the depth at the match point,
the temporal lobes and cribriform plate. and SAD is the source-axis distance (Fig. 9).
586
Fig. 10 3D planning of
cranio-spinal irradiation (CSI)
Ideally, the gap width and collimator rotation
should be recalculated for each junction shift and one
must remember that d may vary significantly along
the extent of the spinal cord. Typically, it is safest to
match at the anterior edge of the spinal cord, although
this does create a small ‘‘cold’’ triangle posteriorly.
Clinical verification of correct calculation of the gap
may be achieved by lowering the treatment couch so
that the beam edges for the upper and lower spine
fields project onto the skin, where they should match
exactly. The upper spine field edge is clinically ver-
ified in a similar fashion except that the matching
lower edge of the cranial field is verified by moving
the patient laterally so that the match line projects
onto the skin.
W. A. Hall and W. J. Curran
All junction lines are moved 0.5–1.0 cm every
8–12 Gy (typically twice during the craniospinal
portion of neuraxis irradiation) to avoid overdosing or
underdosing segments of the cord. This is accom-
plished by shortening the inferior margin of the lateral
cranial fields, symmetrically lengthening the superior
and inferior margins of the posterior spine field, and
shortening the cranial margin of the caudal spinal
field; as mentioned previously, the inferior margin of
the caudal spinal field remains unchanged at the same
location.
Another difficulty is the varying depth of the spinal
cord along the length of the patient and the difference
in separation distance between head and neck. If this
is not taken into consideration, considerable hot or
Central Nervous System Tumors
Fig. 11 Simulation films of
the beam split technique for
cervicothoracic irradiation.
The central axis is placed just
above the shoulders (C4).
a Opposed lateral fields for
the mid and upper spine.
b Single posteroanterior field
for the low cervical and upper
thoracic spine. Potential
overlap of the abutting fields
must be addressed
cold spots may occur along the length of the
treatment field. A true 3D CT simulation allows for
more accurate dosimetric calculation than a sagittal
contour or calculation from lateral simulation films
(Figs. 9, 10).
Typically, in order to achieve homogeneous dose
distribution, some form of compensation must be
used.
6.2.4 Spinal Tumors
Common treatment approaches include a single pos-
terior field (PA), opposed lateral fields, a PA field
with opposed laterals, opposed anterior–posterior
(AP/PA) fields, and oblique wedge-pair fields (Mi-
chalski 1998; Minehan et al. 1995). Normal tissue
constraints and potential toxicities must be considered
when defining field arrangements. For tumors in the
cervical region, an opposed lateral beam approach can
be employed to minimize dose to the anterior neck.
For tumors in the cervicothoracic region, a split beam
approach is often used in anticipation of matching
another palliative treatment field in the future, with
the central axis placed just above the shoulders.
Opposed lateral beams are used to treat the upper
spine, while a PA field is used for the area of the spine
below the central axis (Fig. 11).
Tumors in the thoracic region can be treated with
opposed lateral beams, a 3-field approach using a PA
587
field and opposed lateral beams, a 2-field approach
using AP–PA beams, or a posterior beam prescribed
to an appropriate depth. The tolerance of dose-limit-
ing organs, most commonly the spinal cord and
esophagus, may need to be taken into account by the
radiation oncologist, depending on the clinical sce-
nario. In the lumbar region, care should be taken to
minimize the dose to the kidneys; AP/PA or PA fields
are often used here, but a four-field approach using
AP/PA and opposed lateral beams with the AP/PA
beams preferentially weighted may be useful. Com-
parison of differing treatment setups by means of
DVHs is strongly recommended.
6.3 Spinal Radiosurgery
In addition to conventional AP/PA approaches to the
treatment of metastatic or primary tumors of the spine
the use of hypofractionated radiosurgical doses and
techniques has emerged for the treatment of spinal
tumors. In the past ten years a vast amount of evi-
dence has been generated showing that spinal radio-
surgery is both safe and effective for the treatment of
both primary and metastatic tumors to the spine.
Many of the principles of radiosurgery that have been
used for decades in the brain have been translated into
the management of spinal tumors.
588
The use of stereotactic body radiotherapy (SBRT),
or extracranial radiosurgery, was developed in the
mid 1990s at various institutes around the world.
Possibly the earliest experience describing the SBRT
procedure came from the Karolinska Institute in
Sweden (Blomgren et al. 1995). Around the same
time Hamilton et al. were the first to publish their
experience in treating spinal tumors with Linear
accelerator- based radiosurgery in the setting of fail-
ure of other interventions, either surgical or frac-
tionated radiotherapy (Hamilton et al. 1996). Since
the early days of SBRT development the technique
has become increasingly more important and common
in the management of both primary and metastatic
spinal tumors. Today, CNS stereotactic radiosurgery
has come to be defined as a ‘‘distinct discipline that
utilizes externally generated ionizing radiation in
certain cases to inactivate or eradicate (a) defined
target(s) in the head or spine without the need to make
an incision. The target is defined by high resolution
stereotactic imaging’’ (Barnett et al. 2007).
The principles of spinal radiosurgery focus on the
delivery of a high dose of radiation in a small number
of fractions with a steep dose fall off (Figure Title
Spinal Radiosurgery). In several different large pro-
spective series average doses of radiation therapy
have ranged from 15 to 21 Gy delievered in a single
fraction to metastatic lesions with extremely suc-
cessful rates of pain relief and minimal toxicity.
Average rates of series grade III or IV late toxicities
of 0% have been reported and pain relief of up to 96%
in patients has also been reported with adequate fol-
low- up (Gerszten et al. 2005; Yamada et al. 2008).
The exact features of tumors that are good candidates
for radiosurgery is the subject of some debate. Past
series have had tumor volume averages of approxi-
mately 25 cm3 with outlying voumes on the order of
250 cm3 that were treated successfully with spinal
radiosurgical doses (Gerszten et al. 2006). These
tumors are focal in nature and are positioned such that
a high dose can be delivered while maintaining the
spinal cord dose at acceptable levels.
Important to consider is the safe doses to the spinal
cord which has also been demonstrated in various
prospective trials. According to several safety and
efficacy trials by Gerszten, Yamada, it has been
shown that limiting the max dose to the spinal cord to
15 Gy has resulted in zero incidence of myelopathy at
follow- up as high as 37 months. It is clear that the
W. A. Hall and W. J. Curran
safety and efficacy of radio surgery and its effective-
ness will cause it to play an important role in the
future of radiotherapy. A summary of numerous
spinal radiosurgical series can be seen in Table 5. See
Fig. 6 (Spinal Radiosurgery) an example of a patient
imobilization device commonly used for spinal radi-
osurgery can be seen in Fig. 12.
6.4 The Use of Heavy Charged Particles
in Central Nervous System
Radiotherapy
In the past several the prevalence of heavily charged
particle use has been increasing in the United States,
and has surfaced mainly as proton centers. Advanta-
ges have been demonstrated in a direct pre-clinical
comparison of photon and proton based radiotherapy
in canine models (Kaser-Hotz et al. 2002). For a
variety of reasons heavy charge particle radiotherapy
has several theoretical advantages over traditional
photon based radiotherapy, particularly in the CNS.
The advantage of these particles comes mainly in
their ability to deposit their energy over very short
distances in the so-called Bragg peak. The sharp dose
gradient at the edges of these beams allows the use of
high- dose radiotherapy for tumors in critical loca-
tions in the CNS (Kirsch and Tarbell 2004). This may
have important implications for pediatric tumor where
the sparing of critical normal structures becomes
extremely important as the late effects of CNS
radiotherapy can be devastating for a child’s devel-
opment. Validation of this new technology in the CNS
is underway in a variety of clinical trials.
6.5 Brachytherapy and Radiocolloid
Solutions in the Central Nervous
System
Brachytherapy is defined as a therapy technique
where a radioactive source is placed a short distance
from or within the tumor being treated. This theo-
retically has several advantages for the treatment of
CNS malignancy. With the improvement in dose
gradient of stereotactic radiotherapy delivery recent
enthusiasm surrounding the use of brachytherapy in
the CNS has decreased. However ongoing research as
to the ideal implant choice and optimal dose rate
Table 5 Spine radiosurgical series through December 2010
Authors Institution No Prior Treatment Dose/fraction #/ Spinal cord Histology Median Local Pain Rate of
and year of RT system coverage dose limits F/U (in control improved myelopathy
pts/tx months) rate (percent) (percent)
sites (percent)
Amdur U of Florida 21/ 12/21 In house 15 Gy/1/100% to [12 Gy to Many 8 24/25 6/14 (43%) 0/21 (0%)
et al. 25 (Elekta 95% of PTV 0.1 cc, [ 5 Gy (96%)
(2009) Synergy-S) to 0.5 cc if
prior RT
Gerszten U of 77/ 70/77 CyberKnife 20 Gy (mean)/1/ 9 Gy max Lung 16 87/87 65/73 0/77 (0%)
Central Nervous System Tumors

et al. Pittsburgh 87 80% IDL (mean), range: (100%) (89%)

(2006) 4–12 Gy
Gerszten U of 48/ 42/48 CyberKnife 20 Gy (mean)/1/ 9.7 Gy max. Renal 37 54/60 37/38 0/48 (0%)
et al. Pittsburgh 60 80% IDL (mean), range: (90%) (97%)
(2005) 2.4–14.0 Gy
Gerszten U of 28/ 23/28 CyberKnife 21.7 Gy (mean)/1/ [8 Gy to 0.3 cc Melanoma 13 26/28 27/28 0/28 (0%)
et al. Pittsburgh 36 80% IDL (range: (93%) (96%)
(2005) 0–0.7 cc)
Gerszten U of 50/ 48/50 CyberKnife 19 Gy (mean)/1/ 13 Gy max Breast 16 68/68 55/57 0/50 (0%)
et al. Pittsburgh 68 80% IDL dose (100%) (96%)
(2005)
Gerszten U of 393/ 344/ CyberKnife 20 Gy (mean)/1/ NR [50% 21 440/500 290/336 0/393 (0%)
et al. Pittsburgh 500 500 80% IDL breast, (88%) (86%)
(2007) lung, mela-
noma, renal
Yamada Memorial 93/ 0/93 In house 24 Gy (median)/1/ 11.7 Gy max Many 15 90% NR 0/93 (0%)
et al. Sloan- 103 [61] 92% IDL (average) (median), (actuarial
(2008) Kettering range: at 1 year)
1.8–14 Gy
Chang MD 63/ 35/63 In house Tx 1: 6 Gy/5/ 10 Gy max in 5 Many (40% 21 84% NR 0/63 (0%)
et al. Anderson 74 (Varian 80–90% of PTV tx fractions for tx renal) (actuarial
(2007) 21EX) 2: 9 Gy/3/80–90% 1 at 1 year)
of PTV 9 Gy max in 3
fractions for tx
2
(continued)
589
Table 5 (continued)
590

Authors Institution No Prior Treatment Dose/fraction #/ Spinal cord Histology Median Local Pain Rate of
and year of RT system coverage dose limits F/U (in control improved myelopathy
pts/tx months) rate (percent) (percent)
sites (percent)
Ryu et al. Henry Ford 177/ 0/177 Brainlab 8–18 Gy/1/90% 9.2 Gy (mean) Many (25% 6 NR NR, 41/49 1/177
(2007) Hospital 230 Novalis IDL to \ 10% of breast) (84%) (0.5%)
system cord volume separate
report [47]
Nelson Duke U 32/ 22/32 In house 18 Gy (median)/3 12 Gy to 1% of Many (31% 7 29/33 30/32 0/33 (0%)
et al. 33 (Varian (median)/ cord, renal) (88%) (94%)
(2009) 21EX) BED \ 83 for
retreatment.
Gibbs Stanford U 74/ 50/74 Cyberknife 16–25 Gy/1–5/ Max dose range [50% 9 NR 52/62 (84%, 3/74 (4%)
et al. 102 77% IDL (mean), 3–28 Gy in 1–5 breast, includes
(2007) 98% of PTV fractions lung, mela- other neuro
noma, renal sxs)
Choi Stanford U 42/ 42/42 Cyberknife 20 Gy (median)/2 19.3 Gy max [50% 7 38/51 15/23 1/41
et al. 51 (median)/77% IDL (median) in 1–5 breast, lung (75%) (65%)
(2010) (median) fractions
Degen Georgetown 51/ 38/72 Cyberknife 21 Gy (mean)/3.6 11 Gy max Many (19% 12 69/72 37/38 0/51 (0%)
et al. U 72 (mean)/71% IDL (mean) breast) (96%) (97.3%)
(2005) (mean) to \ 1% of
cord volume
W. A. Hall and W. J. Curran
Central Nervous System Tumors
Fig. 12 Medical intelligence immobilization device
continues and enthusiasm remains regarding the
potential use of this treatment modality for deep
seated tumors or CNS re-irradiation Liu et al. (2010).
7 Simulation Films and Portal Films
After completion of treatment planning in virtual
reality, verification films should be taken on a con-
ventional simulator before treatment; these should
include orthogonal radiographs to verify the isocenter.
If multi-leaf collimation will be employed, portal
images should be taken before beginning treatment to
verify beam shape (if static) and orientation of the
field with respect to the patient as well as orthogonal
isocenter verification films. Portal films are typically
obtained weekly to verify the accuracy of the treat-
ment setup.
7.1 Image Guided Radio Therapy,
General Principles
As previously discussed in Sect. 5.5 various advances
in medical imaging over the past several years have
caused astounding advancements in the delivery of
radiation therapy. While portal images have been
used in the past on a weekly basis to verify the
accuracy of treatment setup, future directions have
made radiation therapy a more conformal and accu-
rate treatment modality.
The rationale for the emerging field of image
guided radiation therapy (IGRT) comes from the
591
concept that frequent images obtained before, during,
or after radiation delivery will enable the discovery of
setup errors early and result in the repositioning of the
patient to more precisely align the delivery of their
radiotherapy. In addition, imaging at the time of
treatment may increase the understanding of target
motion caused by physiologic organ motion or
changes in the treatment volumes. This information
can be used to optimize the irradiated volumes of
tumors, and limit the dose to normal structures.
There are various methods of image guided treat-
ment delivery. At the time of radiotherapy planning
and simulation the motion of thoracic and upper
abdominal organs can be assessed. This can be done
with multislice CT scanners that can show, through
the use of specialized software, temporal changes
from breathing that sorts images on the basis of the
phase of the respiratory cycle; from this information
the scanner can then build a four-dimensional image
including the motion of the organ for respiration.
Movement of tumors in the thoracic and abdominal
region can be seen and accounted for in treatment
planning (Vedam et al. 2003).
Three general categories exist for types of image
guided treatment, non-image based, 2D image based,
and 3D image based. Recent examples of non-image
based targeted radiotherapy treatment use radiofre-
quency transponders that are positioned near a tumor
and detected with external antennas that are calibrated
to the treatment isocenter to detect changes in tumor
position (Balter et al. 2005) (Calypse Medical Tech-
nologies, Seattle, WA). 2D image guided radiother-
apy has been used for decades. With this method
megavoltage radiographs are compaired with those
derived from planning CT and patients are positioned
based on bony landmarks. A variety of technologies
have emerged in the past few years that have enabled
the integration of CT scanners with treatment
machines. This enables a 3D image to be acquired and
patient set up to be assessed on a daily basis. Differ-
ences in patient position based on soft tissue land-
marks can be accounted and corrected for.
As was previously discussed in Sect. 5.5 the role
of image guidance in the CNS is increasing. With
advances in functional imaging a greater role for
image confirmation of normal tissue and tumor
response to radiation may emerge however, the clin-
ical utility of this is presently under investigation with
various studies (Kovacs et al. 2010).
592 W. A. Hall and W. J. Curran

Table 6 Typical fractionation schedules for treatment of spinal cord compression and subsequent functional outcomes (Gy Gray)
Total dose Fraction size Overall percentage of patients References
ambulatory after irradiation (%)
15 Gy, followed by 5 Gy, followed by 57–75 Greenberg et al. (1980);
15 Gy for responders 3 Gy for responders Maranzano et al. (1992)
28 Gy 4 Gy 61–72 Helweg-Larsen et al. (2000);
Sorensen et al. (1994)
8 Gy 8 Gy 71 Hoskin et al. (2003)
20 Gy 4 Gy
16 Gy (one week split) 8 Gy 63 Maranzano et al. (1997)
15 Gy, then 15 Gy 5 Gy, then 3 Gy 76 Maranzano and Latini (1995)
30 Gy 3 Gy
30 Gy 3 Gy 56–60 Rades et al. (2004)
40 Gy 2 Gy

8.2 Metastatic Central Nervous System

8 Dose Prescriptions Tumors

The technical principles of prescribing dose to ICRU
volumes are summarized earlier in this chapter in the
section titled ‘‘General Concepts of Modern Radiation
Therapy Technique’’, as also the concept of compar-
ing DVHs. The following section will briefly discuss
dosing guidelines by diagnosis.
8.1 Primary Central Nervous System
Tumors
When treated definitively, most patients with a diag-
nosis of a primary CNS tumor (benign or malignant)
will typically require between 5 and 7 weeks of
conventionally fractionated radiation therapy. Table 2
gives an overview of the typical doses delivered to the
ICRU volumes by diagnosis. Details and references
are given in the sections for each individual diagnosis.
For patients diagnosed with primary malignant
gliomas who are treated with palliative intent, varying
fractionation schedules ranging from 30 Gy in 10
fractions to 50 Gy in 20 fractions have been described
(Chang et al. 2003; McAleese et al. 2003; Phillips
et al. 2003; Roa et al. 2004). Typically, the prognosis
for these patients is quite poor; if they survive long
enough to complete their initial course of treatment,
their survival time typically ranges from 3 to
9 months under the most favorable circumstances.
The Radiation Therapy Oncology Group (RTOG) has
reported on several large trials with differing fractionation
schedules of whole brain radiotherapy for brain metas-
tases (Gaspar et al. 1997, 2000). In conventional frac-
tionation, 50.4 Gy has been used for post-operative
treatment (Patchell 2003) but, in the typical palliative
setting, larger daily fraction sizes are typically used to
achieve a more rapid response. Doses of 30–37.5 Gy
using fraction sizes in the range of 2.5–3 Gy/day are
commonly used. One should keep in mind that larger
fraction sizes do seem to predict a higher incidence of
radiation-induced late effects if the patient survives for an
extended period of time (Patchell 2003; Quinn and
DeAngelis 2000). Patients presenting with leukemic
brain involvement requiring emergent palliative therapy
are typically treated with total doses to the brain ranging
from 24 to 30 Gy in 1.8 to 3.0 Gy fractions, with a median
dose of 18 Gy given to the spine (Sanders et al. 2004).
In the setting of MSCC, treatment outcomes reported
in the literature vary only a small amount from series to
series regardless of fractionation schedule. An overview
is given in Table 6. Multiple fractionation schedules
ranging from 8 Gy 9 1 to 2 Gy 9 20 have been pro-
posed and evaluated both prospectively and retrospec-
tively (Greenberg et al. 1980; Helweg-Larsen et al. 2000;
Hoskin et al. 2003; Maranzano and Latini 1995; Rades
et al. 2002; Rades and Karstens 2002). Regimens such as
30 Gy in 10 fractions and 37.50 Gy in 15 fractions are
Central Nervous System Tumors
commonly used, but no compelling data are available to
point to poorer outcomes with hypofractionated regi-
mens (Rades et al. 2002). Preliminary data of a ran-
domized trial comparing 16 Gy in 2 fractions to 30 Gy
split-course (15 Gy in 3 fractions followed by 15 Gy in 5
fractions for responders) show no difference in efficacy or
toxicity (Maranzano et al. 2002). Reradiation of a spinal
metastasis may be necessary in some long-term survivors
with recurrent disease. In one series with a median initial
dose of 30 Gy in 10 fractions and a median reradiation
dose of 22 Gy in 11 fractions, and an average time of
9.1 months elapsing between treatment courses, 88% of
patients ambulatory at the end of reradiation remain
ambulatory at the last documented post-reradiation
follow- up (Schiff et al. 1995).
8.3 Stereotactic Radiosurgical Dose
for Metastatic Central Nervous
System Lesions
The importance of stereotactic radiosurgery in the
treatment is that CNS metastasis should not be under-
estimated. The optimal stereotactic radiosurgical dose
has been subject to recent study. Shaw et al. examined
the maximum tolerated dose for a single fraction radi-
osurgery in a dose escalation study RTOG 9005 found
that the maximum dose for single fraction radiosurgery
with tumor diameter less than or equal to 20 mm was
24 Gy, for diameter of 21–30 mm the dose was 18 Gy,
and for diameter 31–40 mm the dose was 15 Gy all
given in a single fraction (Shaw et al. 2000). Addi-
tionally, it has been demonstrated in large randomized
trial, RTOG 95-08, that in patients with 1–3 brain
metastasis when randomized to WBRT plus SRS
compared to WBRT alone that SRS results in a sig-
nificant survival advantage in patients that have
received SRS and WBRT for a single metastatic lesion
(Andrews et al. 2004). An example of a spinal radio-
surgery plan can be found in Fig. 13.
8.4 The Role of Sterotactic Radiosurgery
Versus Whole Brain Radiation
Therapy for Metastatic Central
Nervous System Tumors
The role of WBRT in the setting of metastatic tumors
to the CNS is continuing to evolve. A trial by Patchell
et al. (1998) demonstrated the importance of WBRT
593
Fig. 13 Example of brain radiosurgery plan
in the post-operative setting with respect to recurrence
at the original site and new sites in the brain however
failed to demonstrate an overall survival benefit
with the addition of WBRT. Furthermore, a trial by
Aoyama et al. (2006) demonstrated that in 132
patients with 1–4 metastatic that when comparing
SRS versus SRS and WBRT there was no difference
in the overall survival, neurologic, or KPS preserva-
tion, however, it was demonstrated that the addition
of WBRT reduced the rate of new metastatic lesions
and improved 1-year LC. The question of neuroco-
ginitive status was addressed in a trial by Chang et al.
that demonstrated in patients with 1–3 mets that the
addition of WBRT to SRS caused a worse neuro-
cognitive decline as measured by the Hopkins verbal
learning test. This was despite the better 1 year local
control with the addition of WBRT (Chang et al.
2009). The standard of care remains WBRT for the
patient with brain metastasis however the future
role of WBRT and integration with SRS will need to
be examined in the setting of more randomized trials
and futher follow up of current trials.
8.5 The Use of Invasive Head Frame
Immobilization Techniques Versus
Non-Invasive Immobilization
for Stereotactic Radiosurgery
With increasing use and advantages of image guided
RT the question of the necessity of head frames for
stereotactic radiosurgery (SRS) has been raised, and
several different series have examined this question.
594
Breneman and colleagues published their experience
in 53 patients who underwent SRS for brain metas-
tasis from 2005 to 2006. These were linear accelerator
based radiosurgical treatments and of the 168 treated
lesions local control was demonstrated in 90%. The
major conclusions of this analysis were that frameless
SRS could be performed with similar accuracy as
SRS done with an invasive head frame (Breneman
et al. 2009). Other recent series have confirmed the
possible equivalence of frameless SRS. In a second
recent series by Chen and colleagues it was again
shown that the use of image guided radiosurgery with
a non-invasive mask immobilization head frame
achieved similar outcomes to framed radiosurgery
with respect to actuarial freedom from progression
and local control (Chen et al. 2009).
9 The Role of Chemotherapeutic
Agents in Central Nervous System
Tumors
Over the past five years a new standard of care has
been established with respect to the use of chemo-
therapy in high-grade gliomas. Several new studies
have emerged examining the role of new targeted
agents in the management of intracranial malignan-
cies. In a landmark trial by Stupp and colleagues
(2005) performed by the EORTC/NCIC the adjuvant
use of Radiotherapy and Temozolomide for Glio-
blastomas was evaluated. In this study 573 patients
with newly diagnosed GBM were randomized to RT
alone versus RT and concurrent and adjuvant tem-
ozolomide (given as 75 mg/m2/day) and adjuvant
(150–200 mg/m2/day 9 5 days q4 weeks). It was
shown that concurrent and adjuvant temozolomide
significantly improved OS with a 5- year OS of 9.8%
for RT with temozolomide and 1.9% in the RT alone
arm. This has established the standard of care for
malignant gliomas which now consists of the
administration of RT with concurrent temozolomide
based chemotherapy.
10 Future Directions
Integration of biological data (e.g., MR spectroscopy
and proliferation or hypoxia-specific PET data) into
the treatment planning process may allow further
W. A. Hall and W. J. Curran
optimization of dose based on biological parameters
(Munley et al. 2002; Pirzkall et al. 2000; Kovacs et al.
2010). Dose–function histogram (DFH) analysis using
this technology can display the relative function of a
structure versus dose and may provide additional data
needed to obtain and/or evaluate desired heteroge-
neous dose distributions. The dose could be con-
formed either directly or inversely proportional to the
biological properties of a target and/or normal tissues,
depending on what information the corresponding
functional imaging set represented for a particular
structure. Integrating magnetoencephalography data
into treatment planning together with IMRT imple-
mentation may allow further sparing of normal func-
tional regions of the brain (Babiloni et al. 2004). In
addition to increased prevalence of IMRT use in the
CNS, future development of heavy ion technology
mainly in the form of proton and carbon-ion-based
treatments will likely continue to increase in
prevalence
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 Head and Neck Cancer
Allen M. Chen and K. S. Clifford Chao

10 Unknown Primary ................................................... 620

Contents
11 Design of Low-Neck Portal .................................... 622
11.1 Treatment of Lower Neck in Setting of Opposed
1 Introduction.............................................................. 601 Lateral Fields ............................................................. 622
1.1 Terminology............................................................... 603 11.2 Treatment of Lower Neck in Setting of IMRT........ 622
2 Basic Principles of IMRT ....................................... 603 12 Clinical Outcomes with IMRT............................... 623
3 Larynx ....................................................................... 605 13 Guidelines for Contouring Target Structures...... 623
3.1 Glottic Larynx (Stage T1–T2) .................................. 605
3.2 Glottic Larynx (Stage T3–Favorable T4) ................. 606 14 Guidelines for Dose Prescription and Normal
3.3 Supraglottic Larynx ................................................... 607 Tissue Dose Analysis ............................................... 623
14.1 The QUANTEC Reviews.......................................... 624
4 Hypopharynx............................................................ 608
4.1 Pyriform Sinus........................................................... 608 15 PET and the Use of Radiotracers
4.2 Pharyngeal Wall ........................................................ 608 in RT Planning......................................................... 626
4.3 Postoperative RT of Laryngeal 16 Image Guidance ....................................................... 627
and Hypopharyngeal Tumors .................................... 609
17 IGRT Techniques .................................................... 628
5 Oropharynx .............................................................. 611
5.1 Base of Tongue.......................................................... 613 18 Utility of IGRT to Reduce Treatment Margins ... 630
5.2 Tonsillar Area and Soft Palate.................................. 613
19 Adaptive Radiation Planning ................................. 632
6 Nasopharynx............................................................. 614
20 Proton Therapy........................................................ 634
7 Oral Cavity............................................................... 615
21 Re-Irradiation .......................................................... 635
7.1 Lip .............................................................................. 615
7.2 Oral Tongue, Floor of Mouth, Buccal Mucosa........ 615 22 Future Challenges.................................................... 636
7.3 Postoperative RT for Tumors of Oral Cavity
and Oropharynx ......................................................... 616 References.......................................................................... 637

8 Nasal Cavity and Paranasal Sinuses ..................... 617

9 Major Salivary Gland ............................................. 619
9.1 Parotid Gland............................................................. 619
9.2 Submandibular Gland ................................................ 620 1 Introduction

Technological advances in the field of radiation

oncology have revolutionized the management of head
A. M. Chen (&) and neck cancer over the last decade. As will be
UC Davis Cancer Center, 4501 X Street,
discussed, the transition toward more technologically
Sacramento, CA, USA
e-mail: allen.chen@ucdmc.ucdavis.edu sophisticated methods of radiation therapy (RT) planning
and delivery has presented clinicians with unanswered
K. S. Clifford Chao
Weill Cornell Radiation Oncology, 622 West 168th Street, questions requiring a search for new standards. Given
New York, NY 10032, USA the inherent complexity of many of the radiotherapeutic

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 601
DOI: 10.1007/174_2011_353,  Springer-Verlag Berlin Heidelberg 2012
602
techniques currently used, a thorough understanding of
the strengths and weaknesses of each is imperative so
that the potential for disease cure can be maximized
while keeping side effects to a minimum. Thus, the goal
of this chapter is for the reader to gain an understanding
of these technological issues and to develop an appre-
ciation of the ‘‘art,’’ as well as the ‘‘science’’ of RT for
head and neck cancer. In this chapter, the use of RT
refers to external-beam techniques utilizing high-energy
photons unless otherwise stated.
Although intensity-modulated radiotherapy (IMRT)
has been increasingly adopted as the standard treatment
for head and neck cancer, its widespread use has raised
questions regarding how to optimally integrate this
technology into both academic and community-based
clinics. Historically, the available RT techniques have
been broadly stratified into: (1) 3-dimensional confor-
mal radiotherapy (3DCRT) and (2) IMRT. However, in
recent years, continual advances in technology have led
to the development of treatment machines with inte-
grated planar and volumetric advanced imaging capa-
bilities, providing a new platform for treatment delivery
referred to as imaging-guided IMRT (IG-IMRT), or
simply image-guided radiotherapy (IGRT).
A critical component of each of these RT techniques
(3DCRT, IMRT, and IGRT) is the reliance on high-
quality imaging. Indeed, the past decade has witnessed
such significant advances in medical imaging that they
have become central to RT planning and delivery.
Aspects of this process include: computer-based CT
simulation; accurate delineation of target volumes and
normal structures; accounting for microscopic disease
extension and interfraction variability; techniques to
reproduce patient setup; and anatomical imaging to
verify target localization and dose delivery. In broad
terms, imaging has eliminated many of the uncertainties
associated with RT planning and delivery, and has
provided the clinician with a level of assurance that what
is being targeted, is actually being treated. The impor-
tance of imaging is particularly relevant in the setting of
head and neck cancer since the distance between target
volumes and critical structures such as the brain stem,
spinal cord, and optic structures is frequently a matter of
millimeters. In this region, a failure to reasonably
account for spatial uncertainties could potentially mean
the difference between cure and complication.
Despite the multiple advantages that seem appar-
ent with IMRT, this technology has presented several
novel challenges that are yet to be fully addressed.
A. M. Chen and K. S. Clifford Chao
First, IMRT is a heavily user-dependent process, and
the treated volume is entirely based on the target
delineated by the physician. Compared to 3DCRT, a
much more confident knowledge of the anatomical
routes of spread is necessary to avoid potential mar-
ginal misses. Although various head and neck
‘‘atlases’’ have been proposed to aid in the delineation
of targets, a lack of consensus still exists, particularly
for the node-positive, surgically violated neck (Poon
et al. 2004; Wijers et al. 1999; Levendag et al. 2004).
For instance, one study comparing target volumes
delineated by three diagnostic radiologists and eight
radiation oncologists revealed up to a threefold vari-
ation in volumes outlined by different clinicians
(Logue et al. 1998). Additionally, multiple aspects of
IMRT planning, such as the optimization of beam
angles, prioritization of constraints, and selection of
prescription isodose curve are dependent on the
individual user.
Furthermore, the relative lack of standardized
guidelines for IMRT plan evaluation have likely
resulted in significant variations between prescribed
dose and delivered dose across centers. Indeed, what
constitutes an ‘‘acceptable’’ IMRT plan will almost
certainly vary depending on such factors as the patient
volume of the treating institution, the clinical experi-
ence of the physician, and the technical expertise of the
planner. Lastly, it is becoming increasingly clear that
the generation of more conformal dose distributions
and steep gradients between target and non-target tis-
sues using IMRT may come at the expense of a higher
dose to non-delineated extra-target organs. How and
whether attempting to lower the incidence of mucosi-
tis, brachial plexopathy, and dysphagia, by restricting
dose to such structures as the oral cavity, brachial
plexus, and swallowing structures, respectively, might
affect anatomical patterns of local–regional recurrence
remain uncertain. In this regard, inverse planning
continues to evolve as user-defined constraints become
more refined with the recognition of toxicities associ-
ated with IMRT. Clearly, the importance of a multi-
disciplinary approach with coordination among
radiation oncologists, radiologists, surgeons, and
pathologists, to optimally identify areas at highest and
lowest risk for disease, cannot be overstated.
Additional disadvantages of IMRT may include: (1)
less homogeneous dose distribution, (2) more beam
‘‘on-time’’ leading to increased total body dose due to
scatter, (3) increased treatment planning time for the
Head and Neck Cancer 603

physicists and radiation oncologists, and (4) increased

cost. Therefore, there must be a clear potential advan-
tage for proceeding with IMRT in a particular patient.
Traditionally, the most common reason is to reduce the
dose to the salivary gland(s) in patients receiving RT to
both sides of the neck thereby minimizing xerostomia.
However, as to be subsequently discussed, the indica-
tions for IMRT continue to be expanded and are by no
means restricted to this setting. Regardless of the
technique chosen, treatment planning for head and neck
RT is a complex undertaking that requires a thorough
understanding of not only the basic anatomical and
biological principles, but also the relative strengths and
limitations of the existing technologies in use. This is
particularly true as technology continues to evolve at a
breathtaking pace. Accordingly, this chapter will focus
on the general principles underlying the rationale for
RT decision-making in this setting.

1.1 Terminology

The delineation of the target volume and the normal

tissues that must be protected is based on data obtained
via treatment planning computed tomography (CT).
The terminology in modern RT planning is defined by
the International Council of Radiation Units (ICRU)
reports 50 and 62 (ICRU Report 1993). The gross tumor
volume (GTV) refers to the target volume that includes
the gross tumor as defined by physical examination and
radiographic studies. The clinical target volume (CTV)
includes the GTV and areas at risk for subclinical dis-
ease. Often more than one CTV is defined, depending
on the relative risk for harboring subclinical disease.
Subclinical disease refers to microscopic disease likely
to be present but not apparent on physical examination
or radiographic studies, either by direct extension or
nodal drainage. Typically, patterns of subclinical
spread are based upon the primary disease site, and
therefore, knowledge of the patterns of extension and
lymphatic drainage of tumors is essential. Notably,
considerable research continues to be devoted to
improve defining both the GTV and CTV for the pur-
poses of RT planning. The planning target volume
(PTV) refers to an expanded CTV (usually 3–5 mm in
all dimensions) to account for day-to-day setup vari-
ability and/or organ motion. A schematic illustration of
the boundaries for volumes defined by the ICRU is
shown in Fig. 1. A normal tissue structure is called an
Fig. 1 Schematic illustration of the boundaries of the volumes
defined by ICRU Reports 50 and 62: gross tumor volume
(GTV), clinical target volume (CTV), internal target volume
(ITC), planning target volume (PTV), treated volume, and
irradiated volume
organ at risk (OAR) or an OAR volume (ORV).
Examples of OAR include the parotid glands, the spinal
cord, optic nerves, chiasm, eyes, and brain stem.
Expansion of an ORV for motion of setup variability
produces a planning organ at risk volume (PRV). All
dose specification and analyses should be based on
PTV and PRV rather than on GTV, CTV, or ORV.
2 Basic Principles of IMRT
In contrast to 3DCRT, inverse treatment planning
forms the crux of IMRT, which may yield a more
conformal treatment plan, thereby reducing the dose
to normal tissues and decreasing the likelihood of
acute and late toxicity. IMRT utilizes a computer dose
distribution optimization process to deliver the radi-
ation dose to the tumor while minimizing the dose
604
delivered to the surrounding normal structures. The
delivery of IMRT is based on the use of multileaf
collimators (MLCs) and allows for painting or
sculpting of dose distribution with superb precision
resulting in a rapid dose fall-off near normal tissue.
Although several different treatment planning systems
are available, the basic principles underlying this
technology are similar. IMRT can thus optimize
delivery of radiation to irregularly-shaped volumes
and has the ability to produce concavities in radiation
treatment volumes. IMRT can currently be delivered
using linear accelerators with static multi-leaf colli-
mators (MLC, step and shoot IMRT), dynamic leaf
MLCs, helical tomotherapy, or volumetric arc mod-
ulated therapy (VMAT). Since IMRT delivered using
a simultaneous-integrated boost (SIB) technique
allows for varying doses to be delivered to various
target volumes in a single phase and obviates the need
for field matching and the use of electrons (thus
minimizing dosimetric uncertainties), it has been
adopted as the most widely used IMRT technique
(Wu et al. 2003).
IMRT is based on several equally important steps:
patient immobilization, accurate target delineation,
treatment plan generation, optimization, and review.
Since IMRT is critically dependent on precision, a
mishap in any of these steps can compromise patient
outcome. The immobilization device should at least
include the head and neck, and ideally the shoulders
to further ensure accurate patient setup on a daily
basis. Tongue-depressing stents combined with cus-
tomized dental impression/bite plate devices can be
used to separate areas at high risk for tumor from
critical structures not requiring irradiation. A common
situation is in the postoperative setting for oral tongue
tumors where the hard palate can be displaced out of
the high-dose region with a stent. Patients with lat-
eralized tonsillar cancers without base of tongue
invasion can also benefit from displacement of the
tongue out of the high-dose region. Shoulder straps
are sometimes necessary to retract the shoulders out
of the potential IMRT fields. CT scans will be
required at simulation to define target volumes with
the patient in the treatment position. CT scan thick-
ness should be a maximum of 0.3 cm. Non-ionic
intravenous (IV) contrast is used to visualize vascular
structures unless there is a medical contraindication.
In cases where MRI is useful for defining the target
A. M. Chen and K. S. Clifford Chao
volume, such as nasopharyngeal cancers, an MRI is
also obtained using a Gd-DPTA-enhanced T1-
weighted imaging protocol. Image registration and
fusion applications, if available, should be used to
help in the delineation of target volumes. All avail-
able diagnostic imaging studies, as well as operative
and endoscopic reports, should be reviewed for target
delineation. Although target design is a somewhat
subjective and user-dependent process, general prin-
ciples (as discussed subsequently) can be followed in
order to ensure treatment success.
The benefits of IMRT in sparing the parotid glands
and reducing the incidence of xerostomia have been
well established (Chao et al. 2001a, b; Eisbruch et al.
1999). Salivary flow reduction causes a number of
problems for head and neck cancer patients including
difficulty in chewing, tooth decay, dysphagia, taste-
lessness, and altered speech. These manifestations of
reduced salivary function can impact the quality of
life for head and neck cancer patients after treatment
(Braam et al. 2007). Preservation of salivary flow has
been associated with the volume and total radiation
dose delivered to the parotid glands. Therefore,
restricting the dose and volume to the parotid gland
should result in improvement in long-term salivary
function. Based on a study by Eisbruch et al. (1999)
salivary function and subjective xerostomia was
considerably improved in patients whose parotid
glands received less than a mean dose threshold of
26 Gy. Another commonly recommended constraint
is to keep 50% of one parotid gland volume to a total
dose \30 Gy. Notably, xerostomia-related symptoms
and quality of life continue to improve up to about
12 months after completion of IMRT (Jabbari
et al. 2008).
IMRT may also be useful where preservation of
salivary function is not a goal. One example is
nasopharyngeal cancer where IMRT may be used to
reduce the dose to the temporal lobes, optic apparatus,
and brain stem. Another situation where IMRT is
useful is for cancers located near the thoracic inlet
(i.e. thyroid carcinoma, cervical esophageal cancer)
where the contour of the shoulders makes treatment
with 3DCRT difficult. Similarly, dysphagia is a well-
known toxicity of head and neck radiation treatment.
Multiple factors contribute to swallowing impairment
after radiation including a decrease in pharyngeal
constrictor mobility, decreased saliva, and restriction
Head and Neck Cancer 605

of epiglottic and laryngeal mobility. Interest in spar-

ing the pharyngeal constrictors and esophagus using
IMRT to reduce symptomatic dysphagia and gas-
trostomy-tube dependence is growing (Levendag
et al. 2007; Jensen et al. 2007; Feng et al. 2007).
A prospective study of 36 patients with stage III–IV
oropharyngeal and nasopharyngeal cancer was con-
ducted at the University of Michigan in which
definitive chemoradiation using IMRT was utilized to
spare the structures believed to be related to swal-
lowing (Feng et al. 2007). Larger mean doses deliv-
ered to the pharyngeal constrictors, glottic and
supraglottic larynx were correlated with an increased
incidence of aspiration and dysphagia.

3 Larynx

3.1 Glottic Larynx (Stage T1–T2)

Because the risk of subclinical disease in the cervical

lymphatics is low, the portals are limited to the pri-
mary lesion (Fig. 2). Although a common practice is
to treat early vocal cord cancer with a standard field
size (e.g., 5 9 5 or 6 9 6 cm), a more practical rec-
ommendation is to design the portal to fit the specific
lesion with the assistance of CT-planning. The patient
is treated in the supine position with the neck exten-
ded and the head immobilized in an aquaplast mask.
The physician at the treatment machine checks the
field each day according to palpable anatomic land-
Fig. 2 a Standard 6 9 6 cm radiation field consisting of
marks. This practice allows the treatment volume to opposed lateral beams to treat T1N0 larynx cancer.
be kept at a minimum, while virtually eliminating the b Subsequent treatment plan with the 6,300 cGy isodose line
risk of missing the target. The overall treatment time, represented in red. Treatment was delivered using 6 mv
as well as total dose, is critical in obtaining maximum photons and in 28 sessions using a daily fraction size of
225 cGy
control rates; failure to use the smallest field size
consistent with adequate coverage of the tumor usu-
ally means that either the total dose or dose per cricoid cartilage, 1 cm posterior to the thyroid ala,
fraction must be compromised to limit acute reactions and 1.5 cm anterior to the skin of the anterior neck.
and/or late effects. The patient is treated with parallel The portals may be modified depending on the precise
opposed 6-MV X-ray fields weighted 3:2 to the side extent of the tumor.
of the tumor if it is lateralized. An anterior boost field CT helps determine tumor extent, and therefore
is sometimes employed to deliver approximately portal design, in patients with large T2 cancers. It is
5–10% of the total dose to reduce the high-dose dis- useful in detecting subglottic spread, which may be
tribution laterally. 60Co or 4-MV X-ray beams are submucosal and difficult to detect by direct laryn-
ideal but are not available in most radiation oncology goscopy. T1 and early T2 cancers are often superficial
facilities. The typical borders for a T1N0 cancer are and subtly apparent on the planning CT. The dose
the middle of the thyroid notch, the bottom of the fractionation schedule is 63 Gy in 28 once-daily
606
Fig. 3 A 55 year-old male with T3N0 squamous cell carci-
noma of the glottic larynx undergoing organ-preservation
therapy with definitive chemoradiotherapy with IMRT and
concurrent cisplatin illustrating highly conformal treatment
plans in the a coronal, b sagittal, and c axial planes. The
prescribed dose was 70 Gy to the high-dose PTV including
fractions for T1 cancers and 65.25 Gy in 29 fractions
for T2 tumors. Because the rates of disease control are
lower for T2 tumors, some investigators have pro-
posed using BID fractionation (Garden et al. 2003).
Until the results of a recently completed randomized
trial comparing QD (70 Gy in 35 fractions) versus
BID fractionation (79.2 Gy in 66 fractions of 1.2 Gy
twice-daily) for T2N0 true glottic cancer are reported,
it is reasonable to consider both a hypofractionated
and hyperfractionated approach. The prescribed dose
is the minimum target dose (MTD). The maximum
dose in the irradiated volume is typically less
than 103%.
Although several recent publications have shown
that IMRT can reduce dose to the carotid arteries in
patients with early stage vocal cord cancer, its use is
still considered investigational (Gomez et al. 2010;
Chera et al. 2010; Rosenthal et al. 2010). In a
planning study of 6 patients, Rosenthal et al. (2010)
showed that IMRT dramatically lowered the mean
dose to the bilateral carotid arteries from 64 to
\20 Gy while maintaining target volume coverage.
The authors argued that these dosimetric advantages
may be important for younger patients and for those
with pre-existing carotid artery pathology. Given the
lack of data on actual patients treated by this
approach and persistent concerns about marginal
misses, the use of IMRT for early stage larynx
cancer should be limited to the context of a
clinical trial.
A. M. Chen and K. S. Clifford Chao
gross tumor, 63 Gy to the bilateral cervical necks, and 56 Gy to
the supraclavicular fossa delivered in 35 fractions. Note that the
skull base and retropharyngeal lymph nodes are not encom-
passed in the IMRT plan for this patient with N0 laryngeal
disease
3.2 Glottic Larynx (Stage
T3–Favorable T4)
Based on the results of randomized trials, laryngeal-
preservation therapy with the use of definitive RT
(with or without concurrent chemotherapy) is con-
sidered the standard of care for patients with locally
advanced vocal cord cancer without significant car-
tilage destruction (The Department of Veterans
Affairs Laryngeal Cancer Study Group 1991; Foras-
tiere et al. 2003; Pfister et al. 2006). Although all
patients treated on these clinical trials received
3DCRT using conventionally designed opposed lat-
eral fields, the use of IMRT to spare the parotid
glands is now considered acceptable in this setting.
The total prescription dose to the primary tumor and
all areas of gross lymphadenopathy is 70 Gy in 35
fractions. Because of a 20–25% risk of subclinical
involvement of the jugulodigastric (level II) or mid-
jugular (level III) lymph nodes, these areas are elec-
tively treated to a dose of approximately 60 Gy.
Additionally, the submandibular (level IB) and ret-
ropharyngeal lymph nodes are included as part of the
high-risk PRV for patients with clinically involved
neck nodes. A commonly used IMRT prescription is
to treat three PTVs in 35 fractions using a SIB tech-
nique to doses of 70 Gy to the gross disease, 63 Gy to
areas at high risk for subclinical involvement, and
56 Gy to the supraclavicular fossa (Fig. 3). Both
extended-field and split-field (in which the IMRT
Head and Neck Cancer
Fig. 4 Radiation treatment technique for carcinoma of glottic
larynx, stage T3–T4N0. Patient is treated in the supine position,
and field is shaped with Lipowitz’s metal. Anteriorly, field is
allowed to fall off. The entire pre-epiglottic space is included
by encompassing the hyoid bone and epiglottis. The superior
border (just above angle of mandible) includes jugulodigastric
(level II) lymph nodes. Posteriorly, portion of spinal cord must
be included within field to ensure adequate coverage of
midjugular (level III) lymph nodes; spinal accessory (level V)
lymph nodes themselves are at low risk of involvement. Lower
border is slanted (1) to facilitate matching with low-neck field
and (2) to reduce length of spinal cord in high-dose field.
Inferior border is placed at bottom of cricoid cartilage if patient
has no subglottic spread; in presence of subglottic extension,
inferior border must be lowered according to disease extent
(from Parsons et al. 1989, Fig. 1, p 124; Levitt et al. 2nd edn.,
1999, Fig. 15-2)
field is matched to an anterior low neck field) IMRT
techniques are currently in use (see subsequent sec-
tion, ‘‘Design of the Low Neck Portal’’).
For those treated with non-IMRT techniques, the
initial portals for T3–T4 true vocal cord cancer are
shown in Fig. 4. Areas of subclinical involvement of
the jugulodigastric (level II) or midjugular (level III)
lymph nodes in the cervical neck are electively trea-
ted with 45.6–50 Gy. A small low-neck portal treats
the low jugular (level IV) lymph nodes with a 50 Gy
given dose (at Dmax, the dose at maximum buildup)
over a duration of 5 weeks (see subsequent section,
‘‘Design of the Low Neck Portal’’). Primary fields are
then reduced, and the treatment is continued to the
final tumor dose with fields that are usually slightly
larger than those described for early vocal cord can-
cer. Care must be taken not to underdose tumor that
extends anteriorly through the thyrocricoid membrane
for patients with favorable T4 tumors who are treated
with 6-MV X-rays.
607
3.3 Supraglottic Larynx
Even small cancers of the supraglottic larynx are at
high risk for harboring regional lymphatic disease,
hence treatment of the entire cervical neck is gener-
ally recommended. Definitive RT produces high
control rates for T1, T2, and low-volume T3 supra-
glottic cancers. Unfavorable T3 and T4 tumors are
often treated with laryngectomy and adjuvant RT;
those who receive definitive RT may also be candi-
dates for concurrent chemotherapy. The dose for
T1N0 is 66 Gy; all other tumors are treated to 70 Gy.
Doses of 50–63 Gy are typically delivered to areas at
risk for microscopic disease extension. Although
these tumors were traditionally treated by 3DCRT
using opposed lateral fields matched to an anterior
low neck field, the use of IMRT to comprehensively
treat the primary lesion and neck is now the standard
of care. An example of IMRT volumes used for
tumors of the supraglottic larynx is shown in Fig. 5.
If the neck is clinically negative and tumor does not
extend beyond the larynx, only the level-II and level-
III nodes are included in the high-risk CTV; and level
IB, level IV, level V, and the retropharyngeal lymph
nodes are included in the low-risk CTV. If the base of
the tongue or pyriform sinus is involved or if neck
disease is extensive, the high-risk CTV should also
include the entire jugular chain, spinal accessory
chain (level V), and retropharyngeal nodes. Both
extended-field and split-field IMRT techniques are
currently in use (see subsequent section, ‘‘Design of
the Low Neck Portal’’).
Consideration should be given to leaving a strip of
anterior tissue in the subcutaneous region uncovered
by the CTV except in thin patients, those with very
bulky lymphadenopathy that extends anteriorly, or
those who have lesions involving the infrahyoid epi-
glottis near the anterior commissure. The rationale for
this strategy is that shielding even a few millimeters
of the anterior skin, subcutaneous tissues, and lym-
phatic vessels reduces the likelihood of desquamation
(particularly in patients who receive concurrent che-
motherapy) and may lessen the risk of serious lar-
yngeal edema. Where exactly to spare this region
depends on disease extent. For a false cord or infra-
hyoid epiglottic cancer, the region inferior to the
bottom of the cricoid cartilage is usually chosen. For
an epiglottic tip cancer, the anterior tissue at or above
the level of the true cords, depending on the extent
608
Fig. 5 a Exophytic T3 cancer arising from the left arytenoid
cartilage. b Subsequent IMRT treatment plan with the 70 Gy
isodose cloud represented in the red colorwash, the 63 Gy
isodose cloud represented in the yellow colorwash, and the
56 Gy isodose cloud represented in the magenta colorwash.
Treatment was delivered in 35 fractions using a simultaneous-
integrated boost technique
and growth pattern of disease (infiltrative versus
exophytic), may be used.
4 Hypopharynx
4.1 Pyriform Sinus
The incidence of occult nodal involvement for
patients with even small hypopharyngeal primary
tumors is high, and comprehensive nodal irradiation is
thus recommended for patients presenting with all
stages. Treatment can be delivered using IMRT or
non-IMRT techniques. The conventional portals used
for the initial treatment volume of early and moder-
ately advanced pyriform sinus cancer are shown in
Fig. 6. In addition to the entire jugular lymphatic
A. M. Chen and K. S. Clifford Chao
Fig. 6 a Portals used for initial treatment volume in a patient
with carcinoma (stippled area) of pyriform sinus. Superiorly,
portal covers lymph nodes at base of skull, then sweeps
anteroinferiorly to cover posterior tongue base and level-II
lymph nodes. Anteriorly, at least 1 cm of skin and subcutane-
ous tissues (as viewed from lateral projection) is usually spared.
Inferior border is 2–3 cm below bottom of cricoid cartilage and
is slanted to facilitate matching with low-neck portal and to
avoid irradiating shoulders. Posterior field edge usually
encompasses spinous process of C2 vertebral body.
As treatment progresses, several field reductions are made (to
shield spinal cord and to limit volume of mucosa that receives
high-dose irradiation). b Location of lateral retropharyngeal
lymph nodes in relation to C1–C2 vertebral bodies (from Levitt
et al. 2nd edn, 1999, Fig. 16.3a,b)
chain, the lateral retropharyngeal lymph nodes
(medial to the carotid arteries, usually located just in
front of the C1–C2 vertebral bodies) and level-V
nodes are also at risk and are treated even if the neck
is clinically negative. The pyriform sinus lies poste-
riorly in the pharynx, extending from its upper limit
on the pharyngoepiglottic fold to its apex located
between the superior and inferior borders of the cri-
coid cartilage. For both patients treated by IMRT and
non-IMRT techniques, it is rarely necessary to allow
anterior ‘‘falloff’’ over the anterior skin of the mid-
line. If the primary lesion is so extensive as to require
‘‘falloff’’ anteriorly to achieve adequate coverage,
total laryngopharyngectomy is often the treatment of
choice.
4.2 Pharyngeal Wall
Most pharyngeal wall lesions involve only the poster-
ior wall. With CT, some lesions are seen to extend
posterolaterally, in effect wrapping around the anterior
Head and Neck Cancer
Fig. 7 Radiation treatment techniques for carcinoma of pos-
terior pharyngeal wall. a Computed tomogram of T3 posterior
pharyngeal wall cancer (arrowheads). Horizontal lines repre-
sent two possible placements of posterior field edge. If field
edge bisects vertebral body when spinal cord is shielded, part of
cancer will be in penumbra or altogether outside irradiated
volume. Entire width of vertebral body is always treated in
patients with posterior pharyngeal wall tumors. b Simulation
film shows first field reduction (to shield spinal cord) for a
patient with T3N0 cancer. Note that with reduced portals, little
of larynx remains within treatment volume. Only epiglottis and
part of arytenoids and aryepiglottic folds cannot be excluded.
vertebral body (Fig. 7). If the posterior edge of the
reduced portal splits the middle of the vertebral body,
target miss may result. For patients treated by IMRT
techniques for pyriform sinus cancer, a common frac-
tionation scheme is to treat gross disease to 70 Gy, with
lesser doses of 63 and 56 Gy, to areas at high and low
risk for microscopic disease spread (Fig. 8). The upper
margin of the IMRT field should be at the base of the
skull, to include the retropharyngeal nodes. The initial
lower portion of the IMRT field should include the
entire pharyngeal wall because of these tumors’ pro-
pensity to have ‘‘skip lesions.’’
609
c Isodose plots for reduced portals. In our practice, 6 MV
X-rays are ideal energy. Because of characteristics of high-
energy (e.g., 20 MV) X-rays near field edge, isodose distribu-
tions are constricted compared with low energy beams (2).
Result is reduced dosage to cancer near posterior field edge,
which is undesirable in treatment of posterior pharyngeal wall
cancer. Central axis (CA) is placed at posterior field edge to
provide nondivergent posterior field edge. Wedges are used
to reduce dose anteriorly and to pull isodose distribution
slightly posteriorly. SSD source-to-surface distance (a, b from
Mendenhall et al. 1988a, Fig. 3b,c p 210; c from Levitt et al.
2nd edn., 1999, Fig. 16.4)
4.3 Postoperative RT of Laryngeal
and Hypopharyngeal Tumors
In this situation, the larynx has been removed.
Although 3DCRT using opposed lateral fields have
been traditionally used to treat areas at risk for disease
recurrence, the use of IMRT is also an option. When
3DCRT is used, the primary fields are treated through
lateral parallel–opposed portals (Fig. 9) to include the
anterior and posterior neck from the base of skull to the
top of the tracheal stoma. Techniques with either
anterior or anterior and posterior portals have the
610
Fig. 8 A 65 year-old female with T1N2b squamous cell
carcinoma of the right pyriform sinus undergoing organ-
preservation therapy with definitive chemoradiotherapy with
IMRT and concurrent cisplatin illustrating highly conformal
treatment plans in the a coronal and b axial planes. The
prescribed dose was 70 Gy to the high-dose PTV including the
Fig. 9 Typical postoperative simulation film of a patient with
advanced-stage cancer of the laryngopharynx. Dashed line
initial field reduction (after 50 Gy, to shield spinal cord), dotted
line final reduction (after 60 Gy). Wires mark surgical scars and
stoma. Slanting line used on lower border reduces length of
spinal cord treated by primary field, allows better caudal
coverage of mucosal surfaces while simultaneously bypassing
shoulders, and facilitates matching with low-neck field (from
Amdur et al. 1989, Fig. 1, p 27; Levitt et al. 2nd edn, 1999,
Fig. 16-5)
A. M. Chen and K. S. Clifford Chao
primary tumor and grossly positive lymph nodes in the
ipsilateral neck, 63 Gy to the contralateral cervical neck, and
56 Gy to the upper mediastinum and supraclavicular fossa
delivered in 35 fractions. Note that the retropharyngeal lymph
nodes to the base of skull are encompassed for this patient with
hypopharyngeal cancer
disadvantages of underdosage of lymph nodes at the
base of the skull in the region of the mastoid and
unnecessary irradiation of a large volume of brain tis-
sue in the posterior cranial fossa. The field is reduced
after approximately 45 Gy MTD so that the spinal cord
is no longer in the treatment field; the dose to high-risk
areas behind the plane of the spinal cord may be
boosted with 8- to 10-MV electrons. The low-neck
portal, which usually includes the stoma, is treated as
shown in Fig. 10. The dose at Dmax in most patients is
50 Gy in 25 fractions. In patients at high risk for
recurrence in the low neck (i.e. who have positive
level-IV nodes), a boost dose is occasionally given
through a reduced field. In patients with subglottic
extension, the dose to the stoma and peristomal tissues
is boosted with electrons, usually 12 MV. The energy
selected should be high enough to deliver an adequate
dose to the tracheoesophageal groove (level VI) lymph
nodes. A petrolatum gauze bolus is placed on all scars
and over drain sites. All scars, suture holes, and drain
sites are treated with generous (2–3 cm) margins.
IMRT is increasingly used in the postoperative
setting (Chen et al. 2010; Studer et al. 2006; Daly
et al. 2011). Compared to those generated by 3DCRT
using opposed lateral fields, IMRT creates dosimetric
plans characterized by steep dose gradients resulting
in dramatic fall-offs between areas of high and low
Head and Neck Cancer
Fig. 10 Low-neck field. Beam is vertical (0). Rectangle
(solid line) light field, dashed line central axis, shaded areas
blocked portions of field (stacked lead blocks). Superior border
of neck field is inferior border of primary field. Actual line is
treated only with primary field. Upper border of low-neck field
assumes V shape. In midline of patient, apex of V generally is
at or close to central axis, so portion of beam that irradiates the
spinal cord is nondivergent. At junction of the three fields, short
(2–3 cm) segment of spinal cord remains untreated through any
of the fields (from Amdur et al. 1989, Fig. 1, p 27; Levitt et al.
2nd edn, 1999, Fig. 16-5)
doses of radiation. Naturally, the importance of
accurate target delineation accounting for micro-
scopic spread and patient setup error is paramount to
avoid under-dosing of areas at risk for disease
recurrence. This issue is of particular relevance in the
postoperative setting where surgical changes and
artifactual distortion often obscure anatomical detail
and hinder identification of target tissue.
The consensus guidelines endorsed by the RTOG,
EORTC, Danish Head and Neck Cancer Group
(DAHANCA), Groupe d’Oncologie Radiothérapie
Tête et Cou (GORTEC), and National Cancer Insti-
tute of Canada (NCIC) are routinely used to delineate
the CTV at the time of IMRT treatment planning
(DAHANCA et al. 2010). However, these contouring
recommendations are only applicable for patients
with N0 necks, a situation uncommonly observed in
the setting of postoperative RT. In the postoperative
setting, guidelines are more sparse, but at the very
minimum, the entire operative bed is covered (based
on preoperative imaging, preoperative physical
examination and/or endoscopy, and operative and
pathological findings) and in the case of nodal
involvement, the retrostyloid space up to the base of
skull. In all cases, the CTV also includes the ipsilat-
eral pathologically positive necks. This generally
involves encompassing nodal levels II, III, and IV,
with inclusion of levels IV, IB, V, and the retropha-
ryngeal lymph nodes for node-positive or hypopha-
ryngeal tumors.
611
To help appreciate the anatomical boundaries of the
nodal levels, knowledge of such structures as the neck
muscles (geniohyoid, mylohyoid, platysma, stern-
ocleiodmastoid, and scalene muscles), blood vessels
(carotid artery, jugular vein), and bony-cartilaginous
landmarks (hyoid, mandible, thyroid) are imperative to
CTV design. Even so, controversy exists regarding
‘‘standardized’’ definitions of nodal boundaries
(Eisbruch and Gregoire 2009). For instance, some
investigators advocate using the jugular fossa as a more
appropriate landmark than the caudal edge of the lat-
eral process of C1 for defining the cranial limit of level
II (Palazzi et al. 2004). Similarly, debate exists on
whether the caudal edge of the mastoid process is more
appropriate for defining the cranial limit of level V than
the upper edge of the body of the hyoid bone, as cur-
rently suggested by the consensus guidelines. Special
attention is given to coverage of the retropharyngeal
lymph nodes for patients with node-positive or hypo-
pharyngeal disease with the anatomical borders being
the base of skull (cranially), body of the hyoid bone
(caudally), fascia under the pharyngeal mucosa (ante-
riorly), prevertebral muscles (posteriorly), and medial
edge of the internal artery (laterally).
Notably, many cases in which meaningful bilateral
parotid sparing (typically because of pathological
disease involvement in the bilateral cervical necks)
could not be reasonably achieved are frequently
treated with opposed lateral conventional fields.
Figure 11 illustrates an example IMRT plan. Simi-
larly, those with extremely large tumors and/or who
underwent extensive surgeries, in which the operative
site may have been difficult to delineate were often
times treated without IMRT. A common practice is to
deliver a dose of 60 and 54 Gy in 30 fractions to areas
at highest and lowest risk, respectively, for disease
involvement in the postoperative head and neck
cancer. For patients at high risk for disease (in the
setting of significant extra-capsular extension or
positive margins), doses of 66 Gy (highest-risk CTV),
60 Gy (intermediate-risk CTV), and 54 Gy (lowest-
risk CTV), can be delivered in 33 fractions.
5 Oropharynx
There are two important points in the selection of RT
technique for oropharyngeal cancers. One, the risk of
lymph-node metastases in both the upper and lower
612
Fig. 11 IMRT treatment plan in the a axial and b sagittal
planes for a 79-year-old male status post total laryngectomy
and bilateral neck dissection for T4N0 larynx cancer. Note that
neck is significant, and both areas should be treated
even when the neck is clinically disease free.
Exceptions can be made for well-lateralized, small
tonsillar cancers, where the probability of contralat-
eral neck involvement is low (O’Sullivan et al. 2001).
Two, IMRT has essentially become the standard of
care for the treatment of oropharyngeal cancers due to
its ability to spare critical structures and improve
quality of life (Miah et al. 2010).
The design of IMRT plans in the management of
oropharyngeal tumors is based on the primary site of
disease as well as the extent of spread. The primary
lymphatic drainage of the oropharynx is to the jugu-
lodigastric (level II) nodes located in the upper deep
jugular chain. The retropharyngeal and parapharyn-
geal nodes, located in spaces closely related to cranial
nerves IX through XII, the internal jugular vein, and
the internal carotid artery at the base of skull are also
at risk for disease involvement. In general, treatment
should encompass all gross tumor as well as areas at
high risk for subclinical spread including levels Ib, II,
III, IV, and V bilaterally and retropharyngeal lymph
nodes (if jugular nodes are involved). In special sit-
uations (small, well-lateralized tonsillar cancers), it
may be reasonable to exclude the contralateral Ib and/
or the entire contralateral neck altogether. A common
prescription is to deliver doses of 70, 60, and 54 Gy in
33 fractions to gross disease, high-risk subclinical,
and low-risk subclinical target volumes, respectively,
using a SIB technique. Principles of postoperative
A. M. Chen and K. S. Clifford Chao
the skull base and retropharyngeal lymph nodes are not
encompassed in the radiation field and that attention is given
to minimize dose to the hard palate
therapy are similar to those for tumors involving the
larynx and hypopharynx (Sect. 4.3).
When opposed lateral fields are recommended due
to the inability to meaningfully spare either parotid
gland, the use of long lateral primary fields that
include the larynx and a longer length of spinal cord
than necessary is inappropriate. Dividing the treat-
ment volume into upper (primary) and anterior low-
neck fields is essential so that the larynx can be
shielded from irradiation and the spinal cord dose is
reduced; this is true even in the presence of a large
lymph node that is bisected by the lower border of the
primary field. Although many radiation oncologists
explain that treating the larynx with 50 Gy is
acceptable because ‘‘it can tolerate it,’’ there is little
excuse for exposing a vital structure to a moderately
high dose of irradiation when it is avoidable. Because
the neck is thinner at the level of the larynx than of
the oropharynx, the involved larynx often receives a
higher total dose at a higher dose per fraction than the
primary tumor. Inclusion of the larynx within the
primary portals causes more severe mucositis, which
often leads to unplanned treatment interruptions or
requires treatment with low total daily doses, either of
which results in poor tumor control. Treatment of the
larynx also produces edema and dries the mucous
membranes resulting in unnecessary chronic morbid-
ity. Such treatment may also complicate the man-
agement of the patient who later develops a second
primary cancer in the larynx.
Head and Neck Cancer
Fig. 12 IMRT treatment plans for a 56-year-old female with
T4N2a squamous cell carcinoma arising from the left base of
tongue illustrating highly conformal dose distributions in the
a sagittal and b axial planes. The prescribed dose was
Fig. 13 Radiation treatment technique for carcinoma of base
of tongue. Superiorly, portal treats jugular and spinal accessory
(level V) lymph nodes to base of skull. Posterior border is
behind spinous process of C2. Inferior border is at or just below
thyroid notch, depending on disease extent. Anteroinferiorly,
skin and subcutaneous tissues of submentum are shielded,
except in case of advanced disease. The portals are usually
reduced off of the spinal cord at approximately 45 Gy and a
second reduction occurs at 60 Gy. The portals are usually
equally weighted 3:2 towards the side of the lesion, if it is
lateralized (from Parsons et al. 1998, Fig. 42.1)
5.1 Base of Tongue
Typical IMRT plans for treating a cancer of the base
of the tongue are shown in Fig. 12. Concurrent che-
motherapy is employed for unfavorable T3–T4 and/or
613
6,996 cGy to the high-dose PTV including all gross disease.
The bilateral cervical necks and supraclavicular fossa received
doses of 5,940 and 5,400 cGy, respectively
advanced neck disease. Notably, the base of the ton-
gue is a midline structure, and both sides of the neck
are at fairly high risk of subclinical disease spread.
Direct extension anteriorly can involve the oral ton-
gue; superior and lateral extension can involve the
ptyerygoid muscles and tonsil; and inferior extension
can involve the vallecula, epiglottis, and pre-
epiglottic space. Depending on the location of the
index lesion, consideration should be given to cov-
erage of all of these regions.
5.2 Tonsillar Area and Soft Palate
The preferred RT technique for tonsillar cancers is
IMRT. The exception is when meaningful sparing of
the parotid gland is unfeasible due to bulky neck
disease. In this situation, parallel–opposed portals,
similar to those shown in Fig. 13 are used for lesions
of the base of the tongue. Portals are usually weighted
3:2 or 1:1, depending on the anatomic distribution of
disease. The pterygoid plates up to the base of the
skull should be covered in patients with advanced
disease; if trismus is present, the pterygoids should
remain within the treatment volume for the entire
course of irradiation.
The minimum initial treatment volume for early
cancers of the tonsillar region includes the retromolar
trigone, tonsillar pillars, soft palate, base of the
614
Fig. 14 A 45-year-old male with T2N1 nasopharyngeal car-
cinoma. The patient presented with epistaxis and was found to
have a tumor arising from the right Fossa of Rosenmueller with
lateral extension into the parapharygneal space. He was treated
with radiation therapy alone using IMRT to all PET-positive
areas of disease (a), the highly conformal dose distributions,
tongue, and entire tonsillar fossa. The anterior margin
of the portal varies according to the anterior extent of
disease; in patients with cancer at an early stage, it is
at the level of the second molar tooth, with consid-
eration given to coverage of the buccal mucosa if
infiltrated by tumor.
Anterior extension into the oral tongue is appre-
ciated by digital palpation. For T1–T2, well-lateral-
ized lesions of the tonsillar region with no tongue
invasion, ipsilateral treatment with IMRT with
selection and angling of beams to avoid the contra-
lateral parotid gland can be employed. An alternative
is to employ a wedge pair using 4- to 6-MV X-ray
beams to preserve salivary flow on the contralateral
side.
Lastly, it is important to keep in mind that an
open tonsillectomy generally does not constitute a
definitive oncologic procedure. In this particular
setting, a dose of 66 Gy is often delivered to the
tonsillectomy bed, with lesser doses of 60 and
54 Gy, administered to areas at high and low risk for
disease involvement. Review of all pre-operative
A. M. Chen and K. S. Clifford Chao
designed to deliver a dose of 6,996 cGy to gross disease and
lesser doses of 5,940 and 5,400 cGy to areas at high and lower
risk for microscopic disease involvement, as illustrated in the
b axial and c coronal planes. Dose-volume histogram showed
significant sparing of the parotid glands, temporal lobes, spinal
cord, brain stem, cochlea, and ocular structures
imaging is imperative to ensure adequate coverage
of previously visible tumor.
6 Nasopharynx
Due to its ability to achieve a conformal dose distri-
bution in the skull base, IMRT constitutes the stan-
dard in the radiotherapeutic management of
nasopharyngeal cancer. IMRT plan representations
for patients with advanced-stage cancers of the
nasopharynx is outlined in Fig. 14. The basic plan
must be individualized according to disease extent.
The retropharyngeal lymph nodes are usually
involved and are best seen by magnetic resonance
imaging (MRI). They incidentally fall within the
treatment volume. Because of the high density of
capillary lymphatics in the nasopharynx, the spinal
accessory and jugular lymph node chains are irradi-
ated in their entirety, even in the N0 setting. All gross
disease is treated to 70 Gy, typically in 33 or 35 daily
fractions.
Head and Neck Cancer
To further define the high-risk subclinical region
at the primary disease site, the following must
be included in the CTV: the entire nasopharynx,
anterior 1/2 to 2/3 of the clivus (entire clivus, if
involved), skull base (foramen ovale and rotundum
bilaterally must be included for all cases), pterygoid
fossae, parapharyngeal space, inferior sphenoid sinus
(in T3–T4 disease, the entire sphenoid sinus) and
posterior fourth to third of the nasal cavity and
maxillary sinuses (to ensure pterygopalatine fossae
coverage). The cavernous sinus should be included in
high-risk patients (T3, T4, bulky disease involving the
roof of the nasopharynx). High-risk lymph node
regions include the (a) Upper deep jugular (junctional,
parapharyngeal) bilaterally; (b) Subdigastric (jugu-
lodigastric) [level II] bilaterally; (c) Midjugular (level
III) bilaterally; (d) Low jugular and supraclavicular
(level IV) bilaterally; (e) Posterior cervical (level V):
bilaterally; (f) Retropharyngeal bilaterally. The
bilateral submandibular nodes (level Ib) should also
be included for node-positive patients.
The surrounding critical normal structures,
including the brain stem, spinal cord, optic nerves,
chiasm, parotid glands, pituitary, temporomandibular
(T-M) joints and middle and inner ears, skin (in the
region of the target volumes), oral cavity, mandible,
eyes, lens, temporal lobes, brachial plexus, esophagus
(including postcricoid pharynx) and glottic larynx
should be outlined.
7 Oral Cavity
7.1 Lip
Lip cancer may be treated with external beam, inter-
stitial implant, or both. RT is preferred over surgery
for tumors involving the commissure which would not
yield satisfactory or functional outcomes with exci-
sion. External-beam techniques use orthovoltage
X-rays or electrons; the former is preferred because
there is less beam constriction and the maximum dose
is at the surface. A lead shield placed behind the lip
limits RT to the mandible and oral cavity. The shield
consists of two sheets of lead (each 1/8 inch thick),
overlaid with one sheet of aluminum (1/64 inch) and
is coated with wax or vinyl to prevent excessive
exposure from low-energy-scattered electrons to tis-
sue adjacent to the shield. Dose schemes are similar to
615
those for skin cancer. Protracted treatment schedules
(4–6 weeks) are preferred over short regimens
because short courses are more likely to cause pro-
gressive radiation changes with passing years. For
small T1 lesions, a dose of 45–55 Gy in 15–20 frac-
tions is reasonable. For larger lesions, a dose of
60–70 Gy using 2 Gy fractionation is preferred.
Bulky cancers are often treated first by external
beam (30–50 Gy MTD), followed by interstitial
cesium or iridium-192 implant once the lesion has
flattened (Fig. 15). The use of preloaded implant
devices that allow rapid, accurate positioning if
cesium needles may be employed. Iridium using the
plastic tube technique has an advantage because a
larger volume can be easily implanted, if necessary,
and it can be afterloaded.
The regional lymphatics are not electively treated
in patients with cancer in its early stages because the
risk of metastasis is low. Patients with advanced,
poorly differentiated, or recurrent cancers should
receive elective neck treatment because the risk of
lymphatic involvement is substantial. The risk of
involvement also increases in patients with tumors
that extend onto the wet mucosa of the lip or the
buccal mucosa. Lymphatic spread is to the level-I and
level-II lymph nodes and rarely to a facial node.
7.2 Oral Tongue, Floor of Mouth,
Buccal Mucosa
Surgery followed by postoperative RT when indicated
is the preferred treatment modality for tumors of the
oral cavity. In selected patients in whom surgery may
not be an option, external RT, either alone or in
combination with either interstitial implants or intra-
oral cone RT, has been shown to be a viable treatment
alternative. In general, the treatment area for external
RT should include the primary lesion as well as the
regional lymph nodes. Although studies have shown
that the ability to control the primary tumor is
enhanced by giving all or part of the treatment by
either interstitial implant or intraoral cone, these were
all published before the advent of IMRT, which may
be a suitable alternative for dose-escalation (Wang
et al. 1983; Hosokawa et al. 2001; Fujita et al. 1999).
For patients requiring definitive RT in this setting, the
reader is referred to an excellent reference by Wang
et al. (1992).
616
Fig. 15 a–i. A 67-year-old man had T2N0 squamous cell
carcinoma of the lower lip. a The lesion measured
3.0 9 2.0 9 1.5 cm. Radiation therapy was elected because of
functional deficit likely to result from excision of large lesion.
b Lead mask, 2 mm thick, designed to outline portal. Lead putty
was added to shield to reduce transit irradiation to less than 1%.
Separate lead shield covered with beeswax was inserted behind
lower lip. Patient received 30 Gy in 2 weeks, 3 Gy per fraction,
250 kV (0.5 mm Cu). c By completion of 30 Gy, he had brisk
mucositis of lip and approximately 60–70% regression of
7.3 Postoperative RT for Tumors of Oral
Cavity and Oropharynx
At our institution, the consensus guidelines endorsed by
the RTOG, EORTC, DAHANCA, GORTEC, and NCIC
are routinely used to delineate the CTV at the time of
IMRT treatment planning (DAHANCA et al. 2010).
However, as noted in Sect. 4.3, these contouring recom-
mendations are only applicable for patients with N0
necks. At the very minimum, the entire operative bed is
covered (based on preoperative imaging, preoperative
physical examination and/or endoscopy, and operative
A. M. Chen and K. S. Clifford Chao
obvious tumor. d Single-plane radium needle implant with
double crossing. Pack was tied to top of bar to displace upper lip
away from radiation, and chin pack anchored gingivolabial pack
in place (see e). e Gauze pack (arrows) sewn into gingivolabial
gutter to displace radium from mandible, teeth, and gums. f and
g Anteroposterior and lateral views of implant. Implant added
35 Gy at 0.5 cm. h 2.5 weeks after implantation. Note superficial
ulceration. i 22 months after treatment. No evidence of disease,
and lip was completely healed. Nine-year follow-up revealed no
evidence of disease (from Million et al. 1994b, Fig. 16-7)
and pathological findings) and in the case of nodal
involvement, the retrostyloid space up to the base of skull.
In all cases, the CTV includes the ipsilateral pathologi-
cally positive necks. This generally means encompassing
nodal levels I, IIa, III, and IV, with inclusion of nodal
levels I, IIb, and V in selected circumstances. To help
appreciate anatomical boundaries of the nodal levels,
knowledge of such structures as the neck muscles
(geniohyoid, mylohyoid, platysma, sternocleiodmastoid,
and scalene muscles), blood vessels (carotid artery, jug-
ular vein), and bony-cartilaginous landmarks (hyoid,
mandible, thyroid) are imperative to CTV design.
Head and Neck Cancer
Our current policy is to treat doses of 60–66 Gy
in 2 Gy fractions to areas at high risk for disease
recurrence after surgery. Chemotherapy is utilized
in the presence of adverse pathological character-
istics. Based on our experience and those of others,
particular attention should be directed at covering
the retropharyngeal (skull base), retrostyloid, peri-
parotid, and infratemporal regions of the head and
neck.
In this situation, the larynx is intact, and the portal
arrangements are similar to those used when RT is the
primary treatment. If using conventional techniques,
the primary fields are parallel– opposed matched to a
single anterior en face portal field to treat the low
neck. The junction of the primary and low-neck
portals facilitates shielding of the larynx by a midline
block. The choice of beam, the bolus technique, and
details of treatment volume are similar to those
described for the larynx and hypopharynx (see
‘‘Postoperative Irradiation for Tumors of the Larynx
and Hypopharynx’’, Sect. 4.3).
8 Nasal Cavity and Paranasal Sinuses
Over the past several decades, RT techniques for the
treatment of nasal cavity and paranasal sinus cancer
have dramatically evolved. The reported techniques
have included conventional RT using two-dimen-
sional (2D) imaging, to 3DCRT using CT simulation,
to more recently, IMRT. Proton beam has also been
utilized for the treatment of these tumors but its use is
limited to few centers. Conventional 2D RT and
3DRT techniques have typically incorporated the use
of a 3-field technique with 2 lateral wedged fields that
are angled 5 posteriorly (frequently with the use of
wedges) and an anterior field. Because the dose
required for treatment ranges from 66 to 70 Gy, sig-
nificant toxicity can result from the excess radiation
delivered to adjacent structures, i.e. optic structures,
whose threshold doses for toxicity are below 60 Gy.
Tumors of the skull base, including those involv-
ing the nasal cavity and paranasal sinuses, appear to
be especially well-suited to the use of IMRT, given
the irregular contours of these cancers and the pres-
ence of vital structures in this region such as the brain
stem, optic nerves, optic chiasm, and spinal cord.
Multiple dosimetric studies have eloquently shown
that improved dose distributions with increased dose
617
delivery to the tumor target while minimizing the
dose delivered to the surrounding normal tissues can
be achieved with IMRT when compared with 3DCRT
(Huang et al. 2003; Tsien et al. 2003; Mock et al.
2004). From a practical standpoint, the dose delivered
to the optic pathways can be reduced selectively by
IMRT which has the potential to save binocular vision
particularly for patients who have extensive and large
volume disease in the paranasal sinuses. In a longi-
tudinal analysis of 127 patients treated with radiation
therapy from 1960 to 2005 at the University of Cal-
ifornia, San Francisco, the incidence of grades 3 and 4
late ocular toxicity among patients treated with CRT,
3D-CRT, and IMRT was 20, 9, and 0%, respectively
(Chen et al. 2007).
For cancers of the nasal cavity and ethmoid sinu-
ses, the treatment volume should include the medial
maxillary sinus, ethmoid sinus, medial portion of the
orbit, nasopharynx, sphenoid sinus, and base of skull
(Figs. 16, 17). Orbital invasion is common when
tumor involves the ethmoid sinus. When such inva-
sion is minimal, the major lacrimal gland and lateral
upper eyelid can be contoured as avoidance struc-
tures. An eyelid retractor is sometimes useful to dis-
place some of the upper lateral lid from the treatment
field. However, too narrow a margin around the eye
may result in target miss. The volume should
encompass the entire nasal cavity and ethmoid–
sphenoid complex as well as the medial aspect of the
contralateral orbit, cribiform plate, maxillary antrium,
and all or part of the frontal sinus. For maxillary sinus
cancers, the treatment volumes are similar but should
cover the lowest extent of disease (e.g., tumor track-
ing down the buccal mucosa from the gingivobuccal
sulcus or tumor in the low parapharyngeal or soft
palate regions must be recognized). Generous cover-
age of the skull base to include the appropriate cranial
nerve foramina is imperative to avoid marginal
failure.
The risk of lymph node metastasis and the
controversy surrounding elective nodal irradiation
of the ipsilateral neck in patients with maxillary
sinus carcinoma was addressed in a report by
(Le et al. 2000). In this retrospective review of 97
patients treated at Stanford University and the
University of California, San Francisco between
1959 and 1996, the overall incidence of lymph node
involvement at diagnosis was 9%, with the most
common sites of nodal involvement at levels 1
618
Fig. 16 a–f. Radiation treatment technique for squamous cell
carcinoma filling entire nasal cavity and extending into
nasopharynx. a Tumor mass extends into nasopharynx
(arrows). R roof; SP soft palate; FR right fossa of Rosenmuller.
b Computed tomogram at level of orbit and ethmoids. Mass
bulges into medial aspect of left orbit. Additional views showed
opacification of left sphenoid sinus and left maxillary sinus,
erosion of left pterygoid plates, and possible erosion of
cribriform plate. Site of origin could have been nasal cavity
or maxillary antrum. Tumor is considered unresectable because
of involvement of nasopharynx and possible sphenoid sinus
invasion. c Anteroposterior view (simulation) of anterior portal.
Straight white line is aluminum support for bite block. Patients
can be immobilized with customized Aquaplast masks from
which windows for portals are cut to accomplish skin sparing
(WFR/Aquaplast Corp, PO Box 635, Wyckoff, NJ 07481,
USA). d Radiation is delivered through anterior and left and
right lateral portals. Left upper lateral eyelid and lacrimal gland
are shielded because only medial orbit is involved by tumor.
and 2. Of 36 patients who had neck irradiation,
25 received elective neck irradiation (ENI) for N0
necks. With the median follow-up of 22 months,
the 5- and 10-year actuarial survival rates were 34
and 31%, respectively. Following treatment, the 5-
year risk of nodal relapse was 12%. Squamous cell
histology was associated with a high incidence of
initial nodal involvement and subsequent nodal
relapse. Elective nodal irradiation effectively pre-
vented nodal relapse in patients with squamous cell
histology. There was no nodal relapse in 13 patients
A. M. Chen and K. S. Clifford Chao
e Simulation film of lateral portal (5 posterior tilt). Treatment
volume encompasses base of skull, posterior ethmoid and
maxillary sinuses, posterior nasal cavity, sphenoid sinus,
nasopharynx, posterior one-third of both orbits, pterygoid
plates, infratemporal fossa, and parapharyngeal lymph nodes.
Posterior border of portal is just anterior to external auditory
canal, thereby excluding cervical spinal cord and brain stem.
f Treatment plan is 70 Gy minimum (77 Gy maximum) tumor
dose over 7 weeks. Weighting of given doses is 2–1 in favor of
anterior portal. Right and left upper neck receives 40.5 Gy over
3 weeks through anterior portal with midline shielding. Visible
tumor disappeared during therapy in this patient. Patient
returned to full-time work as a truck driver at 4 months.
A cataract developed in left eye at 36 months. After cataract
extraction, visual acuity was only ‘‘counts fingers at 2 feet’’
because of radiation retinopathy. Patient was free of disease at
8.5 years (a, b, and d from Parsons et al. 1994d, Fig. 22-34 and
Fig. 22–35b; c and e from Ellingwood and Million 1979,
Fig. 3b, c; f from Parsons et al. 1992, Fig. 29-5d)
who received ENI while 6 of 26 patients (20%)
without ENI relapsed in the neck. Nodal relapse
was associated with a high rate of distant metastasis
and poorer survival. The authors advocate the use
of ENI in patients with T3–T4 squamous cell car-
cinoma of the maxillary sinus. However, Dirix
et al. (2007) reported on 127 patients with sinonasal
cancers treated by radiation therapy, none of whom
received ENI. With a median follow-up of
5.6 years, only 6 patients (5%) developed a regio-
nal failure in the neck.
Head and Neck Cancer
Fig. 17 An 85-year-old male with unresectable squamous cell
carcinoma of the nasal cavity treated by definitive IMRT. The
plan was designed to deliver a dose of 7,000 cGy in 35
fractions. The bilateral optic nerves and retinas are delineated
to demonstrate the improved conformality and normal tissue
sparing capabilities of IMRT
9 Major Salivary Gland
9.1 Parotid Gland
RT plays its major role as an adjunct to surgery and is
usually administered postoperatively, although defin-
itive treatment may be considered in medically or
surgically inoperable cases. The minimum treatment
volume includes the parotid bed. In general, this is
defined as the area bounded superiorly by the zygo-
matic arch; anteriorly by the masseter muscle, lateral
pterygoid muscle, and mandibular ramus; posteriorly
by the mastoid process; and inferiorly by the posterior
belly of the digastric muscle. The ipsilateral neck is
electively irradiated for high-grade lesions or when
tumor is found in lymph nodes in the neck dissection
specimen.
Although IMRT is increasingly used for parotid
tumors, treatment has historically been administered
by one of three non-IMRT external-beam techniques.
One technique involves a wedge pair, with the por-
tals aimed either superiorly and inferiorly (to direct
the exit dose away from the orbits and oral cavity)
or anteriorly and posteriorly (with the portals angled
so that the beams pass below the level of the eyes).
619
Fig. 18 Portal for
postoperative irradiation of
parotid gland cancer. Anterior
border is usually at anterior
border of masseter muscle;
inferior border is at top of
thyroid cartilage. Superiorly
and posteriorly, entire parotid
and surgical bed are included.
Electron portal (dashed lines)
is 1.0 cm larger than photon
portal, because of constriction
of electron isodose lines at
depth (from Levitt et al. 2nd
edn, 1999, Fig. 16.32)
The latter technique facilitates matching the low-
neck portal to the primary fields and is preferred.
The wedge pair technique can treat a generous
portion of the base of skull in a homogeneous
manner and is particularly useful when perineural
spread is present or suspected, as in adenoid cystic
carcinoma. Fields are best designed with the aid of
CT simulation and treatment planning. A second
basic technique uses ipsilateral portals shaped to fit
the anatomy (Fig. 18). A treatment scheme using a
combination of photons and high-energy electrons
produces a homogeneous dose distribution and
delivers 30 Gy or less to the opposite salivary
glands. The advantages of the technique are the
ability to shape and reduce the fields easily and the
ease with which an ipsilateral low-neck field may be
adjoined to the primary portal. A disadvantage,
especially in patients with adenoid cystic carcinoma,
is underdosage of possible perineural tumor exten-
sions deep in the temporal bone because of inade-
quate penetration of electrons in dense bone.
Because electrons are subject to perturbations from
tissue inhomogeneity, the risk of deep target miss
must always be kept in mind. When tumor involves
the deep lobe or otherwise extends near the midline,
a third technique, parallel–opposed photon portals
weighted to the side of the lesion, may be necessary.
As illustrated in Fig. 19, IMRT is increasingly
used in the management of parotid tumors. Dosi-
metric studies have shown that IMRT can signifi-
cantly reduce dose to normal structures compared to
traditional techniques (Lee et al. 2008). IMRT is also
useful when it is necessary to treat the nerve pathways
to the foramina in the base of the skull, in the event of
extensive perineural involvement or named nerve
620
Fig. 19 A 61-year-old male status post superficial parotidectomy for acinic cell carcinoma with positive margins. The IMRT plan,
shown in (a) axial) and (b) coronal dimensions was designed to deliver a dose of 6,600 cGy in 33 fractions to the parotid bed
invasion. Regardless of the chosen technique, care
must be taken to limit inadvertent dose to the tem-
poral lobes, ocular structures, middle/inner ears, oral
cavity, and contralateral parotid gland.
9.2 Submandibular Gland
IMRT has largely supplanted 3DCRT as the standard
treatment in this setting due to its improved confor-
mality and ability to minimize dose to the oral cavity
and contralateral salivary glands. Non-IMRT tech-
niques emphasize the use of ipsilateral portals tailored
to the extent of disease found in the surgical speci-
men. The possible sites of local recurrence include the
submandibular triangle, adjacent oral cavity,
pterygomaxillary fossa, base of the skull, parotid
gland, and neck. The energy used depends on the
depth at risk. An electron beam, photon beam, or a
combination of both is selected, depending on the
situation.
10 Unknown Primary
Treatment planning for the patient with squamous cell
carcinoma metastases to the nodes in the neck from a
primary site that cannot be located after multiple
physical examinations, CT, and direct laryngoscopy
with biopsies depends on the location of the lymph
nodes; occasionally histology also plays a role in
determining the treatment volume. Involvement of the
level II lymph nodes typically arises from an occult
primary in the oropharynx or nasopharynx whereas
A. M. Chen and K. S. Clifford Chao
level III metastasis more commonly involves the
larynx. Low-neck presentation commonly arises from
a primary site below the clavicles and palliative
treatment can be considered. Although the treatment
remains somewhat controversial, most institutions
continue to utilize bilateral neck and mucosal axis
irradiation. Traditionally, treatment-related morbidity
with this strategy has been a concern given the vol-
ume of normal tissue typically encompassed in the
radiation portals and the relatively high doses
required to eradicate subclinical disease. Indeed, rates
of chronic xerostomia and gastrostomy-tube depen-
dence after radiation therapy for head and neck cancer
of unknown primary origin have been reported to be
as high as 90% (Nieder et al. 2001; Lu et al. 2009;
De Braud et al. 1989).
IMRT appears well-suited for treating unknown
primary cancer given the large volumes requiring
irradiation. Several series have recently reported on
outcomes after IMRT for head and neck cancer of
unknown primary origin (Frank et al. 2010; Bhide
et al. 2007; Chen et al. 2011). IMRT appears to
improve dose distributions to several critical struc-
tures including the contralateral parotid gland, bilat-
eral ear structures, spinal cord, brain stem, and
temporal lobes. The reductions in dose to these organs
at risk allowed generally accepted constraints to be
more frequently satisfied using IMRT than 3DCRT.
In a treatment planning study involving 6 patients,
investigators from Royal Marsden Hospital showed
that the mean dose to the contralateral (spared)
parotid gland was 50.5, 23.2, and 23.3 Gy, respec-
tively, among patients treated with CRT, five-field
IMRT, and seven-field IMRT (Bhide et al. 2007).
Head and Neck Cancer
Fig. 20 a Coronal and
b axial views of the highly
conformal dose distribution
from an intensity-modulated
radiotherapy (IMRT) plan for
a patient with unknown
primary head and neck
cancer. Color scheme: red,
60; yellow, 56; green, 54;
orange, 45; aqua, 30 Gy
Fig. 21 a, b. Fields for bilateral lower neck irradiation in
patients with base of tongue, midline soft palate, advanced
tonsil, nasopharynx, or advanced oral cavity cancers. a N0
neck. Larynx shield design is important. Because midjugular
lymph nodes lie adjacent to posterolateral margin of thyroid
cartilage, attempts to shield entire thyroid cartilage with 4-–5-
cm-wide block produce low dose area in these nodes. Inferior
extent of larynx shield is usually at cricoid cartilage or first or
second tracheal ring; shield is tapered; nodes in low neck may
lie close to midline. If larynx block is extended for entire length
of low-neck portal, it should probably cast a shadow no wider
than 1.0–1.5 cm in suprasternal notch region. TSD tumor-
to-source distance. In N0 setting, lateral supraclavicular lymph
nodes are at little risk of involvement, except possibly for
patients with cancer of nasopharynx. Usually, only root of neck
is included. The most common error observed in design of low
neck portal is actually a combination of mistakes that results in
underdosage of high-risk areas and unnecessary treatment of
low risk zones by (1) shielding larynx with large, square or
rectangular block, (2) blocking midline with wide (3–4 cm)
block down to level of suprasternal notch, and (3) irradiating
entire supraclavicular fossa bilaterally. b Neck with clinical
evidence of disease. Treatment to each side of neck is
individualized. If extensive neck disease is limited to one side,
entire neck, including all supraclavicular lymph nodes (out to
junction of trapezius muscle and clavicle), is irradiated on that
side. If both sides are involved, treatment on each side is
modified according to disease extent (a from Parsons et al.
1998, Fig. 42-7a, b from Million et al. 1994d, Fig. 6.55a)
621
In particular, greater than 50% reduction in both mean
dose and V30 was observed with the use of IMRT
versus 3DCRT. More importantly, clinical series are
showing that the dosimetric advantages are translating
into an improvement in the therapeutic ratio, as IMRT
appeared to reduce chronic toxicity without compro-
mising disease control (Chen et al. 2011).
IMRT is typically delivered using a SIB technique
with treatment volumes encompassing the bilateral
nodal regions and mucosal axis including the naso-
pharynx, oropharynx, larynx, and hypopharynx
(Fig. 20). For patients treated by primary IMRT, the
GTV is specified as the gross extent of the neck mass,
as demonstrated by imaging and physical examina-
tion. The high-risk CTV includes the GTV plus a
margin of 1–2 cm to account for microscopic disease
spread. For patients treated with IMRT postopera-
tively, the high-risk CTV is defined as the surgical
nodal bed including all areas of extracapsular exten-
sion. In most cases, the majority of the ipsilateral neck
is also included in the high-risk CTV. The low-risk
CTV includes the prophylactically treated contralat-
eral neck. The pharyngeal axis including the retro-
pharyngeal lymph nodes is generally included in the
low-risk CTV. The prescribed dose is typically 70 Gy
for gross disease, 60–66 Gy for high-risk regions, and
54–60 Gy for low-risk regions. Treatment is typically
prescribed to deliver the dose to at least 95% of
the PTV.
For patients treated with 3DCRT, a shrinking field
technique is used with initial opposed lateral fields to
treat the primary tumor bed and upper neck lymph
nodes. In general, the anterior border included the
622 A. M. Chen and K. S. Clifford Chao

Table 1 Published series reporting outcomes after IMRT for head and neck cancer
Study N Primary RT Chemo FU (mo) Endpt Control
site Definitive Postoperative (%) (%)

Chao et al. (2003) 126 Various 52 74 28 26 LRC 85

Eisbruch et al. (2004) 133 Various 60 73 35 32 LRC 82
Schoenfeld et al. (2010) 100 Various 100 0 54 32 LRC 87
Lee et al. (2003) 150 Various 107 43 71 25 LC 95
Yao et al. (2005) 151 Various 99 51 45 18 LRC 92
Chen et al. (2009) 77 Various 42 35 62 19 LRC 77
Daly et al. (2011) 69 Various 46 23 74 25 LRC 90
Montejo et al. (2010) 43 Various 43 0 100 37 LRC 82
De Arruda et al. (2006) 50 OPX 48 2 86 18 LRC 88
Huang et al. (2008) 71 OPX 71 0 100 33 LRC 90
Garden et al. (2007) 51 OPX 51 0 10 45 LRC 94
Abbreviations: IMRT intensity-modulated radiotherapy; RT radiation therapy; OPX oropharynx; Chemo, chemotherapy; FU fol-
low-up; Endpt, endpoint; LRC local–regional control; LC local control

posterior third of the nasal cavities and the anterior
tonsillar pillars; the posterior border was placed
behind the spinous process, the superior border was
placed at the mid-sphenoid sinus or bottom of the
pituitary fossa to encompass the nasopharynx and
base of skull; the inferior border was placed just
above the shoulders. Any surgical scar was wired to
ensure 2 cm coverage in all directions. The lower
neck nodes are treated with a matched low-anterior
neck field using an isocentric technique to eliminate
divergence into treatment fields. Electrons were used
to boost areas overlying or posterior to the spinal cord
after field reductions.
require parallel–opposed portals, both sides of the neck
are irradiated, even in the N0 situation. Failure to
irradiate the low neck in patients with these lesions will
result in at least a 10% rate of failure in the level-III and
level-IV nodes even when the upper neck is clinically
negative. The low neck is irradiated through an anterior
field only. The basic portal design in all these situations
is similar (Fig. 21).
For patients with laryngeal or hypopharyngeal
tumors in which it is necessary to place the junction
immediately above the shoulders and to include the
primary tumor in the opposed lateral fields, a cord
block can sometimes be placed posteriorly.

11 Design of Low-Neck Portal 11.2 Treatment of Lower Neck in Setting

11.1 Treatment of Lower Neck in Setting
of Opposed Lateral Fields
The low-neck portal is designed according to external
anatomic landmarks and findings from the clinical and
radiographic examination of the neck. No simulation
films or portal verification films are taken. The lines are
drawn on the patient’s skin, and lead blocks are stacked
freehand on a tray positioned above the patient to shape
the beam into the desired volume. Alternatively,
a monoisocentric technique may be employed.
For all base of tongue, midline soft palate, advanced
tonsil, all nasopharyngeal, and oral cavity cancers that
of IMRT
There are two options for treating the low neck in the
setting of IMRT: (1) use a separate conventional
anterior portal and (2) include the low neck in the
IMRT fields used to treat the primary tumor and upper
neck. The former is preferred and the low-neck portal
is junctioned with the IMRT portals where the junc-
tion would usually be placed if 3DCRT was
employed. The match line is moved once at 24 Gy if
the low neck done is limited to 50 Gy. The match line
is moved twice at 20 and 40 Gy if part or all of the
low neck receives more than 50 Gy. The match line is
moved in 3 mm increments by moving the inferior
Head and Neck Cancer
jaw superiorly so that the jaw moves superiorly across
the central axis into the IMRT field. A separate low-
neck portal is not employed for tumors arising near
the sternal notch where IMRT is used to treat the
primary site and all of the at risk regional lymphatics.
12 Clinical Outcomes with IMRT
The body of literature demonstrating that satisfactory
clinical outcomes can be achieved with IMRT in the
management of head and neck cancer continues to
accumulate (Table 1). Notably, attempts to draw
comparisons between respective series are compli-
cated by the wide variability in disease characteristics
of the patients treated across institutions. However,
local–regional control rates across all institutions
have been high, and the reported rates of marginal
misses have been small.
The results of the first multi-institutional study of
IMRT for head and neck cancer were recently pub-
lished, RTOG 00-22 (Eisbruch et al. 2010). Sixty-nine
patients with small-volume T1–2, N0–1 oropharyn-
geal carcinoma were enrolled. With a median follow-
up of 2.8 years, the local–regional control rate was
91%. Notably, 2/4 (50%) of patients with major
protocol deviations (with respect to under-dosage)
experienced local–regional failure compared to 3/49
(6%) without such deviations. The rates of grade 2+
xerostomia were 55% at 6 months but declined to 25
and 16% at 12 and 24 months, respectively. These
results are consistent with RTOG 0225, which
reported a 2-year local–regional control rate of 89%
among 69 patients treated by IMRT using a SIB
fractionated scheme to a total dose of 70 Gy (Lee
et al. 2009). Notably, the low rates of toxicity sug-
gested that IMRT represented an improvement in the
therapeutic ratio compared to historical controls.
The results of a small randomized controlled trial
were recently published from the United Kingdom
comparing patients treated with IMRT to conven-
tional 3DCRT using initial opposed lateral fields
(Nutting et al. 2011). Ninety-four patients were
assigned to each treatment arm. With a median fol-
low-up of 44 months, grade 2 xerostomia was
significantly less common with IMRT than with non-
IMRT both in the acute (38% versus 74%) and late
(29% versus 83%) settings. Notably these differences
translated into improvements in dry mouth-specific
623
and global quality of life. There was no significant
difference in non-xerostomia late toxicities, local–
regional control, or overall survival.
13 Guidelines for Contouring Target
Structures
For patients treated with definitive IMRT, the GTV is
specified as the gross extent of tumor as demonstrated
by preoperative imaging and physical examination
including endoscopy. Grossly positive lymph nodes
were defined as any lymph nodes greater than 1 cm or
those with a necrotic center. The high-risk clinical
target volume (CTV1) is defined as the GTV plus a
margin of at least 0.5 cm to account for microscopic
disease spread. However, the CTV margins can be
reduced to as low as 1 mm when the GTV was in
close proximity to the brain stem, spinal cord, or optic
structures. In some cases (e.g., tumors of the naso-
pharynx), MRI is fused with the CT image to assist in
defining the parapharyngeal and superior extent of
tumor. For patients treated with IMRT postopera-
tively, the CTV1 is defined as the surgical tumor bed
at risk for harboring microscopic residual disease. For
both definitively and postoperatively treated patients,
the CTV2 generally includes the prophylactically
treated cervical and supraclavicular neck. In some
additional cases, a CTV3 is created to designate an
area at lowest risk within the prophylactically treated
low neck.
The PTV contains an additional circumferential
expansion of the CTV surfaces to account for patient
setup error to create PTV1, PTV2, and PTV3, if
necessary. The exact margin varies by institution but
has historically been at least 0.5 mm.
14 Guidelines for Dose Prescription
and Normal Tissue Dose Analysis
The IMRT plans are evaluated both quantitatively
with dose-volume histogram (DVH) analysis for PTV
and PRV and qualitatively by visually inspecting
isodose curves on axial slices. DVH displays and
corresponding analyses for targets and normal tissues
record the dose to the PTV and PRV, respectively.
We do not display or analyze dose–volume data
related to the ORV, CTV, or GTV. All IMRT plans
624 A. M. Chen and K. S. Clifford Chao

Table 2 General dose constraints for IMRT planning plans are designed to deliver a dose of 60–66 Gy to at
Structure Recommended Priority least 95% of PTV1. The prescribed dose to PTV3 was
Constraint 54–56 Gy. Commonly used constraints for IMRT
Spinal cord Max \48 Gy High planning are outlined in Table 2. Treatment is by
Brain stem Max \54 Gy High continuous-course radiation with once-a-day treat-
Temporal lobe Max \60 Gy High
ment. Because the goal was to prescribe 1.8 Gy per
fraction to the PTV2 daily, the PTV1 generally
Optic chiasm Max \50 Gy High
receives a higher dose per fraction, typically 2.0 or
Optic nerve Max \54 Gy High
2.12 Gy per fraction.
Retina Max \45 Gy High The basic goals of IMRT planning are to generate
Parotid gland Mean \26 Gy or Intermediate a plan with the prescription isodose lines conformed
(spared) V30 \50%
to the defined PTVs while minimizing the dose
Cochlea Max \50 Gy Intermediate delivered to the specified organs at risk. The plans are
Larynx Mean 40 Gy Intermediate generally normalized to achieve adequate target
Oral cavity Mean 35 Gy Intermediate coverage without excessive dose inhomogeneity (dose
Mandible Max \66 Gy prescription to 90 to 93% isodose lines). The pre-
Brachial plexus Max \66 Gy Intermediate scription dose should generally be defined as the
Lips Mean \25 Gy Low
isodose encompassing at least 95% of the PTV. Tar-
get dose restrictions generally include the following:
Pharyngeal Mean \45 Gya Low
constrictor muscles no more than 20% of any PTV should receive greater
Cricopharyngeal inlet Max \60 Gya Low
than 110% of its prescribed dose, no more than 1% of
any PTV could receive less than 93% of the pre-
Cervical esophagus Max \45 Gya Low
scribed dose, and more than 1% or 1 cc of the tissue
Lacrimal gland V30 \50% Low
outside the PTV would receive greater than 110% of
Abbreviations: IMRT intensity-modulated radiotherapy; Max the dose prescribed to the primary target.
maximum
a The following normal tissues are outlined for
Constraints for these structures are variable depending heav-
ily on the location of the primary cancer and additional gross planning purposes in all patients: skin surface, man-
disease; in general, for tumors of the larynx/hypopharynx, the dible, spinal cord, and brain stem. Additional structures
accepted constraints will be more difficult to satisfy are outlined if relevant to the treatment plan: oral
cavity, glottis, parotid glands, submandibular glands,
lacrimal glands, globe/retinas, lenses, optic nerves, and
are heterogeneity corrected. In accordance with recent
optic chiasm.
documentation guidelines published by the American
Society of Radiation Oncology (ASTRO), the fol-
lowing should be reported for the purpose of quality
assurance: Prescribed (intended) dose, as well as the 14.1 The QUANTEC Reviews
point or volume to which it is prescribed; a fraction-
ation prescription should also be included; the dose In February 2010, a special supplement to the ‘‘Red
that covers 95% of the PTV (D95); the dose that Journal’’ presented the results of the Quantitative
covers 100% of the PTV (i.e. the minimal dose); the Analysis of Normal Tissue Effects in the Clinic
percentage volume of the PTV that receives 100% of (QUANTEC) review group on normal tissue compli-
the prescribed dose (V100); mean and maximal doses cations for various organ systems. These were based on
within the PTV (IMRT Documentation Working accumulated clinical experience on the side effects of
Group et al. 2009). RT as reported in the literature. By necessity, the data
For patients receiving definitive radiation therapy, and the recommendations are rather spotty since it
treatment plans are designed to provide a dose of would be absolutely unethical to deliberately dose-
66–70 Gy to 95% or more of the PTV1 and 60–63 Gy escalate the normal tissues of a living human being. We
to 95% or more of the PTV2 while sparing neighboring present below excerpts from the individual review
critical structures. For patients treated postoperatively, papers for head and neck cancers—readers are strongly
Head and Neck Cancer
encouraged to look at the papers in the February 2010
issue, and to the sources cited therein.
14.1.1 Brain
The recommendations of (Lawrence et al. 2010) are
summarized below:
• For standard fractionation, a 5 and 10% risk of
symptomatic radiation necrosis is predicted to occur
at a BED of 120 (range, 100–140) and 150 Gy
(range, 140–170), respectively [corresponding to 72
(range, 60–84) and 90 Gy (range, 84–102) in 2 Gy
fractions]. The brain is especially sensitive to frac-
tion sizes [2 Gy and, surprisingly, twice-daily RT.
• Cognitive changes occur in children after C18 Gy
to the entire brain. The effect of irradiation on the
cognitive performance of adults is less well-
defined. We have concluded that the 5% risk at
5 years of the partial brain for normally fraction-
ated RT is 72 Gy (range, 60–84).
• For most cancers, there is no clinical indication for
giving fractionated RT [60 Gy and, in some sce-
narios, an incidence of 1 to 5% radiation necrosis at
5 years would be unacceptably high.
• For radiosurgery, toxicity increases rapidly once the
volume of the brain exposed to [12 Gy is greater
than 5–10 cm3. Eloquent areas of the brain (brain
stem, corpus callosum) require more stringent limits.
14.1.2 Optic Nerve and Chiasm
Recommendations of Mayo et al. (2010a) are sum-
marized below:
• The incidence of RION (radiation-induced optic
neuropathy) was unusual for a Dmax \55 Gy,
particularly for fraction sizes \2 Gy. The risk
increases (3–7%) in the region of 55–60 Gy and
becomes more substantial (greater than 7–20%) for
doses [60 Gy when fractionations of 1.8–2.0 Gy
are used. The patients with RION treated in the
55–60 Gy range were typically treated to doses in
the very high end of that range (i.e. 59 Gy).
• For particles, most investigators found that the
incidence of RION was low for a Dmax \54 CGE.
One exception to this range was for pituitary
tumors, in which investigators used a constrained
Dmax of \46 Gy for 1.8 Gy per fraction.
• For single-fraction SRS, the studies have indicated
that the incidence of RION is rare for a Dmax
\8 Gy, increases in the range of 8–12 Gy, and
becomes [10% in the range of 12–15 Gy.
625
Consistent agreement has been reached on the low
risk of RION for a Dmax of B10 Gy, and one
major study indicated a low risk with a Dmax of
B12 Gy.
14.1.3 Brain stem
The recommendations of Mayo et al. (2010b) are
summarized below:
• The entire brain stem may be treated to 54 Gy
using conventional fractionation with limited risk
of severe or permanent neurological effects (3).
Smaller volumes of the brain stem (1–10 mL) may
be irradiated to maximum doses of 59 Gy for dose
fractions B2 Gy. The risk appears to increase
markedly at doses [64 Gy.
• For single fraction SRS, maximum brain stem dose
of 12.5 Gy is associated with low (less than 5%)
risk. Higher doses (15–20 Gy) have been used with
low reported incidence of complication in patient
groups with poor prognosis for long-term survival
(e.g., brain stem metastases) (18, 31). However, the
apparent safety of these higher doses may be an
artifact of the poor survival.
14.1.4 Spinal Cord
Kirkpatrick et al. (2010) recommend the following
two irradiation treatments:
• With conventional fractionation of 2 Gy per day
including the full cord cross section, a total dose of
50, 60, and approximately 69 Gy are associated
with a 0.2, 6.0, and 50.0% rate of myelopathy. For
reirradiation of the full cord cross section at 2 Gy
per day after prior conventionally fractionated
treatment, cord tolerance appears to increase at
least 25% 6 months after the initial course of RT
based on animal and human studies.
• For partial cord irradiation as part of spine radio-
surgery, a maximum cord dose of 13 Gy in a single
fraction or 20 Gy in 3 fractions appears associated
with a less than 1% risk of injury.
14.1.5 Ear
The recommendations for irradiation of the ear from
Bhandare et al. (2010) are as follows:
• For conventionally fractionated RT, to minimize
the risk for SNHL, the mean dose to the cochlea
should be limited to B45 Gy (or more conser-
vatively B35 Gy). Because a threshold for SNHL
cannot be determined from the present data, to
626
prevent SNHL the dose to the cochlea should be
kept as low as possible. For SRS for VS [ves-
tibular schwannomas], the prescription dose
should be limited to 12–14 Gy for hearing
preservation.
• A suggested hypofractionation schedule for VS, to
provide likely tumor control and preserve hearing,
is a total prescription dose of 21–30 Gy in 3–7 Gy
per fraction over 3–10 days,although data on this
schedule are limited.
14.1.6 Salivary Glands
The recommendations of Deasy et al. (2010) include
the following:
• Severe xerostomia (long-term salivary function less
than 25% of baseline) can usually be avoided if at
least one parotid gland has been spared to a mean
dose of B20 Gy or if both glands have been spared
to a mean dose of B25 Gy.
• For complex partial volume RT patterns (e.g., inten-
sity-modulated RT), the mean dose to each parotid
gland should be kept as low as possible, consistent
with the desired clinical target volume coverage.
A lower mean dose to the parotid gland usually results
in better function, even for relatively low mean doses
(\10 Gy). Similarly, the mean dose to the parotid
gland should still be minimized, consistent with
adequate target coverage, even if one or both cannot
be kept to a threshold of\20 or\25 Gy. When it can
be deemed oncologically safe, submandibular gland
sparing to modest mean doses (\35 Gy to see any
effect) might reduce xerostomia symptoms
14.1.7 Larynx
Rancati et al. (2010) presented guidelines for cancer
of the larynx as follows: RT affects voice quality in
locally advanced HN cancer but less so in early stage
larynx cancer. An interesting conclusion follows this
observation: clinically significant vocal dysfunction
requires both the larynx and the surrounding supr-
alaryngeal structures to be affected. The surrounding
tissues might be indirectly affected by a reduction in
salivary function or directly by effects on the intrinsic
musculature and soft tissue. … [I]t seems reasonable
to suggest limiting the mean noninvolved larynx dose
to 40–45 Gy and limiting the maximal dose to
\63–66 Gy, if possible, according to the tumor
extent.
A. M. Chen and K. S. Clifford Chao
15 PET and the Use of Radiotracers
in RT Planning
The accurate identification and delineation of both
GTV and CTV is of critical importance to ensure
treatment success. As stated earlier, MRI is essential
for the delineation of targets near the base of skull in
cases of advanced nasopharyngeal or paranasal sinus
cancers in which the bony anatomy interferes with
CT-based assessment of soft-tissue details. The use of
flurodeoxyglucose-positron emission tomography
(FDG-PET) to determine the GTV has gained
increasing popularity in recent years. FDG is a radi-
olabeled analog of glucose that is selectively absorbed
in tumor cells more than normal tissues, and thus may
be useful in discerning neoplastic growth. Recent
interest has focused on FDG-PET as a tool in tumor
contouring on the use of fused PET image with
treatment planning CT. This may help avoid under-
treating areas of disease involvement and over-treat-
ing areas not involved, thus improving disease control
and decreasing toxicity. Indeed, PET-based planning
can significantly influence the size of the GTV and
also assist in the identification of nodal metastasis not
visualized by traditional imaging modalities. Most
studies have shown that PET-based planning tends to
reduce the GTV, however, some studies have shown
that PET-based planning can increase the size of
volumes contoured (El-Bassiouni et al. 2007; Madani
et al. 2007; Wang et al. 2006). How the use of PET-
based planning ultimately affects long-term clinical
outcome remains uncertain.
Several novel tracers are also being employed in
head and neck RT planning (Choi et al. 2010; Lee
et al. 2008; Chao et al. 2001c). Tumor hypoxia is a
common occurrence in the tumor microenvironment
and has a well-established role in the resistance of
tumors to RT. Recent advances have demonstrated the
potential of ‘‘hypoxia-directed RT’’ using 18-F-mi-
sonidazole (FMISO), a novel tracer that has been
shown to accurately identify hypoxic areas in head
and neck tumors. Lee et al. (2008) used FMISO-PET
to identify hypoxic sub-volumes in 10 head and neck
cancer patients and subsequently escalated the dose to
those areas using an integrated boost technique. In
another study, Chao et al. (2001) used Cu(II)-diace-
tylbis(N(4)-methylthiosemicarbazone) (Cu-ATSM) as
Head and Neck Cancer
a marker for hypoxia and demonstrated the feasibility
of this approach. While these strategies using novel
radiotracers have the potential to improve outcomes
in the future, further research is necessary before
routine implementation into daily clinical use is
accepted.
16 Image Guidance
Although radiation therapy has traditionally been
planned and delivered on the basis of a single CT scan
acquired at the time of simulation, the increasing
utilization of IGRT has resulted in paradigm shifts in
the radiotherapeutic management of head and neck
cancer. With the advent of IGRT, specifically with
techniques enabling soft-tissue imaging while the
patient is undergoing irradiation (i.e. on-board imag-
ing), it is now possible to observe changes in the
shape, volume, and position of target volumes and
normal tissue structures during the entire treatment
course. Since IMRT treatment plans are characterized
by steep gradients between high and low dose regions,
the precise and consistent delivery of radiation ther-
apy on a regular basis is paramount to maximize dose
to target volumes and minimize dose to critical
structures designed as an OAR. The use of IGRT has
been proposed as a powerful means of overcoming
potential uncertainties in setup and accounting for
interfraction variability.
The essential goal of treatment verification is to
minimize and quantify any differences between the
planned treatment and delivered fraction. Historically,
patient setup was aligned with the assistance of portal
images obtained as an orthogonal pair, which were
then compared to digitally reconstructed radiographs
(DRRs) using boney landmarks in a two-dimensional
fashion. The advantage of IGRT is that it provides a
high-quality three-dimensional axial view thus
enabling both soft tissue and bony verification of the
region of interest. This is particularly valuable since it
has been shown that even in a rigid thermoplastic
mask, interfraction motion can still be significant.
Indeed, studies attempting to compare setup errors
between IGRT and standard portal imaging have
suggested that the latter is often inadequate to com-
pensate for potential positional shifts in the setting of
IMRT for head and neck cancer. Li et al. (2008)
627
analyzed 21 head and neck cancer patients who were
immobilized in a thermoplastic mask and setup daily
using orthogonal imaging and then compared how the
use of IGRT impacted positioning. The authors
showed that IGRT resulted in couch shifts in excess
of 3 and 5 cm in 4 and 19% of fractions, respectively.
Hong et al. (2005) similarly showed that verification
checks using planar orthogonal films might not
sufficiently alert the clinician to the magnitude of
three-dimensional offset vectors. These studies, in
aggregate, indicated serious concerns regarding the
possibilities of under-dosing target volumes and over-
dosing normal structures if IGRT is not used.
The contribution of weight loss and anatomical
changes on interfraction uncertainties should also be
considered during head and neck cancer radiation
therapy. Multiple studies have shown that the head
and neck is not an anatomically rigid structure, but
rather is in constant flux, impacted by such phenom-
ena as regression of tumor and nodal volumes,
changes in body mass index, alteration in muscle
mass and fat distribution, subcutaneous edema, and
fluid shift. IGRT is invaluable not only for proper
patient setup in these situations, but also for poten-
tially identifying subtle or even more pronounced
changes in the location, shapes, and sizes of the target
and OARs. Indeed, several studies have shown that
the potential dosimetric consequences of these volu-
metric and positional changes over the course of
radiation therapy can be significant (Barker et al.
2004; Wu et al. 2009; Mechalakos et al. 2009).
Barker et al. (2004) performed a landmark study of
14 patients treated using a linear accelerator inte-
grated with a CT ‘‘on-rails’’ and demonstrated dra-
matic volumetric and spatial alterations in both tumor
volumes and OARs. More specifically, the gross
tumor volumes decreased at a median of 0.2 cc per
treatment day which corresponded to a rate of 1.8%
per treatment day when considering the percentage
of the initial volume. As importantly, the authors
showed positional variations in the mass over time,
suggesting that the pattern of shrinkage was often
asymmetric and difficult to predict. Lastly, they
showed significant reduction in parotid gland volume
(on the order of 0.19 cc/day) with medial displace-
ment (towards the high-dose target volumes) over the
course of radiation therapy. Interestingly, a statisti-
cally significant correlation was detected between the
628
magnitude of medial displacement of the parotid
glands and degree of weight loss.
Others have confirmed that ‘‘what one plans’’ is
not always ‘‘what one gets’’ with respect to the
planning and delivery of radiation therapy for head
and neck cancer, particularly if interfraction vari-
ability is left unaccounted (O’Daniel et al. 2007; Lee
et al. 2008; Han et al. 2008). For instance, studies
using IGRT to visualize internal anatomy during
treatment have consistently shown that the parotid
gland experiences significant volume shrinkage as
well as a systematic medial shift into the high-dose
region, which can potentially compromise parotid-
sparing. O’Daniel et al. (2007) demonstrated that
approximately half of 11 patients treated for head and
neck cancer received a parotid gland dose of 5 to
7 Gy greater than intended at the time of treatment
planning. Lee et al. (2008) similarly used IGRT to
recognize that the daily mean dose of 10 patients
differed from the planned dose (based on the kilo-
voltage simulation CT scan) by 15% on average.
IGRT has confirmed that significant variations
between prescribed dose and delivered dose exist
when using IMRT for head and neck cancer.
Although it remains speculative how these discrep-
ancies may impact clinical outcome, there is no doubt
that IGRT has emerged as a useful tool which can
detect and correct errors in patient setup that can
occur during the treatment delivery process. How to
utilize this information beyond just treatment align-
ment remains an area of active investigation.
17 IGRT Techniques
The purpose of anatomical imaging is to determine
the position of the target and to verify dose delivery
during treatment. Because the snapshot provided
by a single three-dimensional image may not be
accurate during the entire treatment course, misa-
lignments are possible. With non-IGRT approaches,
the patient was positioned before treatment by
inferring the location of internal anatomy from
surface marks typically placed on the immobiliza-
tion mask, which is aligned with lasers. Orthogonal
radiographs were then obtained using X-rays from
the treatment beam (i.e. portal imaging). The major
drawback of this technique relates to the three-
A. M. Chen and K. S. Clifford Chao
Fig. 22 Megavoltage computed tomography images obtained
on the treatment couch for a 65-year-old male with T4N0
squamous cell carcinoma of the left maxillary sinus that was
deemed unresectable. The patient was treated by definitive
radiation therapy to a total dose of 70 Gy to areas of gross
disease. The fused images fusedsimulataneously illustrating
both megavoltage and simulation (kilovoltage) scans in the
axial plane using the split-screen display. The large tumor
occupies essentially the entire maxillary sinus
dimensional projection technique and its relatively
poor contrast resolution.
With IGRT, the immobilized patient is initially
aligned with the assistance of wall-mounted lasers,
and volumetric three-dimensional images are
obtained prior to treatment. The resultant images are
then fused with the treatment planning CT images in
the axial, coronal, and frontal planes. One can verify
the fusion either by comparing anatomical landmarks
in both image sets or by overlaying the regions of
interest that have been defined during the treatment
planning process onto the pre-treatment IGRT scan
(Figs. 22, 23). Once the treating physician has veri-
fied the fidelity of the image fusion, the daily trans-
lational adjustments are manually applied and
delivery of radiation commences. This process pro-
vides significant assurance that what is targeted at the
time of IMRT planning is what is actually treated on a
routine basis (Fig. 24).
Cone-beam CT refers to the tomographic three-
dimensional reconstruction of patient anatomy from a
series of two-dimensional radiographs obtained in a
Head and Neck Cancer
Fig. 23 Fused coronal images demonstrating the registration
between the megavoltage IGRT scan obtained on the treatment
table and the initial kilovotage simulation scan for the same
patient as in Fig. 22
single rotation of source and detector. By acquiring
hundreds of projections while the volumetric recon-
struction proceeds in parallel, high-quality axial
images are obtained with the patient in the treatment
position. Helical tomotherapy refers to an IGRT
approach using a rotating slit-beam and a temporally
modulated binary collimator that rapidly moves the
leaves in and out to create the non-uniform X-ray
beam fluence. In this system, the MV treatment beam
rotates around the patient while the couch moves
through the bore.
Compared to the age-old practice of aligning
radiographs of the patient in the treatment position to
reference X-rays created by DRRs showing skeletal
anatomy, IGRT has improved target localization and
dose verification. In general, image-guided adjust-
ments can be grouped into two categories: online and
offline. When the images are evaluated before each
fraction, with corrections occurring at the time of
radiation delivery, this is referred to as online cor-
rection. Alternatively, an offline approach refers to the
acquisition of frequent images during radiation ther-
apy without immediate intervention until systematic
error dictates correction, which can be applied by
repositioning the treatment couch for future fractions.
The offline strategy determines the best patient
629
position through accumulated data gathered during
treatment sessions and resultant shifts are made after a
certain threshold level is breached. These strategies
utilize sophisticated CT hardware for the design of
specific setup parameters or ‘‘action levels’’ to create
future procedures.
Volumetric imaging obtained with the attachment
of a kilovoltage source and flat panel imager on the
treatment accelerator and scanning in cone-beam
geometry comprises the most widely used IGRT
system today. Megavoltage CT, which uses the
treatment beam to obtain an axial scan and hence
provides an alternative method of treatment-time CT
without the need for additional X-ray sources or
detectors, has also been implemented. The limitation
of this method arises from the lower quantum effi-
ciency of a detector at the megavoltage energy and
the lower intrinsic contrast between the various tis-
sues. This drawback is also inherent in helical to-
motherapy, which is dependent on megavoltage CT.
While the patient dose due to a single volumetric
imaging acquisition for IGRT is relatively small
compared to the therapy dose, repeated and daily
image-guidance procedures can subject patients to
additional dose to normal tissues both inside and
outside the field of view. For instance, Islam et al.
(2006) reported on the dosimetric properties of the
cone-beam CT (CBCT) used on an Elekta linear
accelerator (Synergy, XVI system, Elekta, Crawley,
UK). Dose measurements were performed at the
center, periphery, and surface of 30 and 16 cm
diameter cylindrical-shaped water phantoms, as a
function of X-ray energy and longitudinal field-
of-view settings of 5, 10, 15, and 26 cm. The
measurements were performed for full 360 CBCT
acquisition as well as for half-rotation scans for
120 kV beams. The doses from a typical IGRT pro-
tocol were reported to range between 2.6 and 3.4 cGy
for 120 kV in a head phantom and dependent on the
size of the field of view, measurement depth, and the
number of projections from CBCT. Sykes et al.
(2005) similarly measured surface doses ranging from
2.6 to 3.1 cGy in a head and neck phantom using a
setting of 130 kV and 40 mA. However, more
recently, Lehmann et al. (2007) reported that the
measured air kerma value could be as high as
6.28 cGy depending on machine settings and tech-
nique. Doses of similar magnitude have been reported
630
Fig. 24 Intensity-modulated
radiotherapy plan
demonstrating dose
distribution for the patient
described in Figs. 3 and 4.
a Coronal image; b Sagittal
image. The patient was
treated with a simultaneous-
integrated boost technique
with the orange colorwash
representing 70 Gy, the
yellow colorwash representing
63 Gy, and the green
colorwash 56 Gy
in the IGRT acquisition of a helical tomotherapy MV
CT scan (Meeks et al. 2005; Kan et al. 2008).
With respect to head and neck radiation therapy,
Kan et al. (2008) showed that the total additional dose
to normal structure such as the lens, brain stem, and
spinal cord could reach 2.0, 1.7, and 1.4 Gy, respec-
tively, assuming the delivery of 35 fractions with
IGRT using the standard settings. Notably, the highest
incidental dose as a result of IGRT was delivered to
the thyroid/thymus (11.1 cGy per scan), which the
authors attributed to the reduced X-ray attenuation
through the air cavity and the thinner diameter of the
neck. Besides the thyroid, the highest doses were
found on the skin (6.7 cGy) and lens (6.2 cGy). The
absorbed doses for other organs within the primary
beam varied from 3.8 to 5.9 cGy. For regions outside
the primary beam, the measured doses were much
smaller. The effective dose to the body was estimated
at 10.3 mSv. Whether and how this additional incre-
ment in total dose might result in an increase in the
risk of developing second malignancy is uncertain.
The other potential drawback that needs to be
considered with IGRT relates to its resource-intensive
nature. Although the process of actually acquiring an
IGRT image only takes a few minutes per day, the act
of registering the information and manually making
adjustments can result in significantly increased time
to each treatment session. Over the course of 30–35
A. M. Chen and K. S. Clifford Chao
fractions for each patient, the IGRT process can
occupy up to several hours of potentially valuable
manpower and machine time. Furthermore, physician
review and approval of each IGRT scan is required
prior to the scheduled delivery of the next fraction.
While the specific IGRT approaches vary across
institutions and no ‘‘standard’’ currently exists, the
technologically demanding aspects of this procedure
demand a high level of quality assurance so that
continual re-evaluation can occur. In particular, the
documentation of IGRT technique (kilovoltage versus
megavoltage; online versus offline; frequency of
IGRT; etc.) is highly recommended so that reliable
comparisons and conclusions can be drawn in the
future.
18 Utility of IGRT to Reduce
Treatment Margins
The improved target localization attributed to IGRT
has forced the concept of PTV to be re-evaluated.
Although the published literature on optimal CTV-
to-PTV margins is limited, it is becoming recognized
that this depends largely on the method and frequency
of verification imaging used in treatment. Studies, for
instance, have shown that a minimum of 5 mm mar-
gins is required when displacements are measured
Head and Neck Cancer
using boney landmarks from orthogonal planar
films (O’Sullivan et al. 2001; Miah et al. 2010;
Wang et al. 1983). With the increasing utilization of
IGRT, however, the reduction in CTV-to-PTV mar-
gins may be possible. The theoretical advantage of
reducing CTV-to-PTV margins is to decrease the
amount of normal tissue irradiated resulting in
improvements in both treatment tolerability and
quality of life. Van Asselen et al. (2002) showed
that reducing the CTV-to-PTV margin from 6 to
3 mm, for instance, resulted in an approximate 20%
reduction in normal tissue complication probability
(NTCP), with respect to xerostomia (Hosokawa et al.
2001). However, this reduction in NTCP must be
balanced by potential reduction of dose to the target
structures. Clearly, clinical data with long-term
follow-up is needed to validate that the use of IGRT
with reduced CTV-to-PTV margins actually translate
into actual therapeutic gains.
Several mathematical formulae have been recom-
mended for generating CTV-to-PTV margins.
Classically, setup errors have been categorized into
systematic and random components. Whereas the
dosimetric effects of random errors tend to cancel
each other out, the effects of systematic errors accu-
mulate over several fractions potentially causing a
shift of the cumulative dose distribution relative to the
target. Using coverage probability matrices and dose-
population histograms, Stroom et al. (2002 and Van
Herk et al. 2004) have suggested formulae incorpo-
rating this differential effect. Stroom’s formula
(2R ? 0.7r) ensures that on an average, 99% of the
CTV receives more than or equal to 95% of the pre-
scribed dose. The formula by van Herk (2.5R ? 0.7r)
seems to be the most appropriate as it ensures that
90% of patients in the population receive a minimum
cumulative CTV dose of at least 95% of the pre-
scribed dose. Studies have shown that daily IGRT
improves setup accuracy by directly eliminating sys-
tematic and random errors; while less frequent IGRT
is likely only effective at reducing systematic error
(Yan et al. 1997; Den et al. 2010; Zeidan et al. 2007;
Yu et al. 2010).
Houghton et al. (2009) analyzed 15 patients treated
with IGRT for head and neck cancer in an attempt to
determine optimal CTV-to-PTV margins. They esti-
mated that CTV-to-PTV margins of 2.8, 3.1, and
4.1 mm in the mediolateral, superior–inferior and
anterior–posterior directions, respectively, were
631
needed to compensate for setup errors in the setting of
non-daily IGRT. With the use of daily IGRT, how-
ever, the authors believed that 3 mm margins were
sufficient. Den et al. (2010) similarly recently repor-
ted on 28 patients treated with IMRT for head and
neck cancer and showed that in the absence of daily
IGRT, a CTV-to-PTV margin of 3.9, 4.1, and 4.9 mm
is minimally required in the medial–lateral, supero-
inferior, and antero-posterior dimensions, respec-
tively, to ensure that 95% of the prescribed treatment
dose is delivered to 90% of the CTV.
While it has been generally established that more
frequent imaging during a course of radiation therapy
improves patient setup, at some point the tradeoffs
associated with increased IGRT begin to exceed the
potential benefits. The question of how often to per-
form IGRT in the clinic is also of practical impor-
tance given its resource-intensive nature. Zeidan et al.
(2007) analyzed alignment data from 24 patients (802
fractions) treated with daily IGRT and hypothetically
tested various temporal protocols including IGRT
weekly, every-other-day, and before the first 5 frac-
tions. The authors showed that none of these less-
than-daily protocols could replicate the effectiveness
of daily IGRT in reducing systematic and random
setup error. For example, in the setting of alternating
day IGRT, 29 and 11% of all fractions were subject to
residual setup errors greater than 3 and 5 mm,
respectively.
These findings are consistent with data on 103
patients treated with daily IGRT at the University of
California, Davis, cautioning against the use of less-
than-daily temporal protocols in the setting of
reduced (i.e. 3 mm) CTV-to-PTV margins (Yu et al.
2010). A mathematical vector analysis showed that
3 mm margins result in acceptably low rates of
geometric miss when daily IGRT is used for verifi-
cation. Importantly, the rates of geometric miss
increased significantly with non-daily IGRT if CTV-
to-PTV margins were maintained at 3 mm. With
IGRT on the first day only, weekly IGRT, and
every-other-day IGRT, the rates of geometric miss
were 51, 34, and 16%, respectively, in the setting of
3 mm margins (Fig. 25). If IGRT is unavailable on a
daily basis (as a result of resource limitations, for
instance), then a move to larger CTV-to-PTV mar-
gins (i.e. 5 mm) is strongly recommended. Recently
published clinical data on patients treated with either
3 or 5 mm CTV-to-PTV margins support the notion
632
Fig. 25 Incidence of geometric miss among patients treated
with IMRT for head and neck cancer using 3 mm CTV-to-PTV
margins based on data on 103 patients at our institution
that daily IGRT may safely allow for margin
reductions (Fig. 26).
19 Adaptive Radiation Planning
As previously discussed, the volumetric information
provided by IGRT has made it possible to observe not
only variations in positions, but also changes in
patient anatomy and shape during a course of radia-
tion therapy. Adaptive radiotherapy has been pro-
posed as a means of customizing the radiation plan in
response to anatomic changes, which invariably occur
throughout treatment to ensure that the prescribed
dose is what is actually delivered to the target. This
concept is critically dependent and related to IGRT,
which can facilitate this process by (1) potentially
identifying potential spatial abnormalities that can
‘‘trigger’’ re-planning and (2) providing a platform for
re-planning without the logistical need of obtaining a
new simulation CT.
Although the primary reason for adaptive re-
planning is to ensure adequate target coverage,
numerous other scenarios exist which may prompt re-
planning. For instance, migration of the parotid gland
towards high-dose regions after tumor shrinkage and/
or weight loss may subject a patient to unnecessary
toxicity, which could be potentially avoided with
adaptive radiotherapy (Figs. 27, 28). Another exam-
ple arises in the setting of tumors near the skull base
(i.e. nasopharynx) in which target volumes frequent
abut critical OARs of the central nervous system
including the brain stem, temporal lobes, and optic
chiasm. In these situations, dose is commonly
A. M. Chen and K. S. Clifford Chao
Fig. 26 Local–regional control according to CTV-to-PTV
expansion margins among 225 patients treated with IMRT for
squamous cell carcinoma of the oropharynx, oral cavity,
nasopharynx, larynx, and hypopharynx at the University of
California, Davis, Cancer Center (Chen et al., Int J Radiat
Oncol Biol Phys, in press)
delivered to the brink of commonly accepted normal
tissue tolerances (if not higher), and adaptive radio-
therapy may be instrumental in ensuring that the
doses to critical OARs are kept as low as feasibly
possible.
In a study of 13 patients treated with IMRT for
head and neck cancer, Hansen et al. (2006) demon-
strated significantly reduced doses to target volumes
and increased doses to critical structures if
re-planning had not occurred. The dose to 95% of the
high-dose PTV was reduced in 92% of patients by
0.2–7.4 Gy; the maximum dose to the spinal cord and
brain stem increased in nearly all patients by 0.2–15.4
and 0.6–8.1 Gy, respectively. Bhide et al. (2010)
additionally suggested that the most pronounced
alterations occur during the first week of treatment
and confirmed that significant under-dosing of targets
occurred if re-planning was not instituted. For
instance, the minimum dose to the PTV was reduced
by 2–3.9 Gy at week 2, resulting in large differences
between the true cumulative doses and the doses of
the original plan. These data eloquently demonstrate
the potential utility of adaptive radiotherapy to
improve treatment delivery, and possibly, improve
outcomes.
Adaptive radiotherapy is critically dependent on
two interrelated processes: deformable registration
and image segmentation. The former refers to the
concept of fusing images representing the same
anatomy acquired under dissimilar conditions at
Head and Neck Cancer
Fig. 27 Examples of parotid displacement among 2 patients
undergoing radiation therapy for head and neck cancer: The
parotid glands (as shown in yellow and brown) as designated on
Fig. 28 Relative parotid gland volume at the completion of
radiation therapy is depicted in relation to the total weight loss
(determined as a percentage of initial body weight) for six
patients. cp contralateral parotid; ip ipsilateral parotid
633
initial simulation CT (far left image) are superimposed on the
planning IGRT scans (acquired with MVCT) obtained on
fractions 15 and 35 (second and third images)
different times for the purpose of dosimetric calcu-
lation and re-planning. Deformable registration is
necessary because it is impossible to superimpose the
anatomy of the simulation CT on the IGRT scan to
achieve a perfect ‘‘match,’’ and a correction protocol
is needed to best ‘‘deform’’ the test image (repre-
senting current anatomy) onto the reference image
(obtained at simulation). However, deformable reg-
istration of the simulation CT with the IGRT image is
often hampered by the variation in quality with
respect to noise and contrast resolution, among other
factors, between the two modalities. While rigid-body
registration can at most align the bony structure, this
strategy is unacceptable for clinical use given the
offsets in internal anatomy that can occur.
For adaptive radiotherapy to be effective, the
ability to register the contours of the target volumes
and OARs (as delineated on the simulation CT
634
used for treatment planning) exactly to each IGRT
scan is also imperative. This process, referred to as
image segmentation, is a prerequisite for quantitative
dosimetric analysis and allows for the possibility of
real-time dose-calculation and if necessary, re-opti-
mization of the dose distribution to reflect the current
anatomy based on the IGRT scan. Since manual re-
delineation of the target volumes and OARs consti-
tutes a resource intensive task, which needs to be
performed in a relatively short period (so that adap-
tive radiotherapy can be as ‘‘real-time’’ as possible), it
is therefore not suitable for routine clinical use.
Various methods of automated segmentation includ-
ing voxel-based, model-based, and multi-scale map-
ping have been proposed (Nithiananthan et al. 2009).
Indeed, the process of reliably registering the IGRT
image to the simulation CT and subsequently
‘‘adapting’’ the original plan to the IGRT data cur-
rently comprises the limiting step in adaptive
radiotherapy.
Numerous computerized algorithms employing
various models have been proposed for deformable
registration and auto-delineation of both target
volumes and OARs (Voet et al. 2011; Stapleford
et al. 2010). Mohan et al. (2005) described a
strategy employing deformation of the intensity
distributions of each beam in the original IMRT
plan based on the deformation of each beam in the
original IMRT plan. By online deformation of
intensity distributions and modification of the cor-
responding leaf sequences, a platform for adaptive
radiotherapy was proposed. Commercial software
packages (Velocity AI, Velocity Medical Solutions,
Atlanta, GA; Mimvista, MIM Software, Cleveland,
OH) have also been marketed for adaptive radio-
therapy. Practical considerations that need to be
overcome in the process relate to speed, efficiency,
and resolution.
While adaptive radiotherapy is an appealing con-
cept, how to best integrate this concept into contem-
porary radiation therapy for head and neck cancer in
the setting of a busy clinical practice remains inves-
tigational. Although continued research on automa-
tion of planning and error correction in the context of
IGRT before re-planning will expedite this process,
the need to optimize deformable registration and
automatic segmentation algorithms is critical. Online
models to identify ‘‘triggers’’ which may prompt
adaptive radiotherapy are also needed to improve
A. M. Chen and K. S. Clifford Chao
efficiency. These technological gains may eventually
allow for techniques to calculate daily and accumu-
lated dose-volume statistics for both target volumes
and OARs while allowing for real-time modification
of the treatment plan.
20 Proton Therapy
When high-energy charged particles, protons, or carbon
ions, for example, move through matter, these ionized
atoms deposit their energy along their path. At the end of
their path immediately before the particles come to rest,
they release most of the energy before rapidly dropping
to zero. This is called the Bragg peak, after William
Henry Bragg who discovered it in 1903. Note that the
depth at which the Bragg peak occurs varies approxi-
mately linearly with the initial energy of the charged
particle, and for a given energy the peak is very sharp,
roughly 1 cm of depth. In contrast, MV photons deposit
most of their energy in the first 5–10 cm of depth, with a
long tail extending to more than 30 cm.
To vary the width of the peak, a technique named
spread-out Bragg peak (SOBP) can be used to
encompass the location and depth of tumor into the
irradiated tissue. By allowing a range of proton
energies, or by variation of the monoenergetic beam
energy, one can obtain quite an isotropic beam profile
over a targeted depth range. As a reference, using the
equations proposed by Bortfeld one can calculate that
the Bragg peak shifts smoothly from about 16 cm for
150 MeV protons to about 24 cm for 190 MeV pro-
tons, using water as target (Bortfeld 1997). Hence one
can ‘‘paint’’ the dosage to a desired depth range by
employing a window of beam energies.
At the end of 2008, there were a total of 26 proton
therapy centers in Canada, China, England, France,
Germany, Italy, Japan, Korea, Russia, South Africa,
Sweden, Switzerland, and United States; and over
60,000 patients had been treated. Indications for
particle therapy can be categorized into two clinical
scenarios:
• To escalate tumor dose while maintaining normal
tissue exposure at a similar level of photon therapy.
These include (but are not limited to) uveal mela-
noma (ocular tumors), skull base and paraspinal
tumors (chondrosarcoma and chordoma), and
unresectable sarcomas. Charged particle therapy for
ocular tumor (uveal melanoma) requires only a low
Head and Neck Cancer
energy (about 70 MeV) proton beam. In all these
cases, proton therapy achieves significant
improvements in the probability of local control
over conventional radiotherapy (Miralbell et al.
1992; Brown et al. 1989; Steneker et al. 2006)
• To reduce short- and long-term side effects but
limiting the dose to normal tissue. In this case,
tumor dose will remain the same so that there is no
increase in tumor control. These include but are not
limited to pediatric neoplasms such as medullo-
blastoma (Fossati et al. 2009). In the case of pedi-
atric cancers, there is convincing clinical data
showing the advantage of sparing developing
organs by using protons, and the resulting reduction
of long-term damage to the surviving child.
21 Re-Irradiation
The role of re-irradiation in the treatment of recurrent
and new primary cancers of the head and neck is
controversial. Although historically avoided due to
concerns of serious complications, several reports
have demonstrated that re-irradiation is feasible and
effective in carefully selected patients using a variety
of techniques and fractionation schedules. Evidence is
accumulating that IMRT may improve the therapeutic
ratio in the setting of re-irradiation due to its ability to
offer highly conformal target coverage while mini-
mizing radiation to uninvolved normal tissues (Lee
et al. 2007; Sulman et al. 2009; Dawson et al. 2001;
Mendenhall et al. 2008). Lee et al. (2007) reported on
105 patients including 74 patients treated with IMRT
who underwent re-irradiation for recurrent head and
neck cancer at Memorial Sloan-Kettering Cancer
Center. Notably, patients treated with IMRT had a
dramatically superior local–regional control at 2 years
compared to those treated by non-IMRT techniques
(52% versus 20%, p\0.001). Additionally, the acute
and late grade 3+ toxicity rates of 23 and 15% com-
pared favorably to historical controls. Similarly,
Sulman et al. (2009) reported on 78 patients
re-irradiated for head and neck cancer at M.D.
Anderson Cancer Center with IMRT. The two-year
local–regional control rate was 64%, and the toxicity
profile was believed to be acceptable.
The doses and fractionation schedules used in the
setting of re-irradiation have varied across published
reports. It has been established, however, that the
635
higher the dose that can be safely delivered, the greater
the probability of disease control. Salama et al. (2006)
reported three-year overall survival and local–regional
control rates of 30 and 56%, respectively, for patients
who received doses of 58 Gy or greater compared to
only 6 and 33%, respectively, among those who
received \58 Gy. In a multivariate analysis, the
authors found that re-irradiation dose was the most
important prognostic indicator for overall survival. It is
likely that dose escalation above 60 Gy may have been
hampered in older studies by the techniques available
at the time of radiation. We currently recommend a
dose of 60–70 Gy using IMRT with image guidance
considering such factors as prior radiation dose,
amount of overlap between the previously treated site
and proposed area for re-irradiation, interval between
radiation courses, tumor bulk, and whether chemo-
therapy will be given concurrently.
The proximity of tumor to critical structures must
also be considered in decisions regarding re-irradiation
dose. Numerous preclinical data have attempted to
determine the normal tissue tolerance to repeated doses
of radiation (Salama et al. 2006; Nieder et al. 2000;
Langlois et al. 1985; Emami et al. 1987; Ang 2001).
Some have suggested that the soft tissue can tolerate as
high as approximately 90% of the original dose with re-
irradiation. Again, it is likely that the dose is heavily
dependent on the volume of overlap as well as the time
interval between radiation courses. Although clinical
toxicity data analyzing the dose–response relationship
is relatively limited, most investigators agree that the
dose-limiting organs are those of the CNS (particularly
the spinal cord) and soft tissue. While some experi-
mental data have suggested that cumulative biologi-
cally equivalent doses of up to 130 Gy may be safely
tolerated to the head and neck, most trials have rec-
ommended limiting cumulative spinal cord dose to
50 Gy if possible (Salama et al. 2006). Based on
experimental animal data, however, this is likely an
unreasonable limit. Additionally, the tolerance of the
carotid artery is somewhat uncertain, especially when
the tumor abuts or invades this structure or if prior
surgery has placed the carotid close to the pharynx or
the skin surface. Regardless of these uncertainties,
cumulative doses to these areas should be carefully
monitored and recorded whenever possible, and the
importance of reviewing prior radiation details
including dose-volume histograms of critical struc-
tures cannot be overly emphasized.
636
Given concerns of late toxicity, the initial clinical
studies on re-irradiation to the head and neck utilized
hyperfractionated fractionation schedules with a
planned break as a potential means of optimizing the
therapeutic ratio. Notably, all of these regimens also
incorporated concurrent chemotherapy. Pioneering
work from the University of Chicago and the Institut
Gustave-Roussy demonstrating that re-irradiation can
lead to long-term survival helped establish a frac-
tionation regimen of 60 Gy delivered in 1.5 Gy
fractions, twice-daily, with treatments delivered
alternating weeks as the standard schedule used by the
RTOG (Salama et al. 2006; De Crevoisier et al.
1998). It is important to recognize that these pub-
lished experiences were performed utilizing older
techniques. Nonetheless, they ushered in an era in
which clinical trials exploring the feasibility of head
and neck re-irradiation became widespread. Salama
et al. (2006) summarized the results of 115 patients
treated on 7 consecutive prospective protocols
employing hyperfractionated re-irradiation with a
variety of chemotherapy regimens. Among 115
re-irradiated patients, 17 were alive and disease-free
at most recent follow-up with another 13 having died
of intercurrent illness without disease. Although the
investigators asserted that re-irradiation is a viable
treatment option, toxicity was significant with 19
patients dying of treatment-related complications
including carotid artery hemorrhage, soft tissue
necrosis, and respiratory arrest.
Given these relatively promising data with hyper-
fractionation and chemotherapy, the RTOG moved
forward with 2 large multi-institutional trials, both of
whom were recently published. RTOG 96-10 reported
on 86 patients treated by 60 Gy at 1.5 Gy twice-daily
fractions administered every other week with 5-fluo-
rouracil and hydroxyurea (Spencer et al. 2008).
Although nearly all patients successfully completed
re-irradiation, 6 treatment-related fatalities were
reported. RTOG 99-11 similarly reported on 105
patients treated by this same radiation fractionation
regimen with cisplatin and paclitaxel. Again, the high
incidence of treatment toxicity and grade 5 compli-
cations raised caution (Langer et al. 2007). Since both
these trials were designed to assess feasibility, local–
regional control was not reported in either study.
The heterogeneity of published series with regard
to radiation dose and fractionation schedules makes it
difficult to draw definitive conclusions regarding the
A. M. Chen and K. S. Clifford Chao
optimal radiation regimen in the setting of re-irradi-
ation. However, the results of more contemporary
series using IMRT have largely used once-daily
fractionation. This avoids the loss of effect on tumor
that occurs with split courses and hyperfractionation
and uses physical dose distribution rather than bio-
logical attempts to spare normal tissues. It is our
opinion that planned breaks and split-course re-
irradiation regimens may not be necessary using
contemporary radiation techniques and should be
avoided whenever possible. Regardless of the chosen
dose and fractionation schedule, careful attention to
the technical aspects of radiation planning and
delivery is critical to optimize outcomes.
22 Future Challenges
Modern radiotherapy is critically dependent on the
use of sophisticated technology to deliver treatment in
a precise, accurate, and consistent manner to achieve
optimal local tumor control while minimizing side
effects. Nowhere is the use of this technology more
relevant than in the radiotherapeutic management of
head and neck cancer. It is likely that radiotherapy
will continue to become more complex as techniques
continue to be refined with respect to the following:
computer-based CT simulation; accurate delineation
of target volumes and normal structures; accounting
for microscopic disease extension and interfraction
variability; techniques to reproduce patient setup;
anatomical imaging to verify target localization and
dose delivery.
The impetus for many of the technological changes
revolves around the need for target localization and
verification of dose delivery, especially given the
steep dose gradients available with IMRT. The
implementation of IGRT-capable treatment machines
in which kilovoltage or megavoltage CT images are
routinely acquired by a variety of techniques has
revolutionized care. Such systems provide volumetric
images of the patient in the treatment pos, and using
online software and hardware, patient position can be
determined accurately with a high degree of precision
and, subsequently, setup parameters can be adjusted
to deliver the intended treatment. IGRT has also
served as a powerful platform for adaptive radio-
therapy, which has the potential to make rapid
adjustments in the treatment plan in response to
Head and Neck Cancer
changes in body anatomy. Although clinical outcomes
are still preliminary and just now starting to be
reported, IGRT has moved the field of radiation
oncology from a three-dimensional to four-dimen-
sional basis, and the goal of individualizing radiation
therapy for patients with head and neck cancer is fast
becoming a reality.
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 Breast Cancer: Intact and Post Mastectomy
Elizabeth S. Bloom, Philip Poortmans, Marianne Aznar,
Thomas A. Buchholz, and Eric A. Strom

Contents 8 Oligometastatic Disease......................................... 658

8.1 Oligometastatic Disease: Bone................................ 658
8.2 Oligometastatic Disease: Central
1 Introduction ............................................................ 642 Nervous System ....................................................... 659
8.3 Oligometastatic Disease: Visceral........................... 659
2 Anatomy of the Breast .......................................... 642
2.1 Lymphatics............................................................... 642 9 Radiation Techniques: Breast Conserving
2.2 Lymphatic Drainage ................................................ 643 Therapy ................................................................... 660
9.1 Target Definition Breast and Primary
3 Pathologic Classification ....................................... 644
Tumor Bed ............................................................... 660
4 Diagnostic Workup ................................................ 645 9.2 Simulation ................................................................ 660
4.1 History and Physical Examination.......................... 645 9.3 Target Volume Delineation (see also Chapter
4.2 Mammography ......................................................... 645 ‘‘Quality Management and Safety in Radiation
4.3 Biopsy ...................................................................... 645 Oncology’’) .............................................................. 662
4.4 Magnetic Resonance Imaging ................................. 645 9.4 Treatment Planning.................................................. 662
4.5 Ultrasound ................................................................ 646 9.5 Prone Position.......................................................... 667
4.6 Other Studies ........................................................... 646 9.6 Boost ........................................................................ 667

5 Staging..................................................................... 647 10 Radiation Techniques: Post Mastectomy

Radiation Therapy and Regional Radiation
6 Prognostic Factors Influencing Management..... 647 Therapy combined with BCT............................... 670
7 General Management ............................................ 655 10.1 Target Definition ..................................................... 670
7.1 Noninvasive Breast Cancer ..................................... 655 10.2 Simulation ................................................................ 670
7.2 Invasive Breast Cancer............................................ 655 10.3 Treatment Planning.................................................. 672
7.3 Inflammatory Breast Cancer ................................... 657 10.4 Electron Beam Chest Wall Fields........................... 677
7.4 Locoregionally Recurrent Breast Cancer................ 657 10.5 Partially Wide Tangential Pair Fields..................... 678
7.5 Adenocarcinoma in Axillary Lymph Nodes 10.6 Boost ........................................................................ 679
of Unknown Breast Primary ................................... 658 References.......................................................................... 679

Abstract
E. S. Bloom (&)
T. A. Buchholz
E. A. Strom
Division of Radiation Oncology, In most industrialized countries, breast cancer
The University of Texas M. D. Anderson Cancer Center, constitutes a very important part of the number of
Houston, TX 77030, USA patients referred for radiation therapy. There has
e-mail: ebloom@mdanderson.org been a transition from simulator-based 2D tech-
P. Poortmans niques to modern, highly individualized CT-based
Department of Radiation Oncology, Institute Verbeeten, techniques. It is therefore not surprisingly that
Tilburg, The Netherlands
measures are being undertaken to diminish the
M. Aznar workload by introducing altered fractionation
Department of Radiation Oncology,
Rigshospitalet/Copenhagen University Hospital, schedules including the simultaneous integrated
Copenhagen, Denmark boost technique and hypofractionation. Regarding

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 641
DOI: 10.1007/174_2011_163,  Springer-Verlag Berlin Heidelberg 2012
642 E. S. Bloom et al.

this, it should be recognized that this is only possible

when applying modern techniques to optimize dose
homogeneity. In addition, there is an increased
awareness of the risk for late toxicity due to
irradiation of cardiovascular structures, lung tissue,
and the contralateral breast, as the number of breast
cancer survivors increase. Whereas technical solu-
tions including respiratory control offer very prom-
ising dosimetric results, the acceptance of consensus
based guidelines on target volume delineation as
well as target volume selection remains a challenge
for current investigators.

1 Introduction

Radiation is an integral component in the manage-

ment of both early-stage and locally advanced breast
cancer. The target, whether the intact breast or post
mastectomy chest wall, axilla, ipsilateral internal
mammary (IM) lymph nodes, and the supraclavicular
lymph nodes depends on the clinicopathologic fea-
tures of an individual patient’s disease. This chapter
will begin with a review of breast anatomy and
lymphatic drainage patterns, pathologic classification,
and workup and staging of breast cancer. This will be
followed by a discussion of the general management
of breast cancer with specific focus on the technical
aspects of radiation therapy in the intact breast and
post mastectomy settings.
Fig. 1 Distribution of lymphatic trunks draining breast and
chest wall musculature. Intercostal lymphatics are probably
also directing route of spread. (Reprinted with permission from
(Haagensen 1986))
the breast has a portion of tissue extending into the
axilla, known as the axillary tail of Spence. A not
uncommon site for primary tumors, this area can
become so prominent that it can form an apparent
axillary mass or give the appearance of a secondary
breast mound (Fig. 1).

2 Anatomy of the Breast 2.1 Lymphatics

The extent of the mammary or breast tissue is quite
variable from one patient to another. It also depends
on a number of items including patients’ age and her
position. Generally spoken, it will rarely exceed the
following borders: the edge of the sternum medially
to the latissimus dorsi muscle laterally, up to the
inferior edge of the clavicle superiorly and the
inframammary fold inferiorly. The posterior border of
the breast is bounded by the pectoralis major muscle
and fascia. The breast mound is from near midline to
the anterior axillary line, although the largest volume
of tissue is located in the upper-outer quadrant. Often
There is a well-developed lymphatic system within
the breast with drainage to the axilla, supraclavicular,
infraclavicular, and IM lymph nodes as shown in
Fig. 1. Part of this drainage moves superiorly and
laterally toward the axillary lymph nodes. These then
drain into the confluence of the internal jugular and
subclavian veins in the base of the neck under the
insertion of the sternocleidomastoid muscle to the
head of the clavicle. The lymphatic trunks are there-
fore located in the medial portion of the supracla-
vicular area. There are three trunks of primary
importance: the subclavian trunk from the axilla, the
Breast Cancer: Intact and Post Mastectomy
Fig. 2 Anatomy of axilla (pectoralis major and minor
muscles partially removed to demonstrate anatomic levels of
lymph nodes). Internal mammary artery and vein (1),
substernal cross drainage to contralateral internal mammary
lymphatic chain (2); subclavian muscle and Halsted’s liga-
ment (3); lateral pectoral nerve (from lateral cord) (4);
pectoral branch from thoracoacromial vein (5); pectoralis
minor muscle (6); pectoralis major muscle (7); lateral thoracic
vein (8); medial pectoral nerve (from medial cord) (9);
pectoralis minor muscle (10); median nerve (11); subcapsular
vein (12); thoracodorsal vein (13); internal mammary lymph
nodes (a); apical lymph nodes (b); interpectoral (Rotter’s)
lymph nodes (c); axillary vein lymph nodes (d); central lymph
nodes (e); scapular lymph nodes (f); external mammary lymph
nodes (g). Level I lymph nodes lateral to lateral border of
pectoralis minor muscle; level II lymph nodes behind pecto-
ralis minor muscle; level III lymph nodes medial to medial
border of pectoralis minor muscle. (Reprinted with permission
from (Osborn 1987))
jugular trunk from the neck and supraclavicular area,
and the bronchomediastinal trunks. All the trunks
combine in a variety of ways to empty on the right
side into a short common trunk, the right lymphatic
trunk, and on the left side into the internal jugular
vein, subclavian vein, or the thoracic duct.
The axillary lymph nodes are separated into three
anatomically continuous levels using the pectoralis
minor muscle as a point of reference as shown in
Fig. 2. This muscle has its origin from the anterior
part of the 3rd, 4th, and 5th ribs inserting onto the
coracoid process of the scapula. The three levels are
• Level I (proximal)—nodes located inferior (lateral)
to the pectoralis minor muscle.
643
• Level II (middle)—nodes directly beneath the
pectoralis minor muscle.
• Level III (distal)—nodes superior (medial) to the
pectoralis minor muscle.
2.2 Lymphatic Drainage
The clinically most relevant drainage of the breast
tissue is to the ipsilateral lower axilla. Analysis of the
degree of axillary lymphatic involvement by the
tumor provides the most important single prognostic
factor for patients with breast carcinoma. In general,
axillary lymphatic involvement occurs in an orderly
fashion. In a series of 1,446 patients, Veronesi et al.
showed that the incidence of skip metastases is quite
rare, with only 1.2% showing invasion in level II
without involvement at level I. Conversely, when the
nodes at level I were positive, approximately 40% of
higher level nodes were also involved (Veronesi et al.
1990). The distribution of nodal metastases by level is
shown in Table 1.
The other major route of lymphatic spread is via
the ipsilateral internal mammary chain (IMC). These
nodes are small, about 2–5 mm in diameter, and can
be structural nodes or poorly organized collections of
lymphocytes in connective tissue. These nodes are
grouped around and travel with the IM artery and
vein, generally within a few centimeters of the lateral
edge of the sternum. They usually lie on the thoracic
fascia in the interspaces between the costal cartilages
with rare exceptions underneath the edge of the costal
cartilage. They are primarily found in the first three
intercostal spaces with fewer lymph nodes identified
in the 4 and 5th interspaces. Ultrasound and lym-
phoscintigraphy can be used to determine the location
of these structures. Ultrasound can detect small vol-
ume metastases based on architectural changes. Ret-
romanubrial lymphatics connecting at the level of the
first interspace occurs between the right and left
lymphatic trunk 20% of the time (Haagensen 1971).
Supraclavicular nodal involvement generally rep-
resents stages of advanced regional disease and car-
ries a poorer prognosis. The major route of cancer
spread to the supraclavicular lymph nodes, is via the
axillary lymph nodes. Lymph fluid can become
644 E. S. Bloom et al.

Table 1 Distribution of 839 Levels involved Number of cases (%)

cases according to metastatic
involvement by level I 455 (54.2)
(Veronesi et al. 1990) I ? II 187 (22.3)
I ? II ? III and I ? III 186 (22.2)
Total number of cases with regular distribution 828 (98.7)
II 10 (1.2)
III 1 (0.1)
Total number of cases with ‘‘skip’’ distribution 11 (1.3)
Total 839 (100.0)

Table 2 The frequency of Tumor quadrant Number of Patients (%) Rate of drainage to IMC (%)
internal mammary chain
(IMC) drainage as a function Upper outer 128 (46) 14.1
of primary tumor location Upper inner 30 (11) 16.7
(P = 0.017)
Lower outer 19 (7) 31.6
(Shahar et al. 2005)
Lower inner 14 (5) 42.9
Central 88 (31) 28.4

Table 3 Relationship Variable Number of Patients (%) Rate of drainage to IMC (%)
between tumor location and
drainage to internal mammary Analysis: upper versus lower – –
chain (IMC) lymph nodes. Lower quadrants 33 (12) 36.4
Subgrouping 1, P = 0.003;
Central breast 88 (31) 28.4
subgrouping 2, P = 0.077
(Shahar et al. 2005) Upper quadrants 158 (57) 14.6
Analysis: medial versus lateral – –
Medial quadrants 44 (16) 25.0
Central breast 88 (31) 28.4
Lateral quadrants 147 (53) 16.3

obstructed in the lymphatic trunks or the internal
jugular–subclavian venous confluence, resulting in
retrograde spread into the lateral supraclavicular
lymph nodes and spread more posteriorly or in a
cephalad direction (Reed et al. 2008). The supracla-
vicular lymph nodes at greatest risk of tumor
involvement are difficult to examine, located behind
the sternocleidomastoid muscle, while the supracla-
vicular lymph nodes located more laterally are easier
to detect on physical examination.
The widespread introduction of sentinel lymph
node surgery has re-established preoperative
lymphoscintigraphy as an important diagnostic tool.
Shahar et al. looked at 297 patients with breast
carcinoma with at least one positive sentinel lymph
node. Of these patients, 279 had drainage to the
regional lymph node basins seen on lymphoscintig-
raphy. Dual drainage to both the IMC and axilla was
seen in 59 patients, and 4 patients had drainage to the
IMC only. IMC drainage is correlated with tumor
location. IMC drainage rates differed significantly
between upper and lower tumors (lower 36.4% vs.
central 28.4% vs. upper 14.6%, but not between
medial and lateral tumors) (Shahar et al. 2005).
IMC drainage patterns can be found in Tables 2
and 3. The identification rate of internal mammary
lymph nodes also depends on the technique of
the procedure itself: it is highest with an intra-tumoral
injection of the tracer, followed by a peri-
tumoral injection and lowest with a subdermal
or periareolar injection (Tanis et al. 2001; Pinero-
Madrona et al. 2007).
Breast Cancer: Intact and Post Mastectomy 645

Table 4 Histopathologic subtypes of breast cancer (From the spine, pelvis, hips, and ribs), unusual cough or short-
AJCC Cancer Staging Handbook, Seventh ed. Edge et al. ness of breath, headache, dizziness, or change in
(2010))
vision or mental status should be documented.
In situ Carcinomas
NOS (not otherwise specified)
Intraductal
4.2 Mammography
Paget’s disease and intraductal
The initial workup of a breast cancer patient begins
Invasive Carcinomas
with a bilateral diagnostic mammogram. All areas of
NOS the breast must be imaged, with palpable areas of
Ductal concern marked. Magnification or spot compression
Inflammatory views of any suspicious areas should be performed
Medullary, NOS during the same examination. Breast lesions are
Medullary with lymphoid stroma measured in two dimensions, and skin thickening
Mucinous
should be noted. If the mass is associated with mic-
rocalcifications, the extent of microcalcification and
Papillary (predominantly micropapillary pattern)
its relationship to any mass lesions should be docu-
Tubular
mented. Clustering and type of microcalcification
Lobular should also be noted. It is also important to document
Paget’s disease and infiltrating multicentricity and multifocality since this may
Undifferentiated influence the choice of local treatment.
Squamous cell
Adenoid cystic
Secretory 4.3 Biopsy
Cribriform
It is highly desirable to sample any suspicious or
ambiguous lesions including secondary lesions in
patients with documented cancers. Short interval
3 Pathologic Classification re-imaging (i.e., 6 months) should only be used to
verify findings that are most probably benign (BIR-
As noted in the AJCC Cancer Staging Handbook, the ADS 3) (Sickles 1995). Stereotactic or ultrasound-
histopathologic subtypes of breast cancer are divided guided core biopsy is suitable to obtain tissue samples
into in situ and invasive carcinomas, as outlined in with minimal disturbance of the breast.
Table 4 (Edge et al. 2010).

4.4 Magnetic Resonance Imaging

4 Diagnostic Workup
4.1 History and Physical Examination
The routine use of screening mammography has
resulted in the frequent presentation of breast cancer as
an asymptomatic finding. The first and most important
step in the workup of breast cancer is to obtain a clear
history and to perform an appropriate physical exam-
ination. Important elements of the history and physical
examination are listed in Tables 5 and 6, respectively
(Morrow et al. 2002). Any symptoms suggesting sys-
temic disease, such as bone pain (especially in the
Magnetic resonance imaging (MRI) of the breast may
also be recommended in the clinical evaluation of
patients with newly diagnosed breast cancer. Breast
MRI is indicated for women at an increased risk for
mammographically occult disease, such as those with
dense breast tissue on mammography, as seen espe-
cially at young age. In addition, breast MRI is recom-
mended in patients who present with axillary nodal
adenocarcinoma, but without a primary breast tumor
identified on physical examination, diagnostic mam-
mography, or ultrasound. Breast MRI may also play a
role in screening and diagnostic evaluation of patients
646
Table 5 Elements of a breast cancer-specific history (Morrow et al. 2002)
History of previous diseases, including cancer
History of any prior irradiation, chemotherapy or hormonal treatments
Family history (up to second-degree relatives, more extended if positive) including age at diagnosis, for breast and ovarian
carcinoma
History of any prior irradiation
Presence of implants (type and location)
Last menstrual period
Systemic symptoms
Nipple discharge; spontaneous versus induced, color of discharge
Table 6 Elements of a breast physical examination (Morrow
et al. 2002)
Tumor location and size, if palpable
Fixation to skin
Ratio of breast size to tumor size
Axillary node status: size and mobility
Supraclavicular nodal status
Evidence of locally advanced disease:
Skin ulceration
Peau d’orange
Skin erythema, edema
Fixed axillary nodes
Lymphedema of the ipsilateral arm
Nipple changes
Appearance of the opposite breast and axilla
with a known predisposing germline mutation (Lehman
et al. 2009). A point of debate is the use of MRI to
document the tumoral extent in patients with invasive
lobular histology as this might lead to an ablative
approach without any clinical argument to defend this
(van den Broek et al. 2007; Mann et al. 2010).
MRI can be especially helpful to monitor tumor
response to primary systemic treatment, on one hand
to adapt the approach in the case of a lack of tumor
shrinkage and on the other hand to evaluate which
patients can be converted from an ablative to a breast
conservative treatment (Straver et al. 2010a).
4.5 Ultrasound
Ultrasound of the breast is often recommended after
mammography to further characterize any lesions and
E. S. Bloom et al.
to help localize them for biopsy. Ultrasound is also
used for locoregional staging in patients with locally
advanced breast cancer to evaluate not only the breast
but also the axillary, infraclavicular, supraclavicular,
and IMC lymph nodes. Ultrasound-guided fine-needle
aspiration biopsy may be performed on suspicious
lymph nodes prior to treatment. The biopsy results
may lead to more accurate locoregional staging of the
disease and thereby alter treatment management. In
patients undergoing neoadjuvant chemotherapy,
markers may be placed in the primary tumor under
ultrasound guidance to demarcate the location of the
tumor bed to facilitate breast-conserving surgery
(BCS) after chemotherapy-induced tumor shrinkage
(Whitman and Strom 2009).
4.6 Other Studies
Chest CT-scan can be useful to monitor the effect of
primary systemic therapy on enlarged lymph nodes at
the internal mammary chain. Laboratory staging
studies include complete blood count, platelet count,
liver function and alkaline phosphatase tests (Carlson
2010).
Systemic staging evaluation is performed in
patients presenting with locally advanced breast
cancer or in the presence of signs and symptoms
suggesting possible spread beyond the breast and the
regional lymph nodes to evaluate for distant meta-
static disease. These staging studies include chest
imaging, bone scan, and abdominal imaging with
computed tomography (CT). Bone scan is also indi-
cated if the patient complains of bone pain or has
elevated alkaline phosphatase. Abdominal imaging
should be performed if the patient has abnormal liver
function tests, abdominal symptoms, or abnormal
Breast Cancer: Intact and Post Mastectomy
abdominal physical examination. Chest imaging is
recommended if pulmonary symptoms are present.
18
F-fluorodeoxyglucose positron emission tomogra-
phy/computed tomography imaging is recommended
only when standard staging studies are equivocal or
suspicious (Carlson 2010).
5 Staging
Disease staging provides a common language for
physicians to succinctly communicate the extent of
disease in breast cancer patients. Clinical stage (c) is
determined before the patient undergoes surgery or
neoadjuvant systemic treatment. Pathologic stage (p)
is determined after the patient has undergone surgery
and includes the pathologic findings at surgery. For
patients who received neoadjuvant systemic treat-
ment, the designation ‘‘yp’’ is utilized to designate
pathologic staging after possible tumor stage reduc-
tion (Edge et al. 2010).
The current staging system standard for breast
cancer is a collaborative work of the American Joint
Committee on Cancer and the Union for International
Cancer Control. Tables 7 and 8 present the 7th edition
(2010) TNM staging classification schemes and stage
groupings (Edge et al. 2010). Changes since the 6th
edition (2002) include the recommendation of grading
all invasive breast cancers using the Nottingham
combined histologic grade (Elston–Ellis modification
of Scarff–Bloom–Richardson grading system) and the
introduction of the M0(i+) category, which represents
molecularly or microscopically detected circulating
tumor cells in the blood, bone marrow, or other non-
regional nodal tissue, no larger than 0.2 mm, in the
absence of clinical or radiographic evidence of distant
metastases.
6 Prognostic Factors Influencing
Management
Several prognostic factors influence both the local and
systemic treatment recommendations for patients with
breast cancer. The size of an invasive breast cancer, in
relation to the overall breast size, in a patient desiring
breast-conserving therapy (BCT) will determine if
neoadjuvant chemotherapy is required to reduce the
647
size of the primary tumor. Patients with multicentric
tumors and inflammatory breast cancer (IBC) are not
considered candidates for BCT. Patients with multi-
focal tumors within a single quadrant of the breast,
which can be removed in a single segmental resection
specimen with clear margins and a cosmetically
acceptable result, may be considered candidates for
segmental resection followed by whole breast irradi-
ation, but they would not be considered candidates for
accelerated partial-breast irradiation (APBI) because
the limited dosimetric coverage of APBI has not been
tested in the clinical setting of multifocal primary
tumors, as will be described in this chapter. Patients
who are BRCA1 or BRCA2 mutation carriers should
receive extensive counseling to discuss the possible
approaches, including BCT and mastectomy includ-
ing prophylactic contralateral mastectomy given their
estimated increased risk of developing a second pri-
mary breast cancer in either breast in the future
(Fourquet et al. 2009; Pierce et al. 2010).
Age may also influence treatment recommenda-
tions. For instance, patients older than 70 years with
estrogen receptor-positive T1 primary tumors may
chose to forgo whole breast irradiation, if they accept
receiving 5 years of endocrine therapy, because of
their lower risk of an in-breast recurrence (Lehman
et al. 2009). However, whole breast irradiation in this
setting does reduce the risk of local recurrence risk by
at least two-thirds (Hughes et al. 2004). Moreover,
adjuvant hormonal treatment—which also carries side
effects-can be avoided if radiotherapy is given.
In patients with clinically negative nodes, the
axilla is surgically addressed by sentinel node biopsy.
If the sentinel node biopsy results are negative, no
additional axillary treatment, either with surgery or
radiation, is needed. An axillary lymph node dissec-
tion is still recommended for patients with a positive
sentinel node biopsy, as well for those with known
axillary metastases prior to treatment. In the near
future, we expect that this approach might very well
be substituted by axillary radiation therapy based on
the early results of the EORTC AMAROS trial
(Straver et al. 2010b).
Size of the primary tumor, tumor grade, lymph
node involvement, estrogen and progesterone receptor
status, and HER-2/neu status, all influence the possible
benefit of systemic therapy and determine the selec-
tion of the its’ type (endocrine therapy, chemotherapy,
trastuzumab, or a combination of these), and timing.
648 E. S. Bloom et al.

Table 7 AJCC Breast Staging Form (Reprinted with permission from Edge et al. (2010))
Breast staging form
Clinical Stage category definitions Pathologic
Extent of disease before any treatment Extent of disease through completion of
definitive surgery
h y clinical-staging completed after neoadjuvant Tumor size Laterality h y pathologic-staging completed after
therapy but before subsequent surgery __________ h left neoadjuvant therapy AND subsequent
h right surgery
h bilateral

Primary tumor (T)

h TX Primary tumor cannot be h TX
assessed
h T0 No evidence of primary h T0
tumor
h Tis Carcinoma in situ h Tis
h Tis (DCIS) Ductal carcinoma in situ h Tis (DCIS)
h Tis (LCIS) Lobular carcinoma in situ h Tis (LCIS)
h Tis (Paget’s) Paget’s disease of the nipple h Tis (Paget’s)
is NOT associated with
invasive carcinoma and/or
carcinoma in situ (DCIS and/
or LCIS) in the underlying
breast parenchyma.
Carcinomas in the breast
parenchyma associated with
Paget’s disease are
categorized based on the size
and characteristics of the
parenchymal disease,
although the presence of
Paget’s disease should still
be noted
h T1 Tumor B20 mm in greatest h T1
dimension
h T1mi Tumor B1 mm in greatest h T1mi
dimension
h T1a Tumor [1 mm but B5 mm h T1a
in greatest dimension
h T1b Tumor [5 mm but B10 mm h T1b
in greatest dimension
h T1c Tumor [10 mm but h T1c
B20 mm in greatest
dimension
h T2 Tumor [20 mm but B50 cm h T2
in greatest dimension
h T3 Tumor [50 mm in greatest h T3
dimension
h T4 Tumor of any size with h T4
direct extension to the chest
wall and/or to the skin
(ulceration or skin nodules)*
(continued)
Breast Cancer: Intact and Post Mastectomy 649

Table 7 (continued)
Breast staging form
h T4a Extension to the chest wall, h T4a
not including only pectoralis
muscle adherence/invasion
h T4b Ulceration and/or ipsilateral h T4b
satellite nodules and/or
edema (including peau
d’orange) of the skin which
do not meet the criteria for
inflammatory carcinoma
h T4c Both (T4a and T4b) h T4c
h T4d Inflammatory carcinoma** h T4d
*Note: Invasion of the
dermis alone does not qualify
as T4.
**Note: Inflammatory
carcinoma is restricted to
cases with typical skin
changes involving a third or
more of the skin of the
breast. While the histologic
presence of invasive
carcinoma invading dermal
lymphatics is supportive of
the diagnosis, it is not
required, nor is dermal
lymphatic invasion without
typical clinical findings
sufficient for a diagnosis of
inflammatory breast cancer.
Regional lymph nodes (N)
h NX Regional lymph nodes h NX
cannot be assessed (e.g.,
previously removed)
h pNX Regional lymph nodes h pNX
cannot be assessed (e.g.,
previously removed, or not
removed for pathologic
study)
h N0 No regional lymph node h N0
metastases
h pN0 No regional lymph node h pN0
metastasis identified
histologically
h pN0(i-) No regional lymph node h pN0(i-)
metastases histologically,
negative IHC
h pN0(i+) Malignant cells in regional h pN0(i+)
lymph node(s) no greater
than 0.2 (detected by H&E or
IHC including ITC
(continued)
650 E. S. Bloom et al.

Table 7 (continued)
Breast staging form
h pN0(mol-) No regional lymph node h pN0(mol-)
metastases histologically,
negative molecular findings
(RT–PCR)
h pN0(mol+) Positive molecular findings h pN0(mol+)
(RT–PCR), but no regional
lymph node metastases
detected by histology or IHC
h N1 Metastases to movable N1
ipsilateral level I, II axillary
lymph node(s)
h pN1 Micrometastases; or h pN1
metastases in 1–3 axillary
lymph nodes; and/or in
internal mammary nodes
with metastases detected by
sentinel lymph node biopsy
but not clinically detected**
h pN1mi Micrometastases ([0.2 mm h pN1mi
and/or more than 200 cells,
but none greater than
2.0 mm)
h pN1a Metastases in 1–3 axillary h pN1a
lymph nodes, at least one
metastasis [2.0 mm
h pN1b Metastases in internal h pN1b
mammary nodes with
micrometastases or
macrometastases detected by
sentinel lymph node biopsy
but not clinically detected**
h pN1c Metastases in 1 to 3 axillary h pN1c
lymph nodes and in internal
mammary lymph nodes with
micrometastases or
macrometastases detected by
sentinel lymph node biopsy
but not clinically detected**
h N2 Metastases in ipsilateral level h N2
I, II axillary lymph nodes
that are clinically fixed or
matted; or in clinically
detected* ipsilateral internal
mammary nodes in the
absence of clinically evident
axillary lymph node
metastases
h pN2 Metastases in Metastases in h pN2
4–9 axillary lymph nodes; or
in clinically detected***
internal mammary lymph
nodes in the absence of
axillary lymph node
metastases
(continued)
Breast Cancer: Intact and Post Mastectomy 651

Table 7 (continued)
Breast staging form
h N2a Metastases in ipsilateral h N2a
axillary lymph nodes fixed to
one another (matted) or to
other structures
h pN2a Metastasis in 4 to 9 axillary h pN2a
lymph nodes (at least one
tumor deposit greater than
2.0 mm)
h pN2b Metastasis only in clinically h pN2b
detected*** ipsilateral
internal mammary nodes and
in the absence of clinically
evident axillary lymph node
metastases
h N3 Metastasis in ipsilateral h N3
infraclavicular (level III
axillary) lymph node(s) with
or without level I, II axillary
lymph node involvement; or
in clinically detected*
ipsilateral internal mammary
node(s) with evident level I,
II axillary lymph node
metastases; or metastases in
ipsilateral supraclavicular
lymph node(s) with or
without axillary or internal
mammary lymph node
involvement
h pN3 Metastases in 10 or more h pN3
axillary lymph nodes; or in
infraclavicular (level III
axillary) lymph nodes; or in
clinically detected***
ipsilateral internal mammary
lymph nodes in the presence
of 1 or more positive level I,
II axillary lymph nodes; or in
more than 3 axillary lymph
nodes and in internal
mammary lymph nodes with
micrometastases or
micrometastases detected by
sentinel lymph node biopsy
but not clinically detected**;
or in ipsilateral
supraclavicular lymph nodes
h N3a Metastases in ipsilateral h N3a
infraclavicular lymph
node(s)
h pN3a Metastases in 10 or more h pN3a
axillary lymph nodes (at
least one tumor deposit
[2.0 mm); or metastases to
the infraclavicular (level III
axillary lymph) nodes
(continued)
652 E. S. Bloom et al.

Table 7 (continued)
Breast staging form
h N3b Metastases in ipsilateral h N3b
internal mammary lymph
node(s) and axillary lymph
node(s)
h pN3b Metastasis in clinically h pN3b
detected*** ipsilateral
internal mammary lymph
nodes in the presence of 1 or
more positive axillary lymph
nodes; or in more than 3
axillary lymph nodes and an
internal mammary lymph
nodes with micrometastases
or macrometastases detected
by sentinel lymph node
biopsy but not clinically
detected**
h N3c Metastasis in ipsilateral h N3c
supraclavicular lymph
node(s)
h pN3c Metastasis in ipsilateral h pN3c
supraclavicular lymph nodes
*Classification is based on
axillary lymph node
dissection with or without
sentinel lymph node biopsy.
Classification based solely
on sentinel lymph node
biopsy without subsequent
axillary lymph node
dissection is designated (sn)
for ‘‘sentinel node,’’ for
example, pN0(sn).
**Note: Not clinically
detected is defined as not
detected by imaging studies
(excluding
lymphoscintigraphy) or not
detected by clinical
examination.
***Note: Clinically detected
is defined as detected by
imaging studies (excluding
lymphoscintigraphy) or by
clinical examination and
having characteristics highly
suspicious for malignancy or
a presumed pathologic
macrometastasis based on
fine needle aspiration biopsy
with cytologic examination.
(continued)
Breast Cancer: Intact and Post Mastectomy 653

Table 7 (continued)
Breast staging form
Confirmation of clinically
detected metastatic disease
by fine needle aspiration
without excision biopsy is
designated with an (f) suffix,
for example, cN3a(f).
Excisional biopsy of a lymph
node or biopsy of a sentinel
node, is the absence of
assignment of a pT, is
classified as a clinical N, for
example, cN1. Information
regarding the confirmation of
the nodal status will be
designated in site specific
factors as clinical, fine
needle aspiration, core
biopsy, or sentinel lymph
node biopsy. Pathologic
classification (pN) is used for
excision or sentinel lymph
node biopsy only in
conjunction with a
pathologic T assignment.
Note: Isolated tumor cell
clusters (ITC) are defined as
small clusters of cells not
greater than 0.2 mm, or
single tumor cells, or a
cluster of fewer than 200
cells in a single histologic
cross-section. ITCs may be
detected by routine histology
or by immunohistochemical
(IHC) methods. Nodes
containing only ITCs are
excluded from the total
positive node count for
purposes of N classification
but should be included in the
total number of nodes
evaluated.
Distant metastasis (M)
h M0 No clinical or radiographic
evidence of distant
metastases (no pathologic
M0: use clinical M to
complete stage group)
(continued)
654 E. S. Bloom et al.

Table 7 (continued)
Breast staging form
h cM0(i+) No clinical or radiologic
evidence of distant
metastases, but deposits of
molecularly or
microscopically detected
tumor cells in circulating
blood, bone marrow or other
non-regional nodal tissue
that are no larger than
0.2 mm in a patient without
symptoms or signs of
metastases
h M1 Distant detectable metastases h M1
as determined by classic
clinical and radiographic
means and/or histologically
proven larger than 0.2 mm

Table 8 AJCC breast staging form (Reprinted with permission from Edge et al. (2010))
Breast staging form
Anatomic stage • Prognostic groups
Clinical Pathologic
Group T N M Group T N M
h 0 Tis N0 M0 h 0 Tis N0 M0
h IA T1* N0 M0 h IA T1* N0 M0
h IB T0 N1mi M0 h IB T0 N1mi M0
T1* N1mi M0 T1* N1mi M0
h IIA T0 N1** M0 h IIA T0 N1** M0
T1* N1** M0 T1* N1** M0
T2 N0 M0 T2 N0 M0
h IIB T2 N1 M0 h IIB T2 N1 M0
T3 N0 M0 T3 N0 M0
h IIIA T0 N2 M0 h IIIA T0 N2 M0
T1* N2 M0 T1* N2 M0
T2 N2 M0 T2 N2 M0
T3 N1 M0 T3 N1 M0
T3 N2 M0 T3 N2 M0
h IIIB T4 N0 M0 h IIIB T4 N0 M0
T4 N1 M0 T4 N1 M0
T4 N2 M0 T4 N2 M0
h Stage Any N3 M0 h Stage N3 M0
T
h Stage Any Any M1 h Stage Any Any M1
T N T N
*T1 includes T1mi
**T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB
h Stage unknown
Breast Cancer: Intact and Post Mastectomy
7 General Management
7.1 Noninvasive Breast Cancer
For noninvasive lobular carcinoma in situ, observa-
tion with consideration of risk- reducing strategies is
recommended similar to the presence of other pre-
cursor lesions. Risk-reducing strategies include the
use of tamoxifen for premenopausal women, and the
use of tamoxifen or raloxifene for postmenopausal
women. For patients at a significantly high risk of
developing breast cancer in the future, bilateral mas-
tectomy with or without breast reconstruction could
be considered.
For noninvasive ductal carcinoma in situ (DCIS),
treatment options depend on the extent of the disease.
For mammographically detected unifocal lesion,
which can be removed in a single lumpectomy speci-
men with good cosmetic results, BCT is an excellent
option. Clear surgical margins of at least 2 mm are
recommended (Dunne et al. 2009). A diagnostic
mammogram with spot compression views should be
considered following surgery but prior to radiation
therapy if suspicious calcifications representing DCIS
were detected in the preoperative mammogram.
Although a radiograph of the specimen is obtained at
the time of surgical resection, the postoperative
mammogram confirms that there are no residual sus-
picious calcifications remaining in the breast. Postop-
erative radiation therapy is intended to eliminate
potentially residual microscopic areas of disease.
Postoperative whole breast irradiation is considered
the standard of care after lumpectomy, as it reduces the
risk of recurrence in the breast by approximately 50–
60% at 10 years of follow up (Fisher et al. 1999, 2001;
Correa et al. 2010). Half of the recurrences are invasive
cancer and half are DCIS, with a similar risk reduction
for both after radiotherapy. APBI may be considered in
women who are 50 years or older, with low-grade
DCIS measuring 3 cm or smaller removed with clear
margins. Ideally, these patients should be treated on
clinical trial because of the more limited long-term
data for APBI compared with those for whole breast
irradiation. Excision alone without radiation therapy
may be occasionally considered in patients at low risk
of recurrence. In these cases, it is recommended that
the negative margins be wide (C10 mm) (Hughes et al.
2009). Factors influencing the risk of local recurrence
655
include tumor size, tumor grade, margin status, mode
of detection, and patient age. Axillary surgical lymph
node evaluation is not required for patients with pure
DCIS because it is associated with an extremely low
risk of nodal involvement. Sentinel node biopsy may
be considered in the presence of extensive or high-
grade DCIS, especially if a mastectomy is performed.
After microscopic detection of invasive disease, a total
mastectomy would preclude sentinel node mapping at
a later date. For patients with more extensive DCIS or
those desiring to avoid radiation therapy, total mas-
tectomy with or without breast reconstruction is the
preferred option.
7.2 Invasive Breast Cancer
There are generally two options for the locoregional
treatment of early-stage invasive breast cancer: (1)
BCT with lumpectomy, surgical axillary staging and
radiation therapy, and (2) total mastectomy with sur-
gical axillary staging with or without breast recon-
struction. In addition to the individual patient’s desires,
the size and site within the breast of the lesion influ-
ences the local treatment recommendations. Candi-
dates for BCT include patients with unicentric disease
that could be removed with negative margins and with
acceptable cosmetic results. With the advent of neo-
adjuvant chemotherapy, more women now have the
option of undergoing BCT because the size of the
tumor may be reduced prior to definitive surgery. As
previously mentioned, after lumpectomy with surgical
axillary staging, the standard of care is whole breast
irradiation. However, APBI is rapidly emerging as a
treatment option for early-stage invasive breast cancer
in certain clinical scenarios. APBI (see also Chapter
‘‘Partial Breast Radiation Therapy’’) may be consid-
ered in women who are at least 50 years old with
tumors that are pathologically 3 cm or smaller and
node-negative, optimally as part of a clinical trial
(Smith et al. 2009; Offersen et al. 2009; Mannino and
Yarnold 2009).
If mastectomy with surgical axillary staging is
selected as the primary surgical treatment option,
recommendations for postmastectomy radiation ther-
apy (PMRT) are based on the risk of locoregional
failure in the chest wall or undissected regional
lymphatics (level-III axilla, infraclavicular region,
supraclavicular region, and IMC) if these areas are
656
not irradiated. If the primary tumor is \5 cm in
diameter and if there is no axillary nodal involvement,
the risk of locoregional failure is less than 10%
without postoperative radiation therapy, so radiation
is not recommended in this clinical scenario
(Katz et al. 2001).
Clinicopathologic factors associated with a high
risk ([20%) of locoregional recurrence without
PMRT include four or more involved lymph nodes,
20% or greater involvement of the number of axil-
lary lymph nodes, T4 tumors, and T3 tumors com-
bined with at least N1 axillary nodal involvement
(Katz et al. 2001) (Ragaz et al. 2005). One to three
positive lymph nodes after neoadjuvant chemother-
apy is also associated with a higher risk of
locoregional recurrence. Therefore, PMRT is rec-
ommended in all those clinical settings (Buchholz
et al. 2002). If total mastectomy with surgical axil-
lary staging is performed prior to chemotherapy, the
current National Cancer Comprehensive Network
guidelines strongly suggest that post chemotherapy
radiation be considered to the chest wall and
undissected regional lymphatics, also in the setting
of one to three positive lymph nodes (Carlson 2010).
A subgroup analysis of the Danish Breast Cancer
Collaborative Group randomized trials demonstrated
that PMRT conferred an overall survival benefit in
this setting that was even higher compared to higher
risk groups (Overgaard et al. 2007). Other clinical
presentations associated with at least an intermediate
risk of locoregional recurrence (10–20%) without
PMRT include tumor size of 4 cm or greater with
one to three positive lymph nodes, (Katz et al. 2000)
three (or more) positive lymph nodes (Strom et al.
2005) age under 40 with lymph node-positive dis-
ease, lobular histology, (Voogd et al. 2001) lym-
phovascular space invasion and positive lymph
nodes, largest axillary node more than 2 cm, gross
extranodal extension of 2 mm or greater, (Katz et al.
2000) fewer than 10 axillary lymph nodes dissected
with positive lymph nodes, T3, N0 disease with
grade 3, and premenopausal status with lymphovas-
cular space invasion. Notwithstanding all those data,
the debate on the use of PMRT in intermediate risk
patient groups continues (Kunkler et al. 2010).
Because of this, most guidelines refer to a combi-
nation of risk factors, e.g. ‘‘if at least 2 of the fol-
lowing risk factors are present, PMRT should be
considered’’.
E. S. Bloom et al.
In the setting of neoadjuvant chemotherapy fol-
lowed by mastectomy, patients presenting with clin-
ical stage III disease (four or more suspicious or
confirmed positive lymph nodes on pretreatment
ultrasound, cT3N1 disease, or cT4 disease) prior to
chemotherapy should undergo PMRT. Patients pre-
senting with clinical stage IV disease who experience
a complete response to systemic therapy or those
being treated with curative intent should be consid-
ered for PMRT as well. In patients with close or
positive margins and clinical T3, N0 disease, PMRT
to at least the chest wall should be considered. PMRT
should also be considered in patients presenting with
T1–2, N1 disease and one or more of the following
clinicopathologic features: residual tumor size greater
than 2 cm, residual lymph node–positive disease after
chemotherapy, age \40 years, and lymphovascular
space invasion.
There are only a few clinical scenarios in which
the level-I and -II axilla should also be targeted in the
setting of breast-conserving therapy or following
mastectomy. For example, in the setting of invasive
disease without surgical axillary evaluation, a positive
sentinel node biopsy without further axillary surgery
or the removal of less than six axillary lymph nodes
during an axillary node dissection (Edge et al. 2010)
Free disease found in the axillary fat after axillary
node dissection is also considered a risk factor for
failure in the dissected axilla, unless a systematic and
complete clearance is performed. Otherwise, the risk
of failure in the levels-I and -II axilla after surgical
dissection is low, so radiation to this region is not
necessary. If delivered, radiation may increase the
risk of arm lymphedema and impaired shoulder
function (Leer et al. 1997).
In the framework of BCT, the same risk factors
should be considered for advising patients of radio-
therapy to the undissected regional lymph nodes, at
least the supraclavicular, infraclavicular, and level-III
axillary lymph node regions, in addition to the whole
breast (Strom et al. 2005).
Another issue that will only be solved after the
analysis of data of recent and ongoing prospective
trials is the selection of the areas to be treated. While
irradiation of the IMC lymph node area is the most
debated, an early analysis did not show an increased
level of toxicity (Matzinger et al. 2010). In Table 9, a
division in three risk categories for locoregional
relapse after mastectomy and axillary clearance is
Breast Cancer: Intact and Post Mastectomy 657

Table 9 Risk categories for locoregional relapses after mas- more likely to be HER-2/neu-positive, hormone
tectomy and axillary clearance. Ax LN ? = involved axillary receptor-negative, and younger at disease presenta-
lymph nodes. (Reprinted with permission from Matzinger et al.
(2010)) tion (Carlson 2010). Given the aggressive nature of
IBC, a staging evaluation for metastastic disease is
Risk category Low Intermediate High
required. If there is no evidence of metastatic disease,
Tumor stage T1–2 T1–2 T3–4 a combined modality approach is recommended.
Number of Ax LN + 0 1–3 [3 Intensive neoadjuvant chemotherapy followed by
Grade 1–2 3 modified radical mastectomy and PMRT is the
Vascular invasion – + mainstay of therapy. In patients with IBC who
Histology Ductal Lobular experience a poor response to neoadjuvant chemo-
Risk (%) \10% 10–20% [20% therapy, a non-cross-resistant chemotherapy regimen
should be used to try to reach resectability. Preop-
erative radiation should be considered in patients
with IBC who experience a poor response to an
Table 10 Indication for irradiation of the different target vol- anthracycline-based chemotherapy regimen as well
umes after mastectomy and axillary clearance as well as for as to a taxane (Chargari et al. 2009).
regional RT in the framework of BCT. (Reprinted with per-
mission from (Matzinger et al. 2010))
Risk category Low Intermediate High
7.4 Locoregionally Recurrent Breast
Thoracic wall No? Yes? Yes Cancer
Supraclavicular No? Yes? Yes
Internal mammary No Yes? Yes? For patients presenting with locoregionally recur-
Axilla No No No rent breast cancer, treatment recommendations are
Yes = evidence and generally accepted; Yes? = evidence but not based on the site of recurrence, extent of recur-
generally accepted; No? = limited evidence, however advocated rence, and previous treatment for the primary dis-
by some authors; No = no evidence. ease. In the setting of an in-breast recurrence after
breast-conserving therapy including whole breast
shown. Based on this, Table 10 is a proposed sum- irradiation, mastectomy is recommended. In the
mary of the indications for radiotherapy for the dif- setting of an in-breast recurrence adjacent to the
ferent target volumes (Poortmans 2007). original tumor site after segmental resection fol-
lowed by APBI, mastectomy is also recommended,
but, depending on the size of the recurrence, exci-
7.3 Inflammatory Breast Cancer sion followed by whole breast irradiation may be
considered. However, if the recurrence occurs away
IBC is an aggressive form of invasive cancer, usually from the original tumor site, meaning that it is
with rapid onset. IBC is a clinical diagnosis that possibly a new primary breast cancer, whether
requires diffuse erythema and dermal edema (peau another attempt at breast-conserving therapy should
d’orange) of at least one-third of the skin of the be considered is still being debated. A second
breast. The clinical presentation is due to blockage of attempt at breast-conserving therapy would entail
dermal lymphatics by tumor emboli. A biopsy con- segmental resection of the new breast cancer fol-
firming breast cancer in breast tissue and/or dermal lowed by either APBI or whole breast irradiation.
lymphatics is necessary. However, the presence of Ideally, these patients would be treated on a clinical
dermal lymphatic involvement on biopsy is neither trial because of the limited clinical outcome data in
required nor sufficient alone for the diagnosis of IBC. these clinical scenarios available to date.
The prognosis of patients with IBC is poorer than In the setting of a chest wall recurrence after mas-
that of patients with noninflammatory locally tectomy alone, local excision with negative margins
advanced breast cancer. It has become clear that IBC followed by postoperative chest wall and undissected
has unique characteristics that require a tailored regional lymphatic irradiation is recommended
treatment approach. In general, patients with IBC are because of the increased risk of additional locoregional
658
recurrences. Additional systemic therapy, either che-
motherapy and/or endocrine therapy, may also be
considered although solid evidence is lacking. In the
setting of a chest wall recurrence after mastectomy
followed by comprehensive chest wall and undissected
regional lymphatic irradiation, reirradiation as such is
not generally recommended because of the increased
risk of treatment-related complications. However,
when all other treatment options, including surgery and
systemic therapy, have been exhausted, limited-field
radiation may be considered. All attempts should be
made to minimize the risk of normal tissue toxicity in
patients in these clinical settings. A very attractive
treatment option for those patients, depending on the
availability, is offered by the combination of hyper-
thermia with radiotherapy. Both experimental and
clinical research has shown that this combination gives
valuable additional effects with a high complete
response rate and acceptable toxicity. In patients with
low-volume disease, sustained local control and maybe
even cure can be obtained. The most used treatment
schedules are eight times 4 Gy, twice a week and 12
times 3 Gray, four times a week, for both schedules
combined with twice a week hyperthermia. Most often,
an electron field set-up is used. In some countries,
including The Netherlands, this combined treatment is
offered as standard to patients with breast cancer
recurring in previously irradiated areas (van der Zee
et al. 1999).
Regional recurrences can also be treated with a
combined modality approach of systemic therapy, sur-
gery, and postoperative radiation when radiation has not
been delivered previously. Treatment recommendations
for these patients should be personalized on the basis of
original disease presentation, primary therapy received,
recurrent disease presentation including disease-free
interval, and performance status.
7.5 Adenocarcinoma in Axillary Lymph
Nodes of Unknown Breast Primary
Approximately 3–5% of all breast cancers present as
axillary metastases from an unknown primary breast
cancer, also known as occult breast cancer. In addi-
tion to a diagnostic mammogram and an ultrasound of
the breast and regional lymphatics, a dedicated breast
MRI is indicated to try to identify the primary breast
cancer. If the primary cancer is identified, the
E. S. Bloom et al.
treatment options are the same as those previously
described depending on disease stage. For patients
diagnosed with axillary adenocarcinoma without
evidence of a breast primary, the staging evaluation
for distant metastases often includes chest and
abdominal CT imaging. For patients with T0, N1, M0
disease, treatment options include either axillary node
dissection plus mastectomy or axillary node dissec-
tion followed by whole breast irradiation. Whereas in
a review by Pentheroudakis (Pentheroudakis et al.
2010), including a total of 446 patients managed with
mastectomy, a small breast primary was identified in
72% of the patients, some argue that treatment of the
breast could be safely withheld (Lanitis et al. 2009).
The need for undissected regional lymphatic irradia-
tion in either the post mastectomy or intact breast
setting would be determined by the pathologic find-
ings. Systemic therapy recommendations would also
be based on the pathologic findings and are similar to
those for patients with demonstrated breast cancer.
For patients presenting with T0, N2–3, M0 disease,
neoadjuvant chemotherapy followed by axillary node
dissection with or without mastectomy is recom-
mended, followed by postoperative chest wall and
undissected regional lymphatic irradiation to decrease
the risk of locoregional recurrence. In the intact breast
setting, whole breast and undissected regional lym-
phatic irradiation would be indicated as well.
8 Oligometastatic Disease
There is a growing interest in the study and treatment of
limited metastatic disease, or oligometastatic disease,
in multiple cancer types, but especially in metastatic
breast cancer. The development of effective systemic
treatment regimens (chemotherapy, hormone therapy,
and targeted therapy) has increased the importance of
the local treatment of oligometastatic disease in breast
cancer (Ly et al. 2010; Ruiterkamp et al. 2010; Le
Scodan et al. 2009; Bourgier et al. 2010).
8.1 Oligometastatic Disease: Bone
Breast cancer commonly metastasizes to bone. Met-
astatic breast cancer confined to the skeletal system is
an indolent disease and has been associated with
prolonged survival (Sherry et al. 1986; Briasoulis
Breast Cancer: Intact and Post Mastectomy
et al. 2004). An ongoing trial at MD Anderson,
NCT00929214, is associated with testing the
hypothesis that adding aggressive local therapy to
systemic therapy can eradicate breast cancer meta-
static foci in patients with metastasis limited to the
skeleton and prolong progression free survival. The
eligible population is breast cancer patients with
newly diagnosed metastases to one to three bone-only
metastases. To be eligible for inclusion in the trial,
patients must have a Karnofsky performance status of
70 or greater. The limited bone-only disease is treated
with definitive doses of 66–72 Gy after chemother-
apy. The radiation technique employed is determined
by the treating radiation oncologist, and it may be 3D
conformal radiation therapy, IMRT, or stereotactic
body radiation therapy in the case of vertebral
metastasis. If stereotactic body radiation therapy is
used for a vertebral metastasis, 27 Gy in three frac-
tions is prescribed on protocol. If there is disease
progression after 3–6 months of chemotherapy, either
palliative doses or no local therapy is recommended.
If the oligometastatic disease is treated with surgery
and is completely resected en bloc with clear margins,
postoperative radiation is not recommended. How-
ever, in the case of close or positive margins, post-
operative radiation to the surgical site is delivered in
doses of 50–60 Gy, depending on normal tissue tol-
erances. In the case of patients not enrolled in this
trial, doses of 50–60 Gy at 2 Gy/fraction are recom-
mended to achieve longer palliative benefit over
shorter, more limited doses of radiation.
For patients presenting with oligometastatic bone
disease at initial diagnosis, treatment begins in gen-
eral with chemotherapy to evaluate the response of
the disease to systemic treatment. If there is a positive
response to systemic therapy, surgical excision of the
primary tumor is recommended, as retrospective
studies have shown an improvement in survival with
aggressive local therapy in bone-only metastatic dis-
ease (Rapiti et al. 2006; Khan et al. 2002).
8.2 Oligometastatic Disease: Central
Nervous System
In the setting of one to three brain metastases, the
addition of stereotactic radiosurgery to whole brain
radiation therapy has been found to yield a therapeutic
benefit. In the Radiation Therapy Oncology Group
659
9508 randomized trial of whole brain radiation therapy
with or without stereotactic radiosurgery, whole brain
irradiation plus stereotactic radiosurgery boost treat-
ment improved survival in patients with a single un-
resectable brain metastasis and improved Karnofsky
performance status in patients with two or three brain
metastases compared with whole brain irradiation
alone (Andrews et al. 2004). Whole brain radiation
therapy has also been found to decrease the risk of
neurologic death after surgical resection of a solitary
brain metastasis (Patchell et al. 1998). In the recent
European Organisation for Research and Treatment of
Cancer phase III trial 22,952-26,001, the value
of adjuvant whole-brain radiotherapy on the duration of
functional independence after surgery or radiosurgery
of one to three brain metastases of solid tumors was
investigated. It was found that it reduces intracranial
relapses and neurologic deaths, but fails to improve the
duration of functional independence and overall sur-
vival (Kocher et al. 2010). Moreover, a recent ran-
domized controlled trial found that adding whole brain
radiation therapy to stereotactic radiosurgery signifi-
cantly decreased neurocognitive function in patients
with one to three brain metastases (Chang et al. 2009).
Thus, in patients with an excellent Karnofsky perfor-
mance status, who are willing to undergo close radio-
graphic monitoring with brain MRI, stereotactic
radiosurgery alone can be considered, with an addi-
tional stereotactic radiosurgery or whole brain irradi-
ation, if there is disease progression (Chang et al. 2009).
8.3 Oligometastatic Disease: Visceral
In highly selected patients, resection of a solitary or a
few liver or lung metastases from a breast primary
tumor may be considered. There is some evidence
suggesting that patients with longer disease-free
intervals from initial diagnosis of breast cancer to
solitary metastases or oligometastases have signifi-
cantly longer survival times when local surgical ther-
apy is used to remove the gross metastatic disease
while systemic therapy is used to treat any remaining
microscopic metastatic foci (Yoshimoto et al. 2008;
Okaro et al. 2005; Pocard et al. 2001). For patients
who are not considered candidates for surgery, ste-
reotactic body radiation therapy is also being investi-
gated in these clinical settings, (Milano et al. 2009)
Percutaneous radiofrequency ablation and cryotherapy
660
of liver metastases has been introduced in the clinic as
well (Livraghi et al. 2001).
9 Radiation Techniques: Breast
Conserving Therapy
9.1 Target Definition Breast and Primary
Tumor Bed
The primary objective of radiation therapy for breast
conservation is to eradicate microscopic residual
disease adjacent to the original tumor site after seg-
mental resection, as well as to eliminate any potential
multicentric disease. Since at least 80% of the early
failures in this patient group are in the same quadrant
as the original primary tumor, achieving adequate
coverage of the remaining breast tissue around the
operative bed is imperative. The risk of failures
elsewhere within the ipsilateral breast away from the
lumpectomy cavity is typically low when small vol-
umes of breast tissue are left unirradiated, particularly
if that volume is located well away from the primary
tumor site. This is in line with the findings of Holland
et al. who found a decreasing tumor cell density with
increasing distance from the primary tumor. Beyond
4 cm from the edge of the primary tumor, in about
10% of the examined mastectomy specimens, tumor
cells could be detected (Holland et al. 1985).
Radiation is administered to the breast alone in all
patients with early-stage invasive carcinomas who
have undergone excision (lumpectomy or segmental
resection) and axillary surgical assessment. Current
standards also recommend the use of postoperative
radiation for most patients with DCIS, although
selective avoidance is considered in patients with
‘‘favorable’’ DCIS—those with very small low-grade
lesions (generally measuring 1 cm or less) removed
with surgically clear margins (Hughes et al. 2009).
Treatment of regional lymphatics is not indicated in
lymph node-negative patients who have undergone an
adequate surgical axillary assessment, sentinel node
biopsy, or axillary node dissection because of the low
risk of axillary failures after these procedures.
9.2 Simulation
The term ‘‘simulation’’ dates back to the days before
the use of CT-based treatment planning when the
E. S. Bloom et al.
treatment fields for patients were ‘‘simulated’’ or
designed on the patient under fluoroscopic guidance.
The ultimate goal of simulation is to develop a
reproducible treatment plan encompassing the oper-
ative bed, surgical clips, whole breast, and lumpec-
tomy scar while minimizing the dose to normal
structures, such as the lungs and heart.
The patient is most commonly placed in the
supine position with her ipsilateral arm abducted and
externally rotated above her head to avoid exposing
this arm to the tangential radiation beams during
treatment. The patient can also be simulated with
both arms abducted and rotated above the head, to
allow a more symmetrical and stable position. This
is easier to accomplish if a wide-bore CT simulator
is available. If the patient has undergone axillary
node dissection, it is important that she has regained
an acceptable range of motion in her arm and
shoulder prior to simulation and treatment. If she has
not, arm exercises are recommended prior to simu-
lation and treatment. In some cases physical therapy
is necessary to aid in the recovery of a normal range
of motion.
The daily reproducibility of the patient’s treat-
ment setup is critical for the success of radiation
therapy, regardless of the disease site. Treatment
setup is achieved by selecting an appropriate patient
immobilization device, mostly consisting of a dedi-
cated ‘‘angle board’’ fabricated from low-Z material
and with devices to support the arms and head. This
also allows the patient to be semi-reclined during
treatment by inclining the board at a specific angle,
such as 108, to improve daily reproducibility of the
treatment setup and to minimize skin reactions. A
semi-reclined position tends to be more comfortable
for the patient, which helps minimize patient motion
during treatment. The angulation also helps com-
pensate for the slope of the chest wall. A drawback
is that by increasing the angle of inclination of the
board, the volume of lung that is included in the
supraclavicular field will be increased as well. The
angle board can be fixed to the treatment table to
ensure exact patient positioning during treatment
(Fig. 3a, b).
Some prefer to manufacture a ‘‘cradle’’ that ‘‘cra-
dles’’ the patient’s upper body in the same position
each day by forming a permanent impression of her
head, shoulders, and abducted arm. The custom-made
cradle can be manufactured from any of several
Breast Cancer: Intact and Post Mastectomy
b Fig. 3 a Treatment setup. A 43-year-old patient, status post-
commercially available materials and can be com-
bined with and fixed to the angle board.
During patient setup, it is important to minimize
any breast and skin folds, such as those in the infra-
mammary, axillary, and supraclavicular regions, to
reduce the risk of radiation-induced moist desqua-
mation of the skin. The presence of skin folds in the
treatment field reduces the skin-sparing effect of the
photon beam. For this reason, some patients are
treated in the prone position.
661
bilateral breast reduction in the past that underwent a left breast
segmental mastectomy for ductal carcinoma in situ removed
with clear margins. For post breast conserving surgery radiation
therapy, the patient is placed in the supine position with her left
arm abducted and rotated above her head in a custom-made
cradle on an angle board inclined at a 108 angle. Laser setup
marks are drawn on the patient at the time of simulation to aid
in positioning the patient on the treatment machine. Note that
the breast does not fold onto the abdomen or itself, which
reduces the risk of radiation-induced moist desquamation of the
inframammary fold during treatment. b A 68-year-old patient
who underwent a lumpectomy with sentinel node biopsy for
early stage invasive breast cancer. The patient is placed in the
supine position with both arms abducted and rotated above her
head on an angle board inclined at 158. Marks representing the
CTV breast (inner circle) and the preliminary field borders
(outer circle) as well as the surgical scar and the postoperative
effects (if present) are drawn on the patient to be marked with
metal wires at the CT-scan to aid in target volume delineation.
Those marks will be washed off after the CT-scan procedure.
Laser set-up marks are put as well (not shown here) to aid in
positioning the patient on the treatment machine. Note the
symmetry of the patient in this position; the position of the head
to avoid skin folds in the supraclavicular region (although not
to be irradiated in this case) and the sagital laser line
After patient setup has been optimized, CT images
are acquired with the patient in the treatment position.
Given the prevalence of large-bore CT simulators, CT
images can be obtained through the targeted breast in
the same treatment position at a slice thickness of
preferably maximal 2.5–3 mm. Laser setup marks are
drawn on the patient at the time of simulation, to aid
in positioning the patient on the treatment machine.
The CT images are then transferred to the three-
dimensional (3D) treatment planning system, where
the virtual simulation of the radiation treatment fields
is performed, after target volume delineation. With
computer-based virtual simulation, unlike with con-
ventional fluoroscopic simulation, the patient does not
need to be present during the generation and design of
the radiation treatment fields. Thus, CT-based treat-
ment planning can be performed in a treatment
planning workroom by the planning team consisting
of the radiation oncologist, dosimetrist, radiotherapy
technologist, and physicist after the patient has left.
3D CT imaging also allows 3D planning of whole
breast irradiation, which was not possible with con-
ventional simulator-based two-dimensional treatment
planning.
662
9.3 Target Volume Delineation
(see also Chapter ‘‘Quality
Management and Safety in
Radiation Oncology’’)
Many uncertainties in the definition of the target
volumes are related to uncertainties in the extent of
the microscopic spread of the disease. The gross
tumor volume including a margin for potential
microscopic spread constitutes the clinical target
volume, after which an additional margin should be
included to account for delineation errors, internal
motion, patient motion, and setup uncertainty to
obtain the planning target volume. The size of this
margin should be dependent on local experience but is
often based on data from the literature. Most spe-
cialists involved in the process of radiation therapy
consider target volume delineation as being currently
the weakest link in the entire quality chain from
diagnosis to follow up. A high variation was seen in
all studies evaluating consistency of volume delin-
eation among physicians. To improve this, a number
of initiatives have been undertaken, after which it has
been demonstrated that training as well as the avail-
ability of clearly written guidelines decreases inter- as
well as intra-observer variability. ESTRO has put
high priority to offer more online educational and
professional services. Within this perspective, a
multifunctional platform for volume delineation is
created. This will also be used to facilitate the orga-
nization of teaching courses and the writing of inter-
nationally accepted guidelines.
In the framework of this book and in the absence
of generally accepted guidelines, we refer to a number
of articles in the literature concerning actual volume
delineation. As far as delineation of the primary
tumor bed concerns, we like to emphasize that sur-
gical clips placed by the surgeon at the time of tumor
resection to mark the boundaries of the surgical cavity
are very useful for identifying the target volume,
especially at the time of boost treatment planning
(Fig. 4a). We should however not forget the fact that
the region to be boosted is not the entire surgical
cavity itself but the primary tumor bed, which can be
quite different in extent and even largely in position in
the case of the use of oncoplastic surgical techniques.
Therefore, surgical clips can be very misleading as
well (Fig. 4b). We should not forget that in the case of
whole breast radiotherapy followed by a boost to the
E. S. Bloom et al.
primary tumor bed, an equivalent of 50 Gy is deliv-
ered to the site of all surgical clips, even if they do not
represent the primary tumor site, meaning that they
should not obligatory be included in the boost volume
(Al Uwini et al. 2009; van Mourik et al. 2010; Dijk-
ema et al. 2004; Khatcheressian et al. 2006; Kiricuta
et al. 2000; Kirova et al. 2010).
9.4 Treatment Planning
Using a 3D treatment planning system, one can start
with the traditional field borders that are often marked
at the CT scan with a metal wire, for whole breast
irradiation and then modify these fields as needed to
optimize coverage of the surgical bed and the rest of
the breast while minimizing the dose to cardiac and
pulmonary structures. To ensure coverage of the whole
breast, the proposed starting borders of the treatment
fields start out at the midaxillary line laterally, the
midsternal line medially, just below the medial cla-
vicular head superiorly, and approximately 1–2 cm
below the inframammary fold inferiorly. This should
be adapted to factors including the site of the primary
tumor within the breast, the extent of the lumpectomy
scar and the amount of subcutaneous fatty tissue of the
patient. To limit early skin and late reactions in the
axillary area, the superior border of the treatment fields
can be modified to ensure coverage of the entire breast,
while minimizing the volume of superficial axillary
tissue that is irradiated. Volume delineation should
include the breast, the primary tumor site, the lymph
node areas, and the organs at risk including various
parts of the heart and the lungs. Based on this, a much
higher degree of conformality of the treatment fields
and the resulting treatment planning can be obtained.
On the digitally reconstructed radiograph of the
treatment fields, one can evaluate the volume of lung
included in the treatment fields and the distance from
the surgical bed or surgical clips to the field edge. In
general, there is approximately 1.0–2.0 cm of lung
tissue between the rib cage and the posterior field
edge on the digitally reconstructed radiograph. In
addition, on the digitally reconstructed radiograph one
can confirm full coverage of the target volumes for
breast, primary tumor bed, and lymph node areas. The
posterior border of each tangential beam is matched,
providing a non-divergent posterior field edge, to
minimize the dose to the lung parenchyma (Fig. 5).
Breast Cancer: Intact and Post Mastectomy 663

Fig. 4 Surgical clips:

a Planning CT images of the
patient shown in Fig. 3a,
showing the surgical clips
placed at the time of
segmental mastectomy. The
surgical clips aid in the
contouring of the primary
tumor bed. b Mammography
and planning CT-scan,
demonstrating a case where
the clips do not at all
represent the primary tumor
bed. Especially with
oncoplastic surgery, clips
might rather represent the
surgical bed than the primary
tumor site
664
Fig. 5 Non-divergent
posterior field edge. Planning
CT images of the patient
shown in Fig. 3a,
demonstrating that the deep
edge of each tangential field
matches in a non-divergent
fashion to ensure that the
same volume of lung
parenchyma is included in
each field and that no
additional volume of lung
tissue is unnecessarily
irradiated
A greater volume of lung would be irradiated if the
tangential fields were planned directly opposed to
each other (1808 apart). Matching the deep edge of all
tangential fields ensures that the same volume of lung
parenchyma is included in each field and that no
additional volume of lung tissue is unnecessarily
irradiated.
Standard whole breast irradiation consists of a dose
of 45–50 Gy delivered at 1.8–2.0 Gy/fraction over
4.5–5 weeks, often followed by a boost dose to the
primary tumor bed. Shorter fractionation schedules
(hypofractionated dose schedules) to a total dose of
39–42.5 Gy in 3 weeks are recently confirmed to be
appropriate if 3D-CRT is used to ensure an homo-
geneous dose delivery. Randomized studies by
Whelan et al. and by Yarnold et al., reported an
equivalent outcome for tumor control and normal
tissue effects at 5–10 years of follow up. In an
exploratory subgroup analysis of the Canadian study,
patients with high-grade tumors treated with the
E. S. Bloom et al.
hypofractionated regimen had a higher incidence of
local recurrence than those treated with the standard
fractionation whole breast irradiation regimen (Whe-
lan et al. 2010). At The University of Texas MD
Anderson Cancer Center, we restrict the use of the
hypofractionated whole breast irradiation regimen of
42.4 Gy at 2.65 Gy/fraction to postmenopausal
women with pT1, N0, M0 invasive breast cancer of
low to intermediate grade that is estrogen receptor-
positive. We often follow this with a boost dose of
10 Gy in four fractions to the surgical bed and scar. In
most Dutch centers, the schedule of 42,56 Gy in 16
fractions is being adopted for a varying but in general
quite broader range of patient subgroups.
In the US, the dose to the whole breast is specified
to an isodose line, generally following along the
pectoralis muscle surface. This results in the specified
dose becoming the breast minimum dose. According
to the ICRU criteria, the reported dose should then be
calculated at the ICRU reference point. Following
Breast Cancer: Intact and Post Mastectomy
this, in most European centers, the dose is prescribed
to the ICRU reference point after which treatment
planning is performed to cover the entire target vol-
ume with at least the 95% isodose line, while simul-
taneously keeping the ICRU maximum dose within
107% of the prescribed dose. After the widespread
introduction of 3D CT-based treatment planning, it is
now a common standard to evaluate the dose depos-
ited in every area of the breast, not only in a single
plane at the midlevel of the breast, as was the case in
the era of two-dimensional treatment planning. In
addition, modern dose calculation algorithms can take
into account the heterogeneity of the various tissues,
such as the breast parenchyma, bone, and lungs,
included within the treatment field (it should however
be remembered that the accuracy of those algorithms
varies, and can account for significant differences in
estimated doses, especially to the lungs). Thus, most
whole breast plans can be individualized as such that
they do not have volumes of tissue that exceed 105–
107% of the prescribed dose. This is done in most
modern radiotherapy departments using the ‘‘field-in-
field’’ technique for breast treatment planning,
sometimes referred to as ‘‘forward-planned IMRT’’.
This technique provides excellent dose homogeneity
in all three dimensions of the areas that need to be
irradiated—namely, the breast and primary tumor
bed. It can also help minimize the acute and long-term
side effects of radiation therapy, which include moist
desquamation of the skin, breast fibrosis, and rib
fractures, by avoiding the delivery of high doses at
those sites. Using this technique of step-and-shoot
dose homogenization, one starts with an open medial
and lateral tangential beam arrangement. Then, high-
dose sub volumes (e.g., 115, 110, 105%) are
sequentially blocked with custom multileaf collima-
tion, generating smaller field segments within the two
main open tangential fields. These smaller field seg-
ments can be delivered as individual fields or as part
of the original fields with a step-and-shoot technique
(Fig. 6). By delivering a percentage of the overall
planned dose each day with these smaller fields within
the main open field, one can deliver a more homo-
geneous dose throughout the breast than was previ-
ously possible with two-dimensional wedge
techniques (Fig. 7). Another advantage is that the
dose delivered to the contralateral breast with the
field-in-field technique is less than the dose delivered
with a conventional wedge technique (Borghero et al.
665
2007). Several similar methods are used at different
treatment facilities around the world. A forward-
planned field-in-field breast intensity-modulated
radiation therapy (IMRT) technique
(such as the one described above), a forward-planned
step-and-shoot breast IMRT method, and an inversely
planned breast IMRT technique can all improve dose
homogeneity compared with a conventional wedge
technique. For patients with larger breast sizes and
separation distances, forward IMRT techniques by
themselves may not be able to achieve the desired
dose homogeneity. In such patients, improved dose
distributions can be achieved by using higher energy
photons for a component of their treatment. With
inverse-planned IMRT techniques, an improved dose
distribution in the target volume can be obtained as
well if additional beam angles are used, but the dose
to the heart, contralateral breast, and both lungs
must be carefully evaluated (van der Laan et al.
2010; Moon et al. 2010).
Historically, treatment planning protocols defined
constraints for irradiation of lung tissue based on the
amount of lung tissue included in the tangential fields,
most often at the central axis of the beams (the so-
called central lung distance). Nowadays, the criterion
of acceptability is most often based on dose volume
histogram evaluation with constraints for the volume,
receiving more than 20 Gy (V20) and the mean lung
dose (MLD). The constraints vary considerably on the
target volume to be included (breast only vs. locore-
gional) as well as on the department.
There is ample evidence suggesting that cardiac
irradiation is detrimental, although cardiac conse-
quences of breast irradiation have long latencies
estimated to only begin to be seen at 15 years after
delivery of radiation therapy. Patients with early-stage
breast cancer have a high probability of long-term
survival; therefore, minimizing cardiac irradiation is a
critical aspect of treatment planning. The Early Breast
Cancer Trialists’ Collaborative Group overview of
randomized trials suggests that in the absence of
careful treatment planning, a survival benefit for
radiation therapy, even in the context of early breast
cancer, becomes at least partially offset by increased
cardiovascular deaths (Clarke et al. 2005). Therefore,
it is important that the delivery techniques also min-
imize the risk of long-term potential cardiac effects
due to radiation. In the case of left-sided tumors, the
anterior lateral aspect of the heart, including the left
666
Fig. 6 Step-and-shoot dose homogenization. The top row
shows the lateral tangential field with two additional fields
within it, sequentially blocking volumes receiving significantly
higher doses with the open fields. The bottom row shows the
medial tangential field with additional fields within it, blocking
anterior descending artery, is very close to the pos-
terior borders of conventional tangential fields. In
some cases, changing the gantry angle, the collimator
angle, or the borders of the medial or lateral fields can
result in adequate coverage of the primary tumor site
and most of the breast while excluding the heart from
the treatment fields. In other cases, small cardiac
blocks or MLC leaves can be placed to avoid car-
diac irradiation. A minimum 5 mm margin on the
cardiac profile is recommended to ensure that the
heart is not irradiated during daily treatments (Fig. 8a,
b). These treatment field modifications can be
customized to the normal tissue anatomy of the
individual patient, the location of the primary tumor
bed, and the contour of the breast. In addition, in
cases where the tumor bed is very close to the heart,
treatment planning and delivery can be performed
E. S. Bloom et al.
other volumes receiving significantly higher doses with the
open fields. The calculation point marked in blue, is placed
such that the entire breast will achieve full dose, while the 98%
isodose line stays just above the rib cage. See Fig. 7
during the inspiratory phase of the respiratory cycle,
which displaces the heart in an inferiomedial direction
away from the treatment fields (Korreman et al.
2006). Respiratory gating, performed in a coached
deep-inspiration phase, has indeed been shown to
reduce significantly the dose to the heart and lungs of
left-sided breast cancer patients. At deep inspiration,
the heart is moved in an inferiomedial direction away
from the chest wall, while the relative lung volume
included in the treatment fields is reduced (though the
central lung distance may not change) (Fig. 9a, b).
Another benefit of respiratory gating is motion man-
agement: patient breathing will cause the breast to
move during irradiation and may deteriorate the dose
distribution in the target volume. Planning target
volume (PTV) margins can partially compensate for
this effect in 3D-CRT but may not be sufficient for
Breast Cancer: Intact and Post Mastectomy
Fig. 7 The resultant homogeneous cumulative treatment plan
developed using the step-and-shoot technique demonstrated in
Fig. 6. The 5,000 cGy (50 Gy) isodose line fully encompasses
the breast parenchyma and surgical bed, sculpting just above the
ribs yet including the border of the pectoralis muscle and
posterior breast tissue. A small hot spot can be seen of 5,254 cGy
(52.54 Gy)
more modulated delivery techniques (forward or
inverse-planned IMRT).
9.5 Prone Position
Patients with large pendulous breasts may be treated
in the prone position. This approach is especially
important when the breasts rest on the abdominal wall
after positioning in the standard supine position. The
prone position minimizes skin folds in the breast, such
as the inframammary fold. The prone position is also
useful when the location of the heart in relation to the
surgical bed in the supine position, is such that
excluding the heart from the treatment field would
also exclude a portion of the surgical bed. Placing the
patient in the prone position allows the surgical bed to
fall farther away from the rib cage, increasing the
distance between the cardiac structures and the
lumpectomy site. This ensures coverage of the sur-
gical bed and the breast while minimizing irradiation
of the heart (Fig. 10).
Several commercially available prone breast posi-
tioning boards can be used to elevate the patient off
the treatment table. An aperture in the board allows
667
the breast to be suspended above the treatment table.
The patient is rotated slightly to allow the ipsilateral
breast and chest wall to extend through the board
aperture. The contralateral breast rests on a custom-
designed region of the board, which maximizes
patient comfort and spares this breast during irradia-
tion. At the time of simulation or scanning, radi-
opaque wires are placed as usual at the preliminary
field edges both laterally and medially or circular
around the breast. Orthogonal setup marks are placed
by the radiotherapy technologist on the posterior and
bilateral aspects of the patient’s torso to ensure
accurate patient positioning during each treatment
session. The isocenter is marked in the middle of the
breast depending on the local protocol either based on
the CT images obtained during simulation or at a
fixed reference point (Kirby et al. 2010).
9.6 Boost
As previously mentioned, the whole breast is typically
treated to an equivalent of 45–50 Gy in 25 fractions
followed by an additional equivalent of 10–16 Gy in
five to eight fractions to the primary tumor bed. In the
case of positive margins, re-excision should be con-
sidered, provided the amount of breast tissue is suf-
ficient, to ensure the lowest failure rate and avoid the
consequences of higher radiation doses (Schnitt et al.
1994). When no re-excision is planned, in the case of
only focally involved margins, a boost dose of 16–
26 Gy in eight-thirteen fractions is prescribed. For
more widely involved margins, re-excision or mas-
tectomy is recommended.
The purpose of the boost is to deliver additional
radiation to the area at highest risk of harboring
microscopic residual disease—namely, the primary
tumor bed and immediately surrounding breast
parenchyma. Multiple studies have shown that this
area has the highest risk for recurrence in the breast
(Bartelink et al. 2007; King et al. 2000) It should be
noted that the lumpectomy scar, included in the whole
breast radiotherapy, does not form an obligatory
component of the boost target volume. Electrons used
to be typically utilized for the boost. (Poortmans et al.
2004). The advantage of using electrons over photons
is that they have a finite range, allowing a very simple
boost technique. The higher their energy, the greater
the distance in tissue they travel and higher the
668 E. S. Bloom et al.

Fig. 8 Cardiac shielding:

a Cardiac block. A small
cardiac block with multileaf
collimation can be designed to
ensure that the heart is
excluded from the tangential
beams while blocking only a
small amount of breast tissue.
Example from the MD
Anderson Cancer Center.
b Cardiac shielding using the
MLC. The position of a
number of leaves can be
adapted to ensure that the
heart is excluded from the
tangential beams while
blocking only a small amount
of breast tissue. Example from
Tilburg

surface (skin) dose they deliver. Electrons travel
greater distances through lower-density tissue such as
lung tissue. Therefore, the goal is to select an electron
energy that results in the deposition of at least
85–90% of the prescribed dose just distal to the CTV
of the boost—as no margin alongside the beam axis is
needed for the PTV—which minimizes the dose to
deeper seated normal breast tissue, thoracic wall
structures and lung tissue. Among the disadvantages
of using electron beams is the wide penumbra, for
which reason relatively wide fields are required to
adequately cover the PTV of the boost with the 85–
90% isodose line, and the lack of image based posi-
tion verification. Other disadvantages are the less
straightforward beam shaping to conform the field
edges to the PTV and the sometimes large volume of
breast tissue outside of the boost PTV that has to be
passed unnecessary in the case of a deep seated pri-
mary tumor bed. Moreover, the skin dose increases
with the electron energy. In these cases, several
solutions are possible, including delivery of the boost
dose in a modified treatment position such that the
distance from the surface of the breast to the deepest
position of the boost PTV is reduced and the surface
Breast Cancer: Intact and Post Mastectomy
Fig. 9 Deep inspiration breath-hold technique: a Anatomical differences in one patient with left-sided breast cancer. Left during
quiet free breathing; right at coached deep inspiration. b The deep insipration breath hold moves the heart out of the direct
tangential radiation beams
of the breast overlying the surgical bed is flattened. A
breast compression technique can also be used in
these cases (Fig. 11).
Especially in Europe, the use of electrons and
brachytherapy as a boost modality is gradually being
replaced by 3D-CRT photon beam techniques. This
has recently been stimulated with the introduction of
the simultaneous integrated boost (SIB) technique, in
which 28 fractions of 1.81 Gy to the whole breast
with a simultaneous boost of 0.49 Gy (total 2.3 Gy) to
the primary tumor bed is delivered in less then
6 weeks (Fig. 12). In the case of focally involved
tumor margins, 31 fractions of 1.66 Gy to the whole
breast with a simultaneous boost of 0.72 Gy (total
2.38 Gy) to the primary tumor bed is prescribed. Both
treatment schedules are, alongside standard fraction-
ation, currently allowed in the ongoing European
669
‘‘Young Boost Trial’’ evaluating the boost dose in
BCT for patients up to 50 years of age. Whereas we
found an increase of the boost volume with about
50% after the introduction of CT-based treatment
planning, the SIB technique reduces this again sig-
nificantly thanks to both improved conformality and
electronic equilibrium leading to reduced boost field
sizes (Al Uwini et al. 2009; van der Laan et al. 2007).
Very recently, the Dutch platform for radiotherapy in
breast cancer agreed upon a protocol incorporating
this already widely used—with standard fraction-
ation—concept of the (SIB) technique with the hyp-
ofractionated schedule (van der Laan et al. 2007;
Yarnold et al. 2010; Bentzen et al. 2008a, b; Donovan
et al. 2007). The proposed schedule for the standard
boost dose using the SIB technique combined with
hypofractionation consists of 21 fractions of 2.17 Gy
670
Fig. 10 Prone breast
irradiation. In patients with
large pendulous breasts, the
prone setup allows adequate
coverage of the breast while
minimizing breast separation
and skin folds, thereby
decreasing the dose to the
breast parenchyma and the
skin. In addition, dose to the
heart is greatly reduced
to the entire breast and of 0.49 Gy (total 2.66 Gy) to
the boost volume. The proposed schedule for a high
boost dose, as used for patients after a focally
incomplete lumpectomy, consists of a schedule con-
sisting of 23 fractions of 2.03 Gy to the entire breast
and 0.63 Gy (total 2.66 Gy) to the boost volume.
10 Radiation Techniques: Post
Mastectomy Radiation Therapy
and Regional Radiation Therapy
combined with BCT
10.1 Target Definition
The areas at highest risk of recurrence after modified
radical mastectomy are the chest wall and undis-
sected lymph node basins in the level-III axilla,
infraclavicular and supraclavicular region (Katz et al.
2000). Treatment of the IMC lymph nodes, in the
context of post mastectomy radiation therapy
(PMRT), continues to be a controversial topic
(Freedman et al. 2000; Buchholz 2000; Anderson
2010). Although IMC recurrences rarely occur and
E. S. Bloom et al.
are even more rarely detected, women with locally
advanced breast cancer have rates of IMC nodal
involvement of up to 50% (Urban and Marjani
1971). While it may not be useful to treat the IMC in
the majority of patients with early-stage breast can-
cer, treatment of the IMC should be considered for
patients with locally advanced disease at presenta-
tion, inner or central tumors, axillary node-positive
disease, or early-stage disease with primary drainage
to the IMC on lymphoscintigraphy. In the three
randomized clinical trials that have shown an
improved disease-free and overall survival for
women with axillary node-positive disease treated
with PMRT, the IMC lymph node region was irra-
diated in addition to the chest wall and supracla-
vicular regions (Ragaz et al. 2005; Overgaard et al.
1997, 1999).
10.2 Simulation
Whereas in the era of 3D-CRT based on delineated
volumes there might seem to be no direct advantage for
marking of structures or preliminary field borders, this
can assist in as well the difficult task of volume
Breast Cancer: Intact and Post Mastectomy 671

Fig. 11 Breast compression

boost. By utilizing breast
compression, we are able to
flatten out the surface of the
breast overlying the surgical
bed, which decreases the
distance between the surface
of the breast and the deepest
portion of the surgical bed. As
a result, we are able to
decrease the energy of
electron boost fields. The
surface dose is thus reduced,
as well as the exit dose to the
lung

delineation as in the complicated procedure of treat-
ment planning. Within this scope, we provide hereby a
number of guidelines, for as far as they might be useful.
For post mastectomy irradiation, the patient is
placed in the supine position as described for simula-
tion of the intact breast. At the time of CT simulation,
the mastectomy scar, drain sites, and preliminary field
borders encompassing the chest wall are all marked
with radiopaque wire. If the surgical scar or the drain
sites extend to or beyond the preliminary field borders,
they can be moved to obtain adequate margins. How-
ever, if at the time of CT treatment planning, it is found
that moving the borders would require excessive radi-
ation to the lungs or heart, an additional appositional
electron beam field may be used for the portion of the
scar or drain sites that extend beyond the field borders,
if they are considered to be a part of the target volume.
For regional radiotherapy, similar in the frame-
work of PMRT and BCT, the IMC, generally located
at the 4th sternocostal level to include the first three
intercostal spaces including the IM lymph nodes with
the highest likelihood of containing metastatic dis-
ease, is also marked with a thick radiopaque marker.
Preliminary field borders for the IMC field can be
marked about 1 cm across the midline and approxi-
mately 6 cm wide to ensure adequate coverage of the
chest wall, mastectomy scar, and IMC lymph nodes
(Kirova et al. 2006). The ipsilateral border of the IMC
field coincides with the medial border of the chest
wall/breast photon field. The chest wall/breast fields
are tangential to the chest wall curvature, so the inner
border of the tangential fields is most often curved.
The border of the IMC field will therefore also be
curved on the final 3D treatment plan.
The cephalad border of the tangential chest wall
fields is most often just inferior to the clavicular head,
coinciding with the lower border of the supraclavic-
ular field. This anatomic level to match the supra-
clavicular field to the chest wall field provides optimal
dosimetric coverage of the level-III/axillary apex/
infraclavicular region by the supraclavicular field
(Garg et al. 2009).
672 E. S. Bloom et al.

Fig. 12 Simultaneous
integrated boost technique.
With this technique, we are
able to deliver daily a higher
dose to the surgical bed
together with a reduced dose
to the whole breast, which
decreases the total number of
fractions needed. Moreover,
the volume of the boost area
can be significantly reduced

The entire mastectomy region is marked, similar to
the intact breast, to estimate the original position of
the breast, including the scar with a 1–2 cm margin.
During volume delineation on the CT-slices, this
approach can be very useful as a guide. The contra-
lateral breast can often be used to guide delineation.
The isocenter can be placed in the center of the
chest wall fields, just anterior to the rib cage, in a
location that permits easy validation of the treatment
setup. Another interesting approach is to position the
isocenter at a fixed point along the junction line
between the thoracic and supraclavicular fields,
combined with image verification of the isocenter and
one of the tangential beams.
At M. D. Anderson Cancer Center, the lateral border
of the supraclavicular/axillary apex field is marked
with radiopaque wire at the edge of the palpable
pectoralis major muscle. The medial border is marked
along the medial edge of the sternocleidomastoid
muscle. The cephalad border is at the approximate
level of the thyrocricoid groove, just avoiding fall-off
to prevent a brisk skin reaction from a tangential
photon beam over the medial shoulder region.
Once the patient is marked with setup laser lines,
she is released with an appointment to return to start
treatment within a few working days.
10.3 Treatment Planning
The CT images are transferred to the delineation and
3D treatment planning system for contouring of the
target volumes, optimization of the treatment fields,
and dosimetry. The goal is to achieve a homogeneous
Breast Cancer: Intact and Post Mastectomy
dose to the chest wall and undissected regional lymph
nodes while minimizing the dose to normal tissues,
such as the heart, lungs, brachial plexus, esophagus,
trachea, thyroid, and spinal cord. For volume delin-
eation: see Chapter ‘‘Quality Management and Safety
in Radiation Oncology’’ and Sect. 9.3. As for all 3D-
CRT treatment planning, it is required to evaluate the
subsequent dose distribution using the tools that are
made evaluable, including a dose–volume histogram
of all target volumes and organs at risk.
When the isocenter of the photon fields is posi-
tioned at the plane defined by the junction between
the supraclavicular and the tangential fields, a non-
divergent edge of adjacent field borders is provided.
As the required length of the tangential fields often
exceeds the maximum dimensions of the collimator,
the center of those fields might be positioned some-
what lower with an upper collimator setting at e.g.
2 cm with subsequent neglectable divergence. Alter-
natively, to ensure a non-divergent edge of the
superior border of the medial and lateral chest wall
tangential fields, and thus an exact match, the treat-
ment couch has to be rotated so that a superior block
defined by multileaf collimation prevents the chest
wall tangential fields from diverging into the supra-
clavicular field. Tangential photon fields are typically
used to treat all or most of the chest wall. The field
borders that have been marked at the time of simu-
lation and the volumes delineated serve as the starting
points for treatment planning. The chest wall tan-
gential fields are then optimized to provide a non-
divergent deep border, as described for planning of
the intact breast. Generally, 1.0–2.0 cm of lung
parenchyma is seen on the digitally reconstructed
radiographs of the chest wall fields. This allows the
prescription or the 95% isodose line, depending on
whether or not prescription is done on the ICRU
reference point, to follow along the edge of or a few
millimeters into the pectoralis major muscle while
accounting for setup error and respiratory motion. The
thickness of the chest wall flaps will determine if a
field-in-field technique can be utilized to increase the
homogeneity of the plan. Generally, a chest wall
thickness of 3 cm is required for a field-in-field
technique to be used. Whether to use 6 MV photons,
higher-energy photons, or a combination of these
energies depends mostly on the chest wall separation,
which is the distance between the medial and lateral
field borders at the level of the dorsal field edges.
673
Larger chest wall separations ([20 cm) often require
the addition of higher energy photons to decrease
dosimetric ‘‘hot spots’’.
The medial border of the chest wall tangential
fields abuts with the IMC field. The IMC field, which
may be designed with electrons alone or a combina-
tion of photons and electrons, treats the most com-
monly involved IMC lymph nodes located in the first
three rib interspaces as well as the medial portion of
the chest wall target volume not included in the chest
wall tangential photon fields. The IM vessels are
contoured in the first three intercostal spaces, repre-
senting the target volume for potential microscopic
disease in the IMC lymph nodes. If necessary, the
IMC field can be divided into superior and inferior
fields to ensure coverage of the first three interspaces
with a higher-energy electron beam. By using a lower
electron energy for the inferior part of the field, the
transit dose to the lungs and heart is reduced. A dose
of 45 Gy (90% isodose line of the 50 Gy prescribed)
is desired at the deepest aspect of the IM vessels. The
lower IMC field covers the medial portion of the chest
wall. It can be shortened or partially blocked in some
cases based on the target volume of the chest wall/
breast. The IMC fields are often angled at approxi-
mately 10–158 to minimize the dosimetric the ‘‘cold
triangle’’ that can be formed superficially to the
pectoralis muscle at the junction of the tangential
photon fields and the IMC fields. An overlap of up to
5 mm between the IMC and tangential fields can also
be considered during treatment planning to decrease
the cold triangle that forms at this junction. On the
other hand, radiation scatter from the IMC electron
field into the medial aspect of the medial chest wall
tangential field increases the dose to the chest wall in
this area. Because of all this, we have to accept a
certain level of dose inhomogeneity at the junction
zone of the IMC with the tangential fields with typi-
cally the 35- to 40-Gy isodose line skimming the edge
of the pectoralis muscle in the dosimetric cold trian-
gle where the electron and medial chest wall photons
meet, when prescribing 50 Gy at 2 Gy/fraction to the
chest wall and regional lymph nodes (Fig. 13). To
date, we have not observed an increased rate of
recurrence in this volume of tissue. However, if there
was involvement of skin by the primary tumor at
diagnosis, the junction of the electron IMC field and
the medial chest wall tangent would be included in
each field, leading to a larger high dose zone.
674 E. S. Bloom et al.

Fig. 13 Junction of chest

wall tangential photon fields
and internal mammary chain
(IMC) electron field. Due to
the radiation scatter from the
electron field into the medial
aspect of the medial chest
wall tangential field, there is
an increased dose of
5,600 cGy (56 Gy) in the
parenchyma of the chest wall
in this area. As such, we
accept the 4,000-cGy isodose
line skimming the edge of the
pectoralis muscle in the
dosimetric cold triangle where
the IMC electron field and
medial chest wall tangential
photon field meet when
prescribing 5,000 cGy
(50 Gy) at 200 cGy (2 Gy)/
fraction to the chest wall and
regional lymph nodes

The Quality Assurance program of EORTC trial
22922/10925 demonstrated that, over the years, a
wide variety of appropriate treatment techniques are
being introduced for irradiating the IMC (Lievens
et al. 2001; Poortmans et al. 2003). Most participating
radiotherapy departments use the so called standard
technique with a combined supraclavicular and IMC
photon field joined to the radiotherapy fields for the
breast and/or the thoracic wall. Part of the IMC dose
is delivered with electrons. Several departments
therefore developed modifications to improve the
dose homogeneity. Important hereby is that this
should be adapted to the individual patients’ anatomy
and notably to the thickness of the thoracic wall and
to the position of the primary tumor within the breast
(in the case of BCT). About one quarter of the
departments that participated in the EORTC trial
developed a highly individualized CT based treatment
technique (Fig. 14a, b). The dose homogeneity is
improved when compared to the standard treatment
technique; however, at the cost of a somewhat larger
amount of irradiated lung tissue. Another advantage
of photon-only treatment techniques is that they can
be delivered in an easy semi-automated way, which is
impossible with electron fields (Poortmans et al.
2001).
For locally advanced breast cancer, tissue equiva-
lent material (bolus) (3–10 mm in thickness depend-
ing on the patients’ anatomy, beam energy used, and
whether an electron beam chest wall boost is planned
for an additional 10 Gy) should be applied to the
chest wall tangential photon fields and the infracla-
vicular portion of the supraclavicular photon field to
increase the surface dose to the chest wall, as the skin
in those patients is also targeted during PMRT. The
amount and frequency of the use of bolus varies
considerably from every other day for the first
2 weeks of treatment to daily for the full course. This
might be guided by an evaluation of the skin reaction
in the fourth week of treatment, keeping in mind that
an electron chest wall boost of an additional 10 Gy is
used routinely at some centers. If the patient has only
developed mild erythema or hyperpigmentation, the
use of additional days of bolus will be considered. In
patients with IBC, a more brisk skin reaction is
desirable to decrease the risk of recurrence in the skin
and subcutaneous tissue of the chest wall (Barker
et al. 1976). Thus, more days of bolus on the tan-
gential chest wall and the infraclavicular portion of
the supraclavicular region are used in this clinical
setting of IBC. In Tilburg, bolus is used rather
infrequently, based on a clinical comparison between
Breast Cancer: Intact and Post Mastectomy
Fig. 14 Isodose distribution of highly individualized 3D-CRT
of the chest wall and the IMC using multiple photon fields
alone. a A high conformality can be reached with a limited dose
to the heart and lungs. The dose is shown in percentages. b Skin
view from the same patient, displaying the projection of all
photon fields used to treat the complex set of target volumes
consisting of chest wall, IMC and supraclavicular region. Also
shown here is the use of multiple supraclavicular fields with
varying caudal borders to increase dose homogeneity at the
junction zone with the tangential fields
patients treated with cobalt-60, 6 MV photons, and
6 MV photons with 0.5 cm of bolus. Contrary to our
expectations and the TLD-based measurements that
we performed, the early and late skin reactions were
similar for cobalt-60 and for 6 MV while they were
significantly increased in patients treated with 6 MV
and bolus.
The caudal border of the supraclavicular field is
defined by the isocenter of the field to provide a non-
divergent edge. The plane is either selected on the
axial slice of the CT image that falls at the base of
the clavicular head or predefined at the time of the
planning CT-scan. The undissected lymph node
regions of the level-III axilla and the infra- and
supraclavicular region should be contoured to opti-
mize treatment planning. The supraclavicular field is
675
angled at 15–208, with the patient’s head turned away
from the treatment field, to minimize skin folds in the
medial shoulder region, which, if present, could
increase the skin reaction, unnecessarily. This angu-
lation also allows the esophagus and trachea to be
either completely excluded from the treatment field or
in the penumbra of the isodose distribution. Further-
more, this angulation ensures that the spinal cord is
excluded from the treatment field. By contouring the
targeted lymph node regions, the photon energy
(6, 10, 18 MV or a combination of these energies) and
prescription depth can be optimized to achieve at least
45 Gy to the deepest lymph node volume when pre-
scribing 50 Gy at 2 Gy/fraction (Liengsawangwong
et al. 2007). A dose of 45 Gy is considered an ade-
quate dose for potential microscopic disease in the
undissected lymph node regions of the infra-/supra-
clavicular region, level-III axilla, and IMC (Fig. 15).
A zone of concern is the inner-lower part of the
supraclavicular region where it follows the vessels
behind the sternoclavicular joint to communicate with
the IMC region. The target volume at this zone is
often quite deeper, compared to the upper and the
lower parts of the regional target volumes. A solution
can be offered by a technique utilizing multiple
supraclavicular fields with varying caudomedial field
borders partially overlapping the thoracic wall/breast
and the IMC fields which is in use in Tilburg (Fig 14b
and 16c).
Radiation directed to the levels-I and -II axilla is
rarely required since failure in this area is very
uncommon after modified radical mastectomy and
chemotherapy. Therefore, supplemental radiation
therapy to the dissected axilla is not warranted in most
patients. However, this technique can be used (1)
when residual disease is found in the axillary fat (2) in
patients who undergo an inadequate or no axillary
node dissection, or (3) for preoperative irradiation
(reserved for patients with inoperable N2 disease).
The goal of axillary irradiation is to deliver 45 Gy to
the midaxilla. The levels-I and -II lymph node regions
are contoured on the treatment planning system.
Depending on the depth of the lymph nodes, which
depends on the anatomy of the individual patient, a
dose of 45 Gy may be delivered by the anterior
supraclavicular field alone, depending on beam
energies utilized. In some cases, a posterior axillary
supplement is required to achieve a dose of 45 Gy to
the targeted axillary region when a dose of 50 Gy is
676
Fig. 15 Supraclavicular and axillary apex field. In this case, a
208 gantry angle is used on the treatment field, with the
patient’s head turned away from the treatment field, to
minimize the skin folding in the medial shoulder region,
which, if present, could increase the skin reaction unnecessar-
ily. The esophagus and spinal cord are both completely
excluded from the treatment field. By contouring the targeted
prescribed from the anterior supraclavicular field to
avoid hot spots in the anterior part of the axilla. As it
is expected that the EORTC AMAROS trial will
demonstrate that axillary irradiation will be as effi-
cient and with less morbidity compared to axillary
surgery, the subsequent EORTC POWER trial allows
for physician based treatment selection for partici-
pating patients that are allocated to axillary treatment.
Therefore, the indication for this treatment might
increase significantly in the near future.
In the case of the posterior axillary supplement, the
machine is rotated to ±1808 without moving the
patient. The field borders are individually shaped
based on the delineated target volumes. Generally,
1.5–2.0 cm of lung is present at the cephalad medial
aspect of the field, while a smaller amount of lung is
E. S. Bloom et al.
lymph node regions, the photon energy (6, 10, 18 MV, or a
combination of these energies) and prescription depth can be
optimized to achieve at least 45 Gy to the deepest lymph node
volume when prescribing 50 Gy at 2 Gy/fraction to an isodose
line individualized based on the patient’s anatomy and target
volume
often present at the caudal medial aspect of the field,
as the level-I axillary lymph nodes are more lateral to
the chest wall when the patient’s ipsilateral arm is
abducted above her head. The lateral and inferior
borders in general match those of the anterior supra-
clavicular field. The posterior axillary portal supple-
ments the dose from the anterior portal to deliver the
desired dose (45 Gy if the axilla is dissected and
50 Gy if it is undissected) to the deepest contoured
target volume. Forty-five Gy is recommended to the
dissected axilla, to minimize the risk of lymphedema.
In addition, to decrease the risk of complications,
such as arm edema, the dose contribution from the
anterior and posterior fields should not exceed
2.0 Gy/fraction at midplane with a standard frac-
tionation treatment schedule.
Breast Cancer: Intact and Post Mastectomy
b Fig. 16 Electron beam treatment of the chest wall. a Electron
10.4 Electron Beam Chest Wall Fields
As current electron beams have a less pronounced
effect on the skin, the entire chest wall may sometimes
be treated with electron beam fields (Kirova et al.
2007). Although this technique may permit improved
conformation of the treatment volume to the target
volume, there is a somewhat increased risk of local
677
beam chest wall and lymphatic fields in a patient with fairly
curved chest wall. Two separate low-energy fields are used with
the anterior field treated straight on and the lateral field at a 358
lateral tilt, with junctions moved weekly. b Five field electron
beam technique to treat the chest wall and, if required, the IMC
nodes. The electron energy for all beams can be individualized.
Tissue equivalent material can be used for patients with a very
thin thoracic wall. All beams are treated daily. Parts of the
thoracic wall outside of the target volume (especially lower-
inner and lower-outer) can be shielded with a thin layer of lead
on the patient or fixed to the electron beam applicator. A dose
of 42.56 Gy in 16 fractions is prescribed. Care is taken that the
85% isodose line (36.18 Gy) encompasses the entire target
volume. c Skin view from the patient from Fig 16b, displaying
the projection of the five electron fields. Part of the chest wall
can still be blocked by a thin layer of lead. Also shown here is
the use of multiple supraclavicular fields with varying caudal
borders to increase dose homogeneity at the junction zone with
the electron fields
geographic miss of the targeted tissue or an excessive
amount of lung irradiation. Patients with irregular
chest surface contours make treatment planning with
this technique extremely difficult. Mastectomy scar
extension onto the contralateral breast, upper abdo-
men, or arm can also be treated with electrons, often
with small fields added to the tangential photon fields.
Drain sites are included if possible; however, recur-
rences are rarely noted at these sites.
The field borders are identical to those for a tan-
gential photon field technique. Medially, it will be
contiguous with the ipsilateral border of the IMC
field, if present. Because of the slope of the chest
wall, it can be separated into two fields; medial and
lateral, with the lateral field angled at approximately
358. The medial field is not angled to avoid too large a
hot spot from overlap into the higher-energy IMC
field. To avoid dose buildup at the junction of the
medial and lateral chest wall fields, the junction is
moved 0.5 cm laterally each week (Fig. 16a). Several
other technical approaches have been described,
including for example a 5-field technique as devel-
oped in Tilburg which delivers a homogeneous dose
to the thoracic wall (and the IMC if indicated) with
much less burden to the underlying lungs and heart
compared to tangential fields, especially in patients
with a markedly curved thoracic wall (Fig. 16b, c).
The dose prescribed in the postoperative setting is
the same as that previously described for the photon
fields (i.e., 50 Gy at 2 Gy/fraction or a hypofraction-
ated schedule). The electrons are generally prescribed
to depth at maximum dose, Dmax (100% isodose line).
678
Fig. 17 Partially wide tangential pair fields. The patient has a
history of a pT1, cN3, cM0 invasive ductal carcinoma of the
right breast for which she underwent segmental mastectomy
and axillary node dissection. A total of 9 of 15 axillary lymph
nodes were involved with tumor, as well as two of two Rotter’s
Usually, 4–9 MeV electron energies provide suf-
ficient depth of coverage of the chest wall tissue after
a modified radical mastectomy. CT planning is used
to determine chest wall thickness to avoid harm due to
excessive volume of lung tissue irradiated, With the
advent of the skin-sparing ability in newer accelera-
tors, the use of bolus can still be required with the
electron beam chest wall technique, with a similar
schedule as described for photon beam treatments.
The objective is to obtain a degree of skin reaction
commensurate with the stage of the original tumor,
yet not precipitate an unplanned treatment break.
Bolus can also be used to increase dose homogeneity,
if needed in a varying thickness over the thoracic
wall, after which the required electron energy might
increase up to 10–12 MeV.
10.5 Partially Wide Tangential Pair Fields
The partially wide tangential approach targets the
IMC lymph node region along with the chest wall,
E. S. Bloom et al.
nodes, ranging in size from 0.2–4.2 cm with extranodal
extension. Given the extensive nodal involvement and lower
inner quadrant location of the primary, irradiation of the IMC
was indicated in the intact breast setting
reconstructed breast, or intact breast in a single pair of
fields. This technique is used primarily in the context
of intermediate to advanced risk breast cancers when
a separate IMC field cannot be employed due to the
patients’ anatomy. Because more of the contralateral
breast, ipsilateral lung, and occasionally cardiac sil-
houette are included in the high-dose volume than
would be the case for a three-field approach, this
technique is primarily useful for patients with unusual
anatomic considerations. For example, this approach
is appropriate for post mastectomy irradiation when
an immediate reconstruction has been performed. In a
way, it is to some extent similar to the individualized
photon-only treatment techniques as described above.
After acquisition of the planning CT images in the
usual manner, target volumes are delineated. The
constraints for lung dose should be carefully moni-
tored. The lower portion of the tangential pair is
shallower by shielding of the deep, non-divergent
edge with a block or multileaf collimator (Fig. 17). In
Copenhagen, where deep-inspiration gating is rou-
tinely used in left breast (and selected right breast)
Breast Cancer: Intact and Post Mastectomy
treatments, partial wide tangents are also the standard
technique for IMC irradiation.
10.6 Boost
Depending on the risk factors for local recurrence, the
chest wall may be targeted for a higher radiation dose
because it is the site at highest risk of recurrence.
Although a chest wall boost is commonly used rou-
tinely at some centers in the United States, a chest
wall boost is in most parts of Europe only used after
R1 excisions and after chest wall recurrences. A boost
of 10–16 Gy in five to eight fractions, or 20–26 Gy in
10–13 fractions in case of an incomplete resection,
can be delivered to the chest wall after a dose of
50 Gy at 2 Gy/fraction.
Depending on the size of the boost volume, one or
more electron boost fields may be required. The fields
can include from most of the chest wall in extensive
high risk disease, encompassing the mastectomy scar
and the chest wall areas located at the site of the
original tumor, up to small regions at highest risk like
after local excision of a chest wall recurrence. A field
size reduction after 10 Gy may be considered. Areas
of brisk skin reaction can be excluded. In general, 4,
6, or 9 MeV energies are used, depending on the chest
wall thickness seen on planning CT, at the location of
the boost fields. Dose is prescribed to the 100%
isodose line.
In contrast to the standard post mastectomy setting,
patients with locoregional recurrences have higher
locoregional failure rates when treated to 45–50 Gy
plus a boost (Ballo et al. 1999). Since the late 1990s at
M. D. Anderson Cancer Center, these patients have
received a 10% dose escalation. All areas treated pro-
phylactically receive 54 Gy in 27 fractions, and all
areas boosted because of potential microscopic disease,
such as the chest wall, receive an additional 12 Gy in
six fractions, totaling 66 Gy in the boost volume. In
most radiation oncology departments in Europe, a dose
of 50 Gy is given to the entire chest wall, followed by a
boost to 16 Gy in the case of complete excision of the
recurrent tumor and up to 20–26 Gy, after field size
reduction, in the case of a (focally) incomplete exci-
sion. Especially in those cases, radiation therapy might
be combined with hyperthermia.
Patients with IBC can be treated with twice daily
PMRT. A dose of 51 Gy in 34 fractions is delivered at
679
1.5 Gy/fraction BID over 17 treatment days to the
chest wall and regional lymph nodes. This is followed
by a boost of 15 Gy in 10 fractions to the chest wall
over a period of five treatment days, totaling 66 Gy in
the boost volume. Accelerated fractionation is used to
treat patients with IBC considered to be at an
exceedingly high risk of locoregional recurrence,
which includes younger patients and those with
residual nodal disease after neoadjuvant chemother-
apy (Liao et al. 2000).
Acknowledgments The authors would like to thank Mr. Lio-
nel Santibañez, from the Department of Scientific Publications,
The University Texas, MD Anderson Cancer Center, as well as
their colleagues for their support and providing clinical material
and experience.
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 Accelerated Partial Breast Irradiation
Ben Wilkinson, Laurie Cuttino, Dorin Todor, and Frank Vicini

Contents
1 Introduction.............................................................. 685
2 Pathologic Basis of Partial Breast Irradiation..... 686
3 Summary of Delivery Techniques ......................... 687
4 Patient Selection....................................................... 691
5 Target Definition...................................................... 693
6 Radiobiology of APBI ............................................. 695
Abstract
Accelerated partial breast irradiation has become an
important component of the management of early-
stage breast cancer. While local control following
APBI continues to be excellent with acceptable rates
of acute and late toxicities, further refinement of
patient selection guidelines and completion of the
ongoing Phase III trials remain priorities for this
growing segment of radiation oncology.

7 Surgical Considerations .......................................... 696

8 Physics of Accelerated 1 Introduction
Partial Breast Irradiation....................................... 698
9 Treatment Planning................................................. 703 Landmark studies published by Fisher et al. and
9.1 Interstitial Brachytherapy .......................................... 703 Veronesi et al. in the early 1980s, whose outcomes
9.2 Applicator-Based Brachytherapy .............................. 704 were verified in the 2005 systematic overview of the
9.3 3D Conformal Radiation Therapy ............................ 707
Early Breast Cancer Trialists’ Collaborative Group
9.4 IMPORT LOW PBI Technique ................................ 708
9.5 Intraoperative Radiotherapy ...................................... 708 (EBCTCG), established whole breast irradiation
(WBI) as a standard component of breast conserving
10 Clinical Outcomes.................................................... 710
therapy (BCT) for all invasive and most intraductal
11 Future Directions..................................................... 711 carcinomas of the breast (Fisher et al. 2002; Veronesi
References.......................................................................... 711 et al. 2002; Clarke et al. 2005). Additional studies
conducted by Bartelink et al. and Polgar et al. have
documented that, especially in younger women,
localized radiotherapy in the form of a boost to the
B. Wilkinson  F. Vicini (&) lumpectomy bed following WBI produces a statisti-
Department of Radiation Oncology, cally significant reduction in ipsilateral breast tumor
Beaumont Cancer Institute,
Oakland University William Beaumont recurrences (IBTR) with modest effects on cosmesis
School of Medicine, (Bartelink et al. 2007; Polgar et al. 2002). Thus, the
Royal Oak, MI 48073, USA standard of care for women with early stage breast
e-mail: fvicini@beaumont.edu cancer following partial mastectomy with negative
L. Cuttino  D. Todor surgical margins is WBI followed by a boost to the
Department of Radiation Oncology, lumpectomy bed. The benefits are not confined to local
Massey Cancer Center,
Virginia Commonwealth University, tumor control as adjuvant radiotherapy also produces
Richmond, VA 23298, USA long-term reductions in breast cancer mortality and

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 685
DOI: 10.1007/174_2011_164, Ó Springer-Verlag Berlin Heidelberg 2012
686
all-cause mortality. In trials activated between 1976
and 1991, an average of 20 IBTR and five breast cancer
deaths were prevented at 15 years for every 100
women randomized to WBI after breast conservation
surgery (Clarke et al. 2005).
Although adjuvant radiation therapy has proved to
be an important part of BCT, many women eligible for
conservation of their breast receive either a mastec-
tomy or lumpectomy alone. These decisions are likely
related, in part, to the protracted course of whole breast
radiotherapy. For at least some women, the proximity
of a radiation oncology center also influences whether
they receive complete BCT or breast conserving sur-
gery alone. A study by Athas et al. (2000) confirmed
this by showing an increased rate of complete breast
conservation for patients who live close to a radiation
center. Approximately 20% of patients with early stage
breast cancer who receive breast conserving surgery
forgo radiation treatments (Athas et al. 2000; Nattinger
et al. 2000; Baxter et al. 2004), which places them at a
three-fold increased risk of recurrence when compared
to patients who receive proper adjuvant therapy (Fisher
et al. 2002; Veronesi et al. 2002; Clarke et al. 2005).
The protracted time course required to complete
standard whole-breast radiotherapy is thought to play
a significant role in the under-utilization of post-
operative treatment. Although treatment of the entire
breast for presumed occult disease can be safely
accomplished in as few as 15 or 16 treatments
(Bentzen et al. 2008a, b; Whelan et al. 2010), there
has been a concern that further hypofractionation over
a similar abbreviated time course could create
increased late tissue toxicity (Baillet et al. 1990). The
UK’s Faster Radiotherapy for Breast Cancer Patients
(UK FAST) trial and the subsequent FAST FOR-
WARD trial did not, however, show decreased rates
of cosmesis when the hypofractionated RT was
delivered over 5 weeks (Brunt and Yarnold 2009). An
alternative to delivering large doses of radiation to the
whole breast is to limit the prescription dose to the
volume of tissue at greatest risk for local recurrence
(i.e. partial breast irradiation or PBI), which makes
further reduction in treatment time possible since less
normal breast tissue is being treated.
Accelerated partial breast irradiation (APBI) has
been investigated in highly selected patients with early-
stage breast cancer (Arthur and Vicini 2005). APBI
limits the radiation target to the volume of tissue
immediately surrounding the lumpectomy cavity and
B. Wilkinson et al.
reduces the overall treatment time from approximately
6 to less than 1 week. If proven equivalent to standard
whole-breast radiotherapy, such an approach may
improve the utilization of breast-conserving treatment,
decrease treatment-related toxicity, and improve the
quality of life for breast cancer patients (Athas et al.
2000).
Although there is no long-term data comparing WBI
to accelerated partial breast RT, several Phase III
studies being conducted in both the United States and
Europe have either reported preliminary results or are
close to completing their accrual. These include the
National Institute of Oncology of Hungary trial (Polgar
et al. 2007), the Targeted Intraoperative Radiotherapy
(TARGIT) trial (Vaidya et al. 2010), the Intraoperative
Radiotherapy with Electrons (ELIOT) trial (Veronesi
et al. 2010), the National Surgery Adjuvant Breast and
Bowel Project (NSABP) B-39/Radiation Therapy
Oncology Group (RTOG) Phase III trial (2005), and the
UK Intensity Modulated Partial Organ Radiotherapy
Trial (IMPORT LOW) (Coles and Yarnold 2006).
2 Pathologic Basis of Partial Breast
Irradiation
Besides the logistical benefits of shortening the length
of treatment, there is pathologic support for decreas-
ing the amount of breast tissue treated with adjuvant
radiotherapy. Vicini et al. (2004) showed that for
tumors that initially met NSABP criteria for negative
microscopic margin (no tumor on ink), if residual
carcinoma was present, it was typically limited to the
first 1 cm beyond a lumpectomy margin. This study
examined lumpectomy re-excision specimens and
showed that residual microscopic disease was limited
to the first 1 cm from the original lumpectomy margin
in[90% of cases. In a study of 1,598 patients treated
with BCT by Kurtz et al. (1990), 179 had a recur-
rence; of which 79% occurred within close proximity
to the lumpectomy bed. Other studies support these
findings showing recurrences after BCT typically
occur within the same quadrant of the treated breast and
that IBTR in different quadrants occur at a rate of\4%
(Veronesi et al. 2001; Clark et al. 1992; Uppsala-
Oreboro Breast Cancer Study Group 1990). As more
time passes from the original BCT, the study by Kurtz
et al. (1990) also noted that an increasing number of
IBTR or ‘‘elsewhere failures’’ occurred in a different
Accelerated Partial Breast Irradiation
Table 1 Location of IBTR after BCT*
In-breast failures
(%)
Author # pts Median f/u mo’s No WBI
Veronesi et al. (2001) 579 109 20.5
Clark et al. (1992) 837 43 25.7
Uppsala-Oreboro (1990) 381 33 5.7
*Adapted from Arthur (2003a)
a
Recurrence at the site of lumpectomy
b
Recurrence beyond the site of lumpectomy
quadrant of the breast. Interestingly, the number of
‘‘elsewhere failures’’ within the same breast occur at a
similar frequency in patients who receive breast con-
serving surgery alone vs. those who receive surgery
plus whole breast irradiation (Table 1) (Arthur 2003a).
The proximity of IBTR to the primary tumor site is
not, however, a universally reported observation. In the
EORTC trial of tumor bed boost vs. no boost following
BCT and WBI (n = 5,318), only 29% of the 278 IBTR
occurred outside the original tumor area and 13% were
described as diffuse (Bartelink et al. 2007). Other recent
studies suggest that the distinction between local
recurrence and new primary is not always straightfor-
ward. For example, in a molecular based clonality
investigation of 57 IBTR following WBI or APBI by
Vicini and colleagues, 22 (39%) presented at a distance
from the primary site, of which 12/22 (55%) were
clonally related to the primary tumor (McGrath et al.
2010). In other words, it seems that a significant
minority of IBTR present in other breast quadrants and
represent true local recurrences. Analysis of IBTR and
contralateral breast cancers after BCT including WBI in
a UK radiotherapy fractionation trial suggests that WBI
may indeed have an impact on the risk of other-quadrant
IBTR, including new primaries (Gujral et al. 2010).
Even if the risk of other quadrant IBTR proves to
be higher after APBI compared to WBI, the absolute
excess risk is likely to be very small, especially in the
light of recent decreases in the rate of ipsilateral
tumor recurrence. There is evidence that local relapse
rates have fallen steeply in recent years (Mannino
and Yarnold 2009). For example, investigators at the
MD Anderson Cancer Center found that IBTR at
5 years were significantly lower (1.3 vs. 5.7%,
p = 0.001) for patients treated in the last 2 years of
their study, which was attributed to increasing use of
systemic agents and improved rates of negative surgi-
cal margins prior to beginning radiation therapy (RT)
687
True recurrencesa Elsewhere failuresb
(%) (%)
WBI No WBI WBI No WBI WBI
5.4 17.6 3.7 2.9 0.7
5.5 22.1 4.5 3.5 1.0
2.2 4.1 1.6 1.5 0.5
(Cabioglu et al. 2005). Until mature data from ongoing
randomized trials of APBI are available, it is reasonable
to assume that the primary benefit of WBI is to prevent
tumor recurrence at the lumpectomy bed (Morrow
2002) and to hypothesize that additional data is needed
to determine whether or not WBI prevents the devel-
opment of new primary carcinomas.
3 Summary of Delivery Techniques
Multi-catheter interstitial brachytherapy (Fig. 1) is the
technique that has been in use the longest and has the
most extensive follow-up of any APBI approach. With
this technique, after-loading catheters are placed
through the breast tissue to surround the lumpectomy
cavity. The exact number of catheters used is deter-
mined by the size and shape of the target, and catheter
placement requires an understanding of brachytherapy
dosimetric guidelines (Kuske 1999, 2006; Kaufman
et al. 2007; Zwicker et al. 1999). In general, catheters
are positioned at 1–1.5 cm intervals along a plane to
ensure adequate coverage and maximize dose homo-
geneity. Most implants require 15–20 catheters,
arranged in two to three planes. Three-dimensional
dosimetric planning is now the standard of care and
allows accurate visualization of implant geometry as
well as optimization of treatment delivery. Although
initial techniques utilized low dose rate (LDR) sources,
essentially all current multi-catheter implants are now
delivered using an HDR after-loaded Ir-192 source.
The most common treatment schedule is 10 fractions of
3.4 Gy each, delivered twice daily for 5 days with a
minimum of 6 hours between treatments.
Arguably the most versatile method of delivering
APBI, the multi-catheter technique can be used
regardless of lumpectomy cavity size, shape, or
location within the breast (Cuttino et al. 2005).
688 B. Wilkinson et al.

Fig. 1 Examples of interstitial brachytherapy technique with template in place prior to needle insertion (a) and after needles have
been replaced by plastic catheters (b). Photos courtesy of R. Kuske (a) and L. Cuttino (b)

Fig. 2 a–c Examples of the MammoSiteÒ RTS implanted the original MammoSiteÒ RTS single-lumen brachytherapy
within a lumpectomy cavity and individually prior to implant. applicator. Photos courtesy of L. Cuttino (a) and Hologic, Inc.
The second and third images show the MammoSiteÒ ML and (b, c)

Implant geometry can be tailored to the specific
clinical scenario, allowing treatment delivery to an
irregularly-shaped target while avoiding significant
dose to normal tissues. The multi-catheter approach
now routinely employs image-guidance during cath-
eter placement to ensure that appropriate target cov-
erage and dose homogeneity are reliably achieved.
The imaging modalities used most frequently for
catheter placement include stereotactic mammogra-
phy, ultrasound, and computed tomography (CT).
Although image-guided techniques reduce operator-
dependence and improve implant quality, interstitial
brachytherapy remains the most technically complex
treatment technique approach.
Accelerated Partial Breast Irradiation
Fig. 3 a–c Examples of the ConturaÒ Multi-lumen Balloon. Photos courtesy of SenoRx, Inc
In an attempt to reduce the technical complexity
and degree of breast trauma associated with multi-
catheter interstitial brachytherapy, the MammositeÒ
Radiation Therapy System (RTS) (Hologic, Inc.,
Bedford, MA) was developed (Fig. 2). This applicator
was designed to approximate the dose distributions of
multi-catheter implants while simplifying catheter
insertion, treatment planning, and treatment delivery.
The device was originally investigated in a multi-
institutional trial, which led to approval for clinical
use by the United States Food and Drug Adminis-
tration (FDA) in 2002 (Keisch et al. 2003). Since its
introduction, tens of thousands of women have been
treated with the MammositeÒ, making it the most
widely used form of APBI in the United States.
The MammositeÒ is a balloon-based catheter
device containing either a single lumen or multiple
treatment lumens for an HDR after-loaded Ir-192
source. Although the device can be placed at the
time of lumpectomy (open technique), post-operative
placement with ultrasound or CT-guidance (closed
technique) is recommended (Cuttino et al. 2008).
After insertion, the balloon is inflated with water or
saline solution, as well as with 2–5 cc of radio-
graphic contrast to allow evaluation of placement by
CT scan. Device placement can then be assessed for
the adequacy of skin spacing (optimally C 7 mm),
balloon asymmetry (B 2 mm difference in radius as
measured on either side of the central lumen), and
conformality of the balloon surface to the lumpec-
tomy cavity ([ 90%). As with multi-catheter
brachytherapy, treatment is accomplished in 10
fractions of 3.4 Gy each, twice daily for 5 days,
although shorter fractionation schemes are currently
689
under investigation. Given the popularity and rela-
tive simplicity of treatment delivery associated with
the MammositeÒ, several other catheter devices for
the delivery of APBI have been developed. These
include the ConturaÒ Multi-Lumen Balloon
(SenoRx, Inc., Aliso Viejo, CA,) (Fig. 3), the Strut-
Adjusted Volume ImplantÒ or SAVIÒ (Cianna
Medical, Aliso Viejo, CA) (Fig. 4), Axxent Elec-
tronic Brachytherapy SystemÒ, (Xoft, Inc., Sunny-
vale, CA), and the ClearPathTM breast brachytherapy
system (Huiheng Medical, Inc., Shenzhen, China).
Multi-catheter interstitial and applicator-based
brachytherapy offer unparalleled conformality in dose
delivery but are associated with a certain degree of
breast trauma. With this in mind, Vicini and col-
leagues at the William Beaumont Hospital developed
an APBI technique using three-dimensional confor-
mal external beam radiation therapy (3D-CRT)
(Baglan et al. 2003). This technique employs a stan-
dard linear accelerator to deliver a dose to the volume
treated with brachytherapy plus a margin to account
for breathing motion and setup uncertainties. Patients
are typically treated in the supine position, and mul-
tiple beams are employed to maximize conformality
(Kozak et al. 2006) (Fig. 5). Limitations of the
3D-CRT technique include increased dose to the
contralateral breast, heart, and lungs. Formenti et al.
have advocated treating patients in the prone position
while using the 3D-conformal APBI technique
(Formenti et al. 2007). This treatment position allows
the lumpectomy cavity to move away from the chest
wall and may facilitate decreased dose delivery to the
heart, ipsilateral lung, and chest wall, although some
authors have shown cases where prone positioning
690 B. Wilkinson et al.

b Fig. 4 a–c Four different sizes of the Strut-Adjusted Volume

Implant (SAVIÒ) for implantation into different sized cavities.
The second and third images show dosimetric examples of the
SAVIÒ being used to minimize dose to the chest wall (b) and
skin surface (c). Images courtesy of Cianna Medical, Inc

may increase the amount of heart exposure to the

radiation field (Chino and Marks 2008; Kirby et al.
2010). The UK IMPORT trial uses mini-tangents to
deliver adjuvant RT to a limited portion of the breast
using standard fractionation (Coles and Yarnold
2006).
In Europe, several centers use intraoperative radi-
ation therapy (IORT) at the time of surgery. The
technique, which includes the ongoing Intraoperative
Radiotherapy with Electrons (ELIOT) Phase III trial,
was originally described by radiotherapy centers in
Paris during the 1980s (Dobelower et al. 1989) and
subsequently refined at the National Cancer Institute
in Milan (Veronesi et al. 2005, 2010; Alberto Luini
2005). Intraoperative partial breast irradiation has the
distinct advantage of visualizing the tumor bed at the
time of surgery. Beyond direct tumor localization,
IORT also offers the potential benefit of treating
residual tumor cells prior to the onset of hypoxia,
which can occur following breast surgery as several
blood vessels are disrupted during excision of the
tumor. Advocates of this technique also point to the
decreased chance of tumor cell proliferation or
accelerated tumor cell repopulation stimulated by the
surgical intervention (Belletti et al. 2008). Intraoper-
ative RT using a 50 kV photon source is presently
being tested as part of the randomized Targeted
Radiotherapy (TARGIT) for Breast Cancer Trial
(Holmes et al. 2007; Vaidya et al. 2010). In the
United States, Memorial Sloan-Kettering Cancer
Center has also developed an intraoperative HDR
brachytherapy technique for delivery of APBI at the
time of surgery (Beal et al. 2009). Another type of
intraoperative radiotherapy is electronic brachyther-
apy using the Xoft AxxentÒ applicator, which uses an
electronic brachytherapy source to deliver adjuvant
RT at the time of surgery (Xoft, Inc.) (Fig. 6). IORT
is an appealing approach since patients complete
adjuvant radiation therapy at the time of surgery.
Whether or not margins have been adequately
excised, however, is not known at the time of IORT.
An involved margin or adverse feature found on
pathology requires approximately 15% of patients to
Accelerated Partial Breast Irradiation
Fig. 5 a–b Examples of beam arrangement for a typical four-field 3D-CRT APBI plan at William Beaumont Hospital. Images
courtesy of F. Vicini
undergo either re-excision or have their intraoperative
dose considered as a boost and go on to receive
standard whole breast irradiation (Vaidya et al. 2010).
4 Patient Selection
Outside of a clinical trial, APBI is regarded to be most
appropriate for women with very-low risk invasive
and intraductal carcinomas of the breast. Several
professional organizations have published guidelines
regarding patient selection for APBI including the
American Society of Breast Surgeons (ASBS 2008),
American Brachytherapy Society (ABS) (Arthur et al.
2003b), NSABP/RTOG (Radiation Therapy Oncol-
ogy Group 2005), and Groupe Européen de Curi-
ethérapie-European Society for Therapeutic
Radiology and Oncology (GEC-ESTRO) (Polgár
et al. 2010a). The GEC-ESTRO guidelines advocate
that ‘‘intermediate-risk’’ patients be treated with
APBI only as part of a clinical trial and that all
patients in their high-risk group should not be eligible
for APBI, even under the guidance of a clinical trial.
Tables 2 and 3 summarize patient criteria for APBI
for each society.
In a similar format to GEC-ESTRO, the American
Society of Radiation Oncology (ASTRO) has also
released a consensus statement on patient selection
691
for APBI, which stratifies patients into three catego-
ries based on demographic and histologic parameters
following breast conserving surgery (Smith et al.
2009). Criteria for the categories are based on the
amount of single-arm prospective data for APBI in
those patient populations. Women who possess a
clinical or pathologic factor that qualifies them for
either the ASTRO ‘‘cautionary’’ or ‘‘unsuitable’’ cat-
egories are not necessarily at higher risk of in-breast
recurrence, but should be encouraged to participate in
clinical trials to better define the role of APBI for
these patients (Vicini 2010a). Table 4 summarizes the
ASTRO categories for patients to be treated with
APBI either on or off of a clinical trial.
Although there is incomplete agreement between
the various professional societies on all aspects of
patient selection for APBI, most authors agree that
patients with EIC, positive LN’s, invasive lobular
carcinoma, and those under the age of 50 should be
enrolled in a clinical trial if they are to be offered
APBI (American Brachytherapy Society Breast
Brachytherapy Task Force 2010; Arthur et al. 2002;
Vicini et al. 2003).
The recent development of consensus statements
and guidelines on APBI are, in part, a response to
pressure from patients and other interest groups to
bring promising early results of partial breast research
into clinical practice as soon as possible. The desire to
692 B. Wilkinson et al.

Fig. 6 a–d Examples of the intraoperative linear accelerator with the Xoft AxxentÒ applicator for APBI. Images courtesy of
used in the TARGIT trial (a) and the treatment console (b), Carl Ziess, Inc. (a) and Xoft, Inc. (b–d)
electronic brachytherapy source (c), and applicator (d) used

Table 2 Guidelines for ABPI

ASBS (2008) ABS (2003) NSABP/RTOG (2005)
Age C 45 Age C 45 Age [ 18
Histology: IDC, DCIS Unifocal IDC DCIS or any histology
Size B 3 cm B 3 cm B 3 cm
Margins C 2 mm No tumor on ink No tumor on ink
LN negative LN negative Up to 3 LN’s +
Accelerated Partial Breast Irradiation
Table 3 GEC-ESTRO APBI Guidelines (Polgár et al. 2010a)
Low risk Intermediate risk
Age C 50 Age 41–49
Unicentric, unifocal disease Margins \ 2 mm
Tumor B 3 cm B 3 LN’s positive
No EIC, invasive lobular histology, or
LVSI*
Margins C 2 mm
pN0
*LVSI = lymphovascular space invasion
*EIC = Extensive Intraductal Component
have selection criteria for APBI published and revised
as new research is released, is both understandable
and potentially beneficial for both patients and prac-
titioners. There are also risks in developing formal
risk groups that should be acknowledged, in that the
GEC-ESTRO and ASTRO guidelines are responding
to rapid changes in practice, not based on mature
outcome data derived from randomized clinical trials.
Of current randomized trials, the National Institute of
Oncology in Hungary (n = 258) is the only trial that
has reported five-year data with a local recurrence rate
of 4.7% after multi-catheter brachytherapy, compared
to 3.4% after WBI (not significant) (Polgar et al.
2007). The TARGIT trial testing IORT has reported
outcome data based on only six local recurrences at a
median follow up of 4 years (Vaidya et al. 2010).
Incorporation of APBI into standard practice guide-
lines at this point represents a departure from our
previous hard-won insistence on mature level I evi-
dence prior to adoption of new techniques or tech-
nology. Until long-term results from the Phase III
trials are available, our priority should be to complete
ongoing randomized trials and generate mature out-
come data.
Intraoperative radiation therapy is generally used in
Europe, although some university and community
centers in the United States are investigating this
technique and have participated with the ongoing
TARGIT trial (Ollila et al. 2007; PR Newswire 2010;
Mayo Foundation for Education and Research 2010).
Patients who may be appropriate for IORT either on or
off of a clinical trial include those over the age of 45,
women with unifocal tumors \ 3 cm in diameter,
negative surgical margins, infiltrating ductal carcinoma
histology, B 3 lymph nodes positive, and no extensive
intraductal component (Orecchia et al. 2009).
693
High risk
Age B 40
Positive margins
Multicentric disease
Tumor size [ 3 cm
LVSI or EIC present
C 4 LN’s positive or unknown axillary LN
status
5 Target Definition
Initial analyses of mastectomy specimens in the 1980s
indicated that most breast cancer was multicentric or
had tumor extensions beyond the typical prescription
treatment volume used in APBI (Holland et al. 1985;
Faverly et al. 1992; Vaidya et al. 1996). These car-
cinomas, however, were large, clinically detected, and
would likely not meet the current selection criteria for
APBI. Contemporary pathologic reviews in an era of
improvements in breast imaging that have shown a
more limited extent of residual disease following
lumpectomy for early-stage breast cancers, especially
when negative margins are obtained.
Goldstein et al. showed that patients with positive
surgical margins following lumpectomy had a 29%
chance of residual disease [ 2 cm from the lumpec-
tomy margin versus only 10% if the initial margin
was negative (using NSABP criteria) (Goldstein et al.
2003). To determine the clinical target volume (CTV)
for APBI, we rely on many of the studies that initially
established support for treating a limited segment of
the breast described previously in this chapter. One
such study showed that in patients with negative
surgical margins following breast conserving surgery
for T1–T2 lesions, it is the first one and a half cen-
timeter rim of peri-lumpectomy cavity tissue that is
most likely to harbor additional microscopic disease.
Vicini et al. (2007) reported 10-year data showing
excellent control rates with large volume implants
where 2 cm margin was treated, while treating just
the surgical cavity with smaller implant volumes had
a 16% rate of short-term local recurrence (Perera et al.
2003). For APBI, a balance between the above data is
reflected in the current lumpectomy bed to CTV
694 B. Wilkinson et al.

Table 4 ASTRO APBI Patient Selection Criteria (Smith et al. Table 4 (continued)
2009) Tumor size 3 cm
A. Suitable T stage T3–4
Factor Criterion Margin status Positive
Age 60 y/o LVSI Yes
BRCA ‘ Not present ER Status Negative
mutation Multicentricity Present
Tumor size B 2 cm Multifocality If microscopically multifocal [ 3 cm
T stage T1 in total size or if clinically multifocal
Margin status Negative by C 2 mm Pure DCIS If [ 3 cm
Grade Any EIC If [ 3 cm
LVSI No Associated LCIS Allowed
ER Status Positive N Stage pN1, pN2, pN3
Multicentricity Unicentric only Nodal surgery None performed
Multifocality Clinically unifocal with total size B Neoadjuvant therapy If used
2 cm *LVSI Lymphovascular space invasion, SLN sentinel lymph
Histology Invasive ductal or other favorable node, ALND axillary lymph node dissection
subtype
Pure DCIS Not allowed expansion guidelines of between one and one and a
EIC Not allowed half centimeters, depending on the treatment modality
Associated LCIS Allowed selected. This rim of peri-lumpectomy tissue is the
N stage pN0 (i-,i+) area at the highest risk for local recurrence and should
Nodal surgery SLN* Bx or ALND*
be encompassed by the highest isodose lines (IDL) of
the APBI treatment plan (Vicini et al. 2004; Goldstein
Neoadjuvant Not allowed
therapy et al. 2003; Ohtake et al. 1995).
Some studies have suggested that younger women
and patients with higher-grade lesions may be prone to
B. Cautionary
more extensive microscopic extension (Veronesi et al.
Factor Criterion 2002; Imamura et al. 2000). Concern over limiting a
Age 50–59 radiation prescription to the first one to two centime-
Tumor size –3.0 cm ters past a lumpectomy margin is that, if disease exists
T stage T0 or T2 outside of that circumference from the surgical mar-
Margin status Close (\ 2 mm) gin, this residual disease is left untreated (Buchholz
LVSI Limited/focal et al. 2005). In this scenario, a new area at risk for
ER Status Negative
recurrence is created just beyond the margin of tissue
treated with radiation. Proper patient selection with
Multifocality Clinically unifocal with total size 2.1–
3.0 cm careful scrutiny of diagnostic imaging and surgical
margins followed by close clinical surveillance, is a
Histology Invasive lobular
strategy to continue to offer APBI in these challenging
Pure DCIS B 3 cm
cases. For example, women who present with calcifi-
EIC B 3 cm cations on their screening mammogram should always
receive a post-lumpectomy mammogram to ensure all
C. Unsuitable suspicious calcifications have been removed prior to
Factor Criterion moving forward with partial breast radiotherapy. Until
Age \ 50 y/o the results of the large Phase III trials are available,
BRCA ‘ mutation Present however, it will be difficult to truly know which
(continued)
patients are at highest risk of residual disease outside
Accelerated Partial Breast Irradiation
of the APBI treatment volume. The current ASTRO
consensus statement on APBI distinguishes younger
age as being less suitable for APBI off of a clinical
trial, but includes all histologic grades within its
‘‘suitable’’ category (Smith et al. 2009).
In the case of balloon-based brachytherapy devices,
it has been accepted that a certain amount of stretching
of the tissue surrounding the lumpectomy cavity
occurs when the device is inflated. Edmonson et al.
(2002) and Dickler et al. (2004) both estimated that the
first one centimeter of tissue surrounding an inflated
MammoSiteÒ balloon is equivalent to a 2 cm CTV
around a lumpectomy cavity. This is reflected by the
fact that a 1 cm CTV is required for MammoSiteÒ
treatment while a one and a half centimeter CTV
expansion is called for in 3D conformal and interstitial
implants in the NSABP B-39/RTOG 0413 Phase III
trial. Although this is the current convention, a recent
volumetric analysis by Shaitelman et al. indicated
that the 1 cm margin for MammoSiteÒ may correlate
with less tissue than originally projected (Shaitelman
et al. 2010).
Like balloon-based brachytherapy, the IORT
technique generally identifies the CTV as the first
10 mm surrounding the lumpectomy cavity. In the
case of the IntrabeamÒ system, used as part of
the TARGIT trial, a dose of 20 Gy is prescribed at the
surface of the applicator, which translates to a dose of
between 5 and 7 Gy at 10 mm from the tumor bed
(Vaidya et al. 2010). TARGIT investigators estimate
that 99% of any remaining tumor cells located within
the first 1 cm of tissue surrounding the lumpectomy
margin will be sterilized with this dose (Vaidya
2009). Physicians who deliver intraoperative radio-
therapy using electrons, as in the ELIOT trial, select
the treatment depth and the applicator will be used at
the time of surgery. A multi-tiered dose escalation
trial was conducted with acceptable acute and late
side effects up to the current dose of 21 Gy, which is
prescribed to the 90% isodose line using between 4
and 10 MeV electrons (Orecchia et al. 2003, 2009).
The UK IMPORT LOW trial defines its partial
breast CTV not as a precise anatomical entity, but
instead attempts to approximate the involved quadrant
of the ipsilateral breast. To do this, surgical clips and
changes in the surrounding tissue architecture
identified on the planning CT are supplemented
with ultrasound or MRI to define the surgical cavity.
A minimum of 15 mm is added to create the CTV and
695
modified according to the individual breast anatomy
and analysis of the surgical margins. This expansion
is restricted posteriorly by the deep fascia (unless the
tumor clearly breaches the fascia) and extends up to
the first 5 mm of skin at the surface of the breast. This
exclusion of 5 mm of subcutaneous tissue is done to
reduce late normal tissue skin changes.
Planning target volume (PTV) expansions are
generally used only in 3D conformal applications of
APBI and partial breast irradiation (as seen in the
IMPORT Low trial). Because interstitial catheters and
brachytherapy devices move together with the lump-
ectomy cavity, the CTV with these treatment modal-
ities is equivalent to a PTV and no additional
expansion is necessary. With IORT, the breast gland
and tissue at risk is directly visualized, which also
precludes the need for a PTV. For 3D-CRT however,
an additional expansion must be added to the CTV to
account for organ motion (respiration, cardiac systole)
and setup error. The NSABP B-39/RTOG 0413 and
the UK IMPORT LOW Phase III trials call for a
10 mm expansion from CTV to PTV for both whole
breast and partial breast mini-tangent radiation plans.
6 Radiobiology of APBI
Initially, it was thought that all tumors had an a/b ratio
of at least 10 Gy. A meta-analysis of the START pilot
trial and START Trial A generated an a/b ratio for
breast cancer of 4.6 Gy (95% CI 1.1–8.1), which is
comparable to the a/b for late responding tissues
(Bentzen et al. 2008a, b; Owen et al. 2006). If this is a
reliable estimate of the average fractionation sensitiv-
ity of breast cancer, small (2.0 Gy) fractions spare
breast cancer as much as the late reacting normal tis-
sues. This means that there should be no disadvantages
to using moderate hypofractionation for breast radio-
therapy. Other radiobiologic factors to consider with
APBI include whether the fractionation scheme of BID
treatment delivery further hampers tumor repopulation
and whether this may provide an additional benefit for
tumor cell kill above once-daily dosing used in WBI.
Direct comparisons of WBI and APBI using the
LQ model are not reliable for a number of reasons,
including marked differences in dose distribution
when brachytherapy techniques are used for APBI.
For example, the dose at the applicator surface when
using a MammoSiteÒ balloon is two times as high as
696
Fig. 7 Control and test arms of the IMPORT Low Trial.
Images courtesy of J. Yarnold
the prescription dose. Other differences to take into
account include the enhanced risk of normal tissue
damage due to incomplete repair when inter-fraction
intervals of 6 hours are used and the normal tissue
sparing effects of treating partial volumes of the
breast. Clinical data from the CHART trials of
accelerated hyperfractionation in head and neck can-
cer suggest that repair half-times for late adverse
effects such as laryngeal edema, cutaneous telangi-
ectasia, and subcutaneous fibrosis are at least 4 hours
(Bentzen et al. 1999). If this applies to the tissues of
the breast, a 6 hour inter-fraction interval need to take
account of incomplete repair when estimating the
biologically effective dose (BED) compared to daily
fractionation. The clinical effects of a higher BED
appear to be partially or completely offset by a strong
volume effect (Bentzen and Yarnold 2010). This is
most clearly shown by the rates of breast fibrosis
recorded in the EORTC tumor bed boost versus no
boost trial (Bartelink et al. 2007). In 5,318 patients,
randomized to a boost of 16 Gy in eight daily frac-
tions versus no boost after 50 Gy in 25 fractions of
WBI, about 20% more patients developed moderate
or marked fibrosis after boost therapy. Based on these
data, the slope of the dose response curve (c value) for
fibrosis after boost radiotherapy is approximately 0.6,
whereas the steepness of the dose response for late
adverse effects after WBI is approximately three
times higher (Bentzen et al. 2008b).
The UK IMPORT LOW partial breast trial used a
hypofractionated schedule of 40 Gy in 15 fractions
delivered over 3 weeks. The partial breast test arms
used shortened tangential fields which treated a field
size in-between WBI and a traditional APBI field
B. Wilkinson et al.
(Fig. 7). The IMPORT LOW trial aimed to test only
the volume effect of partial breast radiotherapy on
tumor control and normal tissue responses by using
the same dose and fractionation in the control and
partial breast arms of the trial.
The biology of the different histologic subtypes of
breast cancer is not yet fully understood. Additional
research is needed to determine if all breast cancers
respond to larger fraction sizes in the same way.
Although they account for a minority of breast cancers,
tumors that are triple negative or HER-2/neu positive
have shown to be more aggressive histologic subtypes
that may or may not respond equally to APBI. A recent
report from William Beaumont Hospital did not show a
difference between patients with receptor positive and
triple negative receptor status breast cancer after
treatment with APBI, however long-term follow up is
necessary (Wilkinson et al. 2011).
7 Surgical Considerations
The surgeon plays a critical role in implementation of
APBI as they often have the first interaction with
patients who may be partial breast therapy candidates.
In addition to appropriate patient selection, surgeons
also are important in the timing of referral to the
radiation oncologist and creation of a suitable lump-
ectomy cavity with negative margins.
Beyond adhering to the previously discussed
patient selection criteria published by ABS, ASBS,
RTOG, GEC-ESTRO, and ASTRO; the location of
the tumor within the breast is important in
determining eligibility for different types of APBI.
In general, tumors located within the lower two
quadrants of the breast are the most amenable to
balloon-based brachytherapy because the volume of
breast tissue is typically larger and skin spacing
becomes less of a concern, except when a tumor is
very superficial. Other tumor locations may be more
suitable to interstitial brachytherapy or 3D-conformal
techniques, although the introduction of multi-lumen
brachytherapy applicators enable treatment of lump-
ectomy cavities that previously would not have
qualified for balloon-based brachytherapy. Subareolar
and axillary tail tumors present unique challenges as a
decision on whether the nipple may be salvaged and
whether there will be adequate axillary tissue to
support an intracavitary device must be considered.
Accelerated Partial Breast Irradiation
Additionally, axillary tail tumors also require special
consideration as the exit point of an implanted
brachytherapy device may affect arm movement and
patient comfort. Peripheral tumors and those involv-
ing either the nipple-areolar complex or inframam-
mary fold may be best treated with an interstitial
implant (Stolier 2009).
Re-excision of the lumpectomy cavity is often an
issue at the time of consultation with the radiation
oncologist. Published rates of the need for re-excision
vary between 10% to one-half of the cases (Waljee
et al. 2008; Fleming 2004). Although different defi-
nitions of clear margins have been used at various
institutions, the current national standard for NSABP
trials is that the margins of the resected tumor must be
histologically free of cancer including DCIS (RTOG
2005), or ‘‘no tumor on ink’’. At William Beaumont
Hospital, physicians advocate for surgical margins of
2 mm or greater and re-excision of the lumpectomy
bed, in general, is required prior to radiotherapy if this
condition is not met (Baglan et al. 2003). If a surgical
margin is close (i.e. \ 2 mm, but not positive), a
discussion should be held with the surgeon to deter-
mine whether additional tissue may be removed.
Following breast conserving surgery, the shape of
the surgical cavity must be assessed. Although exact
geometry is not required, a roughly spherical-shaped
cavity is ideal for most brachytherapy applicators.
Irregularly shaped cavities or those with extensions
near the skin may be better treated with an interstitial
or 3D-conformal approach rather than applicator-
based brachytherapy. One issue is that a spherical
cavity at the time of primary surgery is likely
to become altered to a more irregular shape if
re-excision of one or more margins is required,
although successful tissue conformance to a balloon-
based brachytherapy applicator can still be possible
(Stolier 2009). Newer brachytherapy applicators with
multiple lumens and varied applicator shapes now
allow additional dosimetric flexibility; however, it is
still preferable to secure a tumor within the center of
the surgical specimen with roughly equal margins.
Skin to applicator distance, or skin spacing, is also
a significant consideration in partial breast irradiation.
Over one half of the cases that were not treated as part
of the ASBS MammoSiteÒ registry trial were exclu-
ded because of inadequate skin spacing (Zannis et al.
2005). A CT scan should be performed after lump-
ectomy in a separate appointment before placement of
697
a brachytherapy applicator to assess skin spacing,
distance to chest wall, and geometry of the lumpec-
tomy cavity (Fig. 8). To achieve maximum skin
spacing, superficial tumors should be excised using an
ellipse of overlying skin while deeper tumors should
be excised by dissecting the overlying tissue first,
followed by a circumferential resection. If concern
exists as to whether a device may be placed within the
surgical cavity at all, the surgical space may be
injected with 35 cc of saline to approximate the size
of the smallest MammoSiteÒ balloon.
Tissue conformance of a balloon-based catheter
once inside the surgical cavity can be affected by
balloon asymmetry, which is why all balloons should
be inflated with saline and inspected prior to insertion
into the lumpectomy cavity. Devices may be placed at
the time of surgery or with the assistance of a cavity
evaluation device (CED), which serves as a
placeholder until the actual device is placed. If the
brachytherapy applicator is placed in a separate
procedure after partial mastectomy, the lateral trochar
or closed technique is typically used where a per-
pendicular path to the lumpectomy cavity is created
under local anesthesia using ultrasound guidance to
identify the cavity. Once inside the surgical cavity,
ultrasound can also be used to assess for tissue con-
formance and skin spacing (Wilkinson et al. 2008) or
this may be done at the time of CT-based simulation
with the applicator in place. Some devices have a
central port for aspiration of residual fluid or air
within the surgical cavity at the time the device is
assessed for radiotherapy. Otherwise, small pockets of
fluid or air typically resolve in 24–48 h following
device placement.
For the interstitial catheter or 3D conformal radi-
ation delivery techniques, the shape and size of the
surgical cavity is less important as irregularly shaped
cavities can be compensated for during treatment
planning. Dosimetry and technique for these radiation
therapy options are discussed later in this chapter. For
oncoplastic closure techniques where the seroma
cavity is intentionally closed to improve cosmetic
outcome, interstitial or external beam partial breast
irradiation would be the preferred approach for
adjuvant RT since applicator-based brachytherapy is
often not possible. In this situation, internal fiducial
markers of the tumor bed are essential for accurate
localization of the lumpectomy bed. Standard tita-
nium ligaclips attached in pairs to the four walls of
698
Fig. 8 a–d CT simulation to
determine suitability for
APBI. Images depicting
delineation of the
lumpectomy cavity (a, b),
measurement of skin spacing
(c), and expansion of the
lumpectomy cavity to create
the CTV (d). Images courtesy
of F. Vicini
the excision cavity (radial, anterior, and posterior)
prior to cavity closure with or without volume dis-
placement can be imaged during virtual simulation
and during treatment using kilovoltage imaging
technologies (Harris et al. 2009). Marking the lump-
ectomy cavity with titanium ligaclips has been
adopted as standard of care in the UK for patients
undergoing breast conservation therapy (Coles and
Yarnold 2010).
8 Physics of Accelerated Partial
Breast Irradiation
In the United States, APBI is most frequently deliv-
ered with HDR brachytherapy using Ir-192. The rel-
atively high-energy source (*380 keV) at the tip of a
thin wire is placed, using a computer-controlled af-
terloader device, in precisely specified positions for
time intervals resulting from the planning phase. As
HDR treatment is delivered in a short amount of time
B. Wilkinson et al.
(*10 min) compared with the average half-time of
cellular repair processes (*1 hour), one can establish
an equivalence between multiple sources loaded
simultaneously (LDR) and one HDR source being
placed in specified positions along applicators (dwell
positions) and kept for well specified amounts of time
(dwell times). Thus, for a well determined target, an
HDR treatment plan consists of specifying catheter
number, dwell positions, and their associated dwell
times. Since the radioactive source is placed in the
body but cannot come in contact with tissues, one has
to use an ‘applicator’ to both contain the source and to
guide the wire in the desired positions. Each catheter
is connected to a channel in the afterloader using a
transfer (or guide) tube (Fig. 9).
Dose deposited by an HDR source is the product of
dose-rate and exposure time. The variation of dose rate
as a function of distance from the source is governed
approximately by the ‘‘inverse-square’’ law for dis-
tances of clinical interest (up to 6–7 cm), but a more
in-depth view will reveal that dose is essentially
Accelerated Partial Breast Irradiation
Fig. 9 Multi-lumen applicator implanted in lower-outer quad-
rant and connected to HDR afterloader. Image courtesy of L.
Cuttino
deposited by the contribution of primary and scattered
photons. Since the half life for Ir-192 is 73.8 days, a
correction factor for source decay amounts to
approximately 1% per day. The most commonly used
formalism for computing dose, AAPM TG-43
(American Association of Physicists in Medicine
(AAPM 2010) assumes the source in a water equiva-
lent medium of large size and therefore cannot take
into account tissue or applicator inhomogeneities nor
the finite size of the body (the latter being probably the
factor with the most relevance for the difference
between TG-43 dose and the truly delivered dose)
(Rivard et al. 2006). This is simply due to the fact that
when a source is placed in close proximity to a tissue-
air interface, the lack of scattering material, otherwise
assumed by TG-43 to be present, diminishes the
contribution of the real scattering component. Ana-
lytical methods, collapsed cone superposition algo-
rithms, and Monte-Carlo based algorithms are among
the many attempts to remedy this deficiency. In 2009,
Varian introduced the first clinical treatment planning
system (AcurosTM) capable of computing a realistic
dose taking into account heterogeneities and partial
scatter contributions. The linear Boltzmann transport
equations are solved deterministically and the dose
calculation module is fully integrated with this treat-
ment planning system, leading to calculation times of
the order of a few minutes.
Although it does require specialized training and
considerable experience, the interstitial implant is the
most flexible APBI technique, even from a technical
699
perspective. In an effort to make APBI more accessi-
ble, a number of devices were created with the goal of
reducing the level of invasiveness, making the tech-
nique simpler and more reproducible. Essentially there
are currently two categories of devices: balloon-based
applicators (MammoSiteÒ, ConturaÒ, MammoSiteÒ
ML, and Xoft AxxentÒ) and strut-based applicators
(SAVIÒ and ClearPathTM). MammoSiteÒ, historically
the first balloon device for breast brachytherapy, was in
fact following in the footsteps of another balloon
device used for brain brachytherapy: the GliaSiteÒ
RTS. Unlike the GliaSiteÒ, which is filled with liquid
I-125, MammoSiteÒ is a silicone balloon that can be
placed in a lumpectomy cavity and then inflated with
water to a diameter of 4–5 cm. It has a 15 cm long
central shaft with a 6 mm diameter that contains a
larger ‘‘treatment’’ channel for placement of the high-
dose-rate source and a smaller channel used for infla-
tion. Given the central placement of the lumen used for
treatment, the dose distribution created by one or
multiple dwell positions is always radially symmetri-
cal. Before multi-lumen applicators were available,
lack of symmetry of the central lumen (recommended
to be \ 2 mm) or asymmetry of the PTV (due to
proximity to skin or chest wall) when using a single
lumen applicator could only be dealt with by com-
promising target coverage or increasing dose to the
normal tissue. Compared with a single-lumen device,
multi-lumen applicators now allow the radiation
oncologist to pull the dose away from the skin and/or
chest wall which could allow previously ineligible
patients to receive applicator-based APBI (Fig. 10).
3D rendering is available in most treatment plan-
ning systems, which allows the physician to evaluate
what, if any, dose is extending up to or beyond the
skin surface (Fig. 11). Given that the prescription
dose is always at 1 cm from the surface of the bal-
loon, the radius of the balloon will influence dose to
the surface of the balloon and consequently the dose
gradient in the target. For a medium size balloon
(diameter of about 4.5 cm), the dose at the applica-
tor’s surface is approximately 200% of the prescrip-
tion dose, with slightly lower values for a larger
diameter balloon and slightly higher values for a
small diameter balloon. The anisotropy of dose
observed along the axis of the wire can be somewhat
reduced by use of multiple dwell positions (Astrahan
et al. 2004). Because treatment planning is performed
under the conditions of an inflated balloon, it is
700
Fig. 10 a–b Dosimetric comparison of a plan using the central
catheter only (simulating a single lumen device) vs. a dose-
optimized plan utilizing multiple lumens and dwell positions.
Notice in (b) that in order to protect the skin, the 100% isodose
line (IDL) is pulled back towards the applicator to conform the
dose to the inner surface of the skin and the 150% IDL is
Fig. 11 A skin surface rendering demonstrating extension of
the 25% and 50% isodose volumes through the skin surface
(a). The second image (b) shows the applicator in place with a
critical that the integrity of the balloon is verified
prior to each fraction to avoid delivery of higher than
intended doses directly to the surrounding breast tis-
sue. Typically such verification is done using ultra-
sound, fluoroscopic, or CT images just before each
fraction of applicator-based APBI is delivered.
B. Wilkinson et al.
constricted to the anterior surface of the applicator. On the
opposite side of the applicator (and away from the skin), a dose
configuration more typical of single-lumen balloon-based plans
is seen with the 200% IDL present at the applicator’s posterior
surface and concentric dose gradients extending outward
covering the CTV. Images courtesy of Cianna Medical, Inc
CTV/PTV expansion indicating the area proposed to receive
the 100% dose of 3400 cGy in 10 fractions. Images courtesy of
F. Vicini
The lack of flexibility in treatment planning due to
the constraints of a single lumen led to the creation of
the multi-lumen devices including the ConturaÒ MLB
which was followed by the MammoSiteÒ ML. Both
devices preserved the central lumen with the Con-
turaÒ adding four arc-shaped lumens offset from the
Accelerated Partial Breast Irradiation 701

Table 5 Dose constraints for APBI (10 fractions, delivered BID)

Structure 3D-CRT Interstitial Balloon-based
Heart V2 B 40%* V1.7 \ 40%*
V2 \ 5%** V1.7 \ 5%**
Ipsilateral V11.5 \ 15% V10 B 15%
Contralateral V2 \ 15%
PTV coverage D90% C 90% IDL D90% C 90% IDL D90% C 90% IDL
Thyroid Dmax B 1.0 Gy Dmax B 1.0 Gy Dmax B 1.0 Gy
Uninvolved ipsilateral V19 B 60% V17 B 60% V17 B 60%
Entire ipsilateral V38.5 B 35%
Contralateral Dmax B 1.0 Gy V1 B 3%
Skin Dmax B 100% Dmax B 125–145%***
Rib Dmax B 145% Dmax B 145% Dmax B 145%
3
High-dose regions Dmax B 120% V150% \ 70 cm V150% \ 30–50 cm3
3
V200% \ 20 cm V200% \ 10 cm3
Dose homogeneity index (DHI) C 0.75
*
If tumor located on left side.
**
right sided lesions.
***
B 145% for 4 cm sphere, B 130% for 3 cm sphere.

central axis by 5–6 mm and the MammoSiteÒ ML
adding three lumens placed in parallel with the central
lumen at a distance of 3 mm. The ConturaÒ MLB also
has two vacuum ports at the distal and proximal
aspects of its balloon, which can be used for removal
of air and fluid to improve conformity of the tissue to
the balloon surface. The major advantage of the
multi-lumen devices is the ability to optimize dose
coverage of the target while minimizing the dose to
critical structures.
Historically, toxicity after multi-catheter intersti-
tial implants has been associated with the number of
source dwell positions, the absolute volumes of tissue
receiving 150 and 200% of the prescription dose (V150
and V200, respectively), and inversely related to the
dose homogeneity index (DHI). The DHI is defined as
(1–V150/V100) (Wazer et al. 2006). The clear associ-
ation between these dosimetric parameters and tox-
icity prompted the development of dose constraints;
which are presently used in most institutions
(Table 5). For multi-catheter brachytherapy, NSABP
B39/RTOG 0413 requires the V150 and V200 to be B
70 and B 20 cc, respectively, with a corresponding
DHI of C 0.75.
With the MammoSiteÒ, skin distances B 6 mm
have been consistently associated with unacceptable
toxicity and suboptimal cosmetic outcome (Cuttino
et al. 2008; Benitez et al. 2007; Vicini et al. 2005).
Skin distance, however, only approximates the skin
dose. With a single lumen device, the dose will
depend not only on skin thickness but also on balloon
diameter and dwell position location and dwell time
of the source near the skin. In addition, unlike an
interstitial implant, balloon implants have a confluent
‘‘hot spot’’ at the balloon surface. For this reason,
tighter constraints are required when delivering bal-
loon brachytherapy treatments. For MammoSiteÒ
treatment on the NSABP B-39/RTOG 0413 protocol,
the maximum skin dose must be B 145% of the
prescription dose, and V150 and V200 must be B 50 and
10 cc, respectively. It is very important to note that
since the NSABP B-39 protocol guidelines were
issued, treatment planning systems have evolved in
their ability to optimize dose in the presence of
multiple constraints. Thus, these previously set
guidelines should be improved upon with most
patients receiving a skin dose B 125% with a V150 and
V200 limited to B 30 and 10 cc, respectively.
702
A new intracavitary applicator that is not balloon-
based is the Strut Adjusted Volume Implant (SAVIÒ)
(Fig. 7). This device has between six and ten struts
that project outward in a whisk-type arrangement
where each of the exterior struts may be loaded at
multiple different dwell positions to create the radia-
tion treatment plan. The presence of multiple struts
arranged around the central axis of the device allows
an enhanced number of possibilities in creating a
customized treatment plan if the lumpectomy cavity is
close to the skin or chest wall. Although the SAVIÒ
applicator resembles the original multi-catheter
interstitial technique, this device is not capable of
creating the same PTV coverage as an interstitial
implant since its catheters cannot be placed beyond
the lumpectomy cavity. With the SAVIÒ device, the
catheters are immediately adjacent to the tissue being
treated; however, the struts are not equally spaced
within the ‘target’ but can be ‘clumped’ together,
especially at the ends of the device. For a given target
volume, treatment with the SAVIÒ device will always
be associated with a larger V150 and V200 when
compared with a true interstitial implant. As discussed
above, the SAVIÒ applicator increases flexibility in
plan design, but there are concerns regarding non-
balloon brachytherapy applicators as air and incon-
sistent amounts of fluid within the lumpectomy cavity
may alter dose distribution at the time of treatment.
Heterogeneity dose calculations are not common in
APBI treatment planning software and since there is
no balloon to fully occupy the lumpectomy cavity, the
treatment planning software assume the presence of a
tissue-equivalent material within the cavity that may
in fact not be present. The magnitude of dosimetric
effects depends on the size of the cavity and the
particular plan and dwell times distribution, but
according to Richardson et al., Monte Carlo dose
calculations only show a 5–10% higher dose at the
prescription point than when a TG-43-based homo-
geneous calculation is used (Richardson and Pino
2010).
Three-dimensional conformal radiotherapy for
APBI offers a more homogeneous dose distribution
than other types of PBI. Four to five non-coplanar
beams are centered on the lumpectomy cavity with a
one and a half centimeter margin. Although avoid-
ance of hot spots is generally advantageous, the sig-
nificant dose gradient seen in LDR and HDR plans
result in a higher equivalent uniform dose than a
B. Wilkinson et al.
similar 3D-conformal plan. To account for this, a
slightly higher prescription dose of 3.85 Gy for 10
fractions is used for 3D-CRT, which has been shown
to be equivalent to the typical dose of 3.4 Gy 9 10
fractions that is used for other forms of APBI (Cuttino
et al. 2006).
The fields used in the PBI arm of the IMPORT
LOW trial are created by reducing superior and
inferior aspects of the whole breast fields recom-
mended in the START trials (Fig. 7). The anterior and
posterior dimensions may also be adjusted, depending
on the location of the tumor bed. Dose constraints for
organs at risk are kept similar to the standard treat-
ment by using a tangent pair method and, regardless
of planning technique, dose inhomogeneity should not
exceed ICRU 50 and 62 standards. If the ability of the
treatment planning system to calculate the correct
output with small field sizes and low monitor units
has been checked, then there is no need for individual
patient QA of the plan since normal good practice for
the independent checking of the plan will be
sufficient.
The physics of electron-based IORT is relatively
straight-forward, since 3D planning techniques are
not employed. After tumor removal and mobilization
of the breast gland, an aluminum-lead shield is
inserted between the pectoralis muscle and the breast
tissue. The IORT collimator is then placed, and the
electron energy is selected based on the depth of
tissue to be treated. The area treated is typically
4–6 cm and, in general, length of treatment is\5 min
(Orecchia et al. 2003).
Most of the techniques above utilize radioactive
sources to deliver the prescribed dose to the peri-
lumpectomy tissues. An exception to this is the Xoft
AxxentÒ brachytherapy system that uses a miniature
electronic 50 keV X-ray source. Given the low energy
(*50 keV), the shielding requirements are signifi-
cantly reduced when compared with those for Ir-192.
The low energy also likely produces a higher radio-
biologic effect (RBE), but variation with energy and
depth makes it difficult to derive a correction to the
dose fractions delivered with traditional HDR brach-
ytherapy. Although the Xoft system uses a miniature
X-ray source, it is still larger than a standard HDR
source (5.4 mm diameter vs. \ 1 mm for the Varian
VariSourceTM) because of the need for the Xoft
source to be water cooled. This makes it impossible to
use an electronic brachytherapy source in a non-Xoft
Accelerated Partial Breast Irradiation
applicator due to the size discrepancy between the
two sources.
9 Treatment Planning
Treatment planning requires a CT scan of the
implanted catheters/device for brachytherapy tech-
niques or of the lumpectomy cavity for external beam
techniques. For brachytherapy, the scan only needs to
include the breasts. For external beam techniques, the
scan should include the thyroid and entire lung vol-
umes. For interstitial and applicator-based brachy-
therapy, the CT slice thickness should be no larger
than 3 mm to ensure the accuracy of applicator
delineation. The scan should also be performed with a
breath-hold technique, as respiratory motion can
cause significant artifact. Depending on the speed of
the scanner, increase of resolution should not be done
at the expense of significantly increased scanning
(breath hold) time.
9.1 Interstitial Brachytherapy
Interstitial catheters are inserted into the breast under
local or general anesthesia using either an open
technique at the time of surgery or a closed cavity
placement technique within a 2–6 weeks after surgery
to maximize visibility of the lumpectomy cavity.
Catheters can either be placed freehand under direct
visualization at the time of lumpectomy or using an
image-guided technique after surgery. The closed
cavity technique can employ ultrasound, CT, or
mammography for guidance, and can be accom-
plished freehand or with a template. Although some
centers use a CT-guided freehand technique for
all patients (Cuttino et al. 2005), some reserve a
freehand approach for patients with small breasts or
to address cold spots identified during the dose
optimization process following a template-based
interstitial implant (Kuske 2009). The number and
spacing of needles is provider dependent; however, a
general guideline is that catheters are evenly spaced
around the lumpectomy cavity in approximately 1 cm
intervals. An example of a template used for the
interstitial technique is shown in Fig. 1.
With the open cavity technique, between one and
three planes of interstitial catheters are used without
703
the guidance of a template. The amount of tissue to be
covered determines the number of planes needed
where a target tissue of 1 cm in thickness or less may
be covered in a single plane, 1–2.5 cm in two planes,
and three planes should be used to adequately cover a
tissue thickness of [ 2.5 cm (Kuske 2009). The open
technique carries with it the same issues as intraop-
erative therapy in that the final surgical report is
unknown at the time of catheter placement. If adverse
pathologic features are uncovered (large tumor size,
positive margins, extensive nodal disease), the inter-
stitial catheters should be removed or the treatment
should be considered a boost only. A modified version
of this technique uses ultrasound to guide freehand
placement of catheters into a closed cavity at a sep-
arately scheduled appointment after the pathologic
results of the lumpectomy are known.
To complete the image-guided closed cavity
interstitial technique, the patient is positioned on the
operating table and a two-sided template with coor-
dinating positions for catheter insertion Fig. 1a is
applied to either side of the breast with the surgical
scar visible between the two plates. Under sterile
conditions, and following injection of an anesthetic,
several stabilizing needles are inserted through the
center of the template to secure the device to the
patient and assist in orientation on the treatment
planning software. A local anesthetic is then injected
using a small gauge needle on either side of the breast
to anesthetize the entry and exit points of each cath-
eter. A further diluted anesthetic should also be
injected deeper along the planned path of each needle.
Conscious sedation may also be used to improve
patient comfort, which is typically given prior to
placement of the interstitial template. Obtaining
imaging after injection of local anesthetic agents will
allow additional time for the medication to become
effective prior to catheter insertion. With the template
in place, a CT scan is obtained and the images are
transferred to the treatment planning software so that
the surgical cavity can be defined on each CT slice to
create a 3D target volume. The lumpectomy cavity is
then expanded by between 1.5 and 2 cm to create the
CTV. This is the volume used to guide catheter
insertion to ensure appropriate coverage of the target
as guided by the planning software. If the lumpec-
tomy cavity is difficult to identify on CT, a small
amount of contrast may be injected under ultrasound
guidance to assist with target definition (Kuske 2009).
704
Fig. 12 a–b Dose optimization of an interstitial brachytherapy
plan showing the creation of an avoidance structure around the
CTV. This helps the treatment planning software generate a
To create the interstitial implant, a single (deep) plane
is typically placed 0.5 cm posterior to the lumpec-
tomy cavity. A second, more superficial plane is
placed approximately 1 cm posterior to the surface of
the skin near the anterior edge of the lumpectomy
cavity. Additional catheters are inserted to ensure
appropriate coverage of the CTV with spacing of
catheters typically 1 cm from each other. It may be
necessary to generate an asymmetric implant with a
portion of the breast receiving three planes of cathe-
ters while the remaining portion, involving less breast
tissue, only receives one or two planes. Once all metal
catheters are in place, they are attached to plastic
catheters that are pulled through so that the metal
needle is removed and only a plastic guide tube
remains within the tract of each initially placed nee-
dle. As significant swelling may occur immediately
following insertion of the catheters, a CT scan for
treatment planning purposes will likely be obtained
24–48 h following the implant procedure to allow
completion of the treatment planning process.
Because the needles used in an interstitial implant
move together with the target as the patient breathes,
the CTV is equivalent to the PTV as organ motion and
setup error do not need to be accounted for with this
technique. A PTV_EVAL (discussed in greater detail
in the following section) is created by subtracting the
first 5 mm from either skin or chest wall adjacent to
the target volume for the purpose of dosimetric
planning. Once all catheters have been reconstructed
within the treatment planning software, dwell
B. Wilkinson et al.
plan that contains the highest doses within the CTV while
minimize extension of dose to unaffected areas of the breast (a).
Images courtesy of L. Cuttino
positions and times are selected using the software’s
dose optimization algorithms so that the PTV_EVAL
is adequately covered by the prescription dose. It is
important to analyze each slice of the final brachy-
therapy plan to ensure a generalized homogeneity
exists throughout the target volume and that hotspots
([ 150% of the prescription dose) do not become
confluent with each other between individual cathe-
ters. An acceptable plan will cover [ 90% of the
PTV_EVAL with over 90% of the prescription dose
while adhering to within 5% the normal tissue dose
constraints summarized in Table 5. Figures 12a and
12b illustrate the regions of interests (ROI’s) for an
interstitial case and an example of dose optimization
for the interstitial technique. The use of an avoidance
structure, pictured in Fig. 12a, may be used in treat-
ment planning. This is discussed in greater detail in
the following section.
Recent advances in the treatment planning soft-
ware (e.g. BrachyVisionTM v8.0 and up) makes
automated catheter delineation an easy to manage task
(Fig. 12a). If a treatment planning software system
only offers manual delineation, catheter localization
can be a very tedious and time consuming task.
9.2 Applicator-Based Brachytherapy
Once a CT scan is obtained, the planning phase for
balloon or applicator-based brachytherapy treatment
planning includes delineation of anatomical and
Accelerated Partial Breast Irradiation
planning structures, delineation of the applicator,
establishment of ‘allowed’ positions for the radioac-
tive source within applicators (dwell positions), and
dose optimization (Fig. 13a–f). At the time of CT
acquisition, photographs of the treated breast are
obtained for a number of purposes including catheter
identification and proper connection of the applicator
to the afterloader channels, device positioning for
balloon and strut devices, as well as overall setup and
patient positioning.
A majority of the seroma will be expelled when the
applicator is placed; however, some additional fluid
may be present at the time of simulation. If the
amount of fluid is too great to proceed with treatment
planning ([ 10% of the volume of the applicator), a
24–48 h period of time may be allowed for the fluid to
reabsorb, at which point, a repeat CT scan would be
performed with the applicator in place to observe if
sufficient absorption had occured. In the case of the
ConturaÒ MLB, fluid and/or air may be removed
using the device’s two vacuum ports.
Optimization can be formally and succinctly
described by the following: for a given source
strength, using defined source positions, given targets,
and ‘normal tissue’ structures, optimization finds the
dwell times that would maximize the target dose
coverage, minimize dose inhomogeneity within the
target, and minimize dose to ‘normal tissues’. The
GTV for a multi-catheter implant is the lumpectomy
cavity. Even in the presence of surgical clips, out-
lining the lumpectomy cavity can be a challenging
task, prone to inter-physician variability. This uncer-
tainty is removed by the balloon-based devices, where
the surface of the balloon itself is a reproducible
surrogate for the lumpectomy cavity. For strut-based
devices, the lumpectomy cavity is delineated through
the surrogate surface defined by all the struts. Unlike
the balloon devices, the tissue may become com-
pressed or stretched unevenly, making it more diffi-
cult to justify a uniform margin. Lumpectomy margin
tissue may also interdigitate between the struts to
different degrees, which cannot occur with balloon-
based applicators. A CTV (also equal with PTV) is
created by expanding the GTV by a uniform 1.0 cm.
Because the dose in the region close to the skin-air
interface is notoriously uncertain (unless one per-
forms a Monte Carlo or similar dose computation),
the concept of a PTV_EVAL was created, by
removing a 5 mm layer of skin from the PTV. Besides
705
improved dosimetry, limiting the target to 5 mm from
the skin surface also minimizes the risk of telangi-
ectasia. The PTV_EVAL also excludes the chest wall,
pectoralis muscle, and ribs under the assumption that
only the breast tissue surrounding the lumpectomy
cavity is at risk and therefore should be the only target
of the radiation treatment. Various other structures
(anatomical or for planning or evaluation purposes
only) are typically outlined including the skin, ipsi-
lateral lung, heart (for left sided tumors), and any ribs
that would fall within the 70% isodose line of a typ-
ical balloon-based brachytherapy plan.
If air or fluid is retained within the lumpectomy
cavity after inflation of the applicator’s balloon, the
displacement of the lumpectomy cavity away from
the applicator’s surface must be accounted for. The
air/fluid trapped should be contoured separately on
each CT slice and a total volume should be calculated
to determine the percentage of the PTV_EVAL that is
displaced. This percent displacement must be limited
so that:
ð% PTV EVAL coverageÞ
 ½ðvol: trapped air=vol PTV EVALÞ x 100
¼  90%
As with an interstitial plan, ideal dosimetric cov-
erage will be 90% of the PTV_EVAL receiving 90%
of the dose. If the amount of air or fluid trapped is
[ 10% of the PTV volume, this will not be possible
for a single lumen device as too much of the PTV
volume will be pushed outside of the range of the
central catheter. Additional elements that should be
assessed include balloon symmetry, which should not
deviate [ 2 mm from expected device dimensions.
After the ROI’s have been drawn and the sym-
metry of the applicator has been confirmed, the
geometry of the applicator must be defined on the
planning CT image set. For the balloon-based devi-
ces, a rigid relative geometry of the treatment lumens
(e.g. Contura MLB) allows the importing of the
applicator from a template library. This dramatically
reduces the time needed to outline the applicator
while also ensuring a perfect and reproducible defi-
nition of the applicator, even on less than optimal
quality image set. Once applicators are delineated, the
physicist or physician defines the dwell positions for
each lumen or strut identifying a starting dwell posi-
tion, dwell increments (typically between 1 and
706 B. Wilkinson et al.

Fig. 13 a–f Dose optimization of a balloon-based brachyther- highest doses within the CTV while minimize extension of dose
apy plan showing the creation of an avoidance structure around to unaffected areas of the breast (c). A second avoidance
the CTV. As in the interstitial example above, this assists the structure is also used here to minimize dose to the chest wall
treatment planning software generate a plan that contains the (e). Images courtesy of L. Cuttino
Accelerated Partial Breast Irradiation
5 mm), and an ending dwell position. Once all dwell
positions have been defined, dose optimization algo-
rithms assist with determining dwell times for each
source location.
During treatment planning for both interstitial and
applicator-based brachytherapy, the physician or
physicist may use an avoidance structure. This dosi-
metric entity is generated within the treatment
planning software to help shape and contain dose
within a specific area of the implant. A typical
avoidance structure is either a thin (3–4 mm) con-
centric layer placed around the PTV_EVAL of a
balloon applicator or, in the case of an interstitial
implant, the avoidance structure is placed 4–5 mm
outside of the PTV_EVAL. These dosimetric entities,
displayed in Fig. 13a, are particularly efficient for
‘containing’ dose, increasing conformity, and
decreasing normal tissue dose.
While there are many ways of creating a dose
distribution, the only ‘true’ optimization is the so-
called ‘volume’ or DVH-based optimization. Each of
the structures that will be subjected to dose-volume
constraints are sampled in a number of points (typi-
cally hundreds to a few thousands) depending on the
volume. The reason for doing this is that in order to
speed up the optimization process, one can choose to
calculate dose in a much smaller number of points
than the total number of dose voxels that the structure
inherently has, based on the resolution of the dose
matrix. Figure 13b shows an example of this, using a
multi-lumen catheter implant. While upper and lower
constraints are placed on the dose volume histogram
for the target PTV_EVAL, the avoidance structure
placed slightly outside the target is the one limiting
higher than prescription dose ‘spilling’ into the nor-
mal tissue and thus driving the dose conformance.
Good structures and good constraints will produce
optimal plans. If one needs to manually ‘tweak’ an
already optimized plan, it is very likely that either the
optimizer is not performing adequately (might be too
sensitive and easily ‘captured’ by local minima) or the
set of constraints does not adequately reflect the goals
of the plan. When a well streamlined process
produces optimal plans easily, it is a good practice to
present the attending physician with a number
of plans that can be easily compared and which
reflect different philosophies in reaching compro-
mises between sometimes irreconcilable constraints.
In general, exceeding 5% of a normal tissue dose
707
constraint or failing to meet the 90% PTV_EVAL
coverage with 90% of the dose planning parameter
would be considered inappropriate treatment plans.
9.3 3D Conformal Radiation Therapy
As with applicator-based brachytherapy, patients
undergo CT-based simulation in the supine position
with the addition of an alpha cradle or similar device
for immobilization and to keep the patient’s arms
elevated above the head. Prone positioning of the
patient for 3D-CRT may also be performed using a
specialized adaptor to the treatment table allowing the
ipsilateral breast tissue to fall away from the chest
wall (Formenti et al. 2007). Radioopaque catheters
should be placed at the time of simulation to define
the superior, inferior, medial, and lateral clinical
borders of the breast. The CT scan is obtained at
3 mm increments beginning with the mandible supe-
riorly to several centimeters below the inframammary
fold so that the whole ipsilateral lung is included in
the scan. If the tumor was located in the left breast
and the patient is young, methods for minimizing
dose to the heart and ipsilateral lung, including active
breathing control, may be employed (Remouchamps
et al. 2003; Krauss et al. 2005). After the images have
been imported into the treatment planning software,
the lumpectomy cavity (the area encompassing
architectural distortion and surgical clips), the ipsi-
lateral breast and lung, skin, thyroid, and heart (for
left sided tumors) should be contoured. The ipsilateral
breast is defined as the volume of tissue encompassed
between the radioopaque catheters, the skin, and
5 mm anterior to the lung/chest wall interface. An
isocenter should be set at the time of simulation at the
center of the lumpectomy cavity. The CTV is then
created by uniformly expanding the lumpectomy
cavity by 15 mm. The PTV should be defined by
adding 5 mm to the CTV for breathing motion and an
additional 5 mm for setup error. This PTV volume,
along with an additional expansion to account for
penumbra, is used to generate beam aperture. For
superficial cavities, the PTV may extend beyond the
surface of the patient. For this reason, a PTV_EVAL
is created by subtracting the first 5 mm of either skin
or chest wall from the PTV. The PTV_EVAL is only
used for dose volume histogram (DVH) analysis and
is not used determine beam arrangement or aperture.
708
Beam arrangement typically consists of four to five
non-coplanar beams; however, as few as three and as
many as nine beams may be used. A typical set
up is four beams including a left anterior supe-
rior-to-inferior oblique (L ASIO), left anterior inferior-
to-superior oblique (L AISO), right anterior inferior-
to-superior oblique (R AISO), and a right posterior
superior to inferior oblique (R PSIO). Beams should be
oriented away from critical structures including the
heart, lung, or contralateral breast. To maximize breast
tissue sparing, the medial beams should have a 10–20°
steeper entry angle than the lateral beam. The energy
selected to deliver the treatment is typically between 6
and 18 MV and may use combined energies to create
the desired dosimetric effect.
At William Beaumont Hospital, 3D-CRT plans are
manually optimized using 60° wedges and varied beam
weights to ensure the CTV is covered by the 100% IDL
and the PTV is covered by the 95% IDL. Additional
factors considered during beam weight optimization
include keeping the ipsilateral breast V19 and V38.5 to B
60% and 35% of the prescription dose, respectively.
Other normal tissue dose constraints for the 3D-CRT
technique (including the heart, lung, thyroid, and
contralateral breast) are summarized in Table 5.
IMRT-based planning can deliver multiple segments
per beam and typically involve additional anterior
beams, which has been shown to spare more normal
tissue in the ipsilateral breast when compared to tra-
ditional 3D-CRT-based planning (Rusthoven et al.
2008).
An acceptable 3D-CRT plan will meet normal tis-
sue dose constraints (within 5%) while also delivering
at least 90% of the dose to 90% or more of the
PTV_EVAL. As referenced above, protocols at
William Beaumont Hospital, as well as others, have
used higher standards for coverage of the PTV_EVAL,
which are typically obtainable for most tumor loca-
tions. Unlike other APBI plans, 3D-CRT plans should
be more homogeneous and should not have a max dose
greater than 120% of the prescription dose.
9.4 IMPORT LOW PBI Technique
As discussed briefly in the physics section of the
chapter, the IMPORT LOW trial approach to PBI is to
use tangential fields for all arms of the study. Plan-
ning is based on a helical CT image set and correction
B. Wilkinson et al.
for tissue inhomogeneity is mandatory. The tangent
pair incorporates a non-divergent posterior border.
The treatment is linear accelerator-based and the
treatment plan to be delivered, is likely to require
simple dose compensation such as the ‘field-in-field’
approach to achieve ICRU 50 and 62 dose distribution
guidelines. The fields for the partial breast volume are
reduced in field size compared to whole breast but
maintain the same gantry angles. For test arm 1,
where both whole and partial breast are treated
together, a single isocenter is used. This is placed in
the center of the partial breast volume, halfway
between lung and skin surface. A forward planned
IMRT method may be used to achieve good dose
homogeneity while encompassing the whole or partial
breast radiation fields. The aim of the treatment
planning process is to cover the PTV by the 95%
isodose contour of the relevant dose prescription
(36 Gy to the whole breast and 40 Gy to the partial
breast volume).
The whole breast tangential fields are used for
patient verification at the time of treatment using MV
electronic portal imaging. For test arm two, where
only the partial breast is treated, a verification-only
whole breast field is created for treatment planning
purposes only. This allows verification to be carried
out in the same way for all patients. A recommended
off-line protocol is to image the first three fractions to
determine the systematic error, then correct this on
fraction number four and then re-image weekly.
9.5 Intraoperative Radiotherapy
IORT is delivered using a single treatment of either
photons or electrons at the time of surgery. Following
tumor removal, confirmation of hemostasis is verified
as blood in the surgical cavity could potentially affect
dosimetry. In the case of photon-based IORT
(TARGIT trial), an appropriately sized applicator is
then placed within the surgical cavity under sterile
conditions and the surrounding tissue is temporarily
sutured together using purse-string type subcuticular
closure. Dermis judged to be too close to the appli-
cator’s surface (within 1 cm) may either be resected
or a piece of saline-soaked gauze may be introduced
between the breast tissue and the overlying dermis to
minimize dose to the patient’s skin (Vaidya 2009).
Skin and the chest wall can also be further protected
Accelerated Partial Breast Irradiation 709

Table 6 Interstitial and balloon-based APBI trials

Institution # Follow- Local Toxicity
Patients Up recurrence
(yrs) (%)
National Institute of Oncology- 45 12 9.3 \ 3% Grade III
Hungary (Polgár et al. 2010b)
William Beaumont Hospital 199 9 5
(Antonucci et al. 2009)
Oschner Clinic (King et al. 2000) 71 6.25 8 Grade III (late)
LDR: 3.8%
HDR: 7.7%
Tufts Medical Center 32 5 6 Fat necrosis, skin, and subcutaneous toxicity
(Kaufman et al. 2007) declined with additional follow up
RTOG 95-17 (Arthur et al. 2008) 99 5 3 (HDR) Grade III (late)
6 (LDR) LDR: 18%
HDR: 4%
ASBS MammoSite registry 1,449 5 3.80
(Vicini 2011)
William Beaumont Hospital- 80 3.5 2.90
MammoSite (Chao et al. 2007)
Multi-institutional (VCU) 493 2 1.20 9% infection rate
(Cuttino et al. 2008) (5% if closed cavity technique used)

using tungsten-filled polyurethane material, if neces-
sary. As opposed to the ELIOT system, further dis-
section of the breast tissue to separate it from the skin
and chest wall is not necessary. Energy used with this
system is 50 keV, which creates a radiobiologic effect
(RBE) of approximately 1.5. The dose rate delivered
using the Intrabeam system depends on the size of the
applicator (3–5 cm) selected at the time of surgery
and the energy of the beam. Both of these factors can
be optimized depending on the clinical details of the
case. As an example, a 3.5 cm spherical applicator
delivers a dose at the applicator’s surface, of between
18 and 20 Gy, which attenuates to approximately
5 Gy at 1 cm. Because of the higher RBE, it is felt
that this dose at 1 cm into the tissue, is sufficient to
cover any microscopic residual disease within the
lumpectomy cavity. Treatment time with photon-
based IORT is between 20 and 25 min. If the facility
where the primary surgery is performed does not have
the Intrabeam system, TARGIT-style IORT may be
delivered as a separate procedure in a different loca-
tion, which has occured in approximately 25% of
patients enrolled on the TARGIT trial (Vaidya 2009).
For electron-based IORT, as used in the ELIOT
trial, steps involved in the treatment delivery process
include tumor removal with a minimum of a 1 cm
margin, mobilization of the breast tissue away from
the skin and chest wall, which is followed by insertion
of the IORT collimator. Following surgical prepara-
tion for IORT, an aluminum shield is placed between
the pectoralis muscle and then the breast tissue is
sutured together on top of the shield to recreate the
pre-lumpectomy appearance of the breast gland. Once
the shield is in place, the IORT collimator is intro-
duced into the surgical cavity using an applicator of
between 3 and 12 cm that is either flat or beveled at
an angle between 15 and 45°. The size of the appli-
cator, electron energy, treatment depth, and appro-
priate isodose coverage are selected by the IORT
team at the time of surgery. Shields are then assem-
bled around the operating room table to protect the
rest of the room from scattered X-rays that will be
generated during the intraoperative treatment. A real-
time calculation is then performed to determine the
number of monitor units (MU) needed to deliver the
desired treatment. Since a treatment planning system
is not used, appropriate physical attributes of each
applicator and energy combination are available to the
treating physician at the time of intraoperative therapy
(Orecchia et al. 2009). The area treated is typically
710 B. Wilkinson et al.

Table 7 3D-CRT APBI Trials

Institution # Patients Follow-up (mo) Local recurrence (%) Grade III Toxicity (%)
William Beaumont Hospital 96 47 1 4
(Chen et al. 2010)
RTOG 0319 (Vicini et al. 2011) 52 42 6 4
NSABP B-39/RTOG 0413 338 32 – \2
(Radiation Therapy Oncology Group 2005)
Tufts University (Hepel et al. 2009) 64 15 – 8.3
Rocky Mountain CC (Leonard et al. 2007) 55 10 0 3.6

Table 8 Ongoing phase III collaborative APBI trials

Institution Current # Expected Details
patients accrual
NSABP B-39/RTOG 0413 3,800 4,300 Anticipated closure: September 2012
(Radiation Therapy Oncology Group 2005)
Canadian RAPID OCOG Trial 1,500 2,128 Anticipated closure: January 2012
*
GEC-ESTRO 1,202 – Activated May 2004
IMPORT Low trial 2,015 2,015 Accrual closed Aug 2010
(Coles and Yarnold 2006)
Barcelona trial 46 – Interim analysis showed no Grade 3 toxicity
in PBI arm at
18 months.
Florence Trial (Livi et al. 2010) 259** 520 Only Grade 1 (5%) and Grade 2 (0.8%) acute
skin toxicity with interim analysis (2009)
University of Erlangen – 1,300 WBI versus APBI using HDR and Pulsed dose
rate (PDR) brachytherapy. Activated May 2006.
*
As of June 2009
**
As of August 2008

4–6 cm and, in general, the length of treatment is
\ 5 min (Orecchia et al. 2003). A typical dose for
electron-based IORT is 21 Gy delivered to 90% IDL
for electrons and 20 Gy delivered to the lumpectomy
bed for photon-based radiation therapy.
With IORT, if a surgical margin is determined to
be positive or if an adverse pathologic factor is
identified on final review of the surgical specimen, the
intraoperative treatment is considered a boost and the
patient returns for daily outpatient whole breast
irradiation.
10 Clinical Outcomes
Many single-institutional and collaborative series on
APBI have been published and updated in the litera-
ture including long-standing series from William
Beaumont Hospital, Virginia Commonwealth Uni-
versity, Tufts Medical Center, New York University,
and others (Tables 6 and 7). The results of two Phase
III trials comparing APBI and WBI are available. The
National Institute of Oncology in Hungary conducted
a randomized trial of 258 patients, reporting five-year
interim analysis in 2007 showing equivalent control
between the study arms with a local recurrence of
4.7% in the partial breast irradiation arm and 3.4% in
the WBI arm (not statistically significant) (Polgar
et al. 2007). Cosmesis was improved in the patients
receiving HDR partial breast irradiation versus those
who received standard WBI. The TARGIT trial
reported the outcomes of a randomized trial testing
single fraction IORT against standard WBI at a
median follow up of 4 years. Very low local relapse
rates were reported in both trial arms and no signifi-
cant differences was seen between them. Several
Accelerated Partial Breast Irradiation
Table 9 European IORT trials
Institution # Patients
TARGIT (Vaidya et al. 2010) 2,232
ELIOT trial (Milan) 1,822
(Veronesi et al. 2010; Holmes et al. 2007)
European Institute of Oncology 1,303
institutions are in the process of accruing patients for
ongoing Phase III trials comparing APBI to WBI. The
preliminary accrual results and anticipated closure
dates for several of these trials are summarized in
Table 8. Assuming an IBTR rate of 2.5% at 5 years
after breast conservation surgery and WBI, exclusion
of 3% inferiority after APBI with 90% power at the
5% significance level requires a total of 53 IBTR
events gathered over a minimum follow up period of
5 years. This would require 1548 patients to be fol-
lowed for [ 5 years, something that currently com-
pleted studies fall far short of providing.
The consistency of the data presented in both the
single and multi-institutional series, however, is
important. At this stage, the length of follow up is
short, compared to the experience of WBI data, but if
partial breast irradiation continues to demonstrate
excellent local control rates at both 5 and 10 years in
patients with low risk to breast disease, APBI will
continue to grow as an important component of
adjuvant therapy following breast conserving surgery.
Intraoperative radiotherapy is also likely to continue
to gain interest in the United States and elsewhere,
more so if as the results of the European Phase III
trials continue to show non-inferiority between WBI
and intraoperative therapy (Table 9).
11 Future Directions
Accelerated partial breast irradiation has an exciting
future. The continued results of the Phase III trials
will help shape patient selection and help give
definitive answers to the extent of breast irradiation
needed following partial mastectomy. Some addi-
tional aspects evolving in the general breast cancer
arena including gene microarray, histologic subtyp-
ing, and improved patient survival, will have impor-
tant implications for APBI.
711
Follow up (mo) Outcome
48 mo. LR 1.2% for APBI vs. 0.95% for WBI (p = n.s.)
36 mo. LR 2.3%
OS 97.4% (5 yr)
89.7% (10 yr)
– Pending, trial closed in 2007
Continued development of safe and effective
fractionation schedules will also continue to be
important. At least two of the companies that manu-
facture brachytherapy applicators have sponsored
Phase II trials using two-day dose fractionation
schedules in the United States. In addition, the
application of APBI to previously treated breasts will
remain an important area of investigation with the
recently opened RTOG 1014 trial (2010).
Finally, the sequencing of surgery and radiation
and whether radiation can be omitted in select groups
of very-low risk patients will continue to be debated
within the oncology community.
Acknowledgments We wish to acknowledge Prof. John Yar-
nold and Dr. Ellen Donovan from Royal Marsden Hospital
and Dr. Charlotte coles from Cambridge University Hospitals
for their important contributions to this chapter regarding
ongoing clinical trials and radiotherapy techniques in Europe.
Without their assistance, this chapter would not have been
possible.
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 Esophageal Cancer
Brian G. Czito and Christopher G. Willett

Contents 17 Radiation Therapy Alone ....................................... 740

18 Preoperative Radiation Therapy ........................... 740
1 Anatomy.................................................................... 718 19 Postoperative Radiation Therapy .......................... 741
2 Lymphatic Drainage................................................ 719 20 Postoperative Combined Chemoradiation............ 741
3 Natural History and Patterns of Spread .............. 720 21 Preoperative Chemotherapy................................... 741
4 Local Failure ............................................................ 723 22 Preoperative Chemoradiation Versus Surgery
5 Clinical Presentation ............................................... 723 Alone.......................................................................... 742

6 Diagnostic Work-up ................................................ 723 23 Preoperative Chemoradiation Versus

Preoperative Chemotherapy................................... 744
7 Staging Systems........................................................ 726
24 Radiation Therapy Alone Versus
8 Pathologic Classification ......................................... 726 Chemoradiation........................................................ 744
9 Radiation Therapy Techniques.............................. 726 25 Chemoradiation Versus Chemoradiation
9.1 Simulation .................................................................. 726 followed by Surgery ................................................ 744
10 Treatment Planning................................................. 730 26 Brachytherapy.......................................................... 745
10.1 Target Design ............................................................ 730
27 Palliative Treatment ................................................ 746
11 Field Design .............................................................. 731
28 Treatment Sequelae................................................. 747
12 Dose Constraints ...................................................... 738
29 Future Considerations............................................. 749
13 Doses of Radiation ................................................... 738
30 Summary................................................................... 749
14 Brachytherapy.......................................................... 739
References.......................................................................... 750
15 Results of Therapy .................................................. 739
16 Surgery Alone .......................................................... 739
Abstract
Less than 15% of patients diagnosed with esoph-
ageal cancer are cured, with half of patients
presenting with unresectable or metastatic disease.
B. G. Czito (&)
This chapter will review the natural history and
Department of Radiation Oncology,
Duke University Medical Center, treatment of esophageal cancer, including anat-
Morris Bldg, Box 3085, omy, patterns of spread and failure, staging,
Durham, NC 27710, USA radiation planning techniques, toxicity data and
e-mail: Czito@radonc.duke.edu
future treatment strategies.
C. G. Willett
Department of Radiation Oncology,
Duke University, Durham, NC, USA

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 717
DOI: 10.1007/174_2011_368, Ó Springer-Verlag Berlin Heidelberg 2012
718 B. G. Czito and C. G. Willett

1 Anatomy

The esophagus is a thin-walled, hollow tube approx-

imately 25 cm in length. It is lined with stratified
keratinized squamous epithelium, extending from the
cricopharyngeus muscle at the level of the cricoid
cartilage superiorly to the gastroesophageal junction
inferiorly. The lower third (5–10 cm) of the esopha-
gus may contain glandular elements. Replacement of
Fig. 1 Diagram of esophageal wall (Used with the permission
the stratified squamous epithelium with columnar of the American Joint Committee on Cancer (AJCC), Chicago,
epithelium is referred to as Barrett’s esophagus, often Illinois. The original source for this material is the AJCC
occurring in the lower third. The Z-line refers to the Cancer Staging Manual, Seventh Edition (2010) published by
endoscopically visible junction of the squamous and Springer Science and Business Media LLC, http://www.
springer.com.)
glandular epithelium. The esophageal wall is com-
posed of three layers: the mucosa, submucosa and
muscularis propria (Fig. 1). The mucosal layer con-
tains the epithelium, lamina propria and muscularis
mucosae. The epithelium is separated from the lamina
propria by a basement membrane. In the portion of
esophagus containing columnar-type epithelium, the
muscularis mucosae may consist of two layers. The
mucosa may be divided into distinct layers, including
M1 (epithelium), M2 (lamina propria) and M3
(muscularis mucosae). Similarly, the submucosal
layer may be divided into inner (SM1), middle (SM2)
and outer (SM3) layers. The muscularis propria con-
sists of a circular inner layer and a longitudinal outer
layer. The adventitia (periesophageal connective tis-
sue) lies directly on the muscularis propria (American
Joint Committee on Cancer 2010). No serosa is
present, facilitating extra esophageal spread of
disease.
Although somewhat arbitrary, the esophagus is
frequently divided into cervical and thoracic compo-
nents. The most recent American Joint Committee on
Cancer (AJCC) report divides the esophagus into four
regions: cervical, upper thoracic, mid-thoracic, and
lower thoracic (American Joint Committee on Cancer
Fig. 2 Anatomy of the esophagus. Note the lengths of the
2010); (Fig. 2). The cervical esophagus begins at the various segments of the esophagus as measured from the upper
cricopharyngeus muscle (approximately the C7 level or central incisors (Used with the permission of the American
15 cm from the incisors) and extends to the thoracic Joint Committee on Cancer (AJCC), Chicago, Illinois. The
inlet (at approximately the T3 level or at approximately original source for this material is the AJCC Cancer Staging
Manual, Seventh Edition (2010) published by Springer Science
20 cm from the incisors, at the level of the suprasternal and Business Media LLC, http://www.springer.com.)
notch), and therefore lies within the neck. The thoracic
esophagus extends from approximately the level of T3
(beginning at about 20 cm) to T10 or T11 (American superiorly by the thoracic inlet and inferiorly by the
Joint Committee on Cancer 2010; Rosenberg et al. lower border of the azygos vein, extending from
1981). The upper thoracic esophagus is bordered approximately 20–25 cm. Radiographically, tumors in
Esophageal Cancer
Fig. 3 Siewert classification of the gastroesophageal junction
cancers according to the location of the tumor (Reprinted from
EORTC-ROG expert opinion: Radiotherapy volume and treat-
ment guidelines for neoadjuvant radiation of adenocarcinomas
of the gastroesophageal junction and the stomach Ó 2009
Elsevier Ireland Ltd. All rights reserved (Matzinger et al.
2009))
this location would be located between the sternal notch
and azygos vein. The middle thoracic esophagus
extends from the lower border of the azygos vein to the
inferior pulmonary veins, extending from approxi-
mately 25–30 cm. The lower thoracic esophagus
extends from the inferior pulmonary veins and to the
stomach, and is inclusive of the gastroesophageal
junction, typically extending from approximately 30–
40 cm. Endoscopically, the gastroesophageal (GE)
junction is often defined as the point where the first
gastric fold is encountered, although this may be a
‘‘theoretical’’ landmark. The location of the GE junc-
tion can be accurately defined histologically as the
squamocolumnar junction. In the most recent AJCC
staging system, cancers with an epicenter in the lower
thoracic esophagus, gastroesophageal junction or
within the proximal 5 cm of the stomach (i.e. cardia)
and extending up to the GE junction or esophagus are
staged as an adenocarcinoma of the esophagus. If the
epicenter is greater than 5 cm distal to the gastro-
esophageal junction or within 5 cm of the gastro-
esophageal junction but does not extend to the
junction/esophagus, tumors are classified as stomach
719
cancers. Useful landmarks in reference to endoscopy
include the carina (approximately 25 cm from the
incisors) and gastroesophageal junction (approxi-
mately 40 cm from the incisors).
Siewert and colleagues characterized cancer
involving the gastroesophageal junction according to
the location of the tumor (Fig. 3). If the tumor center
is located [1 cm up to 5 cm above the gastroesoph-
ageal junction (Z-line), the tumor is classified as a
type I adenocarcinoma of the distal esophagus. If the
tumor center is located within 1 cm cephlad to 2 cm
caudad to the gastroesophageal junction, it is classi-
fied as type II. If the tumor center is located [2 cm
below the gastroesophageal junction, the tumor is
classified as type III (Rudiger Siewert et al. 2000).
However, locally advanced/bulky tumors can make it
difficult to accurately distinguish where tumors
originated in relation to the GE junction.
2 Lymphatic Drainage
The esophagus has an extensive, longitudinal inter-
connecting system of lymphatics. The esophageal
lymphatic network is primarily located within the
submucosa; however, channels are also present within
the lamina propria, facilitating spread of even super-
ficial cancers of the esophagus involving the mucosa.
In addition to these longitudinal lymphatics, intra-
mural lymphatics may traverse the muscularis pro-
pria, facilitating tumor spread to regional lymphatic
channels and paraesophageal nodes. Supporting this,
autopsy series have demonstrated a relatively high
incidence of directly draining channels extending
from the submucosa lymphatics into the thoracic duct
(Fig. 1), facilitating systemic spread. Lymph can
travel the entire length of the esophagus before
draining into lymph nodes (Rosenberg et al. 1981),
and thus the entire esophagus is at potential risk for
lymphatic involvement. Up to 8 cm or more of
‘normal’ tissue can exist between gross tumor and
micrometastases ‘‘skip’’ areas secondary to this
extensive lymphatic network (Goodner et al. 1956).
Additionally, as many as 71% of frozen tissue
sections scored as margin-negative by conventional
histopathology show involvement by lymphatic mi-
crometastases with immunohistochemistry (Hosch
et al. 2001). Lymphatics of the esophagus drain into
nodes that usually follow arteries, including the
720 B. G. Czito and C. G. Willett

Table 1 Distribution of metastases by anatomic site patients. In patients with cervical lesions, lymph node
Site No. of Patients Percentage metastases to the abdominal lymph nodes are rare.
Lymph nodes 58 73 Distant metastasis can occur at almost any site
(Table 1); (Anderson and Lad 1982).
Lung 41 52
A review of 1077 patients with squamous cell
Liver 37 47
carcinoma of the thoracic esophagus undergoing
Adrenals 16 20 esophagectomy further characterized patterns of
Diaphragm 15 19 nodal spread. Primary disease was located in the
Bronchus 13 17 upper (5%), middle (63%) and lower (32%) thoracic
Pleura 13 17 esophagus. In total, 47% of patients had lymph node
Stomach 12 15 metastases. On multivariate analysis, T stage, tumoral
Bone 11 14 length and degree of differentiation significantly
Kidneys 10 13
correlated with incidence of lymph node metastases.
In approximately 6% of cases, skip metastasis (distant
Trachea 10 13
lymph node metastases without regional lymph
Pericardium 9 11
node metastasis) occurred, usually in patients with
Pancreas 9 11 poorly differentiated, large and deeply invasive
From Anderson and Lad (1982) with permission tumors. Of involved nodes, 37% were macroscopi-
cally involved versus 63% microscopically involved,
indicating that most lymph node metastases would be
inferior thyroid artery, the bronchial and esophageal below the resolution of detection using contemporary
arteries, and the left gastric artery (celiac axis) imaging tools. Lymph node involvement was grouped
(Sharpiro and Robillard 1950). into 5 categories; cervical, thoracic upper mediasti-
num, thoracic middle mediastinum, thoracic lower
mediastinum and abdominal lymph nodes. Figure 4
3 Natural History and Patterns shows the incidence of nodal metastases based on
of Spread primary tumor location (Huang et al. 2010).
For lower esophageal and gastroesophageal junc-
Squamous cell carcinoma is characterized by exten- tional adenocarcinomas, approximately 70% of
sive local growth and proclivity to lymph node patients will have nodal metastases at presentation.
metastases. Because the esophagus has no covering This is influenced by tumoral depth of penetration,
serosa, direct invasion of contiguous structures may with nearly all T3 and T4 lesions exhibiting metas-
occur early. Lesions in the upper esophagus can tases in surgical series. Pathologic resection data from
impinge on or invade the recurrent laryngeal nerves, (Dresner et al. 2001) showed rates of lymphatic
carotid arteries and trachea. If extra esophageal involvement for lower esophageal and GE junctional
extension occurs in the mediastinum, tracheoesopha- tumors of 45, 85 and 100% for T2, T3 and T4 tumors
geal or bronchoesophageal fistula may occur. Tumors respectively (Dresner et al. 2001); (Fig. 5). In patients
in the lower third of the esophagus can invade the with lower esophageal cancer, involvement of both
aorta or pericardium, resulting in mediastinitis, mas- mediastinal and abdominal lymph nodes is common
sive hemorrhage or empyema. (Dresner et al. 2001); (Fig. 6). The primary direction
A review correlating the incidence of lymph node for lymphatic flow for the lower esophagus is toward
metastases with depth of penetration revealed that the abdomen. According to the classification by
18% of patients with spread to the submucosa had Siewert, nodal metastases are often seen in the
lymph node involvement (Holdscher et al. 1995). For mediastinum and abdomen for type I tumors, whereas
T1 lesions, the reported incidence of nodal spread is Type III tumors metastasize almost exclusively infe-
14–21%; for T2 lesions, this rises to 38–60%. The riorly, toward the celiac axis. Type II tumors are
location of involved lymph nodes is influenced by the intermediate, preferentially spreading inferiorly and
origin of the primary tumor. At autopsy, lymph node less frequently into the mediastinum. The primary
metastases are found in approximately 70% of value in the Siewert classification is to the guidance of
Esophageal Cancer 721

Fig. 4 Positive lymph node

distribution according to the
location of the primary tumor,
squamous cell carcinoma
(Reprinted from Pattern of
lymph node metastases
and its implication in
radiotherapeutic clinical
target volume in patients with
thoracic esophageal squamous
cell carcinoma: A report of
1077 cases Ó 2010 Elsevier
Ireland Ltd. All rights
reserved (Huang et al. 2010)

Fig. 5 The incidence of

nodal metastases related to
depth of tumor invasion,
adenocarcinoma

Fig. 6 Distribution of nodal

metastases by frequency of
site involved for
adenocarcinoma
722 B. G. Czito and C. G. Willett

Fig. 7 Locations of lymph

node stations. (Adapted from
Japanese Gastric Cancer
Association. Japanese
classification of gastric
carcinoma—2nd English
edition—response assessment
of chemotherapy and
radiotherapy for gastric
carcinoma: Clinical criteria.
Gastric Cancer 2001; 4:1–8.
Ó 2001 by International and
Japanese Gastric Cancer
Associations)

appropriate type surgery (i.e. type I tumors are gen-
erally treated with esophagectomy and mediastinal
lymph node resection, with types II and III approa-
ched through the abdomen (Rudiger Siewert et al.
2000). Generally speaking, the incidence of abdomi-
nal nodal involvement increases as one proceeds
distally in the esophagus to the gastroesophageal
junction. For patients with tumors arising from the
gastroesophageal junction, mediastinal involvement is
less common. Nodal metastases above the level of the
carina are rare in lower esophageal and junctional
tumors (Monig et al. 2002). Additionally, histologic
analyses of lower esophagus and gastroesophageal
junction adenocarcinoma specimens suggest that
many patients without nodal involvement on con-
ventional histopathology actually have involvement
when assessed by immunohistochemistry (Schurr
et al. 2006).
Extensive nodal mapping has been performed
by Japanese investigators, who have devised the
Japanese Gastric Cancer Association Classification
(Matzinger et al. 2009); (Fig. 7). Using this system of
nodal classification, investigators from Erlangen
evaluated 326 patients with esophagogastric junction
carcinoma undergoing primary resection. Tumors
were stratified as AEG type I (distal esophagus), II
(gastric cardia) and III (subcardia). Note that there
was significant overlap in the majority of tumors for
all stages, with an overall incidence of lymph node
metastasis of 71%. In T1 patients, only 17% exhibited
lymph node metastasis, whereas 78, 86 and 90% of
T2, T3 and T4 had involved nodes. Figure 8a–d
shows varying patterns of nodal spread based on
T stage as well as AEG location. Additional gener-
alizations from this study include that lymph vascular
invasion was highly predictive of nodal spread and
Esophageal Cancer
that proximal extension of type II and III tumors into
the distal esophagus (particularly beyond the Z line)
predicted for an increasing incidence of paraesopha-
geal lymph node involvement (Meier et al. 2008).
4 Local Failure
Aisner and colleagues (Aisner et al. 1983) and
LePrise and associates (LePrise et al. 1995) reviewed
the patterns of failure in esophageal cancer after
radical irradiation, radical surgery or a combination of
both (Table 2); (LePrise et al. 1995). These data
suggest that high rates of local recurrence occur when
either radiation therapy or surgery alone is used. In a
series at the Hospital of the University of Pennsyl-
vania and Fox Chase Cancer Center of patients with
adenocarcinoma of the esophagus and gastroesopha-
geal junction treated with surgery alone, the local–
regional recurrence rate was 77% (Whittington et al.
1990). In contemporary randomized trials, local fail-
ure rates with surgery alone range from 32–45%
(Hulscher et al. 2002; Kelsen et al. 1998; Law et al.
1996; Urba et al. 2001). Data from recent randomized
trials of esophageal cancer using ‘definitive’ chemo-
radiation also indicate local failure as a major cause
of failure, with approximately 50% of patients failing
locally (Table 3). In many trials, patterns of failure are
reported as first site of recurrence. This fact, along with
infrequent post therapy imaging and inability to detect
subclinical recurrences, likely underestimates local
recurrence rates. These data clearly emphasize the need
for improvements in local treatment modalities.
5 Clinical Presentation
Symptoms of esophageal cancer often start 3–4 months
before diagnosis. Location of the primary tumor in the
esophagus may influence presenting symptoms. Dys-
phagia is seen in more than 90% of patients regardless
of location. Odynophagia is present in up to 50% of
patients (Rosenberg et al. 1989). Weight loss is
common, with 40–70% of patients reporting a loss
of [5% of total body weight. This extent of weight
loss has been associated with a worse prognosis. Less
frequent symptoms may include vague chest pain,
hoarseness, cough and glossopharyngeal neuralgia
(Moertel 1982).
723
Advanced lesions can produce signs and symptoms
from tumor invasion into local structures. Hematem-
esis, hemoptysis, melena, dyspnea and persistent
cough secondary to tracheoesophageal or broncho-
esophageal fistula may occur. Compression or inva-
sion of the left recurrent laryngeal nerve or the
phrenic nerves can cause dysphonia or hemidia-
phragm paralysis, respectively. Superior vena cava
syndrome and Horner’s syndrome can also occur for
very advanced lesions. Pleural effusion and exsan-
guination resulting from aortic communication may
also be seen (Rosenberg et al. 1989). Abdominal and
back pain may occur with celiac axis nodal involve-
ment with lower esophageal tumors.
6 Diagnostic Work-up
After a thorough history and physical examination, all
patients with suspected esophageal cancer should
have a work-up similar to that outlined in Table 4.
Attention should be paid to cervical and supracla-
vicular lymph node basins. Basic blood counts and a
metabolic panel with liver function tests should be
obtained.
Although the esophagogram may be used to
define lesion extent, endoscopy is the best tool to
diagnose and define the extent of the lesion
(Thompson 1983). During flexible endoscopy, bio-
psies and brushings should be taken of the primary
site and suspicious areas harboring satellites or
submucosal spread. Additionally, accurate endo-
scopic measurement and characterization of tumor
and gastroesophageal junction in relation to the
incisors facilitates radiation treatment planning.
Examination with panendoscopy of the oral cavity,
pharynx, larynx and tracheobronchial tree may also
be performed at the time of esophagoscopy in
patients with squamous cell carcinomas given the
high incidence of second tumors in the head and
neck and upper airway (Rosenberg et al. 1981).
Additionally, bronchoscopy should generally be
performed in patients with proximal malignancies to
evaluate for the presence of tracheal or carinal
invasion, particularly for patients with tumors abut-
ting these structures on computed tomography (CT).
CT of the thorax and abdomen is critical to identify
metastases to the liver, upper abdominal nodes or
adrenals. However, CT may not adequately assess
724 B. G. Czito and C. G. Willett

a b

lower paraesophageal 29 74

left paracardial
right paracardial
36 47 43 45
splenic artery
celiac left gastric splenic hilum
6 38 55 27 36
18 39 11

71 61
greater curve
17 37
lesser curve
17 left gastroepiploic 33

9 29
right gastroepiploic

T2 frequency (%) of nodal involvement (modified from Meier et al) T3-4 frequency (%) of nodal
involvement

c d

55 39

44 47 46
35

30 51 9 14 20 41 18 15

61 71
26 21
25 21

18 13

AEG type I tumors frequency AEG type II/III frequency (%) of

(%) of nodal involvement nodal involvement

Fig. 8 a Frequency of nodal involvement for T2 tumors. b Frequency of nodal involvement for T3–4 tumors. c Frequency of
involvement for AEG type I tumors d Frequency of nodal involvement AEG type II/III tumors
Esophageal Cancer 725

Table 2 Patterns of failure in esophageal cancer

Recurrence (%)
Modality No. of Local Marginal Neck Mediastinal Local Distant
Patients and
Distant
Irradiation alone (30–80 Gy) 517 25–84 25 10–43 23–65
Radical surgery alone 266 21–50 44 33 17–65
33
Abdominal
nodes
17 Liver
6 Lung
Combined radiation therapy and surgery 2,078 22–87 53a 20a 7–43b
(primarily preoperative irradiation, 35–
50 Gy usual dose)
Radiation therapy and chemotherapy 254 15–39 5–25
alonec
6–25
Preoperative radiation therapy and 150 2–36 5–38 16–29
chemotherapyc
a
From one study
b
From two studies
c
Data from LePrise et al. (1995)
Modified from Aisner J, Forastiere A, Aroney R. Patterns of recurrence for cancer of the lung and esophagus. In: Wittes RE, ed.
Cancer treatment symposia: proceedings of the Workshop on Patterns of Failure after Cancer Treatment, vol 2. Washington, DC:
U.S. Department of Health and Human Services, 1983:87, with permission

Table 3 Local failure rates from randomized trials evaluating chemoradiation alone in esophageal cancer
Dose (Gy) Local failure (crude) Local failure (2 yr)
(%) (%)
RTOG 85-01 (al-Sarraf et al. 1997) 50 45 47
INT 0123 (Minsky et al. 1999) 50 55 52
INT 0123 (Minsky et al. 1999) 64 50 56
German (Stahl et al. 2005) [60 51 58

periesophageal lymph node involvement or accu-
rately define the true extent of the primary tumor
(Lea et al. 1984; Picus et al. 1983). Conventional CT
scan can accurately determine resectability in only
65–85% of cases. Furthermore, CT accurately pre-
dicts T Stage in approximately 70% of cases and
nodal involvement in only 50–70% of cases (Griffith
et al. 1999; Rankin et al. 1998; Kole et al. 1998).
To more accurately assess periesophageal and
celiac lymph node involvement and transmural extent
of disease, endoscopic ultrasonography (EUS) should
be performed. EUS provides accuracy rates of 85–
90% for tumor invasion (T stage) and 75–80% for
lymph node metastases, when matched to surgical
pathology (Kelly et al. 2001; Konski et al. 2005;
Rosch 1995). However, the accuracy of endoscopic
ultrasound following neoadjuvant therapy is signifi-
cantly less, ranging from 27–48% for T staging and
38–71% for N staging. This is possibly due to the
failure to discriminate tumor from post radiation
inflammation and fibrosis (Beseth et al. 2000; Laterza
et al. 1999; Zeccaro et al. 1999).
726
Table 4 Diagnostic work-up for esophageal cancer
Multidisciplinary evaluation (Surgical, Radiation and Medical
Oncology)
History and Physical
Complete blood count and chemistry profile.
Upper gastrointestinal endoscopy and biopsy.
Chest, abdomen and pelvic CT with oral and IV contrast
(preferably correlated with PET scan).
PET evaluation (preferably in conjunction with contrasted
CT)
Endoscopic ultrasound, with FNA if indicated (if no evidence
of distant metastases)
Bronchoscopy if tumor located at or above the carina or
suspected airway involvement
Nutritional assessment and consideration of feeding tube
(nasogastric or feeding jejunostomy) in selected situations
Surgical staging procedures, including thoracos-
copy, mediastinoscopy and laparoscopy, may provide
additional staging information and are considered in
selected patients at some institutions (Jaklitsch et al.
1994).
Patients with significant obstruction with inability
to maintain their weight may require placement of
feeding tube. If surgery is planned, gastric tube
placement is generally avoided given the stomach will
ultimately serve as the ‘‘neoesophagus’’ following
resection.
More recently, positron emission tomography
(PET) has proven to be a valuable staging tool in
esophageal cancer patients. The addition of PET to
standard staging studies such as CT can improve the
accuracy of detecting stage III and stage IV disease by
23 and 18%, respectively (Blackstock et al. 2006;
Flamen et al. 2000). Overall, it is estimated that PET
will detect distant metastatic disease in approximately
20% of patients who are considered to have local
regional disease only by CT. However, PET also
appears to have a lower accuracy in detecting local
nodal disease compared to CT alone or in combina-
tion with endoscopic ultrasound. Importantly,
emerging data suggest that PET can be used to predict
response to therapy, with ‘‘PET responders’’ experi-
encing significantly improved outcomes compared to
‘‘nonresponders’’ (Monjazeb et al. 2010). Addition-
ally, PET has been used to predict response to treat-
ment early during the treatment course. This has led
to ongoing investigation of early treatment response
as measured by PET as a surrogate for therapeutic
efficacy and clinical outcomes (Weber and Ott 2004).
B. G. Czito and C. G. Willett
7 Staging Systems
Esophageal staging can be based on pathologic or
clinical criteria. Pathologic staging is performed after
invasive procedures including esophagectomy, medi-
astinotomy or thoracotomy. Clinical staging is often
employed with ‘‘definitive’’ and neoadjuvant chemo-
radiation approaches and is less accurate. With the
combination of CT, PET and EUS, clinical staging
closely correlates with pathologic stage. Note that the
most recent AJCC staging system takes into consid-
eration tumor type, grade as well as involved number
of lymph nodes (Table 5).
8 Pathologic Classification
Squamous cell carcinoma and adenocarcinoma com-
prise 95% of all esophageal tumors, although other
rare histologic subtypes are occasionally seen (Oota
and Shin 1977).
For squamous cell carcinomas, some investigators
have proposed that the degree of cellular differentiation
influences survival, (Yang 1980) although others have
reported no association of cellular differentiation to lymph
node involvement or survival (Rosenberg et al. 1981).
Adenocarcinoma is now the predominant histo-
logic type of esophageal cancer in the United States
and many European countries. Adenocarcinoma may
arise from foci of ectopic gastric mucosa or intrinsic
esophageal glands. However, it is believed the vast
majority arises from Barrett’s esophagus. As above,
both tumor histology and grade are now considered in
esophageal cancer staging.
9 Radiation Therapy Techniques
9.1 Simulation
When patients are simulated, the radiation oncologist
should know the extent of disease based on imaging
(barium swallow, CT, PET) as well as endoscopy. CT
simulation is appropriate for treatment planning.
During simulation, the patient is positioned in the
supine position, straightened and immobilized on the
simulation table. An immobilization device is used to
minimize variation in daily setup. Arms are generally
Table 5 Esophageal Cancer Staging, American Joint Committee on Cancer, 7th Edition
Extent of disease before any treatment Stage Category Definitions Pathologic
Extent of disease through completion of definitive
surgery
y clinical- staging completed after neoadjuvant therapy but y pathologic- staging completed after neoadjuvant
Esophageal Cancer

before subsequent surgery therapy AND subsequent surgery

Primary Tumor (T)
TX Primary tumor cannot be assessed TX
TO No evidence of primary tumor TO
Tis High-grade dysplasia* Tis
T1 Tumor invades lamina propria, muscularis mucosae, T1
or submucosa
T1a Tumor invades lamina propria or muscularis T1a
mucosae
T1b Tumor invades submucosa T1b
T2 Tumor invades muscularis propria T2
T3 Tumor invades adventitia T3
T4 Tumor invades adjacent structures T4
T4a Resectable tumor invading pleura, pericardium, or T4a
diaphragm
T4b Unresectable tumor invading other adjacent T4b
structures, such as aorta, vertebral body, trachea, etc.
*High-grade dysplasia includes all non-invasive
neoplastic epithelium that was formerly called
carcinoma in situ, a diagnosis that is no longer used
for columnar mucosae anywhere in the
gastrointestinal tract.
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed NX
NO No regional lymph node metastasis NO
N1 Regional lymph node metastases involving 1 to 2 N1
nodes
N2 Regional lymph node metastases involving 3 to 6 N2
nodes
(continued)
727
Table 5 (continued)
728

Extent of disease before any treatment Stage Category Definitions Pathologic

Extent of disease through completion of definitive
surgery
N3 Regional lymph node metastases involving 7 or more N3
nodes

Distant Metastasis (M)

M0 No distant metastasis (no pathologic MO; use M0
clinical M to complete stage group)
M1 Distant metastasis M1
Anatomic Stage – Prognostic Groups
Squamous Cell Carcinoma*, Clinical or Pathologic Adenocarcinoma, Clinical or Pathologic
Group T N M Grade Tumor Group T N M Grade
Location**
0 Tis(HGD) N0 M0 1 Any 0 Tis(HGD) N0 M0 1,X
IA T1 N0 M0 1,X Any IA T1 N0 M0 1-2, X
IB T1 N0 M0 2-3 Any IB T1 N0 M0 3
T2-3 N0 M0 1,X Lower, X T2 N0 M0 1-2, X
IIA T2-3 N0 M0 1,X Upper, middle IIA T2 N0 M0 3
T2-3 N0 M0 2-3 Lower, X IIB T3 N0 M0 Any
IIB T2-3 N0 M0 2-3 Upper, middle T1-2 N1 M0 Any
T1-2 N1 M0 Any Any IIIA T1-2 N2 M0 Any
IIIA T1-2 N2 M0 Any Any T3 N1 M0 Any
T3 N1 M0 Any Any T4a N0 M0 Any
T4a N0 M0 Any Any IIIB T3 N2 M0 Any
IIIB T3 N2 M0 Any Any IIIC T4a N1- M0 Any
2
IIIC T4a N1- M0 Any Any T4b Any M0 Any
2
T4b Any M0 Any Any Any N3 M0 Any
Any N3 M0 Any Any IV Any Any M1 Any
IV Any Any M1 Any Any Stage
unknown
B. G. Czito and C. G. Willett
*or mixed histology including a squamous component or NOS
**Location of the primary cancer site is defined by the position of the upper (proximal) edge of the tumor in the esophagus
General Notes:
For identification of special cases of TNM or pTNM classifications, the ‘‘m’’ suffix and ‘‘y’’,’’r’’ and ‘‘a’’ prefixes are used. Although they do not affect the stage grouping, they
indicate cases needing separate analysis
m suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM
Esophageal Cancer

y prefix indicates those cases in which classification is performed during or following initial multimodality therapy. The cTNM or pTNM category is identified by a ‘‘y’’ prefix.
The ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination. The ‘‘y’’ categorization is not an estimate of tumor prior to multimodality
therapy
r prefix indicates a recurrent tumor when staged after a disease-free interval, and is identified by the ‘‘r’’ prefix: rTNM
a prefix designates the stage determined at autopsy: aTNM
surgical margins is data field recorded by registrars describing the surgical margins of the resected primary site specimen as determined only by the pathology report
neoadjuvant treatment is radiation therapy or systemic therapy (consisting of chemotherapy, hormone therapy or immunotherapy) administered prior to a definitive surgical
procedure. If the surgical procedure is not performed, the administered therapy no longer meets the definition of neoadjuvant therapy
Additional Descriptors
Lymphatic Vessel Invasion (L) and Venous Invasion (V) have been combined into Lymph-Vascular invasion (LVI) for collection by cancer registrars. The College of
American Pathologists’ (CAP) checklist should be used as the primary source. Other sources may be used in the absence of a checklist. Priority is given to positive results
Lymph-Vascular Invasion Not Present (absent)/Not Identified
Lymph-Vascular Invasion Present/Identified
Not Applicable
Unknown/Indeterminate
Residual Tumor (R)
The absence or presence of residual tumor after treatment. In some cases treated with surgery and/or with neoadjuvant therapy there will be residual tumor at the primary site after
treatment because of incomplete resection or local and regional disease that extends beyond the limit of ability of resection
RX Presence of residual tumor cannot be assessed
R0 No residual tumor
R1 Microscopic residual tumor
R2 Macroscopic residual tumor
729
730
placed overhead and knee support underneath the legs.
Palpable neck disease should be marked with a radio-
opaque wire. The administration of oral contrast to
delineate the esophagus is generally used and helps
define the extent of mucosal irregularity. For GE
junctional tumors (particularly with significant gastric
involvement), it may be advisable to have the patient
come in with an empty stomach. For cervical and upper
thoracic lesions, an immobilization mask may assist in
an accurate reproducibility. Some authors have also
advocated that mid-esophageal primaries be simulated
in prone position to maximize distance between the
target volumes and the spinal cord (Minsky 2007). The
patient is placed on the CT simulator in the treatment
position, and a scan of the entire area of interest with
margin is obtained. At the minimum, 3–5 mm slices
should be used, allowing accurate tumor characteriza-
tion as well as improved quality of digitally recon-
structed radiographs. If patients lose greater than 10%
of their body weight during therapy, consideration
should be given to repeat CT planning. Arterial phase
IV contrast is generally used to delineate mediastinal
and abdominal vascular nodal basins, including the
celiac axis and to allow the radiation oncologist to
discern normal vasculature from other adjacent normal
structures, potential adenopathy, etc. The tumor and
vital structures are then outlined on each slice on the
treatment planning system, enabling a 3-dimensional
treatment plan to be generated. The use of respiratory
gating or breath hold techniques may help reduce target
motion with respiration and, therefore, avoidance of
normal tissue irradiation associated with larger margins
used in free-breathing approaches, particularly for
lower esophageal cancers. Additional techniques to
minimize physiologic motion include abdominal
compression devices. Four-dimensional CT scan may
be appropriate to assess tumoral motion, facilitating
appropriate margin placement on the target volumes,
particularly in lower esophageal tumors and/or disease
involving the stomach.
10 Treatment Planning
10.1 Target Design
In the design of radiation fields for esophageal cancer,
it is important to define varying target volumes,
including gross disease as well as potential areas of
B. G. Czito and C. G. Willett
subclinical involvement (i.e. the GTV/gross tumor
volumes and CTV/clinical target volumes, respec-
tively). Defining gross tumor volume is based on
multiple studies, including endoscopic descriptions
(from both esophagogastroduodenoscopy (EGD) and
endoscopic ultrasound). The proximal and distal
aspects of the tumor should be standardly defined by
the gastroenterologist based on distance from the
incisors, as well as relationship to varying landmarks
as measured from the incisors (eg. the GE junction).
The Radiation Oncologist is able to use these
measurements to help correlate with disease extent
visualized on planning CT scan, using varying ana-
tomic land marks (example the GE junction, which is
frequently located around 40 cm from the incisors in
many patients), as well as carina (which is frequently
located around 25 cm in most patients) to help more
accurately define the GTV. Esophageal wall thick-
ening correlating to the gross tumor volume can
frequently be visualized on diagnostic and radiation
planning CT. Similarly, endoscopic ultrasound
appears to be the most reliable test in detecting
lymphadenopathy related to nodal spread. As in EGD,
the endoscopist should be encouraged to accurately
define not only the primary disease extent on EUS as
measured by distances from the incisors, but also
depth of penetration and potential involvement of
adjacent structures which can also be used to help
guide GTV delineation. Similarly, EUS may detect
lymph nodes which may not be appreciated on CT or
PET imaging, and the endoscopist should describe the
size as well as location (example distance from inci-
sors, relationship to adjacent mediastinal structures,
etc.) of such, further facilitating accurate definition of
potentially involved lymph nodes, either adjacent to
or well removed from the primary tumor itself.
Additionally, radiographic areas of lymphadenopathy
should similarly be included in the GTV.
While the utility of PET in esophageal cancer
staging primarily lies in its ability to detect distant
metastases not fully appreciated on CT imaging (and
thereby altering treatment approach of these patients)
(Luketich et al. 1999; van Westreenen et al. 2004),
diagnostic PET/CT has more recently been integrated
into radiation planning of esophageal cancer patients
and definement of GTV. Generally, gross disease as
defined on PET is characterized by a standard uptake
value (SUV) above 2–2.5 (Zhong et al. 2007).
Generally speaking, PET avid nodes should be
Esophageal Cancer
included within the GTV volume. In a study from Fox
Chase Cancer Center, the mean GTV length as
determined by PET/CT closely correlated with
endoscopy findings (Konski et al. 2005). Another
study from Australian investigators reported that
CT-alone based definement of GTV excluded PET-
avid disease in a majority of patients, resulting in a
potential geographic miss of disease in a significant
minority of patients (Leong and Everitt 2004). Simi-
larly, the fusion of CT-PET has been shown to prompt
GTV and PTV modification in a majority of patients
(Zobotto et al. 2005). Recent analysis of PET/CT-
based (as compared to CT alone) radiotherapy plan-
ning of esophageal cancer patients indicated a
reduction of intra- and inter-observer variability in
GTV delineation (Vesprini et al. 2006).
Finally, although the routine use of fluoroscopic
barium swallow in esophageal cancer has decreased,
this study may still be useful to the Radiation Oncol-
ogist for field design. A study from Chinese investi-
gators suggested that, as compared to CT, endoscopy
with barium swallow more accurately defines the true
length of middle and lower esophageal tumors,
although CT appeared to better determine such for
tumors located at the GE junction (Gao et al. 2007).
In summary, accurate definition of primary and
nodal gross disease is paramount in radiation esoph-
ageal cancer planning. It is important to rely on all
diagnostic studies, including barium swallow (when
available), endoscopy, endoscopic ultrasound, CT as
well as PET scan.
The identification of potential direct and nodal
pathways for spread of subclinical disease (i.e. CTV
definition) in esophageal cancer is also of paramount
importance. These areas vary significantly depending
on site of origin of disease, making esophageal cancer
planning somewhat complex. In terms of direct dis-
ease extension along the esophagus itself, varying
reports have assessed the histologic findings at pri-
mary esophagectomy to determine subclinical extent
of disease. One prospective analysis of 66 resection
specimens showed that placement of a 3 cm margin
proximally and distally on the primary tumor would
cover microscopic disease extension in 94% of
squamous cell carcinomas. Similarly, in GE junc-
tional carcinomas, a 3 cm proximal margin included
subclinical disease extension in 100% of patients,
while 5 cm distally covered 94% of subclinical spread
(Gao et al. 2007).
731
As described previously, the esophagus is charac-
terized by a rich submucosal network of lymphatics
that facilitates early lymph node spread of disease,
even for superficial esophageal cancers. The appro-
priate cranial and caudal margins remain a matter of
debate in the treatment of esophageal cancer.
Historically, very large fields were treated, encom-
passing potential pathways and lymphatic spread
from the thoracic inlet down to the celiac axis region;
however, such fields are potentially fraught with
treatment-related toxicity and may be difficult for
patients to tolerate, particularly in the context of
concurrent chemotherapy delivery. Most contempo-
rary radiation trials have used margins of 3–5 cm
cranially and caudally on the GTV along with a 2 cm
radial margin. With disease located at or above the
carina (or middle/upper third of the esophagus in
some instances), many of these trials recommended
fields inclusive of the supraclavicular lymph node
basins, while celiac axis nodal basin coverage was
recommended for disease of the distal esophagus
(Hazard et al. 2008). Further description of lymph
node basin coverage follows below.
11 Field Design
Historically, the treatment of very proximal (cervical)
esophageal cancers has been challenging. Because of
the changing contour from the neck to the thoracic
inlet, treatment of lesions in the upper third of the
esophagus can present a difficult technical problem.
Lesions in the upper cervical or postcricoid esophagus
are treated from the laryngopharynx to the carina,
depending on extent of disease. Supraclavicular and
superior mediastinal nodes are irradiated electively.
Using older/conventional methods, this can be
achieved with lateral parallel opposed or oblique
portals to the primary tumor and a single anterior field
for the supraclavicular and superior mediastinal nodes
(Hussey et al. 1980). Another historical technique that
treats lesions in this region is by means of a four-field
box approach, using a wax bolus to build up the lack
of tissue above the shoulders, acting as a compensa-
tor. A high-energy beam ([15 MV) is used, and both
sides of the neck are treated prophylactically. Other
methods of treating lesions at the thoracic inlet
include 140° arc rotations, anterior wedged pairs and
three- or four-field techniques using posterior oblique
732
Fig. 9 a–c Examples of PTV in a 62-year-old female with a
cT3N1 squamous cell carcinoma of cervical esophagus.
PTV = red volume, GTV = blue volume d Three-dimensional
reconstruction of PTV from above patient. GTV = dark blue,
portals combined with a single anterior portal or
anteroposterior–posteroanterior fields (Hussey et al.
1980). Using 3-D approaches, varying techniques
have been implemented, including treatment of the
primary tumor and lymph nodes using an AP/PA
approach to 39.6–41.4 Gy at 1.8 Gy/fraction, fol-
lowed by a left or right opposed oblique pair to bring
the total dose to 50.4 Gy, thereby limiting the spinal
cord dose. This technique will generally exclude the
supraclavicular fossa and a separate electron field is
often added, treating to a depth of 2–3 cm depending
upon individual anatomy. More recently, however,
B. G. Czito and C. G. Willett
PTV = red, carina = yellow, spinal cord = brown, lungs =
light blue. e Isodose curves of the above patient treated with a
9-field IMRT plan. Note that beams are primarily anteriorly
oriented (Courtesy of Rodney Hood, CMD)
intensity-modulated radiation therapy (IMRT)-based
planning has facilitated the treatment of upper
esophageal lesions and is the authors’ preferred
method for treating these tumors (Fig. 9a–e). Strict
normal tissue constraints, including normal lung and
spinal cord, are important considerations using these
techniques (discussed below).
Based on the previously described and other
pathologic patterns of spread data in squamous cell
carcinoma of the esophagus, general guidelines in
terms of field design can be made as follows: For
cervical and upper thoracic squamous cell carcinoma,
Esophageal Cancer
Fig. 10 Example field for a mid-esophageal squamous cell
carcinoma. Note that field is inclusive of adjacent mediastinal/
paraesophageal nodes with approximately 5 cm margin supe-
riorly on gross tumor volume as well as slightly larger margin
on inferiorly aspect of GTV based on concern of subclinical
spread at time of endoscopy
the CTV should generally include nodal basins
extending from the lower cervical and supraclavicular
region superiorly to the subcarinal lymph node basin
inferiorly, inclusive of the upper paraesophageal
lymph nodes (Fig. 9a–e). For lower esophageal
squamous cell carcinomas, lymph node basins from
the subcarinal region superiorly to the left gastric and
common hepatic artery/celiac lymph nodal basins
inferiorly should generally be included (described
further below). For tumors of the middle esophagus,
the authors recommend individual field design
according to clinical scenarios, with a more complete
coverage of paraesophageal mediastinal lymph nodes,
particularly in patients with a good performance sta-
tus (Anderson and Lad 1982) (Fig. 10). These are
general guidelines and all plans should be individu-
alized based on available clinical, imaging and
endoscopic data.
In field design, it should also be remembered that
basing potential nodal involvement (and therefore
target volumes) on nodal size is problematic given
that some reports have demonstrated that less than
15% of metastatic nodes are larger than 1 cm, and
733
that average size differences between involved and
uninvolved nodes frequently do not vary (Schroder
et al. 2002). Additionally, FDG PET scanning has a
sensitivity of only 67% of detecting nodal metastases
(Ott et al. 2006). Even endoscopic ultrasound, gen-
erally considered the most sensitive test for detecting
lymph node metastases, is only able to detect such
disease in approximately 75% of patients (Lightdale
and Kulkarni 2005). Therefore, it is not appropriate to
rely exclusively on varying imaging modalities to
define areas of subclinical spread for esophageal
cancer, realizing that patterns of spread data is
important in determining radiation field design.
The design of radiation fields for the treatment of
adenocarcinoma of the esophagus is similar to that of
lower thoracic squamous cell carcinomas, but
deserves special mention. Periesophageal lymph
nodes are generally including in all patients. Given
that lymph node involvement is clearly associated
with depth of tumor penetration (T stage), and the fact
that most patients in the United States and Europe
presenting with GE junctional carcinoma will have
more advanced disease, inclusion of celiac lymph
basins for adenocarcinoma of the distal esophagus/GE
junction is usually indicated. Based on the previously
described patterns of spread data from Erlangen and
others, specific considerations include the following:
Lymph vascular invasion is highly predictive of nodal
spread. Proximal extension of tumors (particularly
beyond the Z line into the distal esophagus for type II
and III tumors) predicts for an increasing incidence of
paraesophageal lymph node involvement. Using an
estimated nodal incidence cut-off of 20% for inclu-
sion, specific considerations include the following: (1)
The lower paraesophageal, paracardial, lesser curva-
ture and left gastric artery nodes should be included in
the CTV. (2) The presence of lymph vascular invasion
predicts for a nodal positivity rate of greater than 20%
in the left and right gastroepiploic, greater curvature,
celiac trunk and splenic hilar regions. (3) In T3/4
disease, the gastroepiploic, greater curvature, celiac
trunk, splenic hilar, splenic artery and common
hepatic artery should be included. (4) High grade
tumors should also include the left gastroepiploic,
greater curvature and celiac trunk nodes in CT design.
(5) Larger and more deeply penetrating tumors should
also include the splenic artery and splenic hilar
nodes as well as those along the greater curvature.
(6) Tumors extending above the diaphragm and those
734
extending greater than 1.5 cm beyond the Z-line
should include the mid paraesophageal nodes, treating
up to the carina. Of note, significant involvement of
the distal esophagus by GE junctional tumors
([1.5 cm beyond the Z line) should lead to consid-
eration of inclusion of not only lower, but also
middle, paraesophageal nodes based on patterns of
spread. However, treating these more extensive fields
must be weighed against the potential side effects of
increased normal tissue irradiation. In summary,
middle and lower paraesophageal nodes should be
included in patients with T2–T4 type I, T2–T4 type II
tumors extending greater than 1.5 cm above the Z line
and T3–4 type II patients. The splenic hilar and artery
nodes are considered ‘‘sparable’’ in T2 tumors, nota-
bly type I (Meier et al. 2008).
Although, historically, 2-dimensional-based radia-
tion planning has been carried out primarily using
anatomic landmarks such as bone, carina as well as
fluoroscopic barium swallow to determine field bor-
ders, contemporary treatment planning using
CT-based planning allows improved visualization of
both target and non-target structures, along with 3-
dimensional reconstruction and creation of a ‘‘beams
eye’’ view of varying fields, allowing improved con-
formality around target structures and improvements
in normal tissue sparing. Because volumetric data can
be obtained by CT scans, dose volume histogram data
can also be generated. A variety of 3-dimensional
techniques are presently used and described below.
Potential beam orientations for the treatment of
thoracic esophageal and gastroesophageal junction
(again defined as tumors involving the gastroesopha-
geal junction with an epicenter within 5 cm proximal
or distal to the GE junction) tumors include an
anteroposterior–posteroanterior (AP/PA) alone
approach, an initial AP/PA approach followed by AP/
RPO/LPO fields, with or without boost, an initial
APPA approach followed by RAO/LPO fields, with or
without boost, a 3-field-technique (AP/PA with left
lateral or oblique field). One of the authors preferred
approaches in lesions of the thoracic esophagus or GE
junction is using an initial AP/PA approach followed
by RAO/LPO fields, with boost fields using laterally
oriented beams. The inferior margin of the initial
fields includes the gastroesophageal junction and, for
lower or middle-third lesions, the celiac axis nodal
basins (generally located at the level of T12 and
identifiable on CT) as well as gastrohepatic ligament.
B. G. Czito and C. G. Willett
Initial fields are treated to 30–36 Gy, after which
oblique fields (opposed right anterior and left pos-
terior oblique) are implemented, taking care to avoid
as much of the heart as reasonably possible while
continuing to minimize the kidney volume in the
radiation field, inclusive of the above nodal basins, to
a total dose of 45 Gy. Reduced fields encompassing
gross disease with an approximate 2 cm margin
through oblique or lateral fields may then be used for
an additional 5.4 Gy. Doses usually do not exceed
50 Gy (discussed below).
A margin of 5 cm above and below the GTV is
generally recommended to cover subclinical sub-
mucosal/nodal disease, as well as an approximate
2.5 cm radial margin, although individual margins are
case dependent. Because it is imperative to account
for daily setup on certainty as well as physiologic
internal organ motion (secondary to respiration,
peristalsis, cardiac motion, etc.), additional margin
must be added to a clinical target volume, particularly
to the more mobile distal esophagus. More recently,
the internal target volume (ITV) has been utilized to
account for physiologic motion of the target volume,
which is included in the PTV. Varying reports ana-
lyzing esophageal motion have shown average ante-
rior and posterior motion ranges from 0.1 to 4 mm,
lateral motion from 0.3 to 4.2 mm and superior to
inferior motion from 3.7 to 10 mm (Hazard et al.
2008). An analysis evaluating interfraction esopha-
geal motion in the right–left and AP direction showed
an average right–left motion of 1.8 ± 5.1 mm
(favoring leftward movement) and average AP
motion of 0.6 ± 4.8 mm (favoring posterior move-
ment) with an average absolute motion of 4.2 mm or
less in the right–left and AP direction. The authors
concluded that a 12 mm left, 10 mm posterior and
9 mm anterior margin are appropriate (Cohen et al.
2010). Some authors have recommended defining a
1 cm radial, 1.5 cm distal and 1 cm proximal margins
from CTV to ITV if target motion data is not avail-
able. Image-guided radiation therapy (IGRT),
including cone beam CT, may also be useful in
localizing tumor and establishing physiologic vari-
ability between daily treatments.
Figure 11a–c show general recommendations for
elective target nodal station coverage in a patient with
a type I GE junctional tumor with an accompanying
example field, respectively. Figure 12 shows general
recommendations for elective target nodal station
Esophageal Cancer 735

bFig. 11 a Recommended nodal basins to be included for type I

GE junctional tumors based on Japanese Gastric Cancer
Association lymph nodes stations (Matzinger et al. 2009).
b Example AP field for a type I GE junctional adenocarcinoma.
c Example oblique field for a type I GE junctional tumor,
inclusive of the above nodal basins (Reprinted from EORTC-
ROG expert opinion: Radiotherapy volume and treatment
guidelines for neoadjuvant radiation of adenocarcinomas of the
gastroesophageal junction and the stomach Ó 2009 Elsevier
Ireland Ltd. All rights reserved (Matzinger et al. 2009))

Fig. 12 Recommended nodal basins to be included for type II

GE junctional tumors based on Japanese Gastric Cancer
Association lymph nodes stations (Reprinted from EORTC-
ROG expert opinion: Radiotherapy volume and treatment
guidelines for neoadjuvant radiation of adenocarcinomas of the
gastroesophageal junction and the stomach Ó 2009 Elsevier
Ireland Ltd. All rights reserved (Matzinger et al. 2009))

coverage in a patient with a type II GE junctional

tumor. Nodal basins are similar to type I tumors with
the exception of inclusion of nodal basins along the
splenic artery course. Figure 13a–c shows general
recommendations for elective target nodal station
coverage in a patient with a type III GE junctional
tumor with accompanying example fields, respec-
tively. Note that in type III tumors there is less
emphasis placed on more proximal (lower mediasti-
nal) nodes and more comprehensive coverage of
the splenic artery course, including splenic hilum.
Figure 14 shows examples of varying nodal locations
on axial CT images.
Another potential approach in the treatment of
thoracic esophageal cancer is the use of intensity-
modulated radiation therapy (IMRT). IMRT also uses
736 B. G. Czito and C. G. Willett

Fig. 13 a Recommended
nodal basins to be included
for type III GE junctional
tumors based on Japanese
Gastric Cancer Association
lymph nodes stations.
b Example AP field for a type
III GE junctional
adenocarcinoma. c Example
oblique field for a type III GE
junctional tumor, inclusive
of the above nodal basins
(Ó 2001 by International
and Japanese Gastric Cancer
Associations)

CT-based planning, again allowing 3-D reconstruc-
tion of varying structures. However, IMRT differs
from 3-D planning through the delivery of radiation
dose by partitioning a radiation field into multiple
smaller fields of varying shapes and sizes, varying the
dose intensity between each area. This is carried out
with either dynamic IMRT (where collimating leaves
move in and out of the radiation beam path during
treatment) or ‘‘step-and-shoot’’ IMRT (where the
leaves change the radiation field shape while the beam
is turned off). Either method is particularly effective
at conforming radiation dose to the target structures
while avoiding dose to normal tissue. Radiation
oncologists must determine which structures are most
critical and weight their importance during the treat-
ment planning process. Importantly, the greater the
number of ‘avoidance’ normal structures, the more
difficult it is to meet all dose constraints. IMRT
utilizes ‘‘inverse planning’’, where an intended pre-
scription dose is placed on target volumes and dose
constraints are placed on normal tissue structures.
Thereafter, computer software algorithms allow
design of unconventional treatment fields which
would not otherwise be possible with standard plan-
ning methods. Radiation oncologists and medical
physicists critically evaluate numerous plans until
dose constraints are satisfactorily met. The result
should be a series of radiation doses that closely
Esophageal Cancer 737

Fig. 14 Examples of lymph node stations on corresponding radiation of adenocarcinomas of the gastroesophageal junction
CT slices (Reprinted from EORTC-ROG expert opinion: and the stomach Ó 2009 Elsevier Ireland Ltd. All rights
Radiotherapy volume and treatment guidelines for neoadjuvant reserved (Matzinger et al. 2009))
738
conform to the target volumes while minimizing dose
to normal tissues. Dosimetric comparisons of IMRT
versus 3D conformal therapy in cervical esophageal
cancer have demonstrated superior target volume
coverage and conformality with decrease normal tis-
sue dose (Fenkell et al. 2008). A potential disadvan-
tage of IMRT is the possibility of delivering low
doses of radiation therapy to normal tissue areas that
might not normally be irradiated using 2-D or 3-D
techniques. The influence of this on toxicity (eg . low-
dose pulmonary irradiation and development of
postoperative pulmonary complications) remains
uncertain at present. Another potential disadvantage
to IMRT is possible dose inhomogeneity, leading to
potential ‘‘hot spots’’ in normal organs. Additionally,
because IMRT requires precise target definition, the
potential for ‘‘marginal miss’’ increases and careful
target delineation is of paramount importance. With
setup uncertainty, physiologic organ motion, etc., care
must be taken to assure accurate and reproducible
setup, including with the use of immobilization
devices, possible respiratory gating/breath hold tech-
niques, etc. Generally, high energy photons (4–18
MV) are recommended when using 3D conformal or
IMRT therapy, potentially facilitating a reduction in
the integral lung dose.
12 Dose Constraints
In radiation therapy planning of esophageal cancer,
normal tissue tolerance should always be considered.
The spinal cord dose is generally limited to 45 Gy
using 1.8 Gy fractions (and potentially less when
delivered with novel systemic agents). Efforts to
minimize radiation to the heart (in particular the left
ventricle in lower esophageal/gastroesophageal junc-
tion lesions), should be made. Adopting an ‘‘off
heart’’ approach using oblique orientations (including
right anterior and left posterior, described previously)
is one potential method of achieving this, although
multiple approaches exist. Similarly, efforts to mini-
mize dose to normal pulmonary tissues should be
made, based on data suggesting that the volume of
irradiated lung may correspond to postoperative
complications and worsened pulmonary function
(described below). Frequently, the volume of irradi-
ated lung can be minimized using a simple AP/PA
approach. However, this sometimes results in
B. G. Czito and C. G. Willett
significant cardiac dose, particularly in lower esoph-
agus and gastroesophageal junction tumors. There-
fore, oblique orientations are sometimes used,
resulting in increased volumes of normal lung being
irradiated. When given concurrent chemotherapy, the
authors generally limit these fields to 13–15 Gy.
Accurate delineation of adjacent organs including
lungs, liver, kidneys, heart and spinal cord are
important. Varying dose-volume normal organ con-
straints have been suggested, including achieving a
lung V20 of \20%, while limiting [2300 cc of
normal lung tissue to less than 5 Gy and mean lung
dose of \18 Gy. Historically, heart dose constraints
have included maintaining 1/3, 2/3, and total heart
volumes \45, 40, and 30 Gy, respectively. Recom-
mended heart constraints include keeping \30% of
the cardiac volume to a total dose of 40 Gy
and \50% receiving 25 Gy. In the setting of
potentially significant volumes of heart in the radi-
ation field, consideration of 4D CT and/or breath
hold techniques should be made. For lower esoph-
ageal and gastroesophageal cancers, it is recom-
mended that at least 70% of one physiologically
functioning kidney receive a total dose of less than
20 Gy, and that, collectively, no more than 50% of
the combined functional renal volume should
receive greater than 20 Gy (Matzinger et al. 2009).
One should also consider the possibility of impaired
kidney function in the context of varying co-mor-
bidities, using nuclear medicine renal studies to
assess individual renal function in such situations or
where significant volumes of kidneys are anticipated
to be within the radiation field. Generally, 30% of
the liver parenchyma should be kept to a dose of
less than 30%. Many of these constraints can be
achieved through the use of three-dimensional
planning with appropriate and careful design of
shielding blocks/multileaf collimation and dose
volume histogram analysis, with the use of IMRT in
select cases.
13 Doses of Radiation
Because local–regional failure is common after con-
ventional chemoradiation, investigators have evalu-
ated dose escalation techniques. Varying series using
doses beyond 50 Gy have shown local control rates
ranging from approximately 77–88% (Burmeister
Esophageal Cancer
et al. 2000; Murakami et al. 1998). However, Minsky
et. al. reported the results of a randomized trial in
which 236 patients with clinical stage T1–4, N0/1,
M0 squamous cell or adenocarcinoma of the esoph-
agus were selected for nonsurgical therapy (Minsky
et al. 2002; Minsky et al. 1999). Patients were ran-
domized to receive 64.8 versus 50.4 Gy, both with
concurrent 5-fluorouracil and cisplatin chemotherapy.
Patients with cervical, mid or distal esophageal cancer
were eligible with the exception of tumors within
2 cm of the gastroesophageal junction, with approx-
imately 85% of patients with squamous cell histology.
This study was closed after interim analysis showed
no probability of superiority in the high-dose arm. No
significant difference in median survival (13 vs.
18.1 months), 2-year survival (31 vs. 40%) or local–
regional failure/persistence of disease (56 vs. 52%)
was seen between the high-dose and standard-dose
arms. Eleven treatment-related deaths occurred in the
high-dose arm compared with two in the standard-
dose arm, with 7 of the 11 high-dose arm deaths
occurring in patients who received 50.4 Gy or less.
The authors performed a separate survival analysis
including only patients receiving the assigned radia-
tion dose. Despite this, no survival advantage was
noted in the high-dose arm. These authors concluded
that higher radiation doses did not increase survival or
local/regional control, and that the standard radiation
dose for patients treated with concurrent 5-FU and
cisplatin chemotherapy is 50.4 Gy. Based on this
data, the standard dose of radiation therapy for
esophageal cancer is usually 50–50.4 Gy at 1.8–
2 Gy/fraction, including delivery of similar doses in
both the definitive, adjuvant (45-50 Gy) or neoadju-
vant (45–50 Gy) settings.
14 Brachytherapy
In addition to external beam radiation therapy
(EBRT), intracavitary brachytherapy can be used with
curative or palliative intent. Brachytherapy has also
been used as a dose escalation tool in addition to
external beam radiation therapy. The advantage of
brachytherapy centers on exploitation of the inverse
square law and quick dose fall-off, thus sparing sur-
rounding tissues from radiation while providing focal
dose escalation. The radioactive source of choice is
usually 192Ir. High-dose-rate (HDR) techniques can
739
deliver 100–400 Gy/h, allowing treatment to be given
in 5–10 min.
With brachytherapy, an afterloading catheter is
introduced through the nose into the esophagus to the
primary tumor site under fluoroscopic guidance. This
is often performed with the patient on the simulation
table. Contrast may be used to define the tumor site.
CT scan can also be used to discern tumor location.
After localization films are taken and dosimetry
generated, the catheter is then attached to a remote
afterloader through a guide cable and the 192Ir source
inserted through remote control. Doses of 5–20 Gy
are usually delivered to a depth of 1 cm from the
center of the catheter. Dose can be shaped and
modified through the use of dwell times.
15 Results of Therapy
The best survival results have been reported in
patients who have esophageal tumors that are truly
localized. Survival rates range from 25–35% at
5 years, and these results have been attained using an
array of treatment approaches. Problems arise in
comparisons of various modalities, however, because
of patient selection factors. Review of the Princess
Margaret Hospital data (Beatty et al. 1979) supported
the concept that extent of tumor, rather than therapy,
is the most important factor influencing survival.
They found a significant correlation between tumor
(T) stage and response to treatment: T1 lesions
showed a 100% response rate, whereas T2 and T3
lesions had response rates of 68 and 58%, respec-
tively. Not unexpectedly, they also found differences
in survival according to T stage, metastasis (M) stage,
and overall stage. Almost 20% of patients with stage I
disease were alive at 3.5 years, whereas only 11% of
stage II patients were alive after the same interval and
all patients with stage III dead of disease by approx-
imately 1.5 years following therapy.
16 Surgery Alone
Surgery remains a benchmark to which other modal-
ities are compared. No one surgical approach has
clearly been shown to be superior with regard to
complications or outcomes, and no one standard
surgical approach exists for esophageal cancer
740 B. G. Czito and C. G. Willett

Table 6 Comparison of Trial Year Patients Patients Median 2-Year 3-Year

surgical arms in randomized (Total) (Surgical) survival survival survival
studies (Months)
Walsh et al. 1996 110 55 11 26 6
Urba et al. 2001 100 50 18 NA 15
Bosset et al. 1997 282 139 19 40 35
Kelsen et al. 1998 440 227 16 37 23
Medical Research 2002 802 402 13 34 NA
Council
Burmeister et al. 2005 256 128 19 NA 31
Gaast et al. 2010 363 188 26 NA 48
Mariette et al. 2010 195 98 44 NA NA
NA not applicable

resection. Following resection alone, however, local–
regional relapse is a common mode of failure. Con-
temporary randomized trials with surgery alone arms
have reported local–regional failure rates of 32–45%
(Hulscher et al. 2002; Kelsen et al. 1998; Law et al.
1996; Urba et al. 2001). It should be remembered that
patterns of failure reports often describe first site of
failure only and may include only patients undergoing
R0 resection, potentially underreporting the true
incidence of local–regional recurrence. These and
other data suggest that even with modern surgical
techniques, local–regional persistence of disease fol-
lowing resection remains a major problem. Prospec-
tive randomized trials using surgery alone in the
treatment of esophageal cancer have reported 3-year
survival rates ranging from 6 to 48% (Walsh et al.
1996; MRC OCWP 2002; Bosset et al. 1997; Gaast
et al. 2010; Mariette et al. 2010; Macdonald et al.
2001; Tepper et al. 2008; Stahl et al. 2009); (Table 6).
Given these high rates of relapse and poor long-term
survival, the integration of adjuvant or neoadjuvant
chemoradiation approaches into the treatment of
esophageal cancer is rational and indicated.
17 Radiation Therapy Alone
There are no randomized studies comparing surgery
alone with radiation alone, and radiation therapy
alone has been usually delivered when lesions are
deemed inoperable because of tumor extent, medical
contraindications and/or palliative treatment is indi-
cated. In general, patients receiving radiation as a sole
treatment modality have a median survival of 6–12
months and 5-year survival of \10%.
An Intergroup randomized study (discussed below)
comparing combined chemotherapy with 5-FU and
cisplatin with radiotherapy (50 Gy) versus radiother-
apy only (64 Gy) showed that 3-year survival with
radiotherapy alone was 0%. These and other data
suggest that treatment with radiation therapy alone for
esophageal cancer patients is palliative in the vast
majority of patients.
18 Preoperative Radiation Therapy
The use of preoperative radiation therapy has poten-
tial biologic and physical advantages, including
increased resectability of tumors, increased tumor
radioresponsiveness secondary to improved tumor
oxygenation, a theoretical decreased likelihood of
dissemination at the time of surgery as well as
avoidance of surgery in patients with rapidly pro-
gressive disease.
There are at least five randomized studies
comparing preoperative irradiation followed by
surgery with surgery alone. These studies demon-
strate no convincing clinical benefit to the use of
preoperative radiation therapy alone. A recent meta-
analysis from the Oeosophageal Cancer Collabora-
tive Group updated data from 5 randomized trials of
greater than 1,100 patients comparing preoperative
radiotherapy alone versus surgery alone. The
majority of patients had squamous cell carcinoma.
At a median follow-up of 9 years, the hazard ratio
Esophageal Cancer
was 0.89, suggestive of an overall reduction in the
risk of death of 11% and absolute survival benefit of
4% at 5 years with the use of preoperative radio-
therapy. However, this was not statistically signifi-
cant (p = 0.06). The authors concluded that there
was no clear evidence that preoperative radiotherapy
improves survival of patients with potentially
resectable esophageal cancer (Arnott et al. 2005). In
general, there were no differences in resectability
rates, local failure nor survival in almost all of the
individual studies. Interpretation of these varying
studies is complicated by differences in radiation
techniques, suboptimal radiation dose and inadequate
radiation volumes. Nonetheless, while preoperative
radiation therapy alone may improve local control,
there is no convincing data that it results in
improved survival in esophageal cancer patients.
19 Postoperative Radiation Therapy
The main advantage to adjuvant versus neoadjuvant
approaches is the knowledge of the pathological
staging to appropriately select patients for therapy
with the former approach. Postoperative therapy may
allow the radiation oncologist to treat areas at risk for
recurrence while sparing otherwise normal radiosen-
sitive structures, thereby decreasing toxicity. In
addition, patients with pathologic T1N0M0 or meta-
static disease may be spared treatment. Postoperative
irradiation has historically been delivered to patients
with esophageal cancer who have bulky tumors with
gross residual disease or histologically proven
microscopic residual disease. Potential disadvantages
of postoperative radiation therapy include limited
tolerance of normal tissues following gastric pull-up
or intestinal interposition and irradiation of a devas-
cularized tumor bed, potentially larger fields com-
pared to a preoperative approach, as well potential
delays in adjuvant treatment delivery. Three ran-
domized trials have assessed surgery alone versus
surgery followed by postoperative radiation therapy
(Teniere et al. 1991; Fok et al. 1993; Xiao et al.
2005). In summary, these studies suggest postopera-
tive radiation therapy may decrease local recurrence,
particularly in the setting of involved margins,
although the impact of radiation therapy alone on
overall survival remains less clear.
741
20 Postoperative Combined
Chemoradiation
A large randomized Intergroup trial evaluating the role
of adjuvant chemoradiation following surgery versus
surgery alone for patients with adenocarcinoma of the
stomach and GE junction was reported. In this study,
patients with resected, margin-negative gastric or
gastroesophageal junction adenocarcinoma were ran-
domly assigned to surgery alone versus surgery with
postoperative chemoradiotherapy. Approximately 20%
of patients had lesions in the gastroesophageal junc-
tion. A significant survival advantage was seen in the
adjuvantly treated group (median survival 27 months
vs. 36 months, p =0.005). On subset analysis, this
benefit was detected in patients with gastroesophageal
cancer (Macdonald et al. 2001). Therefore, in patients
with resected stage group Ib-IV, nonmetastatic GE
junctional carcinoma, it is appropriate to advise
adjuvant chemoradiotherapy in efforts to potentially
improve upon local control and ultimate survival.
21 Preoperative Chemotherapy
Four large randomized trials have shown conflicting
results with the use of neoadjuvant chemotherapy
alone in the treatment of esophageal cancer, with two
of these trials also including gastric cancers. Kelsen
et al. reported the results of an Intergroup study ran-
domizing 440 patients with squamous cell carcinoma
and adenocarcinoma to receive either combined
cisplatin or 5-fluorouracil (5-FU) chemotherapy for
three cycles followed by resection, followed by a
similar regimen of adjuvant chemotherapy, versus
immediate resection with no chemotherapy. No
apparent survival advantage (3-year survival of 23 vs.
26%) was seen in patients receiving chemotherapy.
Additionally, rates of local failure (32 vs. 31%) and
distant metastases development (41 vs. 50%) were not
significantly different between the two groups. The
authors concluded that neoadjuvant chemotherapy
with cisplatin and 5-FU did not improve survival in
patients with resectable esophageal cancer (Kelsen
et al. 1998). Important caveats from this study include
that patients with even microscopic residual dis-
ease following resection (R1/2) fare no better
than patients not undergoing surgery, and that all
742
long-term R1 survivors received adjuvant RT (Kelsen
et al. 2007).
In contrast to the Intergroup study, a similar trial
from the Medical Research Council (MRC) random-
ized 802 patients with squamous cell carcinoma or
adenocarcinoma of the esophagus to either 2 cycles of
combined cisplatin/5-FU chemotherapy versus sur-
gery alone. Patients receiving neoadjuvant chemo-
therapy had a statistically improved 2-year survival
(43 vs. 34%).(MRC OCWP 2002) The reason for
outcomes’ differences between these trials is not
clear.
A more recent European study randomly assigned
patients with resectable adenocarcinoma of the
stomach, gastroesophageal junction or lower esopha-
gus to preoperative and postoperative chemotherapy
with epirubicin, cisplatin and 5-FU (ECF) versus
surgery alone. Although originally designed to
include patients with only tumors of the stomach,
eligibility was later expanded to include tumors of the
lower third of the esophagus. Approximately one-
fourth of patients had adenocarcinoma involving the
lower esophagus or gastroesophageal junction. No
patient achieved pathologic complete response.
Patients receiving perioperative chemotherapy had a
hazard ratio for death of 0.75, which was highly
significant. Five-year survival in patients receiving
chemotherapy was 36 versus 23% in patients under-
going surgery alone (p = .009). Subgroup analysis of
patients with lower esophageal or gastroesophageal
junction tumors showed benefit to the delivery of
perioperative chemotherapy (Cunningham et al.
2006).
French investigators reported the results of a
similar randomized trial of 224 patients assigned to
perioperative chemotherapy (cisplatin and 5-FU)
versus surgery alone. Although originally designed to
include patients with only tumors of the lower third of
the esophagus or gastroesophageal junction, eligibil-
ity was later expanded to include gastric cancers.
Most (75%) of the patients had disease of the lower
esophagus or gastroesophageal junction. Chemother-
apy consisted of 2–3 preoperative and 3–4 postoper-
ative cycles. Patients receiving chemotherapy had
improved overall survival (5–year 38 vs. 24%,
p = 0.02), disease-free survival (5–year 34 vs. 19%,
p = 0.003), and R0 resection rates (84 vs. 73%,
p = 0.04). Only 50% of patients received postopera-
tive chemotherapy. T0 disease (complete pathologic
B. G. Czito and C. G. Willett
response at the primary site) disease was seen in 3%
of neoadjuvantly treated patients. The total local–
regional recurrence rates were 24 and 26% respec-
tively in the chemotherapy versus surgery group, with
distant recurrence rates of 42 versus 56%, respec-
tively (Ychou et al. 2011).
Two recent meta-analyses have suggested that
neoadjuvant chemotherapy resulted in absolute 2 and
5 year survival benefits of 7 and 4%, respectively
(Gebski et al. 2007; Thirion et al. 2007).
22 Preoperative Chemoradiation
Versus Surgery Alone
A detailed discussion of the role of preoperative,
concurrent chemoradiation versus surgery alone is
beyond the scope of this chapter. However, this has
been studied in multiple randomized trials (Urba et al.
2001; Walsh et al. 1996; MRC OCWP 2002; Bosset
et al. 1997; Gaast et al. 2010; Mariette et al. 2010;
Burmeister et al. 2005; Tepper et al. 2008). Outcomes
of these trials are shown in Table 7. Preliminary
results of the largest ever randomized trial assessing
neoadjuvant chemoradiotherapy in the treatment of
esophageal cancer showed a significant survival
benefit in patients receiving preoperative therapy,
with the majority of patients included in this trial
having locally advanced adenocarcinoma (Gaast et al.
2010). In contrast, another preliminary report from
France evaluating primarily early stage squamous cell
esophageal cancer patients randomized to receive
preoperative chemoradiotherapy versus surgery alone
showed no significant difference in outcomes
(Mariette et al. 2010).
Given these conflicting results of contemporary
trials, multiple metaanalyses have been performed.
Two of the largest and most contemporary of these
demonstrated an absolute 2 and 5 year overall sur-
vival benefit of 13 and 6.5%, respectively, when
compared to surgery alone approaches, also sug-
gesting a larger benefit of preoperative chemora-
diotherapy as compared to a chemotherapy alone
approach (Gebski et al. 2007; Thirion et al. 2007).
In summary, the available data suggests that neo-
adjuvant concurrent chemoradiation improves local
control and modestly improves survival versus sur-
gery alone in patients with resected esophageal
cancer.
 Esophageal Cancer

Table 7 Results of preoperative combined chemoradiation versus surgery alone-phase III trials
Study Median follow-up Path Regimen Number Path 3-Year survival Survival
(yrs) of CR difference
patients
Urba (Urba et al. 2001) 8.2 SCC ? Adeno 5-FU-CDDP- Vinb/45 Gy 50 28 CMT/S: 30% P = .15
(Mich) Surg 50 _ S alone: 16%
Bosset (Bosset et al. 1997) 4.6 SCC CDDP/37 Gy Surg 143 20 CMT/S: 33% NS
(EORTC) 138 _ S alone: 36%
Walsh (Walsh et al. 1996) 1.5 Adeno 5-FU-CDDP/40 Gy 58 22 CMT/S: 32% P = .01
(Ire) Surg 55 _ S alone: 6%
Burmeister (Burmeister et al. 2005) 5.4 SCC ? Adeno 5-FU-CDDP/35 Gy 128 16 CMT/S: 35% NS
(Aus) Surg 128 _ S alone: 31%
Tepper (Tepper et al. 2008) 6.0 SCC+ 5-FU-CDDP/ 30 40 CMT/S: 39% (5 yr) P = .008
(USA) Adeno 50 Gy 26 _ S alone: 16% (5 yr)
Surg
Gaast (Gaast et al. 2010) 2.7 SCC+ Pac-Carbo/41.4 Gy 175 32 CMT/S: 59% P = .001
(Netherlands) Adeno Surg 188 - S alone: 48%
Mariette (Mariette et al. 2010) 5.7 SCC+ 5-FU-CDDP/ 97 29 CMT/S: 32 mo NS
(France) Adeno 45 Gy 98 - (med OS)
S alone: 44 mo (med
OS)
SCC—squamous cell carcinoma; adeno—adenocarcinoma; 5-FU—5-Fluorouracil; CDDP—cisplatin, Vinb—vinblastine; Pac-Paclitaxel; Carbo—Carboplatin; CMT—combined
modality therapy; S—surgery
743
744
23 Preoperative Chemoradiation
Versus Preoperative
Chemotherapy
The only contemporary randomized trial comparing
neoadjuvant chemotherapy alone versus neoadjuvant
combined modality therapy was conducted by
German investigators (the ‘POET’ study). Patients
with advanced esophagogastric adenocarcinoma were
randomized to receive (1) cisplatin-5-FU based che-
motherapy alone versus (2) a similar induction che-
motherapy, followed by concurrent cisplatin/
etoposide with 30 Gy of radiation therapy. Both
groups went on to receive surgery. Although this
study was closed early due to poor accrual, patients
receiving preoperative chemoradiotherapy had sig-
nificantly higher N0 rates (37 vs. 64%, p = 0.04),
pathologic complete response rates (2 vs. 16%,
p = 0.03) as well as significant trends toward
improved local control (59 vs. 76%, p = 0.06) and
overall survival (3-year survival 28 vs. 47%,
p = 0.07, hazard ratio 0.67). The authors concluded
that preoperative combined modality improves over-
all survival as compared to chemotherapy alone in
patients with locally advanced esophagogastric
adenocarcinoma (Stahl et al. 2009).
24 Radiation Therapy Alone Versus
Chemoradiation
There are multiple randomized studies comparing
radiation therapy alone with concurrent radiation and
chemotherapy (al-Sarraf et al. 1997; Araujo et al.
1991; Roussell et al. 1988) as definitive therapy. The
landmark trial establishing the superiority of concur-
rent chemoradiation to radiation therapy alone was
RTOG 8501. Herskovic et al. (Herskovic et al. 1992)
reported results of this two-arm trial that treated 60
control patients with radiation alone to a total dose of
64 Gy versus 61 patients with 50 Gy of radiation
therapy with concurrent 5-FU and cisplatin. The
results demonstrated a significant advantage of the
combined-modality arm over the radiation-alone arm.
The median survival in patients treated by radiation
alone was 8.9 months compared with 12.5 months
for those treated with combined therapy, 2-year
survival rate 10% versus 38%, the incidence of local
B. G. Czito and C. G. Willett
recurrence decreased from 24 to 16%, and the 2-year
distant metastases rate decreased from 26 to 12%.
Updated trial results (al-Sarraf et al. 1997; Cooper
et al. 1999) showed that at 5 years, survival rates were
26 and 0%, respectively, for chemoradiation and
radiation therapy alone arms. In conclusion, this study
demonstrated a significant improvement in local
control, median and overall survival, and distant
metastases development with the addition of chemo-
therapy, at the cost of increased side effects.
Comparison of outcomes data from ‘‘definitive’’
chemoradiation approaches suggests that survival
with combined chemoradiation is similar to that
achieved by surgery alone. In previously discussed
studies, median survivals of 14–20 months and 5-year
survival rates of 20–30% were achieved with che-
moradiation alone; in comparison, the MRC trial and
Intergroup trial evaluating surgery alone, median
survivals were 13–16 months with 5-year survivals of
approximately 20%.
25 Chemoradiation Versus
Chemoradiation followed
by Surgery
Two randomized trials have examined whether sur-
gery is necessary following combined modality ther-
apy. A report from French investigators randomized
445 patients with clinically resectable squamous cell
or adenocarcinoma of the esophagus. All patients
received concurrent 5-fluorouracil and cisplatin-based
chemoradiation. Patients who had at least a partial
response were then randomized to either surgery or
additional combined modality therapy of 5-FU and
cisplatin delivered concurrent with radiation. No
significant difference in 2-year survival (34 vs. 40%,
p = 0.56) or median survival (18 vs. 19 months) was
seen between the groups, although 2-year local con-
trol results favored the surgical arm (66 vs. 57%). The
death rate at 3 months following treatment was 9% in
the surgery group versus 1% in the combined
modality therapy alone group. The results of this trial
suggest that surgery following chemoradiation in
responding patients does not further enhance survival
(Bedenne et al. 2007).
In another study from Germany, patients with
potentially resectable squamous cell carcinoma of
the esophagus received induction chemotherapy with
Esophageal Cancer
5-FU, leucovorin, etoposide and cisplatin for 3
cycles, followed by concurrent etoposide and cis-
platin with 40 Gy of external beam radiation ther-
apy. Patients were then randomized to receive
surgery versus continuing with combined chemora-
diation (total radiation dose increased to 60–65 Gy,
with or without brachytherapy). Local control was
significantly improved in patients undergoing surgery
(2-year local control 64 vs. 41%, p \0.05). Despite
this, no significant difference in survival was seen
(median survival 16 vs. 15 months, 3-year survival
31 vs. 24%, p = NS). The ‘severe’ postoperative
complication rate (including infection, leak) was
70%, and the hospital mortality rate was 11%.
Overall treatment-related mortality was significantly
higher in patients undergoing surgery (13 vs. 3.5%).
The authors concluded that (1) surgery following
combined modality therapy improved local control
but had no impact on overall survival and (2) non
responders to induction chemotherapy may benefit
from surgery, and that it may be appropriate to
individualize therapy based on response to induction
treatment (Stahl et al. 2005).
In summary, although surgery following combined
chemoradiation for esophageal cancer appears to
improve local control, its impact on ultimate survival
is unclear.
26 Brachytherapy
Gaspar and colleagues reported the results of a pro-
spective trial evaluating intraluminal brachytherapy in
patients with non-operable esophageal cancer.
Patients initially received 50 Gy of external irradia-
tion with concurrent chemotherapy, followed by a
2 week break and brachytherapy administration.
Patients received either 15 Gy using high-dose-rate
(HDR) techniques over three consecutive weeks
(5 Gy/fraction) or a single administration of 20 Gy
using low-dose-rate (LDR) techniques. Both external
irradiation and brachytherapy were given concur-
rently with 5-FU chemotherapy. Following the
development of fistulas in six patients, the HDR dose
was reduced to 10 Gy in two fractions, and the LDR
arm was ultimately closed because of poor accrual.
Results showed a median survival of 11 months in all
patients. Local disease persistence/recurrence was
observed in 63% of 49 eligible patients receiving
745
HDR therapy. The 1-year actuarial fistula develop-
ment rate was 18%. The investigators conclude that
esophageal brachytherapy, particularly in conjunction
with chemotherapy, should be approached with cau-
tion (Gaspar et al. 2000). Review of other combined
brachytherapy/EBRT series suggests fistula formation
rates range from 0–12%, with a possible trend
towards a higher incidence in patients receiving
concurrent chemotherapy with brachytherapy. The
incidence of brachytherapy-related mortality varies
from 0–8%, with most series reporting rates at 4% or
less (Vuong et al. 2005).
Other studies have suggested that HDR brachy-
therapy is effective for palliation of dysphagia in up to
90% of patients (Vuong et al. 2005). Danish investi-
gators reported the results of a randomized trial of 209
patients with dysphagia due to inoperable esophageal
or gastroesophageal junctional tumors. Patients were
randomized to either endoscopic stent placement or
single-dose HDR brachytherapy. Although trial
results showed a more rapid improvement in dys-
phagia following stent insertion, long-term dysphagia
relief was significantly improved in the group
receiving brachytherapy. The authors concluded that
single-dose brachytherapy is preferable to stent
placement as the initial treatment for patients with
progressive dysphagia due to inoperable esophageal
or gastroesophageal junction carcinoma (Homs et al.
2004).
For patients treated with curative intent (unifocal
thoracic tumors \10 cm, no distant metastases, no
airway involvement or cervical esophageal location),
the American Brachytherapy Society recommends a
brachytherapy dose of 10 Gy in 2 weekly fractions of
5 Gy each (HDR) or 20 Gy in a single course at
0.4–1 Gy/h (LDR). The dose is prescribed to 1 cm
from mid source and delivered through a 6–10 mm
applicator. The recommended active length is the
visible mucosal tumor with a 1–2 cm proximal
and distal margin. Ideally, brachytherapy is started
2–3 weeks following completion of concurrent
external irradiation/chemotherapy to allow mucositis
resolution. Concurrent chemotherapy with brachy-
therapy is not recommended. In palliative cases, a
similar approach is recommended, with delivery of
10–14 Gy in 1–2 fractions (HDR) or 20–25 Gy in a
single course (LDR). In previously untreated patients
with a short life expectancy (\3 months), a dose of
15–20 Gy in 2–4 fractions (HDR) or of 25–40 Gy
746 B. G. Czito and C. G. Willett

Table 8 Selection criteria for brachytherapy in the treatment of esophageal cancer

Good candidates Poor candidates Contraindications
Primary tumor \ 10 cm length Extra esophageal extension Esophageal fistula
Tumor confined to the esophageal wall Tumor [10 cm in length Cervical esophageal location
Thoracic esophagus location Regional lymphadenopathy Stenosis which cannot be
bypassed
No regional lymph node or systemic Tumor involving gastroesophageal junction or
metastases cardia

Table 9 Suggested schema for definitive external beam radiation and esophageal brachytherapya
External beam radiation:
45–50 Gy in 1.8–2.0 Gy fractions, five fractions/week, weeks 1–5
Brachytherapy:
HDR—total dose of 10 Gy, 5 Gy/fraction, one fraction/week, starting 2–3 weeks following completion of external beam
LDR—total dose of 20 Gy, single course, 0.4–1.0 Gy/h, starting 2–3 weeks from completion of external beam
a
All doses specified 1 cm from midsource or mid-dwell position
HDR High-dose rate
LDR Low-dose rate

Table 10 Suggested schema for external beam radiation and brachytherapy* in the palliative treatment of esophageal cancer
Recurrent after external beam radiation and short life expectancy
Brachytherapy:
HDR—total dose of 10–14 Gy, one or two fractions
LDR—total dose of 20–40 Gy, one or two fractions, 0.4–1.0 Gy/h
No previous external beam radiation
External beam radiation:
30–40 Gy in 2–3 Gy fractions
Brachytherapy:
HDR—10–14 Gy, one or two fractions
LDR—total dose of 20–25 Gy, single course, 0.4–1.0 Gy/h
No previous external beam radiation, life expectancy greater than 6 months
External beam radiation:
45–50 Gy in 1.8–2.0 Gy fractions, five fractions/week, weeks 1–5
Brachytherapy:
HDR—total dose of 10 Gy, 5 Gy/fraction, one fraction/week, starting 2–3 weeks following completion of external beam
LDR—total dose of 20 Gy, single course, 0.4–1.0 Gy/h, starting 2-3 weeks following completion of external beam
*All doses specified 1 cm from midsource or mid-dwell position
HDR High-dose rate
LDR Low-dose rate

(LDR) without external irradiation is recommended

(Tables 8–10); (Gaspar et al. 1997). In summary, the
use of brachytherapy in the curative approach to
esophageal cancer does not appear to significantly
improve results achieved with combined external
beam radiation therapy with chemotherapy alone.
27 Palliative Treatment
Although treatment advances have occurred in
esophageal cancer over the last 20 years, the majority
of patients diagnosed with esophageal cancer will die
Esophageal Cancer
of their malignancy. Therefore, palliation remains an
important goal. Dysphagia is a common presenting
symptom, and may significantly impair patient’s
quality of life. Many studies report a 60 to [80% rate
of relief from dysphagia with radiation (Coia et al.
1993). Given the superior outcomes of patients
receiving concurrent chemotherapy with radiation
therapy in nonmetastatic disease, palliative chemo-
radiation is likely preferable to radiation alone for
patients with advanced-stage esophageal carcinoma
who have a good performance status. As described
above, intraluminal brachytherapy has also been used
for palliation of dysphagia.
The palliative management of patients with trache-
oesophageal fistula presents a clinical dilemma. Fistu-
lization usually precludes surgery. These patients are
often treated effectively with the placement of silicone-
covered self-expanding metal stents, often obviating
palliative surgery. Additionally, placement of feeding
gastrostomy or jejunostomy may be appropriate.
Although considered a ‘‘relative’’ contraindication to
radiation therapy, limited data from a Mayo Clinic
series suggests that radiation therapy may not increase
fistula severity and can be administered safely in this
setting; however, the presence of fistula is a poor
prognostic factor (Gschossmann et al. 1993).
28 Treatment Sequelae
Advances in surgical technique as well as improved
pre- and postoperative management have decreased
treatment-related mortality. Contemporary operative
mortality rates are generally \10% (Stahl et al. 2005;
Tsutsui et al. 1992). Complication rates can exceed
75%, including pulmonary and cardiac complications,
anastomotic leak, and recurrent laryngeal nerve
paralysis. Stricture formation can occur in 14–27% of
patients. The addition of preoperative radiation ther-
apy and chemotherapy may enhance surgical com-
plication rates.
More than 75% of patients receiving radiation
experience transient esophagitis and dysphagia and
may require some type of nutritional support. Che-
motherapy-related leukopenia and thrombocytopenia
are common. Additional acute toxicities of radiation
therapy include esophagitis, epidermitis, fatigue and
weight loss in most patients. Nausea and vomiting
are common, particularly in patients with lower
747
esophageal and gastroesophageal junction tumors.
Many symptoms resolve within 1–2 weeks of treat-
ment completion. A perforated esophagus is life-
threatening and can be characterized by substernal
chest pain, a high pulse rate, fever and hemorrhage
(Hussey et al. 1980). The addition of chemotherapy
can significantly increase acute complications. Mod-
erate to severe and even life-threatening toxicities
have been reported in 50–66% of patients (Herskovic
et al. 1992; Baquet et al. 2005; Coia et al. 1991). In
the previously discussed RTOG study treating with
radiation alone vs. chemoradiation, patients treated
with combined therapy had a higher incidence of
acute Grade 3 (44 vs. 25%) and Grade 4 toxicity (20
vs. 3%) compared to patients receiving radiation
therapy alone (al-Sarraf et al. 1997). Chemoradiation
treatment-related mortality rates range from 0 to 3%
(Walsh et al. 1996; Burmeister et al. 2005; Herskovic
et al. 1992; Stahl et al. 2005; Coia et al. 1991).
The most common late effects following radiation
therapy are stenosis and stricture formation. Stenosis
can occur in more than 60% of patients. Stricture
requiring dilatation has been reported to occur at least
15–20% of the time. Dysphagia may be relieved with
two to three dilatations (Coia et al. 1991). Long-term
results from the RTOG study showed that [ late
Grade 3 toxicity was similar in the combined arm
versus radiation–alone arms (29 vs. 23%). How-
ever, [ Grade 4 toxicity was higher in patients
receiving combined modality therapy (10 vs. 2%)
(Cooper et al. 1999). Other complications include
damage to other organs within the radiation therapy
volume, although this is uncommon. Chemotherapy
may further increase the risk of late treatment-related
toxicities.
The effects of radiation on pulmonary and cardiac
function deserve special mention. Pulmonary com-
plications associated with either the definitive or
neoadjuvant treatment of esophageal cancer patients
can be broadly broken up into symptomatic pneu-
monitis following treatment completion and post-
operative pulmonary complications in patients
undergoing resection. While still ill-defined, varying
institutional series have described predictive factors
for these complications (which are not mutually
exclusive) and are described below.
Radiation pneumonitis is a relatively common
complication in the treatment of thoracic (lung)
malignancies, which can range from minimally
748
symptomatic to fatal. Common symptoms include
nonproductive cough, dyspnea and, more uncom-
monly, respiratory distress. Generally, this occurs
2–6 months following radiation therapy completion.
The ability to predict radiation pneumonitis has been
a significant topic of investigation. However, most
data come from patients with lung cancer, who may
have more underlying intrinsic pulmonary/smoking-
related diseases. A variety of predictive parameters
have been suggested including V20 of [25–30%,
mean lung dose [ than 15–20 Gy, V5 [42% and
absolute V5 [3000 cubic cm (Hazard et al. 2008).
In nonoperative patients, an analysis of esophageal
cancer patients from Japan treated definitively to a
dose of 60 Gy with concurrent 5-FU and cisplatin
showed a radiation pneumonitis incidence of 27%.
The authors concluded that an optimal V20 threshold
to predict symptomatic pneumonitis was approxi-
mately 30% (Asakura et al. 2010). In a study of 101
both operative and nonoperative patients (88% distal
esophagus/GE junction) from M.D. Anderson Cancer
Center undergoing a mix of 3D and IMRT radiation
therapy, 59, 5 and 1% of patients experienced Grade
2, 3 and 5 radiation pneumonitis, respectively (Hart
et al. 2008). An analysis from Japan using fields
inclusive of supraclavicular, mediastinal and celiac
regions up to a dose of 60 Gy with concurrent cis-
platin and 5-FU showed a 2-year cumulative inci-
dence of late, high grade cardiopulmonary toxicities
for patients 75 years and older of 29 vs 3% versus in
younger patients. They concluded that older patients
may not tolerate extensive radiation fields (Morota
et al. 2009). Other studies have shown that significant
declines in diffusion capacity and total lung capacity
may occur in patients irradiated for esophageal cancer
(Gergel et al. 2002).
In operative patients, a study of 110 patients trea-
ted with preoperative chemoradiotherapy followed by
resection at M.D. Anderson Cancer Center showed
that mean lung dose, effective dose and absolute lung
dose receiving [5 Gy were predictors of develop-
ment of postoperative pulmonary complications
(Tucker et al. 2006). In a report of patients from the
same institution describing complications in patients
receiving neoadjuvant combined modality therapy,
18% experienced pulmonary complications, with
higher rates when the V10 was [40% (35 vs. 8%) and
V15 [30% (33 vs. 10%), leading the authors to
conclude that minimization of lung volume irradiation
B. G. Czito and C. G. Willett
was important in the preoperative planning of these
patients. This increase in postoperative pulmonary
(pneumonia, ARDS) complications when the V10
was greater than 40% suggests that the volume of
remaining/undamaged functional lung may determine
postoperative pulmonary function i.e., patients with a
small lung volume initially may be at higher risk of
experiencing pulmonary complications, even if the
relative V5 is low, and that patients with small lung
volume with less functional reserve may be more
susceptible to postoperative pulmonary complications
(Lee et al. 2003). Therefore, it is important to not only
consider the dose volume histogram of the lung but
also the total lung volume.
A study from China evaluating patients receiving
chemoradiotherapy followed by resection showed that
the volume of lung spared from doses [5 Gy was the
only independent dosimetric factor on multivariate
analysis in predicting postoperative pulmonary com-
plications (Wang et al. 2006) Wang et al. similarly
described that the relative V5 and all spared volumes
from 5–35 Gy significantly correlated with the inci-
dence of postoperative pulmonary complications,
although on multivariate analysis, V5 was the only
significant independent predictive factor, indicating
that the volume of ‘‘unexposed’’ lung during induc-
tion therapy was predictive. Of note in this study was
that the majority of patients were treated with
induction chemotherapy alone initially (most paclit-
axel), which has been shown to increase rates of
pneumonitis in other disease sites. A significant
association of induction chemotherapy alone prior to
concurrent chemoradiotherapy was seen as a predictor
of [ Grade 2 pneumonitis (49 vs. 14%, p = 0.003),
leading the authors to conclude that induction che-
motherapy alone may sensitize lung tissue to radiation
damage (Wang et al. 2008). In contrast to the above
studies, however, another analysis of 98 patients
receiving preoperative chemoradiotherapy with 5-FU
and cisplatin showed no difference in pulmonary
complications versus patients undergoing surgery
alone, with no correlation of any lung dose-volume
histogram findings with development of postoperative
pulmonary complications seen, leading the authors to
conclude that neoadjuvant chemoradiotherapy had no
detrimental impact on postoperative course (Dahn et
al. 2009). Finally, an analysis from Taiwan of neo-
adjuvantly, IMRT-treated esophageal cancer patients
undergoing resection suggested that preoperative
Esophageal Cancer
(and not prechemoradiation) FEV1 was an indepen-
dent factor associated with postoperative pulmonary
complications and that reducing absolute volume of
the right lung irradiated might decrease the risk of
postoperative pulmonary complications (Hsu et al.
2009).
Radiation-induced cardiac toxicity is a broad term
describing potential radiation injury to a number of
cardiac structures, including pericardium (as mani-
fested by effusion, pericarditis), coronary arteries, the
heart muscle itself, cardiac valves as well as nerve/
conduction injury. Radiation injury primarily consists
of fibrosis and/or small vessel injury. ‘Classic’ radi-
ation tolerance (TD5/5) of the heart is about 60 Gy
when 25% or less of the heart is irradiated, and 45 Gy
if 65% of the heart is irradiated, assuming 2 Gy per
fraction. The mechanism of radiation induced cardiac
injury is relatively poorly defined, particularly in the
context of esophageal cancer. Historical data from the
treatment of Hodgkin’s disease patients have sug-
gested that dose greater than 40 Gy may increase the
risk of cardiac death as well as pericarditis (Cosset
et al. 1991; Hancock et al. 1993). Several studies of
cardiac toxicity and esophageal cancer patient have
demonstrated that a V30 of greater than 46% pre-
dicted for a significant increase in pericardial effusion,
and increasing fraction size (particularly [ 3.5 Gy)
also predicted for the same. Additionally, some
authors have shown a possible trend for decrease in
ejection fraction in patients with increasing V20 of
the left ventricle (Hazard et al. 2008). In a study of
150 esophageal cancer patients receiving chemora-
diotherapy (49 neoadjuvantly), the incidence of peri-
cardial effusion was 28%, usually developing within
15 months of radiation therapy with median onset
time of approximately 5 months. The risk of peri-
cardial effusion was associated with mean pericardial
doses over an array of dose volume points to the
pericardium from 5–45 Gy. A matched pair-analysis
of nonradiation patients receiving surgery versus
those treated neoadjuvantly was performed, with 42%
of patients in the radiation group demonstrating
ischemia/scarring on SPECT images versus 4% in the
surgical group, with a median onset to abnormality of
3 months (Gayed et al. 2006). In a Japanese study,
long-term analysis of 139 patients treated with
definitive chemoradiotherapy (cisplatin/5-FU with
60 Gy EBRT) for squamous cell carcinoma revealed
grade 2, 3 and 4 late pericarditis occurring in 6, 5 and
749
1% of patients, respectively; grade 4 heart failure in 2
patients; grade 2, 3 and 4 pleural effusion develop-
ment in 5, 6 and 0% of patients, respectively; and
grade 2, 3 and 4 radiation pneumonitis development
in 1, 2 and 0% of patients, respectively (Ishikura et al.
2003).
29 Future Considerations
Although modest improvements in survival have been
achieved by combining neoadjuvant chemoradiation
and surgery, patients treated with chemoradiation
alone or with surgery have unacceptably high local–
regional relapse rates and mortality rates. Ultimately,
approximately 75% of patients will succumb to met-
astatic disease. As described previously, efforts at
radiation dose escalation have not resulted in signif-
icant gains in this disease. Given this data, clinical
trials have turned to studies evaluating new and
potentially more effective chemotherapeutic agents
with radiation therapy. Agents, such as irinotecan,
oxaliplatin, capecitabine, epirubicin, gemcitabine and
docetaxel are being investigated in the metastatic
setting as well as ‘‘curative’’ settings in combination
with radiation therapy. Furthermore, there is ongoing
investigation of the use of the vascular endothelial
growth factor inhibitor bevacizumab as well as
inhibitors of the epidermal growth factor receptors,
including the antibodies cetuximab and panitumumab,
in the treatment of esophageal cancer. All of these
agents have radiosensitizing properties. The investi-
gation of these agents with radiation therapy is the
subject of ongoing and future trials.
30 Summary
The prognosis for patients with carcinoma of the
esophagus remains poor despite recent advances in
combined-modality therapies. No firm recommenda-
tion can be made for managing locally advanced
disease. The available data suggests that neoadjuvant
chemoradiation improves outcomes in patients who
are candidates for surgery. Alternatively, randomized
trials have also suggested that perioperative chemo-
therapy improves outcomes in these patients. How-
ever, many patients are not able to tolerate surgery
and combined chemoradiation may be more
750
appropriate in selected patients, as definitive chemo-
radiation has resulted in survival rates comparable to
surgery alone. Locoregional failure remains a signif-
icant pattern of relapse. For patients with stage IV
disease, palliation with single-modality therapy or
several modalities should be used and tailored to the
patient’s specific symptoms. Current unresolved
issues include the following:
1. Which subsets of patients are more likely to ben-
efit from the addition of surgery than others?
2. Which subsets of patients are more likely to ben-
efit from the addition of neoadjuvant and/or peri-
operative therapies?
3. Can introduction of newer chemotherapy/targeted
agents in the neoadjuvant or concurrent setting
improve the results over ‘standard’ chemoradiation
with cisplatin and 5-FU?
4. Will new technologies such as 3D conformal
therapy, PET based planning, intensity-modulated
radiation therapy, proton therapy and image-gui-
ded radiation therapy decrease complication rates
and influence cure rates?
5. Will the identification of molecular prognostic
markers allow ‘‘individualization’’ of treatments
amongst patients?
6. In surgical patients, is there a superiority of either
a neoadjuvant chemoradiation versus a periopera-
tive chemotherapy approach?
7. Will PET scan allow early prediction of both
response to treatment as well as ultimate outcomes
and potentially allow avoidance of delivery of
ineffective treatments early on during the cause of
therapy?
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 Cancer of the Lung
Joe Y. Chang
Contents
1 Introduction.............................................................. 755
2 Diagnosis, Staging, Pathology, and Prognosis...... 756
2.1 Clinical Presentation.................................................. 756
2.2 Workup, Pathology, Staging, and Prognosis ............ 756
3 General Management of Lung Cancer ................. 757
3.1 Non-Small Cell Lung Cancer ................................... 757
3.2 Small-Cell Lung Cancer............................................ 760
4 Radiation Therapy Techniques..............................
4.1 Simulation ..................................................................
4.2 Immobilization...........................................................
4.3 Target Volume Delineation.......................................
4.4 Tumor Motion Management .....................................
4.5 Tumor Tracking.........................................................
5 Elective Nodal Irradiation ...................................... 765
6 Stereotactic Body Radiation Therapy................... 766
7 Three-Dimensional Conformal Radiation
Therapy (3D-CRT) vs. Intensity-Modulated
Radiation Therapy (IMRT).................................... 767
8 Proton Therapy........................................................ 769
9 Endobronchial High Dose Rate
Brachytherapy.......................................................... 770
10 Personalized Adaptive Radiation Therapy........... 771
11 Toxicities and Normal Tissue Tolerance .............. 772
12 Future Directions in Radiation Therapy
for Lung Cancer ...................................................... 772
References.......................................................................... 773
J. Y. Chang (&)
Department of Radiation Oncology, MD Anderson
Cancer Center, Houston, TX, USA
e-mail: jychang@mdanderson.org
S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_108, Ó Springer-Verlag Berlin Heidelberg 2012
Abstract
Lung cancer is the leading cause of cancer death
worldwide. Radiation therapy plays a crucial role
in the management of lung cancer. However,
conventional radiotherapy using two-dimensional
radiotherapy to 60–66 GY is associated with low
local control and potential significant toxicity.
Evolving radiotherapy technologies, such as four-
dimensional (4-D) image-based motion manage-
760 ment, daily on-board imaging and adaptive
760 radiotherapy, have enabled us to improve the
761
therapeutic index for lung cancer by permitting the
761
763 design of image-guided personalized treatments
764 that deliver adequate doses conforming to the
target while sparing the surrounding critical nor-
mal tissues. These achievements have permitted
the implementation of intensity-modulated radia-
tion therapy, stereotactic body radiation therapy,
and proton therapy in lung cancer. These cutting-
edge technologies may improve lung cancer con-
trol and patient survival.
1 Introduction
Lung cancer is the leading cause of cancer death in
both men and women in the United States and the
world (Jemal et al. 2009). Radiation therapy plays a
crucial role in the management of medical inoperable
early-stage lung cancer and in combined modality
treatment of locally advanced lung cancer. Conven-
tional radiation therapy to a dose of 60–66 Gy is
associated with less than 50% local control even
in early-stage disease. In the Radiation Therapy
755
756
Oncology Group (RTOG) 9410 trial, the median
survival time was only 15–17 months and 5-year
survival 13–16% for locally advanced disease even
when concurrent chemotherapy and radiation therapy
were given (Curran et al. 2003). In the same trial, the
incidence of both local failure (43%) and distant
metastasis (45%) was high. To improve local control
and survival, RTOG is conducting a phase III study
(RTOG 0617) to escalate the radiation dose from 60
to 74 Gy with concurrent chemotherapy. The diffi-
culty for dose escalation is toxicity due to tumor
proximity to surrounding critical structures.
Advanced radiation techniques are required to further
improve therapeutic ratio.
Radiation therapy for lung cancer has evolved
from two-dimensional (2D) treatment (RTOG 9410)
to three-dimensional conformal radiation therapy
(3D-CRT), intensity-modulated radiation therapy
(IMRT) (RTOG 0617), stereotactic body radiation
therapy (SBRT) (RTOG 0236), and proton therapy.
Cutting-edge radiation therapy technologies, such as
four-dimensional (4D) image-based motion manage-
ment, daily onboard imaging, and adaptive radiation
therapy, have improved the therapeutic index of
radiation therapy for lung cancer by permitting the
design of personalized treatments that deliver ade-
quate doses conforming to the target while sparing the
surrounding critical normal tissues. SBRT is
increasingly used in the treatment of selected patients
with T1NOMO lung cancer. More clinical studies are
needed to further optimize conformal radiation ther-
apy using individualized treatment adaptations based
on changes in anatomy and tumor motion during the
course of radiation therapy and using functional and
biological imaging to selectively escalate doses to
radioresistant subregions within the tumor. This book
chapter reviews the principles for tumor staging,
workup, and management and the current and future
radiation therapy technology in lung cancer.
2 Diagnosis, Staging, Pathology,
and Prognosis
2.1 Clinical Presentation
Signs and symptoms of lung cancer at presentation
depend on the location and extent of disease.
J. Y. Chang
The symptoms can reflect locoregional spread of
disease (either from the primary mass or distant
metastasis) or systemic manifestation of disease
(constitutional symptoms, paraneoplastic syndrome,
etc.). The most common presenting signs and symp-
toms are dyspnea, cough, weight loss, chest pain,
hemoptysis, clubbing, and bone pain.
2.2 Workup, Pathology, Staging,
and Prognosis
The proper diagnosis and staging of lung cancers
requires a complete history; physical examination;
diagnostic imaging including computed tomography
(CT) of the chest, positron emission tomography
(PET), and magnetic resonance imaging (MRI) or CT
of the brain; and laboratory tests. Figure 1 summa-
rizes the workup for the diagnosis and staging of lung
cancer.
Lung cancers are divided into non–small cell lung
cancer (NSCLC) and small-cell lung cancer (SCLC).
These two types account for approximately 85 and
15% of all lung cancers, respectively. The most
common histologic subtypes of NSCLC in the United
States are adenocarcinoma (50%), squamous cell
carcinoma (35%), and large-cell lung cancer (15%).
Subtypes of adenocarcinoma include bronchoalveo-
lar, acinar, and papillary. Subtypes of large-cell lung
cancer include giant cell and clear cell carcinomas,
both of which have a poor prognosis. Adenocarci-
noma is the histologic type least frequently associated
with smoking.
The American Joint Committee on Cancer
(AJCC) system for staging lung cancer (both NSCLC
and SCLC) is presented in Tables 1 and 2. Typically,
SCLCs are classified as limited or extensive depend-
ing on whether the disease can be encompassed
within a radiation portal (limited) or not (exten-
sive).
Overall survival is determined by treatment- and
patient-related factors. The four strongest adverse
prognostic factors for survival in lung cancers are (1)
advanced stage of disease, (2) poor performance sta-
tus (Karnofsky performance status \ 80%), (3)
weight loss [ 5% in the 3 months preceding presen-
tation, and (4) age [ 60 years.
Cancer of the Lung
Fig. 1 Workup for the
diagnosis and staging of lung
cancer
3 General Management of Lung
Cancer
3.1 Non-Small Cell Lung Cancer
3.1.1 Early Stage
For early-stage NSCLC (stage I/II), lobectomy and
mediastinal lymph node dissection/sampling are
standard treatments if the patient can tolerate the
procedure. Definitive radiation therapy is indicated
for patients who refuse surgery or who are medically
unable to undergo surgery because of a condition such
as poor pulmonary function, recent myocardial
infarction, or bleeding tendency.
Definitive radiation therapy includes a dose of
60–66 Gy delivered in 30–33 fractions, as recom-
mended on the basis of RTOG 73-11 (Perez et al.
1980). However, the biologically effective dose
(BED) of 70.2 Gy provided by this regimen is asso-
ciated with a 3-year local control rate of only 30–50%
757
and a 5-year cause-specific survival rate of only 13–
31% in patients with medically inoperable stage I
NSCLC (T1-2 N0 M0) (Perez et al. 1980; Kaskowitz
et al. 1993). Therefore, 60–66 Gy may not be suffi-
cient to kill all of the cancer cells. Because an
uncontrolled locoregional tumor is a major source of
continuous seeding to distant organs and causes
eventual treatment failure, its eradication is an
essential step to cure. A dose–response relationship
for disease-free survival in stage I NSCLC has been
reported, and doses [ 66 Gy appear to achieve better
local control and survival (Dosoretz et al. 1993).
Until more clinical data can be obtained, a dose
of approximately 70–74 Gy delivered in 2-Gy
fractions should be considered for patients with
stage I/II NSCLC. However, technological advances
such as the advent of stereotactic ablative radiation
therapy (SABR) have contributed to improvements
in local control and survival and a change in the
standard treatment for selected early-stage NSCLC
(see Sect. 6).
758 J. Y. Chang

Table 1 Seventh Edition AJCC TNM classification of lung Table 2 Stage grouping of lung cancers
cancers (NSCLC and SCLC) (2009) M0 T1a T1b T2a T2b T3 T4
Primary tumor (T)
N0 IA IA IB IIA IIB IIIB
Tx Primary tumor cannot be assessed
N1 IIA IIA IIA IIB IIIA IIIB
T1 B3 cm tumor, surrounded by lung parenchyma
N2 IIIA IIIA IIIA IIIA IIIA IIIB
T1a B2 cm tumor
N3 IIIB IIIB IIIB IIIB IIIB IIIB
T1b 2.1–3 cm tumor
M1 IV IV IV IV IV IV
T2 [3–7 cm tumor, involvement of visceral pleura, Source Edge et al. (2009)
invading mainstem bronchus [2 cm from carina, or
causing atelectasis to a single lobe of the lung
T2a 3.1–5 cm tumor patients with a good performance status and inoper-
T2b 5.1–7 cm tumor able stage IIIA or IIIB NSCLC. RTOG 9410 and
T3 [7 cm tumor, tumor invading mainstem bronchus other studies (Curran et al. 2003; Furuse et al. 1999;
\2 cm from carina, invasion of diaphragm, chest Fournel et al. 2005) using 2D radiation therapy have
wall, pericardium, mediastinal pleura, or associated shown that concurrent chemotherapy and radiation
atelectasis or obstructive pneumonitis of entire lung, therapy provide better locoregional control and
or satellite nodule in the same lobe
overall survival rates than do sequential chemother-
T4 Invasion of great vessels or adjacent organs, or
nodules in separate lobe in the ipsilateral lung
apy and radiation therapy. However, the toxicity
associated with chemoradiotherapy has been signifi-
Regional lymph nodes (N)
cantly greater than that associated with sequential
Nx Regional lymph nodes cannot be assessed
chemotherapy and radiation therapy (50 vs. 30% for
N0 No regional lymph nodes metastasis grade C 3 toxicity). It has been reported that 3D-CRT
N1 Ipsilateral hilar or peribronchial nodes reduces toxicity levels and allows a dose escalation
N2 Ipsilateral mediastinal or subcarinal nodes from 60 Gy (in RTOG 9410) to 74 Gy (Socinski et al.
N3 Any supraclavicular/scalene node or contralateral 2001; Schild et al. 2006; Bradley et al. 2010). Our
mediastinal/hilar nodes clinical data show that IMRT further reduces lung and
Distant metastasis (M) esophageal toxicity by decreasing V20, V10, and the
M1a Malignant pleural effusion, pericardial nodules/ total mean dose to the lungs and spares more esoph-
effusions, or lung nodules in contralateral lung ageal and heart tissues (Murshed et al. 2004; Liu et al.
M1b Metastasis to distant organs 2004), thereby improving clinical outcome (see Sect.
7). Although radiation doses of approximately 60 Gy
have, for decades, been considered standard for
3.1.2 Locally Advanced Stage treatment of stage III NSCLC, they have also been
Optimal treatment of locally advanced NSCLC associated with 40–50% locoregional failure, and the
remains controversial. Primary surgery for resectable need for dose escalation is obvious. Several studies
stage IIIA tumors followed by chemotherapy has been have shown the potential benefit in terms of local
the standard. Postoperative radiation therapy (PORT) control and survival rates afforded by image-guided
is indicated for close or positive margins and gross dose-escalated 3D-CRT (Socinski et al. 2001; Schild
residual disease. The role of PORT in treating nega- et al. 2006; Bradley et al. 2010).
tive margins remains controversial but may be indi- In RTOG 9410, the locoregional failure rate after
cated for pathologic N2 disease and any T4 disease concurrent chemotherapy and radiation therapy at a
except separate nodules in the same lobe. Induction standard radiation dose of approximately 60 Gy was
chemotherapy and radiation therapy or induction about 34–43%. To improve the local control rate,
chemotherapy followed by surgical resection have three groups (RTOG, the North Central Cancer
been used to downstage disease and are considered Treatment Group, and the University of North Caro-
options in selected cases of non-bulky, single-station lina) separately performed radiation dose escalation
N2 disease. trials in patients with stage III NSCLC, and their
Concurrent chemotherapy and radiation therapy results supported the safety and efficacy of using
have been considered the standard treatment for 74 Gy concurrently with chemotherapy in this
Cancer of the Lung
Fig. 2 Proposed treatment approaches for NSCLC
population (Socinski et al. 2001; Schild et al. 2006;
Bradley et al. 2010). In one dose escalation study, the
maximal tolerated dose of 74 Gy was reached when
used with weekly carboplatin and paclitaxel in
patients with stage III NSCLC (Schild et al. 2006).
Base on the promising local control and survival rates
and an acceptable toxicity level obtained using
3D-CRT to a dose of 74 Gy with concurrent chemo-
therapy, RTOG is conducting a phase III study com-
paring a dose of 60 Gy versus 74 Gy delivered by
3D-CRT or IMRT concurrently with weekly paclit-
axel and carboplatin plus/minus antibody against the
EGF receptor C225 in patients with stage IIIA or IIIB
NSCLC. In this RTOG trial, image-guided radiation
therapy is strongly recommended, IMRT is allowed if
tumor motion is taken into consideration, and con-
solidation chemotherapy is required.
On the basis of these data, we recommend the
delivery of 60–74 Gy in 1.8- to 2-Gy fractions with
concurrent chemotherapy for stage III inoperable
NSCLC off clinical protocol. For patients who cannot
tolerate chemotherapy, radiation alone to 66–74 Gy
should be considered. There is currently no role for
759
prophylactic cranial irradiation in the treatment of
NSCLC.
Superior sulcus tumors are apical masses that
involve the chest wall, ribs, vertebral body, brachial
plexus, stellate ganglion, and subclavian vessels.
They account for approximately 3% of all NSCLC.
Management is controversial. Some groups advocate
preoperative management with chemoradiation to
45 Gy followed by surgical resection, based on
promising results of SWOG-9416 and INT-0160
(Rusch et al. 2001). Others favor primary resection
followed by adjuvant therapy (chemotherapy and
radiation therapy), based on a series from
M. D. Anderson Cancer Center that utilized hyper-
fractionation (1.2 Gy bid to 69.6 Gy) (Komaki et al.
2005a) to minimize risk to the brachial plexus.
Figure 2 shows proposed treatment approaches for
NSCLC based on the best clinical evidence.
3.1.3 Postoperative Radiation Therapy
Postoperative radiation therapy (PORT) is indicated
for patients with close or positive margins and/or
resected N2 disease. Postoperative radiation therapy
760
improves local control and may improve disease-free
survival duration for patients with pathologic N2
disease (Lung Cancer Study Group 1986). Adjuvant
chemotherapy has been shown to improve survival
duration in patients with stage Ib to stage III NSCLC
and should be considered standard therapy (Strauss
et al. 2004; Douillard et al. 2005; Arriagada et al.
2004). Interestingly, a secondary analysis of the
Adjuvant Navelbine International Trialist Association
randomized study showed that PORT improved
overall survival in patients with N2 disease (Douillard
et al. 2008).
For patients with a negative resection margin but
positive mediastinal nodes, 2–4 cycles of adjuvant
chemotherapy followed by radiation therapy should
be given. For patients with a positive resection mar-
gin, PORT should be given first, followed by adjuvant
chemotherapy. The role of PORT in positive N1
disease remains controversial. Because of the poten-
tial long-term survival of patients with N1 disease,
chronic toxicity associated with PORT is a risk. For
patients with microscopic positive or close margins
but no N1 or N2 involvement, the target volume
should be limited to the site of the positive margin.
The dose should be 60–66 Gy. For patients with
surgically resected N2 disease, the target volume
should be limited to the positive lymph node station
plus or minus the ipsilateral hilar and subcarinal
lymph nodes, depending on the location of the pri-
mary cancer and whether a full lymph node dissection
was performed. The dose should be limited to about
50 Gy delivered in standard fractions. Patients with
extracapsular nodal tumor extension should receive
54-60 Gy in 2-Gy fractions. For gross positive mar-
gins (subtotal resection), patients should receive
definitive radiation therapy to 66–70 Gy in 33–35
fractions, with concurrent chemotherapy if possible.
3.2 Small-Cell Lung Cancer
Small-cell lung cancer (SCLC), whether limited or
extensive, is usually treated with definitive chemora-
diation. Response to chemotherapy is good. For
patients with T1-2N0M0 (stage I) SCLC (\5% of
cases), complete surgical resection with lobectomy
and mediastinal nodal dissection may be considered,
based on the promising outcomes from numerous
surgical series. However, proper staging with
J. Y. Chang
mediastinoscopy or endobronchial ultrasound-guided
biopsy (EBUS) must rule out mediastinal nodal
involvement. Postoperative chemotherapy must be
considered even if surgical pathology demonstrates
no mediastinal nodal involvement. For patients with
pathologic mediastinal nodal involvement, adjuvant
chemotherapy and radiation therapy should be
considered.
For patients with more advanced non-metastatic
diseases (95% of limited-stage cases), the standard of
care is definitive chemoradiation with cisplatin–eto-
poside. Thirteen randomized studies, including a total
of 2,140 patients, have investigated the role of tho-
racic radiation therapy in limited-stage SCLC. Two
meta-analyses of these trials have demonstrated that
adding radiation to chemotherapy is beneficial in
terms of local control and overall survival (Pignon
et al. 1992; Warde and Payne 1992).
The current standard of care is based on the
Intergroup 0096 trial, which combined concurrent
cisplatin–etoposide with radiation therapy to 45 Gy in
1.5-Gy fractions twice daily (BID) (Turrisi et al.
1999). Numerous other trials and meta-analyses have
demonstrated that early radiation is better than
delayed radiation. Nevertheless, the optimal schedule
is currently unknown and is being tested in an
ongoing randomized phase III trial (CALGB 30610/
RTOG 0538) comparing 45 Gy in 30 fractions BID
vs. 61.2 Gy in 34 fractions daily (QD) for the first 16
fractions and then BID for the last 18 fractions
(Komaki et al. 2005b) vs. 70 Gy in 35 fractions QD
(Miller et al. 2007) in combination with concurrent
chemotherapy. Figure 3 shows proposed treatment
approaches for SCLC based on the best clinical
evidence.
4 Radiation Therapy Techniques
4.1 Simulation
Patients are placed on the treatment couch, immobi-
lized, and aligned based on simulation position.
4D-CT simulation to account for tumor motion and to
individualize target volume and margin should be
considered for all patients. If 4D-CT is not available,
spiral CT or extended-time CT simulation (slow CT
scanning) can be done to acquire an average image of
the tumor at all phases of the respiratory cycle.
Cancer of the Lung
Fig. 3 Proposed treatment
approaches for SCLC
If 4D-CT scan is performed, patients are evaluated for
regularity of breathing, ability to follow instructions
to feedback guidance, breath-holding ability, and
suitability for implantation of fiducial markers. Based
on this evaluation, one of the following treatment
delivery techniques is selected:
1. Breath-hold (with or without feedback guidance)
2. Respiratory gating
3. Free breathing (with or without feedback
guidance)
Breath-hold and respiratory gating are used in
patients where large respiratory excursion is seen.
Generally, the upper limit of allowable tumor excur-
sion is 1 cm. Patients with less than 1 cm tumor
excursion can be treated without breath-hold or gating
techniques, but treatment planning should account for
tumor motion by creating a combined image data set
of all possible respiratory positions of the target
(maximal intensity projection [MIP]). Setup should be
verified weekly by orthogonal kilovoltage (kV) or
megavoltage (MV) films based on bony alignment.
For hypofractionated irradiation that requires exqui-
site precision, daily CT imaging (either CT-on-rails or
761
cone-beam CT) should be considered for both tumor
and normal anatomy visualization.
4.2 Immobilization
Patients are placed in the supine position with both
arms up and immobilized with any number of com-
mercially available devices. At M.D. Anderson Can-
cer Center, we use a Vac-Loc bag and T-bar that gives
a setup uncertainty of about 7 mm. Daily imaging
(kV orthogonal X-rays, or cone-beam CT) can reduce
this uncertainty further.
4.3 Target Volume Delineation
The International Commission on Radiation Units
(ICRU) Report No. 50 guidelines for defining targets
have been applied to the treatment of lung cancer.
Gross tumor volume (GTV) is visible by any imaging
modality (the primary tumor) along with any grossly
involved lymph nodes. Clinical target volume (CTV)
762
is the anatomically defined area (the hilar or medi-
astinal lymph nodes or a margin around the grossly
visible tumor) believed to harbor micrometastasis.
Planning target volume (PTV) accounts for physio-
logic organ motion during treatment and the inaccu-
racies of daily setup in fractionated therapy. To
address the issue of tumor motion, ICRU Report No.
62 proposed the internal target volume (ITV), which
is defined as an expansion of the CTV in which target
motion is explicitly measured and taken into account.
4.3.1 Gross Tumor Volume Delineation
The pulmonary extent of lung tumors should be
delineated using pulmonary windows, and the medi-
astinal extent of tumors should be delineated using
mediastinal windows. In general, a lymph
node [ 1 cm in its shortest dimension on CT is
considered positive because of [15% involvement.
F-18 fluorodeoxyglucose positron emission tomogra-
phy (FDG-PET) imaging is quite important for radi-
ation treatment volume planning in stage III disease.
In particular, FDG-PET can help to categorize sus-
pected mediastinal and hilar lymph node adenopathy
and differentiate benign collapsed lung tissue from
tumor. Higher standard uptake values (SUV) may be
predictive of poor survival, poor local control, and
metastatic disease. Lesions with high SUV activity
may indicate possible radiation resistance that may
need aggressive treatment with stronger chemother-
apy and higher doses of radiation (Sasaki et al. 2005;
Klopp et al. 2007). However, false-positive PET scans
can be caused by inflammation, and a biopsy is rec-
ommended if there is any question. If any suspicious
lymph nodes are seen on either PET or CT images,
medianoscopy or EBUS or esophageal ultrasound
(EUS) should be considered to verify the involvement
(Cerfolio et al. 2010).
4.3.2 Clinical Tumor Volume Delineation
As shown by a radiographic–histopathologic study in
lung paranchymal disease (Giraud et al. 2000), GTV
to CTV expansions of 6 mm for squamous cancers
and 8 mm for adenocarcinomas are required to cover
the gross tumor and microscopic disease with 95%
accuracy. Expansions for other histologic types have
not been determined, but a conservative approach
would be to use 8 mm. An appropriate CTV for
mediastinal involvement has not been rigorously
determined. We empirically use 8-mm expansions
J. Y. Chang
around involved nodes (either gross involvement or
FDG-PET positivity). Obviously, these expansions
should not necessarily be applied uniformly along all
axes and should always be individualized on the basis
of the location of the primary tumor and involved
lymph node. In the absence of radiographic proof of
invasion, the CTV of the primary lesion should not
extend into the chest wall or mediastinum. CTV
expansions of lymph node disease should not extend
into the major airways or lung, chest wall, or vertebral
body without evidence of invasion on CT and/or MRI.
4.3.3 Planning Target Volume Delineation
When patients are immobilized with a Vac-Loc bag
and T-bar, expansion of 7 mm along all axes accounts
for 95% of the day-to-day setup uncertainty if weekly
port film is used. Setup uncertainty is likely both
technique and institution dependent and should be
measured individually for each technique. If a daily
kV image is used, the setup uncertainty can be
reduced to 5 mm. If a daily onboard image such as
CT-on-rails or cone-beam CT is used before each
fraction of radiation therapy, day-to-day setup
uncertainty can be reduced to 3 mm. In addition, the
tumor motion may be significant, and motion margin
must be considered. As shown in a recent study of
ours (Liu et al. 2007), tumor motion depends on
tumor location and size. Thus, ‘‘tumor motion’’ mar-
gins should be added to the CTV expansion and setup
uncertainty margin. For upper quadrant lesions, a
6-mm tumor motion margin may be adequate
regardless of tumor size and for middle segment
tumors [50 mm in diameter. For tumors \50 mm in
diameter and located in the middle two quadrants of
the lung, or tumors 50-80 mm in diameter in the
lowest quadrants, a 13-mm tumor motion margin may
be needed. For tumors \50 mm in diameter in the
lowest quadrant, an 18-mm margin may be necessary.
Most tumors move in a superior/inferior direction,
and individualized motion assessment with regular X-
ray fluoroscopy is recommended.
Typically, the PTV should be covered by [95% of
the prescribed dose. However, if dose escalation is
intended for gross disease but not for microscopic
disease, a higher dose can be prescribed to the GTV
plus the setup uncertainty margin with a PTV boost
(integrated boost); for microscopic disease, the final
PTV should be covered by at least 50–60 Gy. If the
patient has very poor pulmonary function or a very
Cancer of the Lung
large GTV, radiation toxicity in addition to optimal
target coverage should be considered. Clinical judg-
ment should be applied to balance these two issues.
For patients who receive induction chemotherapy
followed by chemoradiotherapy, the GTV should
include the lung extent of the GTV after chemother-
apy and abnormal lymph node stations before che-
motherapy. If the patient has a complete response
after chemotherapy, the areas of the lymph node
stations and of lung parenchymal disease before
chemotherapy should be included as the CTV and
treated with at least 50 Gy. If disease progresses
during chemotherapy, the GTV should cover the area
of progressive disease.
4.3.4 Internal Target Volume
One major obstacle to target delineation has been
respiration-induced target motion, or intrafractional
tumor motion, which can add considerable geometri-
cal uncertainty to the radiation treatment. Such motion
requires enlargement of the PTV to cover the excur-
sion of the tumor during treatment. There are multiple
approaches to addressing the issue of tumor motion.
4.4 Tumor Motion Management
Tumor motion consideration is critical for lung cancer
radiation therapy and is best assessed individually for
each patient. With the development of multislice
detectors and faster imaging reconstruction, it is now
possible to image patients as they breathe in real time
and to assess organ motion using 4D-CT (Liu et al.
2007). A recent 4D-CT study showed that [50% of a
tumor moves [5 mm during treatment and that 13%
moves [1 cm (possibly as much as 3–4 cm), partic-
ularly if the lesion is close to the diaphragm. For
patients with tumor motion of \5 mm, simple uni-
form expansion for the PTV margin is adequate.
However, for patients with substantial tumor motion,
particularly [1 cm, an individualized tumor motion
margin in different dimensions should be considered.
This can be addressed by respiratory gating, assisted
breath-hold, or an ITV-based approach (Fig. 4).
4.4.1 Free Breath During the Radiation
Delivery
If patients do not qualify for breath-hold delivery or
do not have regular reproducible breathing or if
763
T50
(Gating)
IGTV:
GTV Path of gross
tumor motion
Lung tumor motion: T0 Motion management:
>10 mm: 10% tumor (BH) 1. ITV to cover IGTV
5-10 mm: 40% tumor 2. Respiratory gating
<5 mm: 50% tumor ITV 3. Breath-hold
PTV 3. Tumor tracking
Fig. 4 Lung cancer motion management. Tumor motion in
lung cancer should be addressed individually. For tumor moves
less than 5 mm, ITV approach should be considered. For tumor
moves more than 10 mm, either breath-hold or respiratory-
gated treatment should be considered. Ideally, we should track
and treat the moving tumor
respiratory gating is not available for treatment
planning, they should be treated using the free-breath
technique.
ITV Approach Based on 4D-CT Simulation
When 4D-CT is available for treatment planning, we
propose a new concept called internal gross tumor
volume (IGTV), defined as the volume containing the
GTV throughout its motion during respiration. The
IGTV can be delineated from 4D images by registering
the tumor volume outlined on the expiratory phase of
the 4D images on other phases of the images to create a
union of target contours enclosing all possible positions
of the target. Alternatively, the IGTV can be delineated
from MIP images by combining the data from the
multiple CT data sets with that from the whole breath
cycle and verifying them in different phases. In this
case, the ITV should consist of the IGTV plus a margin
to allow for microscopic disease (8 mm).
ITV Approach Based on Breath-Hold Spiral CT
During Simulation
When ITV is based on breath-hold spiral CT, images
are acquired by using the standard extended temporal
(ET) thoracic CT protocol. This imaging protocol
requires the patient to breathe normally. The ET CT
images should be acquired at the beginning of the
simulation; the isocenter is then set. Subsequently,
patients should be imaged using a fast CT simulation
protocol while at 100% tidal volume (end of inspira-
tion) and 0% tidal volume (end of expiration).
764
The traces from the RPM system should be recorded.
Separated GTVs and CTVs should be delineated by a
physician on both the 100% tidal volume CT image set
and the 0% tidal volume image set. An ITV is then
generated by combining these two CTVs on the ET CT
scan to form an enveloped ITV that includes the entire
path of the CTV as it moves from inspiration to expi-
ration. Normal tissues should be contoured in the ET
CT images. The IVT should be superimposed on the
slow CT images, which will serve as the basis for
treatment planning.
Slow CT Simulation (Single-Slice Helical Scanner)
If a patient is not treated with either the respiratory
gating or ITV technique, slow CT simulation is rec-
ommended in order to obtain a random motion sam-
pling. The GTV should be contoured based on this
sampling and supplemented with a 0.5- to 1-cm
motion margin plus the setup uncertainty margin
based on tumor size and location.
4.4.2 Breath Control During Radiation
Delivery Techniques
Breath-Hold Treatment Delivery
The breath-hold treatment delivery method is the
most accurate for patients who are able to comply.
Active breathing control and deep inspiration breath-
hold help patients hold their breaths at reproducible
points in the respiratory cycle while radiation is
delivered (Rosenzweig et al. 2000). These two tech-
niques limit patient respiratory excursion to fixed
volumes and limit diaphragm excursion to approxi-
mately 5 mm instead of 10–15 mm. These techniques
require very cooperative patients who are able to hold
their breath for at least 15 s. Unfortunately, patients
with poor pulmonary function (who would most
benefit from reduction in irradiated lung volumes) are
least able to comply with breath-hold techniques, and
their breathing tends to be irregular during radiation
therapy. Visual and/or audio feedback guidance
should be used for all patients who respond well to
training with the feedback devices.
Respiratory Gating
Patients who do not qualify for breath-hold treatment
delivery but are able to breathe regularly and repro-
ducibly should be treated with the respiratory gating
method when it is available. A commercially available
J. Y. Chang
system (the VarianÒ Real-time Position Manage-
mentTM [RPM] system) can be used to gate the linear
accelerator beam. This technique uses an externally
placed fiducial marker that is tracked as the patient
breathes. The radiation beam can be triggered at a
chosen point in the respiratory cycle, typically at end-
expiration because this is the longest and most repro-
ducible portion of the respiratory cycle. This technique
requires patients to breathe slowly in a regular pattern.
In a recent study, we showed that respiratory-gated
therapy was most beneficial for patients with a tumor
volume of\100 cm3 (usually\5 cm in diameter if the
tumor is almost round) and a tumor motion of [1 cm.
In general, tumors in the lower lobes of the lung move
more than those in other locations during breathing. A
5-mm margin is recommended to allow for the
uncertainty of day-to-day respiratory-gated tumor
localization (Nelson et al. 2006). Visual and/or audio
feedback guidance should be used for all patients who
respond well to training with the feedback devices.
Attention should be paid to irregular breathing and
variation in the breathing pattern over the course of
treatment. Even with 4D-CT, the free-breathing sim-
ulation is only a snapshot and a single stochastic
sampling of the patient’s breathing. The uncertainty
of the patient’s breathing during the course of treat-
ment should also be considered.
4.5 Tumor Tracking
At this time, several techniques for the planning and
delivery of radiation are being investigated for their
possible future use in the treatment of lung cancer.
Some explicitly incorporate motion and setup uncer-
tainty into the calculation of radiation doses and
tracking the motion of a moving target for the
delivery of radiation. One of the systems of increas-
ingly widespread use is the CyberknifeTM, which
utilizes a stereotactic guidance system designed pri-
marily for radiosurgery in multiple organ systems to
help a robotically mounted linear accelerator track the
target during treatment. Another novel system, the
Novalis Tx, allows stereo X-ray targeting and adap-
tive gating using the ExacTrac X-ray 6D and snap
verification system. These novel systems may provide
optimal treatment for clinically challenging cases in
patients with poor lung function and/or lesions close
to critical structures. Further studies on these systems
Cancer of the Lung
and techniques will continue to define their role in
adaptive radiation therapy and the definitive treatment
of NSCLC.
5 Elective Nodal Irradiation
For many years, the standard radiation therapy for
NSCLC in the United States was to first deliver
40–50 Gy to the regional lymph nodes (ipsilateral,
contralateral, hilar, mediastinal, and occasionally
supraclavicular) that showed no evidence of tumor
involvement and then deliver 20 Gy to the primary
tumor through reduced fields. This regimen was based
on pathologic information about the high incidence of
hilar and mediastinal lymph node metastases in
patients with bronchogenic carcinoma. Perez and
associates (Perez et al. 1982), in an analysis of pro-
tocol compliance among 316 patients in the RTOG
73-01 trial, reported that survival rates were higher,
but not statistically significantly so (P = 0.35), in
patients with radiographically negative lymph nodes
who had no protocol variations and had adequate
coverage of the hilar and mediastinal lymph nodes.
The rationale against the use of elective nodal
irradiation is the high rate of local disease recurrence
within the previously irradiated tumor and the high
risk of distant metastasis and toxicity associated with
a large radiation volume. Furthermore, if the gross
disease cannot be controlled, there is no point to
enlarging the irradiated volumes to include areas that
may harbor microscopic disease.
Three major factors have changed since the RTOG
73-01 trial established the standard radiation therapy
for NSCLC: the use of chemotherapy, the advent of
3D-CRT, and better staging and target delineation
with PET. Emerging clinical data show that omitting
prophylactic lymph node irradiation does not reduce
the local control rate in patients receiving definitive
radiation therapy. In these patients, the local recur-
rence rates in the isolated outside-field (field of radi-
ation therapy) have been\8%, particularly in patients
with stage I disease and in those who have undergone
PET scanning for staging (Rosenzweig et al. 2001;
Senan et al. 2002; Sulman et al. 2009; Martel et al.
1997). The low isolated outside-field failure rate
could be explained by the fact that (1) incidental
doses to the ipsilateral hilum, paratracheal, and sub-
carinal nodes approach 40–50 Gy when these regions
765
are not intentionally irradiated (Martel et al. 1997)
and (2) patients with lung cancer experience com-
peting causes of mortality. Such patients may die of
local failure, distant failure, or intercurrent illness
before failure is detected in lymph nodes that had
previously shown no evidence of tumor involvement.
A recent randomized study appeared to support
involved-field irradiation approach (Yuan et al. 2007).
The addition of PET to CT has substantially
enhanced the clinical mediastinal staging of regional
lymph nodes and improved sensitivity and specificity
(94 and 86% for PET-CT vs. 75 and 66% for CT
alone) (Pieterman et al. 2000). More accurate clinical
staging with PET may allow the radiation oncologist
to include involved hilar and mediastinal lymph nodes
that might not be appreciated on CT alone and
thereby reduce the probability of treatment failure in
electively treated lymph nodes. As the number of
facilities with dedicated FDG-PET scanners and
specifically combined PET-CT units increases, these
technologies will help radiation oncologists to design
PTVs (Bradley et al. 2004). We recently reported a
series of 118 patients with lung cancer staged by PET
and CT and treated definitively with 3D-CRT to
involved-field volumes without elective nodal irradi-
ation. Although 21% of these patients developed local
recurrence within the radiation field and 50% devel-
oped distant metastases (Sulman et al. 2009), only 4%
experienced failure in lymph nodes that had previ-
ously shown no evidence of tumor involvement.
Recently, EBUS of lymph nodes has become widely
used to evaluate mediastinal involvement in patients
with questionable lymph node involvement and fur-
ther improve staging accuracy (Cerfolio et al. 2010).
Thus, in patients with NSCLC, it is important to
deliver adequate doses of radiation to primary tumor
and involved nodal or mediastinal areas. Irradiation of
other electively treated lymph nodes may not be
necessary, particularly in patients whose tumors are
staged with CT, PET, and EBUS. However, if local
control and survival continue to improve along with
radiation dose escalation techniques, the issue of
elective nodal irradiation may need to be revisited in
future.
For SCLC, elective nodal failure rates of 4% for
FDG-PET-guided treatment (van Loon et al. 2010)
and 2% for PET-CT-guided IMRT treatment (Shervin
et al. 2010) have been reported, and local failure and
distant metastasis remains a major pattern of failure
766
Fig. 5 Stereotactic body radiation therapy in stage I NSCLC to deliver ablative dose to target while sparing critical structures
after radiation therapy to 45-70 Gy and concurrent
chemotherapy (Shervin et al. 2010). The published
data support the omission of elective nodal irradiation
when adequate tumor staging is performed particu-
larly by means of PET-CT.
6 Stereotactic Body Radiation
Therapy
Image-guided hypofractionated SBRT or SABR is
preferred for the management of early-stage NSCLC
over conventionally fractionated radiation treatment,
which yields poor local control and survival outcomes
(Murshed et al. 2004; Nagata et al. 2005; Nelson et al.
2006; Onishi et al. 2004; Onishi et al. in press). The
dosing schemes used should achieve a BED of
[100 Gy, and dose fractionation should be based on
whether the tumor is peripherally or centrally located.
SBRT delivers a high BED ([100 Gy) to the target
while minimizing normal tissue toxicities by using
multiple beams ([6, but typically 9–12) to create a
sharp dose gradient from ablative dose to tolerable
dose (Fig. 5). This translates into improved local
control ([95%) and potentially better survival.
According to Onishi et al. (2004), BEDs of C 100 Gy
are associated with better local control (91.9 vs.
73.6%) and survival rates (88.4 vs 69.4%) than are
BEDs of \100 Gy. To achieve this goal, multiple
regimens have been used, but the optimal regimen
remains unclear. It is quite possible that tumor size
and location may determine optimal regimen. In the
RTOG 0236 trial, 54 Gy prescribed to PTV is deliv-
ered in three fractions with heterogeneity correction
(60 Gy without heterogeneity correction) over
J. Y. Chang
2 weeks. This regimen is well tolerated by patients
with peripheral lesions but too toxic for those with
lesions within 2 cm of the bronchial tree. In the
RTOG 0236 trial, patients with inoperable NSCLC
who received SBRT had a survival rate of 55.8% and
a primary tumor control rate of 97.6% at 3 years
(Timmerman et al. 2010). Many institutions including
M.D. Anderson Cancer Center use 48-50 Gy deliv-
ered in 4 fractions to the PTV for 4 contiguous
treatments (Chang et al. 2008). The local control rates
achieved with these regimens all exceed 95%.
Delivery of 50 Gy in 4 fractions has been shown to be
safe in patients with central lesions when individual
critical structure tolerances are respected (Chang et al.
2008). When normal tissue tolerance cannot be
achieved for lesions near or attached to critical
structures such as the bronchial tree and esophagus,
70 Gy in 10 fractions has been used with no signifi-
cant severe side effects reported (Xia et al. 2006).
SBRT is emerging as a standard treatment for medical
inoperable stage I, isolated lung parenchyma and
recurrent NSCLC (Kelly et al. 2010). Meanwhile, for
operable stage I NSCLC, available data indicate that
SBRT produces outcomes comparable to those of
surgical resection (Onishi et al. in press). Randomized
studies to validate the data are ongoing.
Two important principles of SBRT must be
obeyed: (1) An ablative dose (BED [ 100 Gy) pre-
scribed to PTV is required to achieve [90% local
control and (2) image-guided tumor volume delinea-
tion and onboard image-guided radiation therapy
(IGRT) are required to account for daily target/normal
tissue motion so that the target is not missed and to
avoid normal tissue injury (Chang et al. 2008).
Ablative SBRT is typically delivered in \5 fractions.
Cancer of the Lung
With such a small number of fractions, it is critical to
optimize patient positioning and target coverage for
each treatment. The possibility of a geographic miss
or overdosing of critical structures is increased when
the target moves[1 cm or the lesion is located within
2 cm of critical structures such as the bronchial tree,
esophagus, heart, brachial plexus, and spinal cord.
Toxicity may be severe and even fatal if critical
normal tissue receives an excess dose of radiation
(Timmerman et al. 2006). Therefore, conformal
SBRT is usually optimized to ensure that at least 95%
of the prescribed dose (minimum BED of 100 Gy) is
delivered to the PGTV, usually defined as the IGTV
plus a margin to account for setup uncertainty. Care
must be taken to avoid delivering an excessive dose to
critical normal tissues in close proximity to the tumor
bed. This approach has been shown to achieve [95%
local control with minimal side effects (\ grade 3) in
centrally located lesions (Chang et al. 2008).
Indications for SBRT or SABR include the
following:
1. Medical inoperable stage I (T1-2N0M0 NSCLC
with tumor size \5 cm) NSCLC (including in
patients who refuse surgery)
2. Isolated recurrent lung parenchymal NSCLC
\5 cm in diameter
Centrally located lesions (i.e., those within 2 cm of
the bronchial tree) should be carefully evaluated
because of the potential for significant side effects,
and 54 Gy in 3 fractions should not be used.
7 Three-Dimensional Conformal
Radiation Therapy (3D-CRT) vs.
Intensity-Modulated Radiation
Therapy (IMRT)
Three-dimensional CRT (3D-CRT) is more com-
monly used than IMRT in lung cancer patients for
several reasons. First, there are concerns that IMRT
delivers greater amounts of low, yet damaging, doses
to larger volumes of normal lung tissue than does
conventional 3D-CRT. As a result, use of IMRT in
lung cancer patients has not become widespread, even
though IMRT improves dose conformality and allows
integrated dose escalation/dose painting within the
target. Second, IMRT involves interactions between
tumor motion, respiration, and IMRT dosimetry
which introduce another level of complexity to both
767
the IMRT treatment planning and delivery. This is
problematic since IMRT treatment field may only
cover a portion of the target volume at any particular
time. Third, there is a great concern about the inter-
play between collimator dynamics (either with the use
of sliding window or step-and-shoot) and tumor
motion during IMRT, which may degrade planned
dose distributions (Schwarz et al. 2006). However, a
recent study showed that the main effect of organ
motion in IMRT is to average the dose distribution
over the path of tumor motion rather than cause sys-
tematic errors in dose delivery (Bortfeld et al. 2002).
Therefore, the final dose delivered to the target and
normal tissue by IMRT should be similar to that
delivered by conventional radiation therapy without
intensity modulation, and the additional effects spe-
cific to the IMRT delivery technique appear to be
relatively small. Proposed approaches aimed at miti-
gating the effect of internal tumor motion in IMRT
include expansion of the target margins, motion-cor-
related delivery (e.g., respiratory gating, external
fiducial tracking), and adaptive treatment plan opti-
mization employing a probabilistic description of
motion (Liu 2008). Currently, the Advanced Tech-
nology Consortium (ATC) of the National Institutes
of Health recommends that tumor motion be reduced
to \0.5 cm using compensation techniques such as
breath-hold, respiratory gating, or tumor tracking if
IMRT is used (http://www3.cancer.gov/rrp/imrt.doc).
When planning IMRT for lung cancer, we rec-
ommend limiting treatment to 5–7 fields to reduce
low-dose exposure to normal lung tissue and mini-
mizing the use of very small field sizes if target
motion is significant. In addition, depending on the
target location and critical structures to be spared, we
recommend preferential utilization of anterior/pos-
terior beam angles if sparing normal lung tissue is a
priority and a more lateral beam arrangement if
sparing the heart is a priority (Liu 2008). When dose
distribution, especially in low-dose regions, is pushed
away from the lung or heart, the target conformality
may have to be sacrificed to a certain degree. Virtual
clinical studies (Murshed et al. 2004; Liu et al. 2004)
have shown that IMRT treatment planning may be
more suitable than 3D-CRT treatment planning for
patients who have advanced-stage disease with large
GTVs and complicated tumor/normal tissue anatomy
and for patients in whom sparing the surrounding
critical structures from toxicity is of particular
768
Fig. 6 IMRT in a patients with extensive stage III NSCLC and tumor close to spinal cord
concern (Fig. 6). When using IMRT instead of 3D-
CRT, the median absolute reductions in percentage of
lung volume irradiated to [10 and 20 Gy were 7 and
10%, respectively. Likewise, the volumes of heart and
esophagus irradiated to approximately 50 Gy and the
volumes of normal thoracic tissue irradiated to more
than 10–40 Gy were also reduced. These studies
noted a marginal increase in lung volume exposed to
more than 5 Gy in the IMRT plans in half of the
patients. Lower-dose (\10 Gy) exposure to the lung
could be reduced by limiting the beam arrangements,
as stated above.
Clinical data comparing IMRT and 3D-CRT indi-
cate that IMRT reduces pneumonitis and esophagitis
in patients with stage III NSCLC undergoing con-
current chemoradiotherapy (Yom et al. 2007). A trend
toward improved survival was observed when these
patients were retrospectively compared with patients
in a similar group receiving 3D-CRT (Yom et al.
2007; Liao et al. 2010). A prospective comparative
study is needed to validate these results. Because
IMRT treatment planning is more complex and
sophisticated than 3D-CRT planning, one would
assume that implementing IMRT-based treatment for
J. Y. Chang
lung cancer would impede dosimetric workflow;
however, with the development of mature optimiza-
tion algorithms and automated planning software
(Zhang et al. 2010a; M. D Anderson Cancer Center
auto-plan, unpublished data), our institutional expe-
rience suggests that IMRT takes less time than
3D-CRT when planned by an experienced dosime-
trist. IMRT appears to be a more appealing treatment
option for tumors located in the superior sulcus with
chest wall/vertebral body involvement and may allow
further dose escalation. We recently published our
IMRT guidelines along with detailed techniques for
treating NSCLC (Liu 2008; Chang et al. 2005).
For IMRT, 4D planning is more important than
conventional 3D planning because of the high degree
of dose shaping and conformity required in the IMRT
plans. The logical extension of 4D planning is to
incorporate interfractional anatomic change into the
planning process, so that the actual dose to be deliv-
ered over the entire course of treatment can be esti-
mated and adjusted as needed if the patient’s anatomy
changes significantly during treatment. Such anatomic
changes can be caused by physiologic fluctuation and
tissue response to radiation or chemoradiation.
Cancer of the Lung
Fig. 7 Passive scattering proton therapy 74 Gy with concurrent chemotherapy in stage III NSCLC. a PET/CT before proton
therapy; b complete response at 10 months after treatment; c proton dose distribution
Frequent imaging may be needed to guide treatment
planning and delivery. The scope of 4D planning
should thus include both interfractional and intra-
fractional uncertainties and address such changes
appropriately so as to improve treatment outcome.
8 Proton Therapy
Because of the physical characteristics of protons,
proton therapy delivers its therapeutic dose to a cer-
tain depth (as defined by the Bragg peak) without any
exit dose. Optimizing proton beam angle/intensity and
energy could improve conformality of radiation dose
delivery to the target while avoiding critical struc-
tures. In a retrospective comparison of 3D-CRT,
IMRT, and proton therapy, passive-scattering proton
769
therapy (PSPT) was shown to significantly reduce the
dose delivered to normal lung tissue (particularly at
doses of \10 Gy), heart, spinal cord, and, in certain
cases, esophagus (Chang et al. 2006). This was the
case even when the tumor radiation dose was esca-
lated from 66 to 87.5 Gy in stage I NSCLC and from
63 to 74 Gy in stage III NSCLC (Chang et al. 2006).
Compared with photon-based SBRT, stereotactic
body proton therapy (SBPT) can spare more critical
structures particularly in clinically challenging cases
such as a centrally located lesion (Register et al.
2010). In phase I/II clinical studies of proton therapy
in stage III NSCLC (74 Gy in 37 fractions with
concurrent chemotherapy, Fig. 7) and early-stage
NSCLC (87.5 Gy in 35 fractions), we observed better
efficacy and a lower incidence of toxicity (e.g.,
pneumonitis and esophagitis) than observed
770
historically in patients treated with conventional-dose
(60–66 Gy) 3D-CRT and IMRT (Chang et al. 2009a,
b) Other clinical studies of proton therapy have shown
promising results in stage I NSCLC as well (Bush
et al. 2004; Hata et al. 2007).
Although PSPT appears to reduce toxic effects,
dose-escalated PSPT for lung tumors poses a clinical
challenge in a certain subset of cases, such as tumors
with contralateral hilar and/or supraclavicular lymph
node involvement and tumors adjacent to the esoph-
agus and spinal cord. Because the number of PSPT
treatment fields is typically limited, it is very difficult
to deliver ablative doses to targets with complex
geometry or locations, such as tumors wrapped
around sensitive critical structures. In such cases,
compromised dose coverage must be considered to
avoid damaging critical normal structures. Intensity-
modulated proton therapy (IMPT) using scanning
beams, however, might allow for simultaneous opti-
mization of beam intensities and energies using an
objective function that accounts for both target and
normal tissue constraints. Future studies will be nee-
ded to demonstrate the utility of IMPT.
In a virtual clinical study comparing IMRT and
PSPT, we showed that IMPT improved target cover-
age and reduced the normal tissue dose in patients
with stage IIIB NSCLC and allowed for individual-
ized radiation therapy dose escalation from less than
63 Gy using IMRT to 74–87.5 Gy (relative biological
effectiveness [RBE]) without exceeding the maxi-
mum tolerable dose in these challenging clinical
scenarios (Zhang et al. 2010b). IMPT has also been
shown to be better than photon-based SBRT at spar-
ing surrounding critical structures in centrally located
stage I NSCLC (Register et al. 2010). In our opinion,
IMPT will likely become the optimal conformal
radiation therapy technique in complicated lung can-
cer cases.
However, as mentioned above, proton therapy,
particularly IMPT, is very sensitive to motion and
anatomic changes. Four-dimensional CT-based treat-
ment planning is required to achieve an optimized
plan that accounts for tumor motion (Engelsman et al.
2006). To optimize target coverage while minimizing
normal tissue dose when using PSPT, we base the
compensator and aperture on average values in our
CT database (average CT image) but replace the
IGTV with tissue densities calculated using the MIP
(Kang et al. 2007). However, it must be kept in mind
J. Y. Chang
that tumor and/or anatomy may change significantly
during radiation therapy (and especially during proton
therapy), resulting in a missed target and injury to
normal tissue (Hui et al. 2008). Adaptive treatment
planning is indicated in selected patients. For a proton
scanning-beam approach such as IMPT, treatment
delivery with active beam-scanning introduces the
problem of interplay effects when the pencil beam
moves on a timescale similar to that of intrafractional
tumor motion (Seco et al. 2009). In situations where
fractionation may not provide enough repetition to
blur such interplay effects, repeated delivery or
‘‘repainting’’ of each field several times within a
fraction has been suggested (Seco et al. 2009).
Although proton therapy is precise and allows sharp-
edged fields, the uncertainty of motion and density
change associated with this technique (and particu-
larly IMPT) in the treatment of lung cancer need to be
further addressed.
9 Endobronchial High Dose Rate
Brachytherapy
Indications for endobronchial high dose rate brachy-
therapy (EB-HDR) include the following (Klopp et al.
2006b):
1. Palliation of endobronchial disease recurring after
external beam radiotherapy
2. Palliation of endobronchial disease from meta-
static disease
3. Boost treatment after initial course of definitive
EBRT for primary cancer with endobronchial
component
Techniques for EB-HDR include the following:
1. 100-cm-long 6-French catheter placed under
bronchoscopic guidance
2. Catheter placed distal to area of obstruction with
visualization using dummy wires threaded through
catheter
3. Localization films taken for treatment planning
(determination of length to be treated and initial
dwell positions)
4. Dose prescription point 1 cm from source center
and 1–2 cm linear margin on the target
5. Prescribed dose of 5 Gy in 3–4 fractions or 7 Gy
in 3 fractions with 1-week intervals between
treatments
Cancer of the Lung
Side effects and complications of EB-HDR may
include bronchial stenosis and radiation bronchitis
(*25% incidence), and fatal hemoptysis (*10–20%
incidence, which increases with prior radiation, mul-
tiple brachytherapy courses, and longer segments of
treatment).
10 Personalized Adaptive Radiation
Therapy
As discussed above, radiation therapy for lung cancer
has improved significantly as a result of better image-
guarded (e.g., PET/CT) target delineation and
increased utilization of cutting-edge radiation plan-
ning and delivery systems (e.g., IMRT, SBRT, and
proton therapy) that allow more conformal delivery of
radiation to achieve dose escalation while minimizing
normal tissue toxicity. Advances in the imaging
modalities available for use during treatment planning
and delivery have made it feasible to adapt the target
volume, both within and between treatment fractions,
for factors such as internal motion, tumor response,
anatomic change, and weight loss. Utilizing 4D-CT-
based radiation therapy planning and onboard imaging
for daily image guidance allows more accurate posi-
tioning of the target. This has many advantages, such
as a decreased probability of target miss, smaller setup
margins, and less exposure of normal tissues to high
radiation doses. In addition, novel treatment adapta-
tion algorithms allow treatment plans to be more
easily and effectively adapted to changes in patient
anatomy and organ motion within and between
treatment fractions. This latter category of innovations
has been termed ‘‘adaptive radiation therapy.’’
Multiple studies have examined the causative
factors of interfractional changes and the effect of
these variations on dosimetry throughout treatment
(Fox et al. 2009; Britton et al. 2007). Britton et al.
(2009) analyzed the effect of GTV regression and
motion changes during the course of radiation therapy
in locally advanced NSCLC at MD Anderson Cancer
Center. They found that, in 8 patients with weekly
4D-CT data sets, the tumor volume was reduced by
15–71%. They also noted increased tumor mobility in
the superanterior and anteroposterior directions
throughout treatment and no clear trends in tumor
motion (Britton et al. 2007). In a follow-up study, the
same group found that the dose to 95% of the PTV
771
and ITV calculated with weekly CT scans changed by
approximately 12 and 2.5%, respectively (Britton
et al. 2009). While the lung V20 and mean lung dose
only increased by a mean of 3.1 and 2.2%, respec-
tively, the spinal cord dose changed by a mean of
34.3%. Together, these studies suggest that continued
assessment of the target volume is recommended in
tumors that lie near the spinal cord and other critical
structures.
With the advent of proton therapy, investigators
have recently begun to examine the effect of inter-
fractional motion and anatomic changes on dose
distribution with this technique. This issue is partic-
ularly important for proton therapy because the
impact of motion and anatomy changes is more sig-
nificant for protons than for photons. In a study of 8
patients with locally advanced NSCLC treated with
IMRT, Hui et al. compared conformal PSPT planning
using weekly 4D-CT scans with IMRT planning over
7 weeks of radiation therapy (Hui et al. 2008). They
found that in 1 patient, normal tissue doses increased
and CTV coverage was significantly compromised
(decreased by approximately 8%) with proton therapy
but much less significantly in with IMRT. The authors
concluded that proton therapy is more sensitive to
motion and anatomy changes than photon and inter-
fractional adaptive planning and is indicated in
selected patients (Hui et al. 2008).
Because tumor stage, location, size, motion, and
proximity to critical normal structures vary from
patient to patient, radiation therapy should be per-
sonalized and changes in anatomy/motion evaluated
and adapted as needed during the course of radiation
therapy (Gomez and Chang 2011). This is called
personalized adaptive radiation therapy (PART).
Whenever possible, patients should undergo 4D-CT
simulation to assess internal motion. Motion man-
agement and radiation delivery approach should be
based on individual motion pattern and patient com-
pliance. For selected patients with NSCLC undergoing
6–8 weeks of conventional fractionated radiotherapy,
repeated 4D simulations may be indicated. For
patients with SCLC undergoing hyperfractionated
(twice daily) or dose-escalated/accelerated radiation
therapy for 3 to 7 weeks, repeated simulation should
be routine. Adaptive 4D replanning should be per-
formed if there is the possibility that motion/anatomy
changes may alter target coverage and/or increase
dose to surrounding critical structures.
772 J. Y. Chang

Table 3 Recommended dose–volume constraints for normal tissues in standard fractionation

RT alone Chemo and RT Chemo and RT before surgery
a
Spinal cord Dmax \ 45 Gy Dmax \ 45 Gy Dmax \ 45 Gy
Lungb MLD B 20 Gy MLD B 20 Gy MLD B 20 Gy
V20 B 40% V20 B 35% V20 B 30%
V10 B 45% V10 B 40%
V5 B 65% V5 B 55%
Heart V30 B 45% V30 B 45% V30 B 45%
Mean dose \ 26 Gy Mean dose \ 26 Gy Mean dose \ 26 Gy
Esophagus Dmax B 80 Gy Dmax B 80 Gy Dmax B 80 Gy
V70 \ 20% V70 \ 20% V70 \ 20%
V50 \ 50% V50 \ 40% V50 \ 40%
Mean dose \ 34 Gy Mean dose \ 34 Gy Mean dose \ 34 Gy
Kidneyc 20 Gy \ 32% of bilateral kidney 20 Gy \ 32% of bilateral kidney 20 Gy \ 32% of bilateral kidney
Liver V30 B 40% V30 B 40% V30 B 40%
Mean dose \ 30 Gy Mean dose \ 30 Gy Mean dose \ 30 Gy
Chemo chemotherapy, Dmax maximal dose, MLD mean lung dose, RT radiotherapy, Vn, effective lung volume (total lung vol-
ume - gross tumor volume) receiving a particular radiation dose (Gy)
a
The size of the treated volume of the spinal cord should be considered, as the chance of spinal cord damage increases with
volume treated. When PTV is close to the spinal cord (\1 cm) (e.g., vertebral invasion), the spinal cord may receive a dose higher
than the recommended dose threshold in order to maintain an adequate dose-to-target volume (particularly gross tumor volume
[GTV]). However, the spinal cord should not receive more than 60 Gy, even in a very limited volume. A higher fraction size or
higher daily dose reduces tolerance. If treatment is given in 3-Gy fractions, the constrained dose to the spinal cord should be
approximately 40 Gy
b
For patients who undergo pneumonectomy before RT, we recommend an MLD of \8 Gy, a V20 of \10%, and a V5 of \60%
c
Consider a kidney scan if a large volume of one kidney will be treated with a high dose

It is still unclear whether target volume reduction is
warranted in cases of GTV shrinkage during the
course of radiation therapy. Some physicians advocate
maintaining a constant target volume because of con-
cerns about residual microscopic disease. One option
is to deliver at least 50 Gy, the standard dose for
microscopic disease, to the original target volume, and
then to boost the reduced volume to the full dose. Well-
designed studies addressing this issue are needed.
11 Toxicities and Normal Tissue
Tolerance
Recently, quantitative analysis of normal tissue
effects in the clinic (QUANTEC) has led to updated
dose–volume constraints (Marks et al. 2010). Data
from QUANTEC and our recommendations for dose–
volume constraints are summarized in Table 3. It
should be noted that most toxic side effects (e.g.,
acute esophagitis, fatigue, nausea, vomiting, emertitis,
and pneumonitis) are transitory and can be managed
medically. However, some late side effects (e.g.,
esophageal stricture/fistula, grade [3 pneumonitis)
can significantly compromise long-term quality of life
or in some cases be fatal. Therefore, more attention
should be paid to minimizing them.

Common acute toxicities seen in radiation therapy for

lung cancers include esophagitis, skin irritation, fati-
gue, nausea, and vomiting. Subacute and late toxici-
ties include radiation pneumonitis, pericarditis,
pericardial effusion, esophageal stricture/fistula, and
second cancers. Such toxic effects could be reduced
by observing dose–volume constraints, which depend
on whether the radiation therapy is delivered con-
currently with chemotherapy or followed by surgery.
12 Future Directions in Radiation
Therapy for Lung Cancer
To improve the therapeutic ratio of radiation ther-
apy in lung cancer, better techniques are needed for
conforming high radiation doses to the target
while sparing surrounding critical structures. Evolv-
ing image guidance technologies, such as 4D
Cancer of the Lung
image-based motion management, daily onboard
imaging, and adaptive radiation therapy, now allow
target motion margins to be individualized, reduce the
risk of geographical target miss, and reduce the
uncertainty associated with setup and motion/anat-
omy over the course of therapy. These advances have
also permitted the implementation of highly confor-
mal treatment delivery techniques, such as IMRT,
SBRT, and proton therapy, which are exquisitely
sensitive to organ motion and anatomic change.
More clinical studies are needed to further opti-
mize conformal PART based on changes in anatomy
and tumor motion during the course of therapy and
using functional and biological imaging to selectively
escalate doses to radioresistant subregions within the
tumor. Both intra- and interfraction replanning are
now possible, and investigators have begun to assess
whether tumor response during treatment can lead to
changes in total dose to portions of the target volume
based on the magnitude of tumor response to the
initial phase of treatment. This strategy is particularly
relevant because several studies have shown that dose
escalation in lung cancer improves local control.
Furthermore, prior studies have demonstrated that
areas of high SUV activity and hypoxia are more
likely to exhibit local failure when treated with radi-
ation. It is now possible to achieve adaptive dose
escalation within radioresistant target volumes using
IMRT and IMPT dose painting techniques. However,
future studies are warranted to determine whether
such approaches can improve clinical tumor control
without increasing toxicity.
An additional technologic advancement in adap-
tive radiation therapy is the development of ‘‘real-
time’’ tracking of tumor motion, so that the treatment
can be actively and variably adapted in concordance
with intra- and inter-fractional changes.
PART may improve tumor control and survival in
lung cancer by reducing target misses, escalating
target dose, and minimizing side effects by avoiding
critical structures over the course of radiation therapy.
More prospective studies are needed to implement
and validate these technologies.
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 Cancers of the Colon, Rectum, and Anus
Jonathan B. Ashman, Matthew D. Callister, Michael G. Haddock,
and Leonard L. Gunderson

Contents
1 Colon and Rectal Cancer........................................
1.1 Diagnostic Evaluation ...............................................
1.2 Management...............................................................
1.3 Radiation Therapy Techniques .................................
2 Anal Cancer..............................................................
2.1 Diagnostic Evaluation ...............................................
2.2 Management...............................................................
2.3 Radiation Therapy Techniques .................................
2.4 Treatment Results ......................................................
3 Summary................................................................... 794
References.......................................................................... 794
Abstract
Patients with lower gastrointestinal cancer fre-
777 quently require multidisciplinary management.
777 Concurrent radiotherapy and chemotherapy is
779
780
often used as an adjuvant to surgical resection in
selected patients with resectable but high-risk
787
rectal cancer. In patients with locally unresectable
787
788 rectal and colon cancer, preoperative chemoradi-
789 ation is preferably used as a component of the
793 definitive procedure. For patients with anal cancer,
concurrent chemoradiation has replaced abdomi-
noperineal resection as the principal form of
treatment. Appropriate radiotherapeutic manage-
ment of the patient with lower gastrointestinal
cancer includes proper patient selection and diag-
nostic evaluation, close cooperation by all physi-
cians participating in the patient’s care, and the use
of proper radiotherapeutic techniques. The intro-
duction of intensity modulated radiation therapy
(IMRT) into the treatment of both rectal and anal
cancer provides the potential for reducing toxicity
and improving tumor control with dose escalation.

1 Colon and Rectal Cancer

1.1 Diagnostic Evaluation

J. B. Ashman (&)
M. D. Callister
L. L. Gunderson
Department of Radiation Oncology, The diagnostic evaluation of a patient with colorectal
Mayo Clinic College of Medicine and Mayo Clinic, adenocarcinoma begins with a history and physical
5777 E. Mayo Blvd, Phoenix AZ 85054, USA
examination (Table 1). In taking the history of a
e-mail: ashman.jonathan@mayo.edu
patient with large-bowel cancer, particular attention
M. G. Haddock
should be given to rectal bleeding, change in bowel
Department of Radiation Oncology,
Mayo Clinic College of Medicine and Mayo Clinic, habits, and abdominal pain (Postlethwait 1949). Other
200 2nd St. SW Desk R, Rochester MN 55905, USA presenting features of large-bowel cancer include

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 777
DOI: 10.1007/174_2011_165, Ó Springer-Verlag Berlin Heidelberg 2012
778
Table 1 Diagnostic evaluation for colorectal cancer
History and physical
Colonoscopy
Rigid proctoscopy*
CBC, Chemistry profile, CEA
Abdomen/Pelvis CT
Endorectal ultrasound and/or rectal MRI*
Chest CT (selected patients)
PET/CT (selected patients)
*Rectal cancer
Table 2 Prognostic factors for colorectal cancer
Stage
Weight loss, fever, anemia, performance status
CEA
Location from anal verge (rectal cancer)
nausea, vomiting, weakness, and abdominal mass.
Loss in performance status, fatigue, weight loss,
anorexia, and sweat may indicate distant metastatic
disease (Table 2). Patients found incidentally to have
microcytic anemia should be considered to have
large-bowel cancer until another cause can be proved.
In patients presenting with rectal cancer, careful
attention should be given not only to bowel-related
symptoms but also to symptoms of local tumor
extension into other pelvic structures (bladder/pros-
tate or pelvic wall).
Laboratory studies should include liver function
tests and a complete blood cell count. The pre-oper-
ative concentration of carcinoembryonic antigen
(CEA) is an independent prognostic factor in those
patients with high concentrations having a worse
prognosis. It is preferable to obtain a baseline CEA
concentration preoperatively so that serial measure-
ments can be used postoperatively to identify disease
progression in asymptomatic patients (Martin et al.
1977; Wanebo et al. 1978). Although the usefulness
of CEA in this context may be limited because
patients with relapse may either have symptoms
before the CEA concentration increases (Beart and
O’Connell 1983) or may not have an abnormally high
CEA concentration (Moertel et al. 1993), CEA is
considered the most cost-effective test for detecting
potentially curable disease relapse, and periodic
monitoring is recommended by the American Society
J. B. Ashman et al.
of Clinical Oncology (ASCO) in appropriately
selected patients (Benson et al. 2000). In a Mayo
Clinic analysis of 106 patients with locally recurrent
rectal cancer in whom 42 received intraoperative
irradiation (IORT) as a component of treatment,
asymptomatic patients had better outcomes than those
who presented with symptoms (Suzuki et al. 1995).
If the lesion is palpable, the physician should note
the inferior extent relative to the anal verge, the
location of the tumor on the bowel wall, the degree of
circumference involved, and whether the lesion is
clinically mobile or fixed to extrarectal structures.
If lesions are immobile or fixed, computed tomogra-
phy (CT) or magnetic resonance imaging (MRI) of
the pelvis may be helpful in assessing resectability.
A complete colonoscopy should be performed as part
of the initial evaluation. However, rigid proctoscopy
provides more reliable measurements of rectal
tumors.
CT of the abdomen and pelvis with contrast eval-
uates not only the primary site of disease and regional
lymph nodes but also sites of metastatic disease such
as liver. In the case of rectal cancer, endoscopic
ultrasound (EUS) or high resolution pelvic MRI is
indicated for locoregional clinical staging. Positron
emission tomography (PET)/CT is not recommended
as a standard imaging test but may be useful to
evaluate for metastatic disease if the diagnostic CT is
equivocal. For patients who present with locally un-
resectable disease or local–regional relapse, more
routine use of PET/CT to rule out metastatic disease is
probably indicated, especially if aggressive treatment
approaches with curative intent are planned. The
staging system incorporates the findings from both the
physical exam and radiology studies (Table 3).
The radiation oncologist is sometimes consulted
after a patient’s malignant tumor has been resected. In
this situation, it is necessary to use information from
pre-operative studies as well as operative and patho-
logical findings in the design of radiotherapy fields.
Although endoscopic procedures are of value in
diagnosis, a pre-operative CT of the abdomen/pelvis
will be more helpful to the radiation oncologist in
determining the pre-operative tumor volume. When
endoscopy is performed, a description of the lesion
should be provided, including its position on the
bowel wall, its distance from the anal verge, its size,
the degree of circumference involved, and whether
the lesion is exophytic or ulcerative.
Cancers of the Colon, Rectum, and Anus
Table 3 Colon and rectum staging (AJCC 7th edition)
T1—tumor invades submucosa
T2—tumor invades muscularis propria
T3—tumor invades into pericolorectal tissues
T4a—tumor penetrates to the surface of the visceral
peritoneum
T4b—tumor directly invades or is adherent to other organs or
structures
N0—no regional lymph node metastasis
N1—metastasis to 1–3 regional nodes (N1a, 1 node; N1b, 2–3
nodes)
N2—metastasis to 4 or more regional nodes (N2a, 4–6 nodes;
N2b, C 7 nodes)
M0—no distant metastasis
M1—distant metastasis (M1a—confined to one organ/site;
M1b—more than one organ/site)
Stage I—T1/T2 N0 M0
Stage IIA—T3 N0 M0
Stage IIB—T4a N0 M0
Stage IIC—T4b N0 M0
Stage IIIA—T1-2 N1 M0, T1 N2a M0
Stage IIIB—T3/T4a N1 M0; T2/T3 N2a M0; T1/T2 N2b M0
Stage IIIC—T4a N2a M0; T3/T4a N2b M0; T4b N1/N2 M0
Stage IVA—Any T Any N M1a
Stage IVB—Any T Any N M1b
1.2 Management
1.2.1 Rectum
The foundation of treatment for patients with resect-
able rectal cancer is surgery. When radiotherapy, with
or without chemotherapy, is offered as an adjuvant to
patients who are candidates for surgical resection or
who have undergone a potentially curative surgical
resection, it is, by definition, being administered to a
person who may already be cured by surgery alone.
Therefore, a high standard of scientific evidence for
the efficacy of adjuvant treatment, which is poten-
tially toxic, expensive, and inconvenient, is needed
before its use in routine clinical practice can be jus-
tified. The risk of local recurrence after complete
surgical resection is related to the degree of disease
extension beyond the rectal wall and the extent of
nodal involvement. The incidence of local recurrence
for lesions with involved nodes but with tumor con-
fined to the wall varies in most studies from 20 to
40%. This is similar to the local recurrence risk for
patients without nodal involvement who have
extension beyond the wall. Lesions that have both
779
tumor extension beyond the rectal wall and lymph-
node involvement have nearly an additive risk of
local recurrence—40–65% in clinical studies (Gilbert
1978; Walz et al. 1981; Gunderson et al. 1983;
Mendenhall et al. 1983) and 70% in a reoperative
series (Gunderson and Sosin 1974). A recent publi-
cation of combined results from 3,791 patients trea-
ted on cooperative group trials over the last 25 years
has confirmed the independent importance of tumor
penetration through the wall and nodal status
(Gunderson et al. 2010a).
Selected patients with early T1N0 lesions may be
candidates for local, transanal tumor excision, or
transanal endoscopic microsurgery (TEM). Tumors
which are \3 cm, well to moderately differentiated,
and \30% of the rectal circumference are most
appropriate. After local excision, high risk features
such as high grade lesions, positive margins, lym-
phovascular space invasion, or perineural invasion
should proceed to either radical surgery or chemora-
diation (Russell et al. 2000). Patients with T1N0
rectal cancer and high risk features at the time of
initial biopsy or with T2N0 lesions should have rad-
ical surgery. In the setting of distal lesions
approaching the anal sphincter, neoadjuvant chemo-
radiation may be appropriate even with early stage
disease in order to facilitate a possible sphincter-
sparing operative procedure. Clinical stage I patients
who are not candidates for local surgery should be
managed with radical surgery.
Patients with Stage II or III rectal cancer typically
require a multidisciplinary management approach.
Randomized clinical trials that have compared pre-
operative radiotherapy with surgery alone have
demonstrated improved local control, and one study
demonstrated a survival advantage for this approach
(Swedish Rectal Cancer Trial 1997). This trial was
performed before the widespread adoption of total
mesorectal excision (TME). The Dutch CKVO 95-04
study randomized patients to TME alone or to a short
course of pre-operative radiotherapy consisting of
25 Gy in five fractions followed by TME 1 week
later. Pre-operative radiotherapy improved local
control but not overall survival (Kapiteijn et al. 2001;
Marijnen et al. 2010; Peeters et al. 2007). Two ran-
domized trials demonstrated improved local control
without a survival advantage with pre-operative che-
moradiation compared with pre-operative radiation
alone (Bosset et al. 2006; Gerard et al. 2006).
780
Several randomized trials of post-operative adjuvant
chemoradiation have demonstrated improved local
control and survival compared with surgery alone or
surgery followed by adjuvant radiotherapy with che-
motherapy (Douglass et al. 1986; Gastrointestinal
Tumor Study Group 1985; Krook et al. 1991; Tveit
et al. 1997). Continuous-infusion of 5-FU during post-
operative radiotherapy has been found to be more
effective than bolus 5-FU during radiotherapy
(O’Connell et al. 1994). Oral capecitabine may be a
better tolerated and oral alternative to 5-FU (Das et al.
2006; Hofheinz et al. 2009).
The debate on the issue of whether adjuvant che-
moradiation should be given preoperatively or postop-
eratively to patients with rectal cancer has largely ended
by the landmark German phase-III study by Sauer et al.
(Sauer et al. 2004). In this study, 799 patients with T3 or
T4 or node-positive rectal cancer received 50.4 Gy in
28 fractions, given with two courses of 5-FU (1 g/m2
per day for 120 h) at the beginning and end of radio-
therapy. Patients were randomly allocated to receive
this treatment either preoperatively or postoperatively.
Additional chemotherapy was administered at both
arms of the study. Patients in the pre-operative arm
experienced fewer local recurrences than those in the
post-operative arm (6 vs. 13%, P = 0.006). Also, better
sphincter preservation was reported in preoperatively
irradiated patients with low rectal cancers (39 vs. 19%,
P = 0.004). Sauer also reported that patients in the pre-
operative arm had less acute and long-term toxicity than
in the post-operative arm. No disease-free survival
(DFS) or overall survival (OS) difference was
demonstrated.
On the basis of these results, most patients in the
United States who require adjuvant therapy for rectal
cancer receive pre-operative chemoradiation. How-
ever, a limited number of patients will still require
post-operative adjuvant therapy. For example, if pre-
operative endorectal ultrasonographic staging indi-
cates that a rectal cancer is T2 N0, the patient is at a
low risk for relapse and should be treated with ‘‘up
front’’ surgery without pre-operative chemoradiation.
However, if the pathological specimen shows a more
advanced tumor than indicated by pre-operative
staging, the patient should be considered for post-
operative adjuvant therapy. As pre-operative staging
is not entirely accurate, it is important for radiation
oncologists to be able to give adjuvant therapy, both
preoperatively and postoperatively.
J. B. Ashman et al.
1.2.2 Colon
Colectomy with lymph node dissection is the primary
therapy for resectable Stages I–III colon cancer. The
study of patterns of relapse in patients with colon
cancer is principally of interest because of the role of
radiotherapy in patients with locally advanced
disease.
Data from clinical studies of patterns of failure
suggest that one-third of patients in whom tumor
relapse develops after curative resection have relapse
solely in the liver (Welch and Donaldson 1978).
Patterns-of-relapse studies that do not routinely use
reoperation or autopsy, however, may underestimate
the incidence of locoregional recurrence in patients
with colon cancer. Autopsy and reoperative series
suggest that liver-only relapse occurs in fewer than
10% of cases (Gunderson et al. 1985b; Welch and
Donaldson 1979). Data from autopsy and reoperative
patterns-of-relapse studies must also be interpreted
with caution because only subsets of patients who
have a potentially curative operation subsequently
undergo reoperation or autopsy.
Patterns of relapse in colon cancer have been
analyzed in autopsy, clinical, and reoperation series
(Cass et al. 1976; Gunderson et al. 1985b; Minsky et
al. 1988; Russell et al. 1984; Welch and Donaldson
1978; Willett et al. 1984a, b). Data from these series
suggest that local failure is an important problem after
resection of colon cancer in selected patients. Local
recurrence is highest among patients with tumors that
adhere to surrounding structures and among patients
who have both tumor extension beyond the bowel
wall and metastatic involvement of lymph nodes. In a
retrospective study, the local recurrence rate among
patients with these pathological characteristics was
42%. External beam radiotherapy (EBRT) may be
used for T4 tumors invading fixed structures or for
locally recurrent disease. If possible, EBRT should be
delivered preoperatively with concurrent chemother-
apy and combined with IORT following maximal
surgical resection.
1.3 Radiation Therapy Techniques
1.3.1 Simulation
Proper patient positioning can significantly reduce the
amount of small bowel within the pelvis and limit
toxicity from treatment. In addition to decreasing the
Cancers of the Colon, Rectum, and Anus
volume of bowel receiving maximal organ tolerance
(45–50 Gy), reduction of bowel receiving doses as
low as 5 Gy has been associated with improved
patient tolerance to pelvic radiation (Baglan et al.
2002; Robertson et al. 2008; Tho et al. 2006). Max-
imal displacement of small bowel out of the pelvis is
achieved with prone positioning and bladder disten-
sion. Without the use of a belly-board or lower
abdominal wall compression, however, approximately
25% of patients will have more small bowel in the
pelvis with prone positioning compared to supine
(more commonly in obese patients) (Gallagher et al.
1986). Multiple studies have documented significant
reduction in pelvic small bowel volume with use of a
belly-board device (Martin et al. 2005; Olofsen-van
Acht et al. 2001; Pinkawa et al. 2003) or lower
abdominal wall compression (Gallagher et al. 1986).
Bladder distension may actually contribute more to
bowel displacement than a belly-board, but the effect
of each method appears additive (Kim et al. 2005) and
concurrent use of both techniques should be consid-
ered. Though these efforts displace bowel from the
pelvis, they may be less reproducible, increase vari-
ation in patient set up, and, therefore, be undesirable
when employing highly conformal radiation
techniques.
Although small bowel series are useful during
fluoroscopic simulation, CT-based planning provides
more complete identification of bowel, especially
regions that do not opacify with contrast (Nuyttens
et al. 2001). Small bowel has been shown to be more
mobile in patients treated preoperatively than after
surgical intervention (Nuyttens et al. 2001). To ensure
that there has been no significant change in bowel
positioning during treatment, consideration may be
given to repeat CT imaging at the time of boost
planning for patients whose total pelvic radiation
doses approach or exceed bowel tolerance.
Simulation in the prone position enables access for
digital rectal examination. This allows verification of
lower and middle rectal lesion location in relation to
the anal verge while maintaining the treatment posi-
tion. The anal verge should be marked with a radi-
opaque marker and rectal contrast instilled into the
rectum to assist radiographic identification of the
primary lesion. Insufflation of a small amount of air
into the rectum (50 cc) may further assist in identifi-
cation of the rectal mass (Myerson and Drzymala
2003). Taping the buttocks laterally may reduce their
781
self-bolusing effect on the perianal skin during treat-
ment, but is of questionable reproducibility.
Patients who have undergone abdominoperineal
resection must have the perineal scar marked and
included in the initial pelvic fields, with appropriate
bolus utilized posteriorly if exposed. Perineal recur-
rence has been described in 8–30% of patients in the
absence of adjuvant RT (Ciatto and Pacini 1982;
Moossa et al. 1975; Roberson et al. 1985), but as low
as 2% when the scar is adequately treated (Schild
et al. 1989).
1.3.2 Target Volumes
For patients treated preoperatively, the gross tumor
volume (GTV) includes the primary tumor and any
radiographically enlarged lymph nodes. All clinical,
endoscopic, and radiographic imaging information
must be used to define the maximal extent of the
rectal tumor. Relying solely on one modality risks
underestimation of the tumor extent and inaccurate
field design (especially within boost portals). Though
not mandatory in treatment planning, the addition of
PET/CT to CT in GTV contouring has been shown to
increase the target size by an average of 25% (Bassi
et al. 2008) and to change treatment fields in 17% of
patients (Anderson et al. 2007). Soft-tissue extension
or suspected infiltration of rectal tumors into adjacent
mesorectal fat should be included within the GTV,
particularly posteriorly.
The clinical target volume (CTV) encompasses all
the perirectal tissue, presacral space and lymphatics
of the internal iliac chain (which are not commonly
dissected at the time of surgery). A report of 269
cases of rectal cancer that recurred in the pelvis after
surgery alone emphasized the predilection for rectal
cancer recurrence in the posterior pelvis, specifically
the presacral space. Among patients undergoing
anterior resection, 93% of relapses were at or pos-
terior to the colorectal anastomosis (Hruby et al.
2003). Other studies of rectal cancer failure patterns
have shown infrequent relapse above the S1–S2
interspace, in lateral pelvic nodes, or in the anal
sphincter (Syk et al. 2008; Yu et al. 2008).
Accurate contouring of the pelvic CTV involves
more than simply identifying the internal iliac vessels.
A study comparing locations of external and common
pelvic lymphatics by lymphangiography to vessel
location revealed that lymph nodes are not directly
superimposable upon vasculature (Chao and Lin
782
2002). Myerson and Drzymala 2003 and Roels et al.
(2006) provide an excellent review of CT-based
treatment planning for rectal cancer (Myerson and
Drzymala 2003; Roels et al. 2006). The RTOG also
published a contouring atlas to define consensus
clinical target volumes in the planning of IMRT for
anorectal cancers (Myerson et al. 2009). In the upper
pelvis, the CTV should extend cephalad to include the
sacral promontory, posteriorly to include the anterior
wall of the sacrum, and laterally it should encompass
vasculature and presacral soft tissue to the border of
the iliopsoas muscles. In the mid-pelvis, the CTV
includes similar tissues with care taken to include
perirectal fat anterior to the rectum. In addition,
1–2 cm of posterior bladder or uterus may be inclu-
ded if at risk of subclinical extension of disease for
patients who have adjacent, locally advanced lesions.
In the lower pelvis, the CTV includes all the perirectal
fat inferiorly and laterally extending to the levator ani
muscles. It should extend to the posterior wall of the
prostate or vagina as well. A larger margin of anterior
pelvic organs is indicated for T4 tumors with docu-
mented invasion. The CTV should also include 2 cm
of normal rectum cephalad and caudad to the primary
tumor.
External iliac nodes or inguinal nodes are not a
primary nodal drainage site and should not be inclu-
ded in the radiation fields. The exception to this is
when pelvic organs with major external iliac drain-
age, such as prostate, bladder, vagina, cervix, and
uterus, are involved by direct extension from a rectal
cancer. Treatment of external iliac lymph nodes has
generally been recommended in such cases. This
modification is supported by failure patterns from
patients treated with surgery alone (Hruby et al.
2003). In addition, tumors of the lower rectum which
extend to the dentate line of the anal canal have a
theoretical risk of failure in the inguinal lymph nodes.
However, two studies have called into question the
importance of treating lymph-node groups that are at
risk because of contiguous spread of rectal cancer to
other pelvic organs. Taylor and colleagues found that
patients with contiguous spread of rectal cancer to the
anus (which drains to the inguinal lymph nodes) who
did not receive elective inguinal lymph-node treat-
ment had only a 4% risk of inguinal lymph-node
recurrence at 5 years (Taylor et al. 2001). In a second
series, patients with T4 rectal cancers were treated
with RT portals that did not include the external iliac
J. B. Ashman et al.
or inguinal nodal chains, and regional recurrence of
disease still occurred almost exclusively within the
radiotherapy field (Sanfilippo et al. 2001). Accord-
ingly, although treatment of lymph-node groups
beyond the internal iliac nodes should be considered
in patients with spread of rectal cancer to other pelvic
organs, the ultimate decision is a matter of individual
physician judgment.
In the post-operative setting, treatment volumes
are similar, except that with the removal of the pri-
mary lesion, the entire pre-operative tumor bed must
be reconstructed and included within the CTV (often
identified separately as a boost volume—CTV2).
Review of pre-operative imaging, operative reports
and surgical clip placement is imperative. As above,
the perineal scar must be included in the initial fields
for patients who have undergone abdominoperineal
resection.
To account for internal target motion and patient set
up variability, a planning target volume (PTV) is
delineated beyond the CTV. In the absence of image-
guided radiotherapy (IGRT), a PTV margin of at least
1 cm is appropriate and provides a minimum 4 cm
longitudinal margin from GTV to block edge
(assuming an additional 1 cm beyond PTV to block
edge for dosimetric buildup). Intrafraction movement
of the mesorectum has been evaluated and found on
average to move \4 mm in various dimensions, but
significant individual variability is observed (Tournel
et al. 2008). However, retrospective study of inter
fraction variability has shown that in the patient set up
without IGRT can easily approach these margins,
especially among patients with large body mass index
treated in the prone position (Robertson et al. 2009).
Therefore, given the distensibility of the rectum, more
PTV margin may be indicated anteriorly, especially
for anterior wall tumors of the mid- and upper-rectum.
Bladder, small bowel, and femoral heads should also
be contoured for evaluation of normal tissue tolerance.
1.3.3 Treatment Planning
1.3.3.1 Rectal Cancer
Standard Techniques The internal iliac and presacral
nodes are located posteriorly in the pelvis (Gunderson
et al. 1985a). Therefore, lateral radiotherapy fields
can be used for a portion of the treatment to reduce
the dose of radiation to anterior normal tissues such as
the small bowel (Fig. 1). The use of a three-field
Cancers of the Colon, Rectum, and Anus
Fig. 1 a, b Posterior (a) and lateral (b) pelvic radiotherapy
fields used in adjuvant radiotherapy for rectal cancer. In
patients with tumor adherence to organs drained by external
technique (a posterior field and opposed lateral fields)
can also spare anterior structures, particularly the
small bowel and external genitalia in males. When a
three-field technique is used, wedges, with the heels
posterior, should be used on the lateral fields. The
field size is progressively reduced, with initial radio-
therapy fields designed to treat the primary tumor
volume and regional lymph nodes to a dose of 45 Gy
in 25 fractions. Smaller fields can then be used to
treat the primary tumor bed to an additional 5.4–9 Gy
in three to five fractions, as clinically indicated. Iso-
dose curves for posterior and opposed lateral fields
are shown in Fig. 2. Posterior and anterior radio-
therapy fields should cover the pelvic inlet with a
2 cm margin. The superior margin is usually 1.5 cm
above the level of the sacral promontory. In patients
who have had an anterior resection, the usual inferior
margin is below the obturator foramina or approxi-
mately 3 cm below the most inferior portion of the
tumor bed.
The posterior field margin for lateral fields is
critical because the rectum and perirectal tissues lie
just anterior to the sacrum and coccyx. Accordingly,
the posterior field margin should be at least 1.5–2 cm
behind the anterior bony sacral margin. The entire
sacral canal with a 1.5 cm margin should be included
in patients with locally advanced posterior or pos-
terior/lateral lesions with disease fixation to avoid
local recurrence from tumor spread along nerve roots.
783
iliac nodes, the anterior border of the lateral field is modified to
place it anterior to the symphysis pubis. AR, anterior resection,
APR abdominoperineal resection
The anterior margin can sometimes be shaped to
decrease the amount of radiation to the head of the
femur and bladder inferiorly and the small bowel
superiorly. Anteriorly, the lower one-third of the
rectum abuts the posterior vaginal wall and prostate,
and the posterior portion of these structures should be
included in the radiotherapy field. In females, inclu-
sion of the vagina can be verified at simulation using
a contrast-soaked tampon.
After abdominoperineal resection, the perineum
should be included with the tumor bed and nodal
volumes to prevent marginal recurrences from surgi-
cal implantation of tumor (Gunderson and Sosin
1974; Hoskins et al. 1985; Rich et al. 1983; Schild
et al. 1989). In a study at Massachusetts General
Hospital, the incidence of perineal recurrence with
surgery alone was 8.5% (Rich et al. 1983). The
incidence of perineal recurrence was only 1.7% for
patients who received post-operative irradiation
(Hoskins et al. 1985). In a Mayo Clinic analysis of
patients with rectal cancer who received post-opera-
tive irradiation, the incidence of a perineal component
of recurrence was 2% after abdominoperineal resec-
tion followed by 40 Gy or more to the perineum, but
was 23% when the perineum was not adequately
irradiated after abdominoperineal resection
(P \ 0.05) (Schild et al. 1989). A radiopaque marker
should be used to delineate the entire extent of the
perineal scar (Fig. 1).
784
Fig. 2 a–d Isodose curves for neoadjuvant pre-operative
pelvic radiotherapy for rectal cancer with the use of either
posterior and opposed lateral fields (a, c) or intensity modulated
The inferior and posterior field edges should
include a margin extending 1.5 cm beyond the peri-
neal scar. Inferolaterally, the margin should be the
lateral aspect of the ischial tuberosities. For treatment
of the posterior field, bolus material should be placed
over the perineal incision (thickness depends on beam
energy) to allow delivery of an adequate dose to the
scar surface. If pelvic drains exited through the but-
tocks instead of the perineal wound, bolus material
should also be placed over these drain sites. All
patients in whom the perineum is included within the
radiation fields experience perineal discomfort during
treatment. This can be mitigated by a three-field
technique with posterior and lateral fields.
The perineum can usually be treated to a dose level
of 45 Gy in 25 fractions over a 5 week period with
acceptable short- and long-term tolerance. Because of
skin reactions, patients occasionally require a 7- to 10-
day rest during treatment, sitz baths, topical anesthetic
(such as topical lidocaine), and protective agents such
as petrolatum ointment (e.g., AquaphorÒ). Most
J. B. Ashman et al.
radiotherapy (IMRT) (b, d). Representative axial (a, b) and
sagittal (c, d) imaging planes are shown that demonstrate the
improved sparing of small intestine with IMRT
patients finish on schedule, and limited skin reactions
generally improve markedly within 1–2 weeks after
completion.
CT-based Treatment Planning Although traditional
field orientations (PA and laterals) are usually ade-
quate for three dimensionally reconstructed targets,
field shaping (blocking) can be individualized more
precisely based on a CT-defined CTV. After CTV
expansion of at least 1 cm to create a PTV (without
IGRT), field borders are generally expanded another
5–10 mm in order to achieve sufficient dosimetric
target coverage.
Intensity Modulated Irradiation An IMRT tech-
nique in rectal cancer treatment planning allows for
the construction of a concave dose distribution that
may reduce dose to small bowel, bladder and femoral
heads (Fig. 2). Dose-painting IMRT can be utilized to
deliver 45 Gy to the regional nodal volumes at 1.8 Gy
per day and 50 Gy to the primary boost volume at
2 Gy per day in 25 fractions. Dosimetric studies
comparing IMRT to traditional techniques in rectal
Cancers of the Colon, Rectum, and Anus
cancer have shown clinically significant reductions in
dose to bowel (Engels et al. 2009; Guerrero Urbano
et al. 2006) as well as bladder and femoral heads
(Callister et al. 2006). IMRT can be especially useful
in sparing of normal organs/structures for patients in
whom inclusion of external and/or common iliac
nodes is indicated or preferred.
The successful implementation of IMRT in the
management of rectal cancer has been reported from
multiple institutions generally with dose escalation to
the GTV by and large with favorable outcomes
(Aristu et al. 2008; De Ridder et al. 2008; Freedman
et al. 2007; Ballonoff et al. 2008). In view of the
challenges of internal movement and distensible pel-
vic organs (rectum, bowel, and bladder) as well as the
dose inhomogeneity produced by some treatment
planning systems, caution should be used before
undertaking IMRT in rectal cancer. When IMRT is
used, treatment in the supine position with immobi-
lization may be preferable to prone position with
regard to reproducibility of patient setup.
Specialized Techniques Proton therapy offers
potential advantages beyond IMRT for sparing nor-
mal tissue and tumor dose escalation. Very little
clinical data has been published describing the use of
proton therapy for rectal or anal cancers (Munzenrider
et al. 1985). Two comparative planning studies have
demonstrated dosimetric improvements in rectal
cancer with protons compared to photons (Isacsson
et al. 1996; Tatsuzaki et al. 1992). However, both of
these early studies used three dimensional (3D)
planning techniques. No studies to date have com-
pared IMRT photon planning to proton therapy in the
setting of rectal or anal cancers.
Stereotactic body radiotherapy (SBRT) utilizes
highly conformal techniques and image guidance to
deliver high dose per fraction treatments in 1–5 ses-
sions. While the use of SBRT has rapidly expanded
for the treatment of lung, spine, and liver tumors, it
has not been utilized in the primary treatment of rectal
or anal cancers. One study has reported using SBRT
in highly selected patients with inoperable nodal
relapse of rectal cancer (Kim et al. 2008).
IORT can provide dose escalation through the
physical exclusion of small bowel at the time of
surgery for selected patient with locally unresectable
or locally recurrent disease. Such patients would
preferably receive pre-operative chemoradiation at a
dose of 45–54 Gy in 1.8 Gy fractions (with field
785
reduction after 45 Gy/25 fractions) followed by
maximal resection and IORT with an electron beam
(IOERT) to give a boost of 10–20 Gy to areas of
narrow resection margins or residual tumor, with the
goal of improving disease control and survival.
1.3.3.2 Colon Cancer
For patients with locally unresectable or recurrent
colon cancer, the initial EBRT fields should include
the primary tumor, immediately adjacent lymph
nodes, and adjacent paraortic nodes (Fig. 3). These
fields should receive 45 Gy in 25 fractions. Smaller
boost fields can then be considered for an additional
5.4–9 Gy in 3–5 fractions. In general, total cumula-
tive doses more than 50.4 Gy are not recommended
unless the entire small bowel can be excluded from
fields considered for such doses. A small-bowel
study obtained on the simulator with the patient in
treatment position is helpful for determining the
position of the small bowel for this purpose. These
films sometimes demonstrate that a lateral decubitus
position for a portion of the treatment may be useful
to decrease exposure or to exclude small bowel from
boost fields.
1.3.4 Treatment Results
1.3.4.1 Primary Rectal Cancer
The German pre-operative versus post-operative trial,
sets the standard for clinical stages II–III patients
receiving radiotherapy and 5-fluorouracil (Sauer et al.
2004). Local recurrence at 5 years was reduced in the
pre-operative arm compared to post-operative treat-
ment (6 vs. 13%, P = 0.006). Pre-operative therapy
also resulted in more sphincter–sparing procedures to
be performed among patients deemed to require an
APR prior to therapy (39 vs. 19%, P = 0.004).
However, there were no differences between arms in
the 5-year rates of distant metastasis (36 vs. 38%,
P = 0.84), DFS (68 vs. 65%, P = 0.32), or OS (74
vs. 76%, P = 0.8). A pooled analysis by stage irre-
spective of treatment demonstrated the complex
interaction between T and N stage in determining
outcome (Gunderson et al. 2010a). The 5-year sur-
vival was found to be 75–81, 44–64, 72–74, 41–58,
and 12–44% for patients with Stages I, II, IIIA, IIIB,
and IIIC, respectively.
Several phase III randomized trials using conven-
tional RT planning techniques have reported acute
786
Fig. 3 a, b Idealized external radiotherapy fields used in the
treatment of locally advanced or locally recurrent colon cancer.
After 4,500 cGy in 25 fractions to the large field, a boost field
(broken lines) may be used to deliver an additional
540–900 cGy in 3–5 fractions. a A field designed to treat a
grade 3 or greater GI toxicity in 36–44% of patients
undergoing RT with concurrent 5-FU in prospective
clinical trials (Bosset et al. 2006; Roh et al. 2009;
Smalley et al. 2006). Pre-operative therapy can reduce
both overall acute (27 vs. 40%, P = 0.001) and late
(14 vs. 24%, P = 0.01) Grade 3/4 toxicities (Sauer
et al. 2004). Acute grade 3/4 hematologic toxicity has
been reduced to \10% with continuous infusion of 5-
fluorouracil (Sauer et al. 2004; Smalley et al. 2006).
There are several published single institutional
series of the clinical outcomes of IMRT in rectal
cancer which report encouraging GI toxicity rates and
tumor response (Aristu et al. 2008; De Ridder et al.
2008; Ballonoff et al. 2008). A retrospective review of
92 patients treated at the Mayo Clinic in Arizona
demonstrated a 32% incidence of C grade 2 gastro-
intestinal toxicity among patients treated with IMRT
compared to 62% (p = 0.006) among patients treated
with conventional fields during the same period
(Samulien et al. 2010). More frequent use of IMRT in
selected patients may be useful in improving treat-
ment tolerance to concurrent chemoradiation, espe-
cially when inclusion of external or common iliac
nodes is indicated or preferred.
J. B. Ashman et al.
lesion in the distal descending colon includes the ipsilateral
iliac and para-aortic nodes. b A field designed to treat a lesion
in the mid-ascending colon includes the immediately adjacent
regional nodes and para-aortic nodes
Several clinical trials are ongoing, seeking to
incorporate new agents such as oxaliplatin into the
neoadjuvant chemotherapy regimen. Two phase III
randomized trials have demonstrated increased tox-
icity with oxaliplatin without clear improvements in
pathologic response or clinical outcome (Aschele
et al. 2009; Gerard et al. 2010). A phase II trial
reported utilizing oxaliplatin in combination with
capecitabine in a neoadjuvant induction strategy fol-
lowed by pre-operative RT with capecitabine and
surgery (Chua et al. 2010). Although the toxicities
were deemed reasonable, the clinical outcome was
not clearly superior to the standard pre-operative
chemoradiation without oxaliplatin. Currently still
open to accrual, the NSABP R-04 trial is a random-
ized, four-arm phase III trial for clinical stage II or III
patients comparing pre-operative chemoradiation
with either 5-FU or capecitabine and with or without
oxaliplatin. The Southwest Oncology Group S0713 is
a phase II trial testing a pre-operative regimen of
oxaliplatin, cetuximab, and capecitabine combined
with radiotherapy for this same group of rectal cancer
patients. RTOG 0822 (recently closed) tested the use
of pre-operative IMRT followed by a conformal boost
Cancers of the Colon, Rectum, and Anus
combined with oxaliplatin and capecitabine for
locally advanced rectal cancer.
Future clinical trials will likely explore mecha-
nisms for reducing the intensity of treatments in order
to limit toxicity. This will continue to require multi-
disciplinary efforts to refine clinical staging with
improved imaging, to introduce new systemic agents,
to improve the radiation therapeutic window, and to
continue to advance surgical techniques. With the
introduction of new systemic agents, as well as con-
tinued improvement in pre-operative imaging, certain
patients may be selected to avoid radiation. Alterna-
tively, other patients may be able to avoid radical
surgery after optimized neo-adjuvant therapy with
advanced chemotherapy and radiation therapy deliv-
ery techniques.
1.3.4.2 Locally Unresectable or Recurrent
Colorectal Cancer
For patients who completed a course of EBRT,
maximal resection and an IOERT boost, 5-year
overall survival rates of 20–30% have been reported
for locally recurrent disease and 45–55% for primary
locally advanced disease from Massachusetts General
Hospital and Mayo Clinic (Gunderson et al. 1996a,
1996b, 2010a; Schild et al. 1997; Suzuki et al. 1995;
Haddock et al. 2010). Better outcomes may be pos-
sible for patients who have IORT after gross or
complete resection of the tumor (Haddock et al. 2003;
Lindel et al. 2001; Mannaerts et al. 1999; Schild et al.
1997; Suzuki et al. 1995; Wiig et al. 2002). Although
less favorable outcomes have been reported for
patients who have a previous history of radiation to
the site of recurrent disease, long-term salvage is still
feasible with aggressive combined modality treatment
approaches. In an initial series of patients from Mayo
Clinic who had prior adjuvant EBRT before their
recurrence, treatment with IOERT after maximal
resection (alone or plus low-dose pre-operative
EBRT) resulted in a 5-year OS of 12% (Haddock
et al. 2001). In a more recent Mayo analysis, 248
previously treated patients more frequently received
pre-operative chemoradiation doses of 25–30 Gy,
prior to maximal resection/IOERT, and a systemic
component of treatment, with resultant 5-year OS of
26% (Haddock et al. 2010).
IORT as a component of treatment for patients
with advanced nodal disease from colon and rectal
cancer also provides an opportunity for long-term OS
787
Table 4 Diagnostic evaluation for anal cancer
History and physical (including gynecological exam for
females)
Anoscopy/proctoscopy
CBC, chemistry profile, HIV/CD4 testinga
Abdomen/pelvis CT
Chest CTa
Biopsy inguinal nodesa
PET/CT scana
a
Selected patients
in a substantial minority of patients. At Mayo Clinic,
48 patients with advanced nodal metastases from
rectal and colon cancer received IOERT as a com-
ponent of treatment. Advanced nodal disease
presented as disease relapse in 79% of these patients.
The 5-year OS for this group of patients was 34%
(Haddock et al. 2003).
2 Anal Cancer
2.1 Diagnostic Evaluation
The evaluation of a patient with anal cancer begins
with a thorough history (Table 4). The patient should
be questioned about the common presenting symp-
toms, such as mass sensation in the anal region, pain,
or bleeding. Anal cancer occurs most commonly in
elderly women. Most patients do not have a recent
history of multiple sex partners or a history of intra-
venous drug abuse or other factors that place them at
risk for human immunodeficiency virus (HIV) infec-
tion or sexually transmitted disease. However, a
sexual and drug-abuse history should be obtained
from all patients; anal cancer may develop in some
patients because of these risk factors.
Laboratory studies should include liver function
tests and a complete blood cell count. Routine testing
for HIV is unnecessary in most cases, but all patients
with a history that places them at risk for this infec-
tion should be tested. Identification of patients with
overt acquired immunodeficiency syndrome (AIDS)
is important because they may not tolerate conven-
tional combined modality therapy for anal cancer
(Table 5).
788
Table 5 Prognostic factors for anal cancer
Stage (tumor size and nodal status)
Performance status
HIV status
Response to treatment
Imaging studies should include a CT of the
abdomen and pelvis. Except for very large lesions,
CT is inferior to physical examination for assessing
the primary lesion. Nevertheless, CT is useful for
assessing regional and paraortic lymph nodes and for
evaluating the liver. Because inguinal nodes
involved with gross metastatic disease will be treated
to a higher radiotherapeutic dose than areas requiring
only elective treatment, consideration should be
given to fine needle aspiration of groin nodes of
indeterminate size (C1–1.5 cm) prior to treatment
planning. PET/CT may be of value in detecting
regional or distant spread of disease, not discernable
by CT and may alter the radiotherapy field (Cotter
et al. 2006; Winton et al. 2009). PET/CT may be
indicated more routinely in patients with bulky nodes
or T3-4 primary lesions.
The physical examination should give particular
attention to evaluation of the abdomen, inguinal
lymph nodes, anus, and rectum. During examination
of the anus and rectum, the size and location of the
tumor and whether any perirectal lymph nodes are
palpable should be noted. Attention should be made
to the proximal and distal extent of the tumor in
relationship to the anal margin as well as any perianal
extension of disease. The anatomic extent of disease
reported on anoscopy or proctoscopy should be
carefully reviewed. Thorough examination of the
perianal skin and anorectal canal is imperative for
accurate treatment planning as it often reveals disease
beyond what is visible on imaging studies alone.
When patients have severe anal discomfort that
inhibits adequate examination, such examination can
be scheduled under anesthesia. Biopsy is usually
performed by the gastroenterologist at the time of
endoscopy or by the colorectal surgeon. Pathology
typically demonstrates a squamous cell or epidermoid
cancer. Other histologic diagnoses such as melanoma
are not covered in this chapter. The staging system
mainly is derived from physical exam findings,
although radiographic findings may contribute addi-
tional information (Table 6).
J. B. Ashman et al.
Table 6 Anal cancer staging (AJCC 7th edition)
T1—tumor B 2 cm
T2—tumor [ 2 cm but B5 cm
T3—tumor [ 5 cm
T4—tumor invades adjacent organs
N0—no regional lymph node metastasis
N1—metastasis to perirectal lymph nodes
N2—metastasis to unilateral internal iliac and/or inguinal
lymph nodes
N3—metastasis to perirectal lymph nodes and inguinal lymph
nodes and/or bilateral internal iliac and/or inguinal lymph
nodes
M0—no distant metastsis
M1—distant metastasis
Stage I—T1 N0 M0
Stage II—T2/T3 N0 M0
Stage IIIA—T1–3 N1 M0 or T4 N0 M0
Stage IIIB—T4 N1 M0 or Any T N2/N3 M0
Stage IV—Any T Any N M1
2.2 Management
The primary surgical management of anal cancer has
been replaced largely by sphincter–sparing concurrent
chemoradiation. The results of several published
clinical trials have added substantially to our under-
standing of appropriate management of anal cancer.
The Radiotherapy Oncology Group (RTOG) and
Eastern Cooperative Oncology Group (ECOG) con-
ducted a randomized, inter-group clinical trial com-
paring radiotherapy plus concurrent 5-FU with
radiotherapy plus concurrent 5-FU and mitomycin
C(MMC) (Flam et al. 1996). A continuous 5-FU
intravenous infusion, 1,000 mg/m2 per day, was given
on days 1–4 of radiotherapy and repeated on
days 29–32 of radiotherapy. MMC 10 mg/m2 intra-
venously was given on day 1 and day 29 of radio-
therapy to patients who were randomly allocated to
receive this drug. All patients received 36 Gy in
20 fractions to the primary tumor, pelvic lymph
nodes, and inguinal lymph nodes, followed by a field
reduction to include the primary tumor with a
10 9 10 cm field, which was then treated to an
additional 9 Gy in five fractions for a total dose of
45 Gy in 25 fractions. For patients thought to have
residual tumor after 45 Gy, the final boost field was
continued to a total cumulative dose of 50.4 Gy in 28
Cancers of the Colon, Rectum, and Anus
fractions. The combination of radiotherapy, 5-FU, and
MMC resulted in a lower colostomy rate than radio-
therapy and 5-FU without MMC. A statistically sig-
nificant difference in survival between patients who
received MMC and those who did not was not
observed. The RTOG-ECOG study demonstrated that
MMC is an important component of combined
modality therapy for anal cancer.
Although the RTOG-ECOG trial provided critical
information about combined modality therapy for
anal cancer, it did not definitively address whether
this form of treatment is superior to high-dose
radiotherapy alone. Two randomized trials that com-
pared radiation alone with radiotherapy, 5-FU, and
MMC for cancer of the anal canal provided important
data on this point. A phase-III trial, reported by the
United Kingdom Coordinating Committee on Cancer
Research (UKCCCR), compared radiotherapy alone
with radiotherapy combined with a regimen of 5-FU
and MMC (UKCCCR Anal Cancer Trial Working
Party 1996). All patients in this study received 45 Gy
over a 4- to 5-week period, and most received a boost
of 15–25 Gy after a 6-week break. Patients randomly
allocated to the combined modality therapy generally
received 5-FU, 1,000 mg/m2 per day, on the first
4 days of radiotherapy and for 4 days during the
fourth or fifth week of radiotherapy. A single dose of
MMC, 12 mg/m2, was usually given on the first day
of radiotherapy in the combined modality therapy
group. Some variations on these standard doses was
allowed for selected patients (UKCCCR Anal Cancer
Trial Working Party 1996). The second trial reported
by the European Organization for the Research and
Treatment of Cancer (EORTC) randomized trial
compared radiotherapy alone with radiotherapy, 5-
FU, and MMC in patients with T3, T4, or lymph-
node-positive anal cancer. The treatment program was
similar to that of the UKCCCR study. In both studies,
combined modality treatment resulted in superior
local control and colostomy-free survival without an
overall survival advantage (Bartelink et al. 1997).
A more recent RTOG trial compared the standard
protocol radiotherapy combined with 5-FU and MMC
with an experimental arm using induction cisplatin
and 5-FU followed by cisplatin and 5-FU and RT
(Ajani et al. 2008). Radiation doses were 45–59 Gy
based on T stage and nodal status at diagnosis or
residual disease after 45 Gy. No differences were
observed between the two groups in terms of disease-
789
free survival, local recurrence, or survival. However,
the rate of colostomy significantly favored the group
treated with MMC (see subsequent Results section).
Therefore, chemoradiation with 5-FU and MMC
remain the standard treatment approach.
These randomized studies provide strong evidence
that combined modality therapy should be adminis-
tered to patients with anal cancer, with the goal of
sphincter preservation and cure. Radiotherapy without
chemotherapy should be reserved for patients who are
unable to tolerate combined modality therapy, such as
those with serious co-morbid illnesses (Martenson
and Gunderson 1993). Because most patients with
anal cancer are treated with MMC and an initial 4-day
infusion of 5-FU concurrent with the initiation of
radiotherapy, close coordination with the patient’s
medical oncologist is needed before the treatment
begins. To maximize the interaction of radiotherapy
and chemotherapy, patients should receive treatment
with radiation on each day that 5-FU is infused.
Accordingly, it is preferable to begin treatment on a
Monday or Tuesday. Alternatively, special arrange-
ments can be made for patients to receive radiation
treatments on the first weekend after the initiation of
radiotherapy if treatment is started later in the week.
2.3 Radiation Therapy Techniques
2.3.1 Simulation
The patient is simulated in the supine or prone posi-
tion depending on the treatment technique selected,
though prone positioning may be less reproducible.
The bladder may be distended to decrease the amount
of small bowel within the pelvis. To reduce skin
toxicity, cutaneous folds within the medial groin may
be minimized by moderately abducting the patient’s
legs and using an immobilization device to ensure
setup reproducibility of the lower extremities. The
clinical extent of any visible or palpable perianal
tumor should be demarcated with radiopaque markers
as it may not be apparent on simulation imaging. The
anal verge should also be marked and the rectum may
be visualized with rectal contrast. The amount of
exposed anal tumor posteriorly can vary significantly
depending on degree of perineal extension, body
habitus, and leg positioning. This should be noted at
the time of simulation to ensure proper beam selection
and occasionally bolus may be indicated with
790
posterior beams in a thin patient due to exposed
tumor. Oral contrast assists in small bowel visuali-
zation. The use of CT-based targeting and treatment
planning is critical for accurate treatment of the
inguinal lymph nodes and to complement the findings
of physical examination with regard to the extent of
the primary tumor.
2.3.2 Target Volumes
The radiotherapy target includes the primary tumor,
clinically involved lymph nodes, as well as perianal
tissues and regional lymphatics at risk for subclinical
spread of disease. All diagnostic information should
be used together (imaging, physical exam, and
endoscopy) to define the maximal extent of the GTV
for the primary lesion and any involved lymph nodes.
Treatment planning that relies solely on the images
from a planning CT risks underestimation of the full
extent of tumor involvement.
Adjacent to the primary anal tumor, the CTV
should include a 1–2 cm radial margin of surrounding
soft tissue. Longitudinally, it should include any
portions of the anal canal not involved by tumor,
including at least 2 cm of normal mucosal or skin
margin. The CTV also includes the inguinal and
pelvic lymph nodes. Data from abdominoperineal
resection series document a pelvic nodal involvement
rate of 35% and a subsequent inguinal nodal failure
rate of 13% (without dissection) (Boman et al. 1984).
Similarly, an inguinal nodal failure rate of 15% is
reported in a radiotherapy series without elective
groin treatment (Ferrigno et al. 2005).
Traditional radiotherapy fields have included
inguinal lymph nodes generally based on bony land-
marks and palpation. Accurate definition of this nodal
station by CT imaging requires more than just iden-
tifying the femoral blood vessels. The inguinal lymph
nodes are located within the fatty tissue throughout
the femoral triangle. The medial border of this trian-
gle is the pubic tubercle and the adductor longus
muscle. The lateral border is the sartorius muscle,
including the fatty tissues underneath this muscle. The
inferior apex of the femoral triangle is where the sar-
torius and adductor longus muscle intersect in the
sagittal plane (generally where the deep branches of
the femoral artery and vein originate). The superior
extent of the femoral triangle is the inguinal ligament.
The ligament is difficult to delineate by CT, but can
be reproduced as a line from the pubic tubercle to the
J. B. Ashman et al.
anterior superior iliac spine. The floor of the femoral
triangle is the flexor muscles of the hip, but the lymph
nodes lay in the fatty tissue at and anterior to the level
of the femoral vessels. Extension of radiotherapy
fields to cover the far lateral inguinal region adjacent
to the anterior superior iliac spine may be of little
benefit based on lymphangiogram and surgical dis-
section data (Nicklin et al. 1995).
Pelvic lymph nodes included in the CTV are the
external and internal iliac, perirectal, and presacral
nodal regions. As the superior extent of traditional
fields for pelvic nodal treatment is generally the L5-
S1 interspace, the lower portion of the common iliac
lymph nodes may be included as well. In defining
these nodal areas, contouring should not be limited to
pelvic vasculature alone. The adjacent soft tissues of
the pelvic sidewall and presacral area must be inclu-
ded as done for rectal cancer. The RTOG consensus
atlas also provides an excellent reference for target
volume definition in anal cancer treatment planning
(Myerson et al. 2009). The PTV should be an
expansion of the CTV sufficient to account for organ
motion and patient setup error. A minimum PTV of
1 cm beyond the CTV is appropriate, though smaller
margins may be used if IGRT is employed.
2.3.3 Treatment Planning
2.3.3.1 Standard Techniques
The treatment of patients with anal cancer can be
technically challenging given the complex geometric
distribution of targets, particularly the inguinal nodes,
in relation to normal pelvic structures. Most of the
reported techniques have been devised to enable safe
treatment of the inguinal lymph nodes overlying the
femoral heads, while there has been less emphasis on
techniques to minimize unnecessary dose to the
genitalia, bladder, and small bowel. The risk of fem-
oral neck fracture is rare at doses below 45 Gy, but
significantly increases after 50 Gy (Grigsby et al.
1995). Treatment designed to treat inguinal lymph
nodes but spare the femoral head and neck should be
done cautiously. The deep inguinal lymph nodes
(defined at the depth of the femoral vessels) are
generally much deeper than has been historically
appreciated. These nodes are routinely deeper than
3 cm and in the majority of patients may lie 5–6 cm
from the surface, beyond the effective treatment depth
of some electron techniques (Kalidas 1995; Koh et al.
Cancers of the Colon, Rectum, and Anus 791

1993; McCall et al. 1995). Care must be taken to

determine the depth of the inguinal vessels on the
treatment planning CT and choose an appropriate
treatment technique. Patient body habitus may not
only influence depth of lymph nodes, but the selection
of the optimal technique for delivery of radiation as
well (Brown et al. 2004).
There are several common EBRT techniques for
treating anal cancer. Each approach has relative
advantages and disadvantages, which are somewhat
dependent on the radiation dose prescribed to elective
nodes. The wide AP/narrow PA approach includes the
inguinal lymph nodes in the AP field but excludes the
femoral neck from the PA field (may include a small
fraction of the medial femoral head for margin on the
obturator nodes) (Fig. 4). Due to divergence, it is
occasionally possible to match the lateral exit of the
narrow PA beam with the surface entrance of the wide
AP photon beam and provide sufficient dosimetric
coverage of the groins (Brown et al. 2004). More
commonly, however, supplemental anterior electrons
are indicated. The lateral exit of the narrow PA field is
marked anteriorly on the patient’s groins (easily done
at time of fluoroscopic simulation). This serves as the
medial border for each electron supplement. The lat-
eral border of each electron supplement is placed at or
1 cm lateral (due to beam constriction) to the surface
entrance of the wide anterior photon beam. Particular
attention must be made during treatment, to any shifts
made with the PA field to ensure similar movement in
the anterior electron field junctions. Radiopaque wire
placed on these junctions may assist proper set up
when porting the PA field. Figure 5 demonstrates
representative isodose curves using this technique. To Fig. 4 a, b Anterior (a) and posterior (b) fields for treatment
reduce the complexities associated with electron groin of anal cancer, designed using computed tomographic simula-
setups, photons have also been used to supplement the tion. Precise definition of the inguinal lymph nodes allows
lateral inguinal lymph nodes using the same AP some sparing of the femur, particularly with the posterior field.
GTV gross tumor volume, ing inuinal, LNs lymph nodes
photon field and setup. This can be achieved by the
use of a central (pelvic) partial-transmission block
(Rosenthal et al. 1998) or with multi-leaf collimation electrons, patients can be treated in the prone position,
(Dittmer and Randall 2001; Watson et al. 1999). possibly reducing the amount of small bowel in the
The wide AP/wide PA photon fields are devised to pelvis. The obvious disadvantage is that there is no
encompass the primary tumor and pelvis and laterally sparing of the femoral neck, genitalia, and bladder.
extend to encompass the inguinal lymph nodes (wide) However, if moderate doses are selected for elective
in both the AP and PA fields (Grigsby et al. 1995; nodal irradiation, organ tolerance may still be
Rich et al. 1993). This field arrangement is the most respected. Series from the M.D. Anderson Cancer
simple because it requires no field matching and Center have reported the use of this technique (Hung
reduces the chance of technical error or under-dosing et al. 2003; Rich et al. 1993). The initial dose 30.6 Gy
of the inguinal lymph nodes. Without the use of of radiation to the pelvis and groins is delivered with
792
wide photon AP-PA fields. Subsequently, the patient’s
lower pelvis is re-simulated with prone positioning on
a belly-board using a 3-field technique (narrow PA
excluding lateral groins, and lateral fields) for an
additional 19.8 Gy. During this phase, the patient is
turned supine and the inguinal lymph nodes are sup-
plemented with anterior electrons only if initially
involved with tumor. Finally, the primary tumor is
boosted to an appropriate final dose if needed.
A four-field technique includes the pelvis and
inguinal nodes within the AP and two lateral fields
while the PA field is kept ‘‘narrow’’ to exclude the
femurs. With appropriate beam weighting and energy
selection, sufficient dose can usually be delivered to
the inguinal nodes, as verified with computerized
treatment planning. Patients may be treated in the
prone position, reducing bowel within the pelvis.
There are multiple variations of a four-field tech-
nique. In the two preferred options, an AP field is
simulated ‘‘wide’’ and the PA field is kept ‘‘narrow’’
as above. The lateral fields either include the inguinal
and external iliac nodes with shaped blocking (Gun-
derson et al., 2003) or exclude the inguinal region
(anterior border is placed at the pubic symphysis and
anterior electrons groin fields are then used to sup-
plement the wide AP field; Lee et al. 1993).
2.3.3.2 Intensity Modulated Irradiation
IMRT is the preferred treatment approach at Mayo
Clinic for patients with anal cancer, because of the
marked improvement in the ability to spare normal
organs and structures (small bowel, bladder, femoral
heads, and genitalia). To date, there are only limited
reports evaluating more sophisticated treatment
planning techniques for patients with anal cancer, but
improvements in conformality of dose to targets could
lead to reductions in normal tissue complications.
Vuong et al. have reported encouraging acute toxicity
outcome among 30 patients with anal cancer treated
with a complex 3D conformal technique (Vuong et al.
2003). Initial dosimetric analyses of the use of IMRT
in treating anal cancer has also shown promise in
regards to conformality and sparing of the genitalia,
small bowel, bladder, bone marrow, and femoral
necks (Fig. 5) (Ahmad et al. 2004; Chen et al. 2005;
Mell et al. 2008; Menkarios et al. 2007). A limited
number of series have reported favorable toxicity and
clinical outcomes with IMRT (Milano et al. 2005;
Salama et al. 2007). Preliminary results of RTOG
J. B. Ashman et al.
0529, a phase II trial of IMRT with concurrent che-
motherapy, showed an encouraging reduction in the
expected rate of gastrointestinal, genitourinary and
dermatologic toxicity without an apparent compro-
mise in disease control (Kachnic et al. 2010; Kachnic
et al. 2009). While attempting to spare normal tissues
with these techniques, precise contouring of treatment
targets is critical to avoid inadvertently under-treating
regions of risk previously included in clinical trials.
2.3.3.3 Elective Nodal Coverage
The appropriate dose for elective nodal sites has not
been well-defined. In RTOG 87-04, 30.6 Gy in
1.8 Gy fractions was delivered to initial pelvic fields
with the superior border placed at the L4–L5 inter-
space (Flam et al. 1996). Subsequently, the superior
field borders were reduced to the bottom of the
sacroiliac joints, and the pelvis and inguinal nodes
continued treatment to 36 Gy. Finally, 10 9 10 cm
fields which included the primary tumor and lower-
most pelvis were treated to cumulative doses of
45–50.4 Gy. In RTOG 98-11, the initial pelvic fields
were treated to 30.6 Gy with the superior border
placed at L5-S1 (Ajani et al. 2008). Reducing the
superior border to the bottom of the sacroiliac joints,
the lower pelvis was treated to 45 Gy. The inguinal
lymph nodes electively received 36 Gy. Although
successive pelvic field reductions probably address
the gradient of risk for micrometastatic disease within
lymph nodes, retrospective series suggest that doses
as low as 30 Gy with concurrent chemotherapy may
be sufficient to achieve control of subclinical disease
within nodes or at the primary site after excisional
biopsy of small lesions (Hatfield et al. 2008; Hu et al.
1999; Rich et al. 1993). When concurrently treating
multiple targets at different doses per fraction using
IMRT, higher total doses may be indicated for regions
receiving less than 1.8 Gy per day (Kachnic et al.
2009). Only small primary tumors that have com-
pletely responded to radiation should be treated to
45–50.4 Gy. Larger tumors (T3/T4) and incompletely
responding tumors should receive 54–59 Gy. Multiple
retrospective series have reported superior local
control rates in this dose range compared to lower
doses (Constantinou et al. 1997; Ferrigno et al. 2005;
Rich et al. 1993). For patients treated with radio-
therapy alone, the primary tumor should receive a
cumulative dose of 60–63 Gy (Martenson and Gun-
derson 1993).
Cancers of the Colon, Rectum, and Anus
Fig. 5 a–d Isodose curves for definitive pelvic radiotherapy
for anal cancer with the use of groin electron boost fields
(a, c) or intensity modulated radiotherapy (IMRT) (b, d).
2.4 Treatment Results
The outcome of patients treated with concurrent
chemoradiation is well-described from the results of
randomized trials (UKCCCR Anal Cancer Trial
Working Party 1996; Flam et al. 1996; Bartelink et al.
1997; Ajani et al. 2008). Favorable outcome is
somewhat dependent on clinical stage but long-term
local control, colostomy-free survival, and overall
survival are approximately 70, 70, and 60–70%,
respectively among patients receiving combined-
modality therapy. Among patients who fail treatment
locally, 50% have been salvaged with surgical
resection (Flam et al. 1996).
RTOG 98-11 was designed to test the effectiveness
of cisplatin compared to MMC. At 5 years, both
793
Representative axial (a, b) and sagittal (c, d) imaging planes are
shown that demonstrate improved sparing of normal structures/
organs with IMRT
groups of patients had similar rates of locoregional
control (75 vs. 67%), distant metastasis (25 vs. 19%),
and overall survival (75 vs. 70%) (Ajani et al. 2008).
While the rate of acute Grade 3/4 hematologic tox-
icity was increased in the MMC-treated patients (61
vs. 42%, P \ 0.001), the rate of colostomy was sig-
nificantly superior in the MMC-treated patients at
5 years (10 vs. 19%, P = 0.02). The results suggested
that cisplatin could not substitute for MMC, and the
standard of care remains 5FU/MMC combined with
RT. However, one explanation for the observed
inferiority of the cisplatin arm with regards to colos-
tomy rate in RTOG 98-11 may have been the
increased overall treatment time required in the cis-
platin arm with induction chemotherapy rather than
the use of cisplatin itself (Ben-Josef et al. 2010). Two
794
recent reports comparing MMC to cisplatin without
an induction component found no difference in sur-
vival, relapse, or colostomy rate (James et al. 2009;
Olivatto et al. 2011). Local control still remains
problematic for patients with more advanced disease.
Re-analysis of the data from RTOG 98-11 examined
the impact of TN disease status on outcome and
reported locoregional failure between 58 and 64% in
patients with advanced T3-4 N+ disease (Gunderson
et al. 2010b).
The ability of IMRT to spare normal tissue should
allow dose-escalation in patients with T3–4 or
N+ disease with acceptable toxicity. The recently
reported results of RTOG 0529 trial appear to dem-
onstrate that IMRT can be utilized within the coop-
erative group trial setting without compromising local
control (Kachnic et al. 2010). Although the trial did
not meet its primary end-point of decreasing any grade
[2 toxicity, there was significant improvements in
severe toxicities compared to earlier RTOG trials
(Kachnic et al. 2009). Nevertheless, the finding that
75% of submitted cases for central review on RTOG
required planning revisions emphasize the necessity
for continuing and intensified education regarding
appropriate volume contouring prior to widespread
implementation of IMRT for anal cancer.
The follow-up trial for RTOG 0529 has not yet
been fully designed but future trials will likely focus
on continuing to decrease toxicity in early stage
patients while attempting to escalate doses for
increased tumor control in more locally advanced
disease. In addition, with data suggesting that muta-
tions in the KRAS and BRAF genes are infrequent in
anal cancer, the incorporation of targeted agents such
as cetuximab or other EGFR inhibitors may be
promising (Evesque et al. 2010).
3 Summary
Radiation therapy remains a critical component of the
multidisciplinary approach to lower GI cancer. In
colon cancer, RT has a limited but distinct role as
adjuvant therapy for selected patients. In the setting of
rectal cancer, RT is typically utilized in the pre-
operative setting. A short, hypofractionated course of
RT without chemotherapy is favored in Europe.
Long-course concurrent chemoradiation is more
commonly utilized in the United States. In contrast,
J. B. Ashman et al.
RT combined with chemotherapy is definitive, cura-
tive therapy for most patients with anal cancer.
Designing RT fields for the treatment of both colo-
rectal and anal cancer is challenging because of the
complex geometry of the pelvis and the relatively low
radiation tolerance of the anatomy. Advanced radia-
tion techniques including CT-based planning and
IMRT have the potential to significantly improve the
therapeutic window by decreasing toxicity, allowing
for escalation of the radiation doses, and for allowing
the use of more potent systemic chemotherapy agents.
However, appropriate application of modern radio-
therapy planning requires even greater attention to
technique in order to avoid compromising tumor
control.
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 Bladder Cancer
Peter Han, Marvin Rotman, Alan R. Schulsinger, Bradley R. Pieters,
Caro C. E. Koning, Floris J. Pos, Maarten C. C. M. Hulshof,
and Philip Poortmans

Contents 5.2 Organs at Risk (Including Tolerance Doses) ........... 813

5.3 Treatment Schedules ................................................. 814
5.4 Simulation/3D Conformal Planning.......................... 814
1 Natural History of the Disease (Patterns 5.5 Organ Motion and Image Guidance ......................... 816
of Spread) ................................................................. 802
6 Image-Guided Radiotherapy (IGRT).................... 816
2 Work-Up and Staging ............................................. 803 6.1 IGRT: Whole Bladder Radiotherapy ........................ 816
6.2 IGRT: Boost or Partial Bladder Radiotherapy ......... 817
3 Prognostic and Predictive Factors......................... 805
6.3 Fiducial Markers........................................................ 817
4 General Management .............................................. 807
7 Intensity Modulated Radiotherapy (IMRT)......... 818
4.1 Non-muscle-Invasive Disease ................................... 807
4.2 Muscle-Invasive Disease ........................................... 808 8 Brachytherapy.......................................................... 819
5 Radiation Therapy Techniques (General 9 Future Directions..................................................... 822
Description) .............................................................. 811
5.1 Target Volumes ......................................................... 812 References.......................................................................... 822

Abstract
P. Han (&)  M. Rotman  A. R. Schulsinger
Department of Radiation Oncology, The management of invasive bladder cancer
State University of New York, requires a multidisciplinary approach to optimize
Health Science Center at Brooklyn, the treatment of the disease while maintaining the
450 Clarkson Aven, Box 1211, Brooklyn,
NY 11203-2098, USA
best quality of life. In early-stage disease, combined
e-mail: Peter.Han@downstate.edu surgery and radiation offers good results with
A. R. Schulsinger
sparing of the functional bladder in selected
Department of Radiation Oncology, patients. For patients with locally advanced disease,
Long Island College Hospital, maximal transurethral resection followed by radio-
Brooklyn, NY, USA therapy and possibly chemotherapy can offer a
B. R. Pieters  C. C. E. Koning  M. C. C. M. Hulshof valuable alternative to radical surgical approaches.
Department of Radiation Oncology, A wide variety of planning, dosing, and actual
Academic Medical Center/University of Amsterdam,
P.O. Box 22660, Z0-214, 1100 DD,
therapy techniques is nowadays available. A chal-
Amsterdam, The Netherlands lenge in radiotherapy for bladder cancer is caused
F. J. Pos
by organ motion, which limits the precision of
Department of Radiation Oncology, radiotherapy for bladder cancer. New treatment
The Netherlands Cancer Institute-Antoni van techniques and tools for image guidance and
Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, adaptive radiotherapy increase precision of dose
Amsterdam, The Netherlands
delivery together with a substantial reduction of
P. Poortmans treatment volumes. Further investigations toward
Department of Radiation Oncology, Institute Verbeeten,
Tilburg, The Netherlands
defining optimal fractionation schemes, techniques,

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 801
DOI: 10.1007/174_2011_249,  Springer-Verlag Berlin Heidelberg 2012
802
and systemic agents remain to be continued. The
development of new diagnostic tools utilizing
molecular markers is being explored to further
individualize the treatments to the patient with his/
her specific tumor characteristics.
1 Natural History of the Disease
(Patterns of Spread)
Bladder cancer is the sixth most common cancer in
the United States excluding basal and squamous skin
cancer. It accounts for approximately 4.6% of all
cancers, with an expected 70,530 new cases and
14,680 deaths to occur in the US for 2010 (Jemal et al.
2010). In Europe, there were an estimated 139,500
new cases of bladder cancer and 51,300 deaths in
2008 (Ferlay et al. 2010). The incidence of bladder
cancer is approximately three times higher in men as
opposed to women, reflecting a different exposure to
the risk factors (Jemal et al. 2010).
Risk factors for transitional cell cancer of the blad-
der used to include especially exposure to chemical
carcinogens (i.e., aniline dyes). Nowadays, tobacco
(estimated to account for more than half of all cases that
occur in men and a growing portion in women), coffee,
artificial sweeteners, and phenacetin-containing
analgesics are the most frequent causal factors,
especially in combination with a low fluid intake
leading to a higher concentration of carcinogens in the
urine (Whitmore et al. 1977a, b). Chronic irritation by
foreign bodies (i.e., indwelling Foley catheters, calculi,
and Schistosoma hematobium in endemic areas) are risk
factors for squamous cell cancers. Exstrophy of the
bladder used to be described as the main risk factor for
adenocarcinoma but has become extremely rare
nowadays (Morrison and Cole 1976). Genetic risk
factors include abnormalities of p53, retinoblastoma
gene, p21, p16 (Shariat et al. 2004), altered microRNAs
expression (Wszolek et al. 2009), p63 (Urist et al.
2002), loss of heterozygosity at chromosome 9 (Hirao
et al. 2005; Abraham et al. 2007), and variants in the
epidermal growth factor receptor family (Chow et al.
2001; Charkravarti et al. 2005).
Some of the more common clinical presentations of
bladder cancer include (1) painless hematuria, which
occurs in up to 80% of patients; (2) bladder irritability,
such as urinary frequency, urgency, and dysuria (all of
P. Han et al.
which are suggestive of muscle-invasive disease);
and (3) recurrent urinary tract infections, particularly
in men. Some of the less common clinical presenta-
tions include (1) flank pain or anemia associated with a
pelvic mass; (2) pelvic mass associated with lower
extremity weakness, weight loss, abdominal pain, and
(3) suprapubic pain which are all related to extravesical
tumor growth.
Anatomically, the bladder is a hollow muscular
organ that lies in the anterior half of the pelvis. When
full, it contains about 0.5 litre of urine. It occupies a
triangular space bound anteriorly and laterally by the
symphysis pubis and the diverging walls of the pelvis,
respectively. The posterior border is the rectum/
rectovaginal septum. The lateral and inferior portions of
the bladder are supported by the obturator internus and
levator ani muscles, respectively. In males, the prostate
lies between the levator ani and the bladder. The supe-
rior surface of the bladder is covered by peritoneum.
Transitional cell epithelium (urothelium) lines the
bladder, contiguous into the ureters and the urethra.
The mucous membrane is loosely attached, except in
the trigone region where it is firmly attached. The
urothelium lining the bladder is thrown into many folds
in the relaxed state, allowing the bladder to expand
with the filling of urine. Deep to the epithelium, the
wall of the bladder consists of three loosely arranged
smooth muscle and elastic fiber layers which contract
during micturition. These are the inner longitudinal,
outer spiral, and outer longitudinal layers. The outer
longitudinal layer is surrounded by the outer adventi-
tial coat. This coat contains arteries, veins, and
lymphatic channels. Because these lymphovascular
channels reside most abundantly in the outer layer of
the bladder, depth of penetration of tumor cells is
correlated with the incidence of locoregional lymph
node involvement and distant metastasis.
The bladder contains a rich network of intercon-
necting lymphatic vessels, found in the mucosa and
muscular walls of the bladder that are most abundant
in the region of the trigone, which is defined by the
ureteral orifices posterolaterally and by the urethral
aperture at the inferior/anterior angle and leads into
the bladder neck. These lymphatics usually drain into
channels that pierce the muscular layers and then
organize from the superior and inferolateral surfaces
of the bladder to ultimately drain into the external
iliac lymph nodes. From the posterior surface of the
bladder, lymphatic channels drain to both the external
Bladder Cancer
Fig. 1 A bladder diagram is
completed at the time of
cystoscopy and used to record
the cystoscopy findings,
biopsy information, and tumor
characteristics
iliac and internal iliac lymph node chains. Lymphatic
vessels from the bladder neck may combine with
prostatic lymphatic vessels in males, which can ulti-
mately drain to the presacral and common iliac lymph
nodes. Thereby, the primary drainage lymph nodes
include the hypogastric, obturator, internal and
external iliac, and presacral nodes. The primary nodes
then drain into the common iliacs (Edge et al. 2010).
The most common histology in industrialized
countries is transitional cell carcinoma, which makes up
approximately 90% of cases, followed by squamous cell
(7%) and adenocarcinoma (less than 1%) (Pearse 1994;
Johnson et al. 1972). A typical form of an adenocarci-
noma is an urachus tumor which arises in the umbilical
remnant and presents itself in the ventral part of the
bladder. Sarcomas, lymphomas, carcinoid tumors, and
small cell cancers are seen less frequently. About 30%
of bladder cancers present as multiple lesions.
Tumors of the bladder may be papillary in
appearance and generally not deeply invasive—or
solid in appearance and generally deeply invasive.
Most transitional cell tumors are found at the trigone,
followed in frequency by the lateral and posterior
walls and then the bladder neck (Mostofi et al. 1988).
Carcinoma in-situ (CIS), a flat nonpapillary lesion
that spreads typically diffuse and multifocal along the
bladder mucosa, is commonly associated with high-
grade lesions and may ultimately progress to an
invasive carcinoma.
Approximately 75% of bladder cancers present
initially with limited disease and non-muscle-invasive
disease, of which up to 70% will recur after
803
transurethral resection alone (Soloway et al. 2002).
Approximately 30% of those patients later develop
higher grade histology, muscle invasion, and higher
stage disease (Cheng et al. 1999). Tumors progress
by further muscle invasion and by lymphatic
involvement to the external iliac lymph nodes. About
40% of patients with muscle-invasive cancers have
involved lymph nodes at presentation, and almost all
of these patients will ultimately die of locoregional
progression or distant metastasis (Skinner et al. 1982).
The most common sites of distant spread include lung,
bone, and liver.
2 Work-Up and Staging
The basis of the work-up in bladder cancer is to
determine whether the disease is superficial nonin-
vasive cancer, locally invasive lesion, locoregionally
advanced, or metastatic disease. In addition to eval-
uating the bladder, the ureters and kidneys are also
examined for lesions, since multiple tumors of the
urothelium are not uncommon, due to the common
carcinogen exposure or embryology.
Cystoscopy and urethroscopy allow for excellent
visualization and biopsy of lesions. A bladder diagram
should be completed at the time of cystoscopy to record
pertinent findings (Fig. 1). This information can be
quite valuable to the radiation oncologist for treatment
planning, as a precise knowledge of the tumor location
is critical. Urine cytology is a simple screening test that
can be used in follow up for patients after treatment,
804
Table 1 Diagnostic work-up for invasive bladder cancer
Routine
History and physical examination
Pelvic/rectal examination
Complete blood cell count
Live function tests and chemistries
Urinalysis and urine cytology
Chest radiograph
Computed tomography or magnetic resonance scan of pelvis
and abdomen
On indication
Intravenous pyelography
Radioisotope bone scan
Cystourethroscopy
Bimanual pelvic/rectal examination under anesthesia
Biopsies of bladder and urethra
Transurethral resection, if indicated
with a sensitivity at least 90% and specificity of
98–100% for high-grade lesions, but a low sensitivity
for low grade lesions (Brown 2000). Other non-
invasive tests currently available but not widely
accepted include tumor markers such as BTA (bladder
tumor antigen) stat, BTA Trak, BladderChek,
ImmunoCyt/uCyt+, and UroVysion (Budman et al.
2008). A limitation of conventional cystoscopy is that
it may have difficulty identifying flat lesions, particu-
larly carcinoma in situ (CIS). Photodynamic diagnosis
(PDD) is a technique that utilizes a prodrug, like
5-aminolevulinic acid (5-ALA), which has a prefer-
ential uptake in neoplastic cells, emitting a fluores-
cence in the red spectrum, allowing improved
detection rates during cystoscopy. A meta-analysis
reported by Kausch et al. found that PDD allows
detection of more patients with non-muscle invasive
bladder cancers especially patients with CIS (Kausch
et al. 2010). In addition, computed tomography (CT)
and/or magnetic resonance imaging (MRI) are used in
patients with invasive bladder cancer to evaluate
bladder wall thickening from invasion, extravesical
spread, and lymphadenopathy. However, distinguish-
ing between the different layers of bladder is difficult.
CT often understages patients with small volume
extravesicular disease (Paik et al. 2000). Studies
looking a CT and MRI suggest that MRI is more
accurate in staging with an accuracy ranging from 73 to
P. Han et al.
96%, compared to 40–95% for CT, thanks to its better
ability to evaluate deep muscle layer involvement and
adjacent organ invasion (Ng 2006). It should be kept in
mind that edema and hemorrhage seen on MRI and CT
scan obtained shortly after transurethral tumor resec-
tion (TURT) may easily be confused with tumor
(Barentsz et al. 1996, 2000). For this reason, imaging
studies are best performed prior to TURT. An overview
of the suggested staging methods, depending on tumor
stage and symptoms, is shown in Table 1. All patients
should have a complete blood count and serum
chemistries, including liver function tests to evaluate
possible systemic spread. Chest and abdominal CTs are
recommended for invasive disease. Bone scan should
be done in the presence of elevated alkaline phospha-
tase or associated symptoms. The value of positron
emission tomography (PET) scanning using a glucose
analog, fluorodeoxyglucose (18F) for staging, is
unclear. Drieskens et al. described the results of
preoperative staging using FDG-PET/CT in 55 patients
with bladder cancer (Drieskens et al. 2005). The
authors reported a sensitivity, specificity and accuracy
of PET/CT of 60, 88 and 78%, respectively. Recently,
Swinnen et al. evaluated the lymph node status using
PET/CT and CT on 51 patients with bladder cancer.
Sensitivity, specificity and accuracy were 46, 97, and
84% for PET/CT, respectively, and 46, 92, and 80% for
CT, respectively, thereby showing no advantage of a
FDG-PET/CT over a CT alone (Swinnen et al. 2009).
Bimanual examination under anesthesia should be
performed before and after TURT for estimation of
the extent of local infiltration into the surrounding
tissue and whether the mass is freely mobile, tethered,
or fixed and to estimate if macroscopic disease
remained after TURT.
Determination of muscular wall invasion is the
most important aspect of staging. It is often not pos-
sible for the pathologist examining TURT specimens
to determine whether the tumor is confined to the
superficial muscle layers of the muscularis propria,
which is the first muscle layer reached after tumor
cells have already invaded the connective tissue of the
lamina propria, or whether the tumor has penetrated
further into the deeper muscle layers. This inability to
distinguish deep from superficial muscle invasion
leads often to understaging. These limitations to
accurate staging have undoubtedly hampered the
ability of showing the benefit of effective bladder-
sparing treatments. Therefore and according to most
Bladder Cancer 805

Table 2 Comparison of Marshall and AJCC staging system for bladder cancer (Edge et al 2010)
Marshall modification of Jewett- AJCC 7th
Strong classification edition
Tumor extent
Confined to mucosa 0
• nonpapillary, noninvasive Tis
• papillary, noninvasive Ta
Not beyond lamina propria (no mass palpable after complete TURT) A T1
Invasion of superficial muscle (inner half) (no duration after complete TURT) B1 T2a
Invasion of deep muscle (outer half) (induration after complete TURT) B2 T2b
Invasion into perivesical fat (mobile mass after TURT)–microscopic C T3a
–macroscopic T3b
Invasion of neighboring structures: muscle invasion present
Substance of prostate, vagina, uterus D1a T4a
Pelvic sidewall fixation or invading abdominal wall D1a T4b
Nodal involvement (N)
Minimum requirements to assess the regional nodes cannot be met Nx
No involvement of regional lymph nodes No
Single regional lymph node metastasis in the true pelvis (hypogastric, N1
obturator, external iliac or presacral lymph node)
Multiple regional lymph node metastasis in the true pelvis (hypogastric, N2
obturator, external iliac, or presacral lymph node metastasis)
Lymph node metastasis to the common iliac, lymph nodes N3
Distant metastasis (M)
Minimum requirements to assess the presence of distant metastasis cannot Mx
be met
No distant metastasis M0
Distant metastasis M1
a
In the Marshall modification of the Jewett-Strong staging system, D1 disease may involve lymph nodes below the sacral
promontory (bifurcation of the common iliac artery). D2 implies distant metastases or more extensive lymph node metastases
TURT, transurethral tumor resection

guidelines, urologists should perform TURT in several

layers, collecting the material in separate containers
enabling separate pathological examination.
A further difficulty to accurate staging is the use of
both clinical and pathological staging systems in
clinical trials. Caution is therefore required in
the interpretation and comparison of trial results.
The most widely used staging system is the American
Joint Committee on Cancer (AJCC) staging system
(7th edition) (Edge et al. 2010). A comparison
is demonstrated in Table 2 with an older first
established staging system, Jewett-Strong-Marshall
Staging system, first established by pathologist, H.J.
Jewett in 1946 with subsequent revisions. Overall
AJCC staging is presented in Table 3.
3 Prognostic and Predictive Factors
Approximately 70% of patients have Tis, Ta, or T1
disease at presentation. Approximately 20% have
stage T2–T4 disease and another 10% present with
metastatic disease. Superficial tumors can behave
aggressively with repeatedly local recurrences, often
with further and deeper invasion. Eventually, pene-
tration of the bladder muscular layers occurs. Once
muscle is involved, lymphatic and blood vessel
invasion is common. Pathological T2 and early T3
disease have a 30% risk of nodal involvement
whereas this increases in patients with advanced T3 or
T4 tumors to 50–80% (Shipley et al. 1985). As nodal
806 P. Han et al.

Table 3 Stage grouping for bladder cancer Table 5 Recurrence, progression, and mortality by risk group
for superficial bladder cancer
Stage 0a Ta N0 M0
Stage Ois Tis N0 M0 Risk group Recurrence Progression Mortality %
% Kaplan– % Kaplan– Kaplan–
Stage I T1 N0 M0 Meier Meier Meier
Stage II T2a-b N0 M0 Low 37 0 0
Stage III T3a-b N0 M0 Intermediate 45 1.8 0.73
T4a N0 M0 High 54 15 9.5
Stage IV T4b N0 M0 Millán-Rodriguez et al. (2000)
Any T N1-3 M0
M0
Table 6 Weights used to calculate recurrence and progression
Edge et al. (2010) scores for superficial bladder cancer
Factor Recurrence Progression
Table 4 Risk group classification for superficial bladder
cancer Number of tumors
Single 0 0
Low risk Grade 1, stage Ta
2–7 3 3
Grade 1, stage T1, single tumor
C8 6 3
Intermediate risk Grade 1, stage T1, multiple tumors
Tumor size
Grade 2, stage Ta
\3 cm 0 0
Grade 2, stage T1, single tumor
C3 cm 3 3
High risk Grade 2, stage T1, multiple tumors
Prior recurrence rate
Grade 3, Ta
Primary 0 0
Grade 3, stage T1
B1 rec/yr 2 2
Carcinoma in situ association
[1 rec/yr 4 2
Millán-Rodriguez et al. (2000)
T category
Ta 0 0
metastasis is in part an indicator of potential for
T1 1 4
systemic spread, a similar frequency of distant
metastasis is eventually noted for these patients. CIS
Poor prognostic factors at presentation include No 0 0
deeply invasive/high stage tumors, associated CIS, Yes 1 6
vascular invasion, involved lymph nodes, tumor Grade
size [6 cm, urethral obstruction/obstructive uropa- G1 0 0
thy, hydronephrosis secondary to ureteral obstruction, G2 1 0
solid tumor morphology, a palpable mass present on G3 2 5
bimanual examination, visible or palpable tumor fol-
Total score 0–17 0–23
lowing TURT, solid/flat surface tumor histology as
Sylvester et al. (2006)
opposed to papillary histology, high-grade tumors,
hemoglobin \12 g/dl (\7.5 mmol/l), and multiple
tumors (Shipley et al. 1985). with carcinoma in situ (Tables 4 and 5) (Millán-
Millán-Rodriguez et al. reviewed 1529 patients with Rodriguez et al. 2000). Based on 2596 patients with Ta or
superficial bladder cancer and developed a risk group T1 bladder cancer, the EORTC developed a scoring sys-
classification for progression, mortality and recurrence tem based on number of tumors, tumor size, prior recur-
rates based on a multivariant analysis according to pro- rence T category, CIS, and grade to predict the probability
gression, mortality, and recurrence rates. The risk groups of developing recurrence and progression (Table 6)
were stratified into low, intermediate, and high risk based (Sylvester et al. 2006). Table 7 displays the predicted
on Ta vs T1, grade, number of tumors, and association progression and recurrence rates at 1 and 5 years.
Bladder Cancer 807

Table 7 Probability of recurrence and progression according KHL) and chemotherapy (mitomycin C, adriamycin,
to total score for superficial bladder cancer epirubicin, and gemcitabine). These drugs are more
Recurrence Probability Probability efficacious in superficial tumors or after a TURT.
score recurrence recurrence Several randomized trials reported a benefit from the
1 year (%) 5 years (%)
use of immediate intravesical chemotherapy after
0 15 31 TURT (Oosterlinck et al. 1993; Tolley et al. 1996;
1–4 24 46 Gudjonsson et al. 2009). Sylvester et al. reported on a
5–9 38 62 meta-analysis of seven randomized trials including
10–17 61 78 1,475 patients with Ta or T1 bladder cancer (Sylvester
Progression Probability Probability et al. 2004). The authors reported a decrease of the
score progression progression recurrence risk by 39% with one immediate intrave-
1 year (%) 5 years (%) sicular chemotherapy, except in patients with multiple
0 0.2 0.8 bladder tumors. Another meta-analysis reported a
2–6 1.0 6 significant reduction in tumor recurrence with BCG in
7–13 5 17 comparison to TURT alone (Shelley et al. 2001).
14–23 17 45 A recent meta-analysis confirmed the effectiveness of
Sylvester et al. (2006)
immediate post-operative chemotherapy (Shelley et al.
2010). In addition, in intermediate or high-risk
patients, further intravesical induction and mainte-
nance therapy with BCG is recommended.
4 General Management Transurethral tumor resection is often an outpatient
procedure done under transurethral visualization of
Optimal therapeutic options for bladder cancer the lesion(s) in question. The goal is to remove tumor
depend on histology and stage of disease. The man- down to uninvolved tissue. It is a well-tolerated pro-
agement of transitional cell cancers should be based cedure; however, after multiple TURTs the bladder
on whether the patient has non-muscle- or muscle- becomes typically fibrotic and contracted. Local
invading disease. For non-muscle-invading disease, control rates of 60–80% are obtained (Herr et al.
acceptable local control rates and excellent 5-year 1995). Because of possible recurrences and especially
survival rates are obtained with interventions includ- progression to invasive bladder cancer, close follow-
ing TURT and fulguration of the bladder or TURT up with cystoscopy performed at 3–4-month intervals
followed by intravesicular chemotherapy or immu- is recommended.
nomodulators. Patients with other histology should be Interstitial and intraoperative radiation treatment
treated differently. For example, squamous cell cancer of non-muscle-invasive bladder cancer has excellent
tends to fail mainly locally with a proposed man- outcome for selected patients, but is rarely used.
agement consisting of preoperative radiation therapy, However, given that understaging is such a signifi-
chemoradiation, or chemotherapy followed by radical cant problem after TURT, it is possible that intra-
cystectomy. These approaches yield an approximate vesicular therapy only may be undertreating some of
50% 5-year survival rate and are generally considered these patients with ‘‘non-muscle-invasive’’ disease.
to offer the best chance for cure (Awwad et al. 1979; Matsumoto, using intraoperative radiation therapy
Ghoneim et al. 1985; Kassouf et al. 2007). For small delivered by an electron beam, achieved an
cell bladder cancer, an approach similar to small cell impressive 95% local control rate for early-stage
lung cancer is suggested. solitary lesions (Matsumoto et al. 1981). Van der
Werf-Messing et al. implanted radium needles in the
bladder wall and reported 80–85% local control rates
4.1 Non-muscle-Invasive Disease (Van der Werf-Messing and Hop 1981). Harland
et al. did report on a randomized study examining
Early-stage patients are generally managed by maxi- T1G3 transitional cell carcinoma of the bladder to
mal TURT followed by intravesicular drug instillation, either external beam radiation therapy (EBRT)
including immunomodulators (BCG, interferon, IL2, or conservative therapy with no evidence of
808
improvement with EBRT (Harland et al. 2007).
There is, however, prospective, nonrandomized data
from a European series ‘‘that suggests that if radio-
therapy is used routinely and not restricted to unfa-
vorable subgroups, the results are probably better
than with adjuvant intravesical therapy’’ (Rodel et al.
2005). Weiss et al. also reported a large prospective
trial for high-risk T1 bladder cancer treated with
EBRT or with concomitant chemotherapy after
TURT with disease-specific survival of 73% at
10 years with more than 80% survivors preserving
their bladder (Weiss et al. 2006). RTOG is currently
conducting a phase II trial (0926) utilizing con-
comitant chemoradiation therapy for the treatment of
T1 bladder cancer after TURT.
4.2 Muscle-Invasive Disease
For muscle-invasive bladder cancers, radical cystec-
tomy remains the standard of care. Surgery usually
entails a pelvic lymphadenectomy and a form of
urinary diversion. Depending upon the extent of dis-
ease, women may need to undergo resection of the
uterus, urethra, and portion of vaginal wall, and men
may need to undergo resection of the urethra and
prostate. Up to 40% of men undergoing radical cys-
tectomy for bladder cancer have been found to have
prostate cancer (Nixon et al. 2002; Wood et al. 1989).
It has been suggested that men not at high risk of
either bladder cancer involvement of the prostatic
urethra or a second primary prostate cancer should be
considered for prostate sparing cystectomy with a
view toward improved urinary control and sexual
potency (Cookson 2005). Regarding the extent and
completeness of the lymphadenectomy, there has
been a renewed interest in extending the resection
above the ‘‘traditional’’ level of the bifurcation of the
iliac arteries, as this may impact on the disease spe-
cific survival even in patients without apparent lymph
node involvement (Cookson 2005). It must be
remembered, however, that there is an increased risk
of lymphedema in extending the level of resection.
Operative mortality is still about 1-2%, mainly due
to pulmonary emboli, myocardial infarction, and
stroke. There is also significant blood loss associated
with the procedure (Cookson 2005). Additionally,
there are major lifestyle changes brought about by this
procedure, including incontinence (depending on the
P. Han et al.
method of reconstruction) and the loss of sexual
function. Robotic assisted radical cystectomy has
recently been introduced (Nix et al. 2010).
Radical cystectomy for patients with stage T3
disease offers a 20–40% 5-year survival and similar
local recurrence rates (Greven et al. 1992; Montie
et al. 1984; Morabito et al. 1979; Drago and Rohner
1983; Marshall and McCarron 1977). In an attempt to
improve these results, several randomized studies
involving preoperative external beam radiation ther-
apy have been employed (Bloom et al. 1982; Batata
et al. 1981; Timmer et al. 1985; Woehere et al. 1993).
Parsons and Million reviewed the published data and
concluded that addition of preoperative irradiation to
cystectomy for patients with T3 disease increased
5-year survival by 15–20% (Parsons and Million
1988). However, these findings were not confirmed by
a more recent meta-analysis reviewing the data from
five randomized studies (Huncharek et al. 1998).
Therefore, most patients undergoing radical cystec-
tomy do not receive preoperative radiation therapy.
Due to a combination of inherent inadequacies of
clinical staging and of the influence of radical surgery
on quality of life, the management for muscle-invasive
disease remains a matter of debate. With the possible
exception of selected patients with single, small,
superficially muscle-invasive tumors (T2a) that are not
associated with CIS, TURT alone is deemed unac-
ceptable due to high local failure rates (Herr 1987;
Solsona et al. 1992). Treatment options–apart from
radical cystectomy–for the remaining patients include
partial cystectomy in selected cases, radiotherapy,
combined modality treatment, all with a view to
bladder preservation. In patients with T2 disease, a
partial cystectomy alone is reported to offer a 60%
survival in pathologically confirmed stage T2 patients
(Resnick and O’Conor 1972; Brannan et al. 1978). The
role of radiation in this stage of disease is not pro-
spectively confirmed; however, Van der Werf-Messing
et al. reported that selected T2 patients implanted with
radium needles achieved an 80% disease-free survival
at 5-years (Van der Werf-Messing et al. 1983a, b)
which was subsequently replicated by Battermann and
Tierie (1986). External beam radiation series for T2
disease consist mainly of clinically understaged
patients and include medically inoperable, elderly,
and frail patients. Nevertheless, good local control
and survival rates with radiotherapy after TURT are
possible as summarized in Table 8.
Bladder Cancer
Table 8 Outcomes of trials of radiation alone to treat invasive
bladder cancer
Series (ref) Number of Complete
patients response
T2 T3
(%) (%)
Blandy et al. (1980) 704 48 42
Duncan and Quilty (1986) 889 49 41
Smaaland et al. (1991) 146 69 36
Greven and Solin Hanks (1990) 116 36 18
Vale et al. (1993) 60 79 46
Radiation therapy alone in patients with T3 disease
leads to 5-year survival in the 20% range (Bloom
et al. 1982; Goffinet et al. 1975; Quilty and Duncan
1986; Pollack et al. 1994; Edsmyr et al. 1985;
DeWeerd and Colby 1973). These low figures may be
explained, in part, to the fact that many of the patients
who are selected for ‘‘definitive radiation therapy’’ are
patients who initially failed multiple TURTs with
intravesical chemotherapy and/or BCG and either
refused salvage cystectomies or were deemed medi-
cally inoperable. These patients typically have scar-
red, contracted bladders to begin with, and perhaps
have biologically more aggressive tumors as evi-
denced by their history of recurrences. It should also
be kept in mind that a significant number of patients
undergoing cystectomy for clinical stage T3 lesions
are found to have T4 lesions on pathological analysis,
and a significant minority is also downstaged
(Marshall 1952; Richie et al. 1975; Whitmore et al.
1977a, b). For this reason, comparing results from
clinically staged series to pathologically staged series
remains cumbersome. Some radiation series do reveal
fair pelvic local control rates (Table 8), especially if a
salvage cystectomy for residual or recurrent cancer is
included.
Various clinical trials suggest that bladder cancer
is a chemoresponsive tumor. Incorporation of
chemotherapy into the management paradigm of
muscle-invasive bladder cancer offers the theoretical
advantage of ‘‘spatial cooperation’’, where the pri-
mary role of chemotherapy is to control microme-
tastasis at distant sites, while either surgery,
irradiation, or irradiation with radiosensitizing doses
of chemotherapy is used to address the localized
primary tumor. Recent reports of chemotherapy
809
integrated with radiation therapy suggest that results
can be improved by more than 50% over radiation
therapy alone and may obviate the need for radical
cystectomy with its resultant compromised quality of
life (Rotman et al. 1987; Reibischung et al. 1992;
Tester et al. 1993; Cervak et al. 1993; Dunst et al.
1994). Rotman et al. reported on patients with clini-
cally staged bladder cancer who underwent high
doses of external beam radiation therapy in combi-
nation with sensitizing doses of 5-FU chemotherapy
(Rotman et al. 1990). The majority of patients
retained functioning bladders, and minimal toxicity
was noted. More importantly, survival rates were
excellent. Currently, only one small randomized study
showing the advantage of CRT above radiation alone
has been reported (Coppin et al. 1996). Randomized
studies on this subject are currently ongoing. The
major side effect of chemotherapy is generally
hematological toxicity. However, many patients have
coronary artery disease or renal failure, and agents
may cause coronary artery spasm (due to 5-FU) or
renal injury (due to cisplatinum) (Devita et al. 1989;
James and Hussain 2005). There may be an increased
frequency of diarrhea in patients who are treated with
concomitant 5-FU, but these side effects are fre-
quently prevented by prophylactically placing
patients on a combination of supplementary dietary
fiber intake and bismuth subsalicylate prior to initia-
tion of treatment. Table 8 summarizes the complete
response rates for various studies employing the use
of radiation therapy alone. Table 9 summarizes the
results of studies combining maximal TURT followed
by combining concomitant chemotherapy and radia-
tion therapy (Rotman et al. 1987; Cervak et al. 1993;
Sauer et al. 1990; Jakse et al. 1985; Tester et al. 1993;
Richards et al. 1983). Comparison of these results
strongly suggests that the addition of chemotherapy
improves results over standard radiation therapy alone
with response rates of 70% or greater (Devita et al.
1989; Housset et al. 1993; Dunst et al. 1994; Eapen
et al. 1989).
Hyperfractionated EBRT trials draw from the
encouraging results from the Royal Marsden Hospital
where local control for muscle-invading bladder
cancer was enhanced by accelerated multiple daily
treatments (Cole et al. 1992; Horwich et al. 1995).
Incorporating this benefit into combined modality
therapy with maximal TURT and chemotherapy has
resulted in impressive results in both French and
 810

Table 9 Outcomes of trials of chemotherapy and radiation to treat invasive bladder cancer
Reference Number Stage Chemotherapy Radiation dose Sequence Median F/U CR (%) Survival (%)
Rotman et al. (1990) 19 T2-4 5-FU ± MMC 60–65 Gy Conc 38 months 74–89 53.6
Russell et al. (1990) 34 5-FUx2 40 Gy Conc 18 months 81 64
Housset et al. (1993) 54 T2-4 CDDP ? 5-FUx2 24 Gy/8Fx/4 days Conc 27 months 74 59 (3 years)
? 20 Gy boost
Tester et al. (1996) 91 T2-4A MCV ) CDDPx2 39.6 Gy Neo ? Conc 75 62 (4 years)
Sauer et al. (1998) 184 T1-4 CDDP or Carbox2 45 Gy Conc 7.5 years 70–85 47–61 (5 years)
Birkenhake et al. (1999) 25 T3-4 CDDP ? 5-FUx2 59.4 Gy Conc 38 months 88 80
Radosevic-Jelic et al. (1999) 67 T3-4 Carbo weekly 65 Gy Conc 92.5 55 (5 years)
Hussain et al. (2004) 41 T3-4 5-FU ? MMCx2 55 Gy in 20Fx Conc 51 months 71 36 (5 years)
Rödel et al. (2002) 45 T1-4 5-FUx2 54–59.4 Gy Conc 31 months 87 67
Sauer et al. (1990) 67 T1-4 CDDPx2 50.4 Gy Conc 75 66 (3 years)
Danesi et al. (2004) 77 T2-4A MCV ) CDDP 69 Gy 3Fx/day Neo ? Conc 82 months 90.3 58.5 (5 years)
? 5-FU PVI
Kaufman et al. (2009) 80 T2-4A Taxol ? CDDP ) 64.3 Gy 2Fx/day Conc 49.4 months 81a 56 (5 years)
Gem ? CDDP (1.5/1.6 Gy/fx)
Sabaa et al. (2010) 104 T2-T3a Gem ? CDDP 60–65 Gy Neo ? Conc 71 months 78.8 59.4 (5 years)
a
Zietman et al. (2010) 93 T2-4A (a) Paclitaxel ? CDDP 64.3 Gy 2Fx/day Conc 36 months (a) 87 (a) 73 (4 years)b
Vs (1.5/1.6 Gy/fx) (b) 79a (b) 69 (4 years)b
(b) 5FU ? CDDP
) Gem ? CDDP
James et al. (2010) 458 T2-4A (a) 5-FU ? MMC Vs 64 Gy/32 fxs or Conc 40 months Not (a) 62 (2 years)
(b) No chemo 55 Gy/20 fxs (Neo was reported (b) 60 (2 years)
allowed) (4 years)b
CR complete response, conc concomitant, neo neoadjuvant
a
Includes Ta and Tcis
b
Rate of patients alive with intact bladder
P. Han et al.
Bladder Cancer
Italian trials in addition to a phase II EORTC and
recent RTOG trials (Housset et al. 1993; Danesi et al.
2004; Kaufman et al. 2009; Zietman et al. 2010;
Poortmans et al. 2008). Danesi and Arcangeli repor-
ted long-term results on a phase I/II trial in which 77
patients with invasive bladder carcinomas were trea-
ted with or without an initial two cycles of metho-
trexate, cisplatin, vinblastine (MCV) followed by
concomitant continuous infusion of 5-FU and con-
tinuous infusion of cisplatin and irradiation (Danesi
et al. 2004). Treatment consisted of three 100-cGy
fractions per day of radiation, 5 days per week, for a
total dose of 5000 cGy in 3.5 weeks. If required, due
to residual disease, a consolidative dose of 2000 cGy
was given in 1 week. A complete response rate of
90% was obtained. High-grade toxicity was uncom-
mon. With a median follow-up of 82.2 months, 44 of
65 patients who had an initial complete response were
still alive, and 33 (57.1%) of these patients remain
with a tumor-free bladder (61.5%). The 5-year over-
all, bladder-intact, tumor-specific, disease-free, and
cystectomy-free survival rates for all 77 patients were
58.5, 46.6, 75, 53.5, and 76.1% respectively. RTOG
reported on a phase I/II trial (99-06) with muscle-
invasive bladder cancer treated with TURT, twice-
a-day hyperfractionated EBRT with concomitant
chemotherapy consisting of taxol and cisplatin fol-
lowed by cisplatin and gemcitabine (Kaufman et al.
2009). After an induction course of chemoradiation
therapy, patients with disease less than T1 would
proceed with a consolidation course of chemoradia-
tion therapy. The study reported a postinduction
complete response rate of 81% with an actuarial 5-
year OS and DSS of 56 and 71%, respectively.
Recently, a multicenter randomized trial was reported
from the United Kingdom randomizing 458 patients
with T2–T4aN0M0 bladder cancer in a 2 9 2 facto-
rial design to either receive external beam radiation
therapy with or without mitomycin/5FU chemother-
apy (182 CRT vs 178 RT) with a further randomi-
zation of standard radiation treatment volumes versus
a reduced high-dose volume (108 sRT vs 111 rvRT,
respectively) (James et al. 2010). After a median
follow-up of 40 months, the authors reported an
improvement in locoregional disease-free survival
with a HR of 0.61 (P = 0.01) in favor of combined
chemoradiation. There was no significant overall
survival benefit with the addition of chemotherapy.
There was also no significant difference between the
811
two radiotherapy technique arms in terms of locore-
gional disease-free survival or overall survival
(Table 9).
Patients with T4 disease-have a poor survival no
matter what treatment is employed. Some investiga-
tors have examined multi-agent chemotherapy for
these patients. However, long-term results are not yet
available. Possibly, organ preservation chemoradia-
tion protocols may be an option.
Examining the role of neoadjuvant chemotherapy,
the South West Oncology Group trial 8710 (INT-
00800)—a phase-III trial of neoadjuvant methotrex-
ate, vinblastine, doxorubicin, cisplatin (MVAC) plus
cystectomy versus cystectomy alone in patients with
locally advanced bladder cancer—has shown
improved 5-year survival figures for patients treated
with the neoadjuvant chemotherapy with a median
survival of 77 months as compared to 46 months
without chemotherapy (P = 0.06) (Natale et al.
2001; Grossman et al. 2003). One of the largest
trials was reported by the Medical Research Council/
European Organization for Research and Treatment
of Cancer (MRC/EORTC) reporting on 976 patients
receiving either radical surgery or radiotherapy who
were randomized to receive either neoadjuvant cis-
platin-based chemotherapy or no chemotherapy,
showing a non-significant 5.5% survival benefit at
3 years with neoadjuvant chemotherapy (Interna-
tional collaboration of trialists on behalf of the
Medical Research Council Advanced Bladder
Cancer Working Party, et al. 1999). The authors
commented that a study of 3500 patients would be
needed to confirm his benefit. A meta-analysis was
performed by the Advanced Bladder Cancer Meta-
analysis Collaboration reporting on 11 trials con-
cluding that there is a significant improvement of
5% in 5-year survival year and of 9% disease-free
survival in 5 years with cisplatin-based chemother-
apy (Advanced Bladder Cancer Meta-analysis
Collaboration 2005).
5 Radiation Therapy Techniques
(General Description)
A wide variety of planning, dosing, and actual therapy
techniques is available in the treatment of bladder
cancer. The ultimate goal for each of these is optimal
treatment of the tumor, while at the same time
812
minimizing dose to normal tissues. Cystogram, CT,
and MRI studies can assist in identifying target vol-
umes (Rothwell et al. 1983; Graham et al. 2003).
A pivotal problem in radiotherapy for bladder cancer
is caused by organ motion. The bladder is a mobile
and hollow organ which changes in shape, size and
position during a course of irradiation, leading to
considerable variations in bladder wall and tumor
position. This organ motion severely limits the pre-
cision of radiotherapy for bladder cancer. New treat-
ment techniques and tools including adaptive
radiotherapy and kilo voltage cone-beam computed
tomography (CBCT) equipped linear accelerators
allow a substantial reduction of treatment volumes.
5.1 Target Volumes
In radiotherapy the clinical target volume (CTV)
generally consists of the gross tumor volume (GTV)
plus a margin for microscopical spread. Little is
known about the microscopical spread in bladder
cancer and the margins required to define the CTV for
whole bladder irradiation, or irradiation of the bladder
tumor only. Jenkins et al. compared preoperative CT
scans with the pathology of radical cystectomy
specimens of 80 patients with muscle-invasive blad-
der cancer (Jenkins et al. 2009). In patients with
radiological evidence of extravesical disease, the
CTV should comprise the outer bladder wall plus a
10-mm margin. In patients with no evidence of
extravesical disease on CT scans, the CTV should be
restricted to the outer bladder wall plus a 6-mm
margin. These recommendations would encompass
microscopic disease extension in 90% of cases. As for
bladder filling, potential advantage to treating with an
empty as opposed to full bladder is that patients are
more comfortable with an empty bladder and the
bladder location could be more certain. The disad-
vantage, however, is that less of the small bowel is
pushed out of the field of treatment when lymph
nodes are treated simultaneously (potentially resulting
in increased treatment morbidity). In the case of
partial bladder irradiation such as for a boost, it is also
possible to spare more normal bladder mucosa when
the bladder is full and the tumor volume maximally
displaced from uninvolved bladder mucosa.
The value of irradiation of the whole bladder has
never been properly established. Recurrences outside
P. Han et al.
the primary tumor area are believed to develop out of
existing pre-malignant lesions such as dysplasia and
carcinoma in situ (CIS). There are no data indicating
that irradiation of these lesions can prevent the
development of new tumors. Similarly, the value of
elective lymph node irradiation in bladder cancer has
never been properly investigated. Because of all this,
there exists no generally agreed consensus on the
clinical target volume (CTV) in bladder cancer
radiotherapy. Most treat the whole bladder plus tumor
to a dose of 60–65 Gy, while others prescribe
40–50 Gy in combination with a boost dose to the
tumor-bearing region only to 60–67.5 Gy. Some also
include the regional lymphatics up to the level of the
common iliac lymph nodes in their treatment fields up
to 40–50 Gy. More recently, there have been reports
of institutions treating only the tumor thus leaving the
healthy part of the bladder out of the treatment fields,
resulting in partial bladder irradiation (Pos et al.
2006a, b).
The delineation of a CTV for boost treatment or
partial bladder irradiation can be challenging.
Currently, in radiotherapy planning bladder tumors are
delineated on a CT scan. Several causes can lead to
inadequacies of bladder tumor delineation on CT. Due
to previous trans-urethral resection of the tumor
(TURT) or neoadjuvant chemotherapy there is often no
visible tumor left on the CT scan. Alternatively, the
TURT causes bladder wall edema what is hard to dis-
tinguish from tumor on the CT scan. Bladder folds and
unclear descriptions of the tumor location by the
referring urologist might also interfere with a reliable
delineation. Demarcation of the macroscopic tumor
borders with radio-opaque markers or contrast medium
during cystoscopy can be of help for tumor delineation.
Provided this tumor demarcation remains visible
throughout the whole course of external radiotherapy it
could also be used for image guidance (Mangar et al.
2007; Hulshof et al. 2007). Pos et al. and Søndergaard
et al. reported on the injection of the contrast medium
Lipiodol as a fiducial marker (Pos et al. 2009;
Søndergaard et al. 2010). Although the fiducial mark-
ers and the lipiodol deposits were primarily developed
for image-guided radiotherapy, they could also be of
use for bladder tumor delineation. Pos et al. described
that in their experience the tumor extension, or some-
times even the location of the lipiodol spots, was quite
different from what was thought based on the CT scan
and cystoscopy report (see Fig. 2).
Bladder Cancer
Fig. 2 The white line in a shows the delineated tumor on a
planning CT scan without lipiodol, a radiation oncologist and
urologist did the delineation. After the delineation the tumor was
5.2 Organs at Risk (Including Tolerance
Doses)
The critical structures with radiotherapy for bladder
cancer include the bladder itself, the rectum, and the
(small) bowel. To date, there are no studies that have
comprehensively reported the true three-dimensional
bladder dosimetry in relation to toxicity. As stated
before, the bladder is a highly mobile organ with
changes in shape, size, and volume during a course of
radiotherapy. Therefore, a single dose-volume histo-
gram is of limited value. A review on bladder toxicity
following radiotherapy and radiation dose-volume
effects is presented by Marks et al. (1995) and recently
by Viswanathan et al. (2010). Acute side effects that
occur during radiotherapy usually resolve within a few
months. For long-term side effects, one can discrimi-
nate between ‘‘global’’ injury of the whole bladder and
‘‘focal’’ injury to a smaller part of the bladder (Marks
et al. 1995). Symptoms of global injury include urinary
frequency, urgency, decrease in bladder capacity, and
cystitis. Symptoms of focal injury include bleeding,
ulceration, stone formation, and fistula. Global injury is
most common when the entire bladder is irradiated.
Among patients treated with interstitial implants, focal
injury dominates and global injury is not a major
problem. There is some evidence that a high dose per
fraction is associated with a greater complication rate.
Also pre-existing GU morbidity can lead to an increase
in late GU toxicity. Chemotherapy concurrent with
813
marked with lipiodol by the same urologist. The CT scan in b was
made shortly after the injection. Note the difference between the
location of the delineated target and the lipiodol spots
radiotherapy has not been shown to increase the risk of
long-term bladder complications.
The incidence of Radiation Therapy Oncology
Group Grade 3 or greater late bladder toxicity is up to
40% after whole bladder doses of 64–65 Gy in 30–36
daily fractions. Smaller volumes of the bladder might
be irradiated to a higher dose. In the absence of
reliable data, Viswanathan et al. suggest to use the
dose limits listed in the Radiation Therapy Oncology
Group (RTOG) 0415 study of prostate cancer which
included solid bladder constraints: no more than 15%
of the bladder volume to receive a dose [80 Gy, no
more than 25% of the bladder volume to receive a
dose [75 Gy, no more than 35% of the bladder vol-
ume to receive a dose [70 Gy, and no more than 50%
of the bladder volume to receive a dose [65 Gy.
Unfortunately, this is of little help for EBRT for
bladder cancer, as conventional doses fall easily
below all but one of these constraints. The only
advice that can be derived is to limit the whole
bladder dose to *64 Gy or to reduce the field size
after 40–50 Gy and boost only a part of the bladder.
For small bowel toxicity there is a dose-volume
relationship. For large pelvic treatment fields the total
dose is usually limited to approximately 50 Gy (2 Gy
equivalent) because of small bowel toxicity. For
patients treated to small volumes the toxicity only
occurs at relatively high doses. Small bowel compli-
cations following brachytherapy for bladder or gyne-
cological applications cancer are known to be rare.
814
Other critical structures in the pelvis concern include
the rectum. From prostate radiotherapy we have learned
that there is a volume effect for (late) rectal toxicity
(Michalski et al. 2010; Peeters et al. 2006). The volume
of rectum receiving C50–65 Gy is associated with the
risk of Grade C2 rectal toxicity or rectal bleeding.
Therefore, it is advisable to keep the volume of rectum
receiving C60 Gy below 35% (Michalski et al. 2010).
5.3 Treatment Schedules
There is a wide variety in dose and fractionation
schedules used for bladder cancer. The reported total
dose ranges for curative schedules range from 50 to
67.5 Gy with fraction sizes ranging from 1.8 to 3 Gy
(Majewski et al. 2004; Yavuz et al. 2003; Piet et al.
2008; Cowan et al. 2004; Chung et al. 2007; Horwich
et al. 2005). There is no clinical or radiobiological evi-
dence pointing to a certain direction. Slightly hypo-
fractionated schedules (fraction sizes up to 3 Gy) seem
to give similar outcomes when compared to more con-
ventionally fractionated regimens. Large fraction sizes
can result in a higher incidence of late morbidity and are
therefore more suitable for treatment with palliative
intent (Scholten et al. 1997). With the clinical data
currently available, a reliable estimation of the a/b ratio
for bladder cancer is not feasible (Pos et al. 2006a, b).
Clinical data on the influence of overall treatment time
on treatment outcome is scarce. A recently published
randomized phase-III trial comparing accelerated frac-
tionation with conventional fractionation showed no
improvement of the accelerated arm (Horwich et al.
2005). An analysis by Majewski et al. concluded that the
overall treatment time did not significantly influence
treatment outcome (Majewski et al. 2004). Several
groups reported that the total dose is probably associated
with treatment outcome thus suggesting that dose
escalation could be a valuable approach to improve the
outcome of bladder cancer patients after radiotherapy
(Majewski et al. 2004; Pos et al. 2006a, b).
5.4 Simulation/3D Conformal Planning
5.4.1 Traditional Simulation Procedure
Patient is typically simulated supine on a flat table top
using immobilization tools or in a pelvic immobili-
zation device. Oral contrast can be given prior to the
P. Han et al.
procedure to allow for bowel visualization. As pre-
viously discussed, the patient may be treated with
either an empty or full bladder. An optional procedure
includes the utilization of a mixture of air and contrast
that may also be injected into the bladder without
significantly distorting the resting bladder position.
If regional lymph nodes need to be treated in the
presence of a significant amount of low-lying small
bowel, the patient may be treated prone on a belly
board to minimize dose from the lateral treatment
portals. A conformal four-field box is typically uti-
lized. A conventional pelvic field will include the
entire bladder and regional lymph nodes with fields
extending from the mid-sacrum or the promontorium
(depending on the level of lymph nodes to be inclu-
ded) to the lower pole of the obturator foramen,
1–1.5 cm laterally beyond the inner rim of the bony
pelvis at its widest point and 2–3 cm anteriorly/pos-
teriorly to the bladder (Fig. 3). Especially in the
2D-era, beam energies did matter as is illustrated in
Figs. 4, 5 comparing 10 MV with 25-MV photon
energies. With the use of multiple conformal beams,
as with modern 3D-planning, all dose constraints can
be met even with lower photon energies.
5.4.2 CT-Based Virtual Simulation Procedure
The term ‘‘simulation’’ dates back to before the use of
CT-based treatment planning when the treatment
fields for patients were ‘‘simulated’’ or designed on
the patient under fluoroscopic guidance. The ultimate
goal of simulation is to develop a reproducible
treatment plan encompassing all target volumes while
minimizing the dose to normal structures. Nowadays,
in most modern RT departments, the simulator is used
only for simple palliative cases or for beam aperture
verification. In many departments, the simulator has
even been dismantled and all treatment preparation is
done CT-based.
The patient is most commonly placed in the supine
position with the arms bent over the chest wall. The
patient can also be positioned with both arms above
the head. The daily reproducibility of the patient’s
treatment setup is critical for the success of radiation
therapy, regardless of the disease site. Some prefer to
manufacture a ‘‘cradle’’ that ‘‘cradles’’ the patient’s
lower body in the same position each day by forming
a permanent impression of the pelvic region. The
custom-made cradle can be manufactured from any of
several commercially available materials. The same is
Bladder Cancer
Fig. 3 Radiation fields for initial pelvic field treatment.
a Anterior/posterior portal; b lateral portal. c Isodose curve
utilizing a four-field box technique with 180 cGy per fraction
valid for the filling of the bladder, for which clear and
unambiguous instructions should be given to the
patient, that are to be followed strictly during all
phases of treatment preparation and delivery.
815
Fig. 4 Composite isodose curves for whole pelvic irradiation
(isocentric four field with 20:8 weighting) to 50.4 Gy,
comparing 10-MV with 25-MV photons
Fig. 5 Isodose distributions for boost portion of treatment
delivered through opposed lateral fields, comparing 10-MV
with 25-MV photons. These do not reflect effects of beam width
improving device
After patient setup has been optimized, CT images
are acquired with the patient in the treatment position
through the pelvic region at a slice thickness of
preferably maximal 2.5–3 mm. Laser setup marks are
drawn on the patient at the time of simulation to aid in
positioning the patient on the treatment machine. The
CT images are then transferred to the three-dimen-
sional (3D) treatment planning system, where the
virtual simulation of the radiation treatment fields is
performed, after target volume delineation. With
computer-based virtual simulation, unlike with con-
ventional fluoroscopic simulation, the patient does not
need to be present during the generation and design of
the radiation treatment fields. Thus, CT-based treat-
ment planning can be performed in a treatment
816
planning workroom by the planning team consisting
of the radiation oncologist, dosimetrist, radiotherapy
technologist, and physicist after the patient left. 3D
CT imaging also allows 3D-planning of the combi-
nation of target volumes, which was not possible with
conventional simulator-based 2D treatment planning.
5.5 Organ Motion and Image Guidance
A pivotal problem in radiotherapy for bladder cancer
is caused by organ motion. The bladder is a mobile
and hollow organ with changes in shape, size, and
position during the course of irradiation, leading to
considerable variations in bladder wall and tumor
position (Pos et al. 2003, 2006a, b; Miralbell et al.
1998; Meijer et al. 2003; Muren et al. 2003; Fokdal
et al. 2004; Lotz et al. 2006; McBain et al. 2009a, b;
Lalondrelle et al. 2010). Because of the uncertainty in
target location, large CTV to PTV margins of 2–3 cm
are required to account for organ motion. Attempts to
control bladder volumes during radiotherapy with
drinking protocols, restricting fluid intake prior to
treatment or urinary catheter balloons, have so far not
been successful in preventing organ motion.
Mc Bain et al. assessed bladder motion for clinical
radiotherapy practice using cine-magnetic resonance
imaging (cine-MRI) (McBain et al. 2009a, b).
A 28-min cine-MRI was acquired on 10 bladder
cancer patients and 5 control participants. The time
period of 28 min approximately resembles the entire
time frame of a single radiotherapy fraction (from
bladder emptying to completion and including set-up
verification). Instructions were issued to refrain from
fluid consumption the hour preceding imaging and to
empty the bladder before imaging. For bladder cancer
patients, bladder wall displacements were larger than
for controls. The median bladder wall displacement
was 27 mm ranging from 6 to 58 mm.
Most treat bladders empty but others favor treat-
ment with full bladder. Theoretically, treatment with
an empty bladder protocol could provide a more
reproducible treatment volume than treatment with full
bladder. That would allow smaller margins and there-
fore could be an argument in favor of an empty bladder
protocol. There is currently insufficient data to support
either treatment with empty or full bladder with regard
to organ motion. Both show considerable bladder wall
and tumor displacements (Pos et al. 2003, 2006a, b;
P. Han et al.
Meijer et al. 2003; Muren et al. 2003; Fokdal et al.
2004; Lotz et al. 2006; McBain et al. 2009a, b;
Lalondrelle et al. 2010; Muren et al. 2007). Whether
with full or empty bladder, in the absence of image
guidance, CTV to PTV margins of 2–3 cm remain
therefore required to account for organ motion. These
large margins imply relatively large treatment volumes
in bladder cancer radiotherapy. For example, a bladder
CTV of 130 cm3 with a margin of 2 cm will result in a
PTV of approximately 600 cm3. In a study by Cowan
et al. the median PTV volume of the whole bladder
+1.5 cm margin was 815 cm3 varying from 490 to
1362 cm3 (Cowan et al. 2004). These large PTV vol-
umes imply irradiation of large volumes of healthy
tissue, with consequent and dose limiting toxicity in
the bladder cancer population that is generally elderly
or having significant co-morbidity. For this reason,
bladder cancer is an ideal candidate for image-guided
radiotherapy (IGRT).
6 Image-Guided Radiotherapy (IGRT)
IGRT in bladder cancer has specific challenges. Given
the large day-to-day variations in bladder wall and
tumor position, bladder cancer would be an ideal
candidate for online image guidance. A crucial step in
online IGRT is imaging of the treatment target
immediately before treatment so one can adapt the
treatment portals to possible changes in target position,
volume, etc. Unfortunately, the bladder and bladder
tumors are not visible on portal imaging devices. Three
dimensional ultrasound systems to track the location of
the bladder as used in prostate cancer radiotherapy are
not suitable either to reliably locate the bladder and the
bladder tumors. The current CBCT pelvic image
quality is insufficient for automated image guidance.
Manual contouring of bladders on CBCT scans is time
consuming and delineation of bladder tumors on
CBCT scans is challenging. In the following para-
graphs, several IGRT strategies for whole and boost or
partial bladder RT will be discussed.
6.1 IGRT: Whole Bladder Radiotherapy
For each patient several treatment plans can be made
by simulating individual variations of bladder filling.
The variations in PTV and subsequent treatment plans
Bladder Cancer
can be obtained with different bladder volumes
(Lalondrelle et al. 2010) or with PTVs using variable
margins to the empty bladder (McBain et al. 2009a, b;
Lalondrelle et al. 2010). Ultrasound may provide a
practical daily verification tool to identify patients with
prominent volume changes for the selective applica-
tion of the more advanced image guided radiotherapy
techniques (McBain et al. 2009a, b). A CBCT made
immediately before each treatment fraction can be
used to select the most appropriate treatment plan of
that day. Lalondrelle et al. report on a method, which
they called Adaptive Predictive Organ Localization
(A-POLO) (Lalondrelle et al. 2010). For A-POLO,
patterns of individual bladder filling were obtained
with repeat planning CT scans at 0, 15, and 30 min
after voiding. A need for adaptive planning was dem-
onstrated for 51% of the fractions and 73% of the
fractions would have been delivered correctly using
A-POLO. Burridge et al. proposed several PTVs cre-
ated with a variable cranial margin of 5, 10, and 15 mm
(Burridge et al. 2006). This strategy worked for 15 out
of 20 patients. In two patients, the CBCT quality was
too poor to select a fitting plan and in those cases the
15 mm margin plan was selected. Three patients had
systematically smaller or larger variations which
required a re-planning. Mangar et al. showed that the
use of the 10 mm margin treatment plan ensured
complete target coverage if the volume changes of the
bladder were limited to 50% compared to the planning
scan volume (Mangar et al. 2008).
6.2 IGRT: Boost or Partial Bladder
Radiotherapy
IGRT for boost or partial bladder irradiation has some
specific challenges. One can delineate a bladder
tumor on a planning CT scan but mostly the tumor
cannot be reliably identified on ultrasound, MV
imaging or CBCT. Demarcations of the tumor with
fiducial markers or contrast medium (lipiodol) are
promising (Mangar et al. 2007; Hulshof et al. 2007;
Pos et al. 2009; Søndergaard et al. 2010). Provided the
demarcations remain visible throughout the whole RT
treatment these can be used for true online IGRT.
Pos et al. reported on offline adaptive radiotherapy
using repeat CT scans (Pos et al. 2006a, b). On the
planning CT scan the bladder tumor was delineated
(GTVCONV) and expanded uniformly with a 2 cm
817
GTV2 GTVART
GTV1
GTV3
Fig. 6 Illustration of the construction of the GTVART
margin (PTVCONV). The first 2 weeks of treatment
patients were treated to the PTVCONV. During the first
treatment week, 5 daily CT scans were made shortly
before or after treatment and the bladder tumor was
delineated again (GTV1-5). In the second week a
volume was constructed encompassing the GTVs on
the original planning CT scan and the 5 subsequent
CT scans (GTVART) (see Fig. 6). The GTVART was
expanded with a 1 cm uniform margin for the con-
struction of a PTVART. Starting in the third week
patients were treated to PTVART. Repeat CT scans
were used to evaluate treatment accuracy. The offline
adaptive procedure proved to be effective with ade-
quate coverage of the GTV by the 95% isodose line
and reduction of the treatment volumes by 40%
compared to the original plan.
6.3 Fiducial Markers
Fiducial markers or deposits of contrast medium in or
around the bladder tumor can be of help in identifying
the location of a bladder tumor during volume
delineation as well as for position verification.
Mangar et al. and Hulshof et al. have reported on
fiducial markers for bladder tumor localization
(Mangar et al. 2007; Hulshof et al. 2007). They both
use a rigid cystoscope to insert the fiducials into the
bladder wall. The use of a rigid cystoscope for tumor
demarcation by fiducial markers has several disad-
vantages. The most significant drawback is that the
procedure is rather painful, for which reason Mangar
et al. perform the implantation under a short anes-
thetic and Hulshof et al. use a 10 min instillation of
lidocaine before implantation of markers. Another
problem is the loss of fiducial markers during the
course of radiotherapy. In the study by Hulshof et al.,
about half of the markers had disappeared with a
818 P. Han et al.

median interval of 11.5 days after the implantation

(Hulshof et al. 2007). There are several reports on the
injection of the contrast medium Lipiodol as a fiducial
marker (Pos et al. 2009; Søndergaard et al. 2010;
Chai et al. 2010). In this procedure small deposits of
lipiodol are injected around the visible tumor with a
flexible needle through the working channel of a
flexible cystoscope. Because the injections are done
with a flexible cystoscope the procedure is comfort-
able for the patients and no analgesics are needed.
However, there remain quality issues to resolve with
the injection of lipiodol deposits in the bladder wall.
The lipiodol blurs when too much is injected and in a
few patients there was no lipiodol visible on the CT
scan, although lipiodol was injected. Both the fiducial
markers and lipiodol deposits have shown to be of
value for (online) image guidance. Currently several
groups have techniques under development.

7 Intensity Modulated Radiotherapy

(IMRT)

With the aim of targeting tumors and minimizing the

dose delivered to normal surrounding tissues, IMRT
techniques have also been investigated in the field of
bladder cancer. Utilizing an inverse planning algo-
rithm, varying intensity beam profiles can be delivered
with each gantry angle to achieve a highly conformal
isodose plan. IMRT also may allow for dose escalation
to the target volume or to the primary tumor site alone
(simultaneous integrated boost), leading to a differen-
tial dose delivery without increasing treatment mor-
bidity. Redpath et al. reported that IMRT with the use
of IGRT is acceptable (Redpath and Muren 2006). The
authors also reported on the feasibility of simultaneous
boosting of the bladder tumor using IMRT (Muren
et al. 2006). Recently, Sondergaard et al. reported on
IMRT to treat the bladder and the pelvic lymph nodes
(Sondergaard et al. 2009). The authors used a simul-
taneous integrated boost technique treating the bladder
and pelvic lymph nodes to 60 and 48 Gy, respectively.
The author demonstrated a statistically by significant
normal tissue sparing using IMRT for the bowel, bowel
cavity, rectum, and femoral heads. In Fig. 7, a com-
parison is displayed between a four-field box technique
and IMRT. Figures 8 and 9 demonstrate a 3D recon-
struction of the isodose distribution using a five-field
conformal radiotherapy and IMRT, respectively.
Fig. 7 a Isodose distribution for a four-field box technique
prescribed to 150 cGy to the 100% isodose to treat the bladder
tumor (a hyperfractionation scheme was used). b Isodose
distribution for an IMRT plan treating the same target. c The
dose-volume histogram (DVH) which compares the two plans.
Note that the dotted lines representing the IMRT plan have
better sparing of the normal tissues while maintaining coverage
of the tumor
Since there can be significant variability in tumor
position, simultaneous implementation of IGRT is
crucial. Especially treatment plans incorporating
pelvic lymph node coverage may pose a special
challenge if a shift has to be made based on the
bladder positioning. Van Rooijen et al. reported on
the utilization of two IMRT plans, one for the elective
lymph nodes and healthy portion of the bladder and
another for the bladder tumor (van Rooijen et al.
2010). The bladder tumor was delineated with Lipi-
odol, which remained visible throughout the entire
course of treatment. The authors concluded that
Bladder Cancer
Fig. 8 Five-field 3D conformal treatment plan. Excellent
bladder coverage with minimal rectal dosing. (Courtesy of
East Carolina University Department of Radiation Oncology)
Fig. 9 Multi-segment intensity modulated (IMRT) treatment.
Note dramatic dose fall off of dose (red to green) to
surrounding structures and homogeneous dose distribution
(red volume) to the bladder. (Courtesy of East Carolina
University Department of Radiation Oncology)
independent shifts for the elective fields and for the
tumor boost fields give the best target coverage
without introducing additional hot spots.
8 Brachytherapy
Brachytherapy for muscle-invasive bladder cancer is
used as a way to preserve the bladder function. Local
recurrence rates of 34–78% were reported after only a
TURT or partial cystectomy (Herr 2001; Kuczyk
et al. 2002). Because of these high recurrence rates
819
bladder conserving surgical procedures did never
become an accepted treatment option apart for some
highly selected cases. By adding radiotherapy to a
conservative surgical treatment recurrences can be
markedly reduced. Brachytherapy has the advantage
that the radiation therapy can be limited to the tumor
area and sparing most of the healthy bladder wall and
other organs including the small intestine. This tech-
nique was firstly described by Breur et al. in 1956 [ref
extra]. It was the pioneering work of van der
Werf-Messing in the 1980s of the last century that
established brachytherapy for bladder cancer (Van der
Werf-Messing et al. 1983a, b; Van der Werf-Messing
and van Putten 1989). Despite acceptable local
control rates for T2 and T3 tumors this treatment
never got acceptance in other countries beside
The Netherlands, France, and Belgium.
Brachytherapy is only indicated for small-sized
solitary tumors. The maximum tumor size that can be
implanted is 5 cm. A tumor thickness of 5–12 mm can
be implanted with a single layer implant. In selected
cases small T3 tumors with a tumor thickness of more
than 12 mm can be implanted with a double layer
implant. Tumor invasion into the bladder neck is a rel-
ative contraindication for implantation, because this
area is often not well accessible for the implantation
needles. However, with a so-called boomerang device
(a hollow needle that is available in a wide range of
curvatures) areas deep in the pelvis can be reached to
perform the implantation (Van Limbergen and Mazeron
2002). Caution should be taken with the use of after
loading machines, because due to the strong curvature
of catheters the passage of the source can be blocked.
Bladder implantations are performed together with
an urologist. The laparotomy, cystostomy, and some-
times a partial cystectomy is performed by the urolo-
gist, while the radiation oncologist does the bladder
wall implantation. It is not necessary to perform the
surgical procedure at the institute with brachytherapy
facilities, because in general the patient can be trans-
ported the day after surgery from the community hos-
pital to the radiation oncology institute. The policy
toward the need for performing a partial cystectomy at
the time of the implant varies between the countries.
In The Netherlands, a partial cystectomy is generally
only performed if the tumor is too thick for a single
layer implant or if the tumor is located in the dome of
the bladder or in a diverticle. In general, the implanta-
tion is performed after a preceding TURT of the tumor
820
Fig. 10 Surgical procedure for brachytherapy. The bladder
tumor is clearly visible. a Three hollow needles are introduced
through the boost area; b Tubes for afterloading are brought in
followed by external beam radiotherapy to the entire
bladder with or without the pelvic lymph nodes.
In France a partial cystectomy prior to the implantation
is a more common procedure. The policy toward a
lymph node dissection also varies between the
European countries. In The Netherlands it is common
practice to inspect and palpate the lymph node areas
with removal of suspicious lymph nodes only. Our
French colleagues prefer to perform a homolateral iliac
node dissection for laterally located tumors and a
bilateral dissection for centrally located tumors.
Because of the increased risk for toxicity, routine lymph
node dissection was abandoned in Amsterdam as well as
in most other Dutch institutes (Blank et al. 2007).
Modern brachytherapy for the bladder is per-
formed with the plastic tube technique. The operation
starts with a median suprapubic laparotomy or a
Pfannenstiel incision. The bladder is opened by a
P. Han et al.
Fig. 11 Simulator X-ray of bladder implant using three
catheters with the use of an intravesical spacer ensuring
parallelism and delineation of the clinical target volume
cystotomy procedure in order to be able to perform
the implantation. Hollow steel needles are introduced
in the bladder wall to enable the implantation of the
flexible plastic tubes (Fig. 10). The tubes exit the
bladder and are thereafter led through the abdominal
wall. The implantation is performed according to the
Paris-system rules, based on which the thickness of
the CTV determines the spacing between catheters.
The number of catheters and the active source length
should be chosen as such to cover the CTV com-
pletely. Usually two to three plastic tubes suffice.
Figure 11 displays a case where after a TURT the scar
with a 1 cm margin is implanted for the clinical target
volume (CTV). No extra margin is used for the
planning target volume (PTV), because geometric
uncertainties in brachytherapy are very limited. If a
partial cystectomy was performed, the implantation
will cover the dissection planes with the needles
generally placed perpendicular to the scar. Also then,
a 1 cm margin is added at both sides of the scar at the
level of the original tumor site as CTV. The target
length is marked by metallic clips at the entrance and
exit points of the tubes at the outer side of the bladder
wall for identification of the length of the CTV. An
intravesical spacer can be used to ensure parallelism
and definition of target length (Fig. 11) (Van’t Riet
et al. 1997). As the intravesical spacers are placed at
the border of the CTV, they can also be used for
identification of the CTV on simulator X-ray films or
the CT-scan. For easy removal after treatment the
Bladder Cancer
Fig. 12 Example of an implanted bladder. CT images dem-
onstrating axial (a) and sagittal (b) views
intravesical spacers are sutured to the Foley balloon
catheter. Buttons on the abdominal skin fix the cath-
eters at that level on both the entrance and exit sides.
The usual operation time is between 1.5 and 2.5 h.
One or two days after the implantation the patient
is transported to the radiation department. Recon-
struction of the implant is done by two orthogonal
X-ray films made with the simulator or by recon-
struction on a CT-scan (Fig. 12). For treatment
planning the Paris-system rules are also applied.
Brachytherapy can be delivered as a sole radiation
treatment or as a boost to external beam radiotherapy.
Low grade-low stage tumors (pT1 G1-2, pT2
G1-2 B 3 cm) are treated with low dose preoperative
radiation (e.g., 3 9 3.5 Gy) to the entire bladder to
prevent tumor cell implantation in the surgical wound
(Van der Werf-Messing et al. 1983a, b), followed by a
dose of 60–65 Gy low-dose rate (LDR) or pulsed-
dose rate (PDR) with brachytherapy. High grade and
high stage tumors (pT1 G3, pT2 G1-2 [ 3 cm, pT2
G3, small pT3) are generally treated with 40 Gy
external beam radiotherapy to the pelvis followed by
a brachytherapy boost of 25–32.5 Gy. In case of a
821
partial cystectomy a lower dose can be given (50–
60 Gy total dose).
The source and catheters are removed as soon as
brachytherapy is finished. After removal of the but-
tons the catheters are removed by cutting one side at
the level of the skin and pulling the other side through
the abdominal wall. If intravesical spacers are used,
these can be removed by withdrawing the Foley bal-
loon catheter, in which case a new Foley balloon
catheter is introduced to ensure urine passage. Total
hospitalization time varies between 1 and 3 weeks
depending on post-surgical recovery.
Local control rates are nicely illustrating the ability
to preserve the bladder with brachytherapy: the
reported figures are 73–89% local control rate at
5 years with about half of the recurrences (2–14%)
occurring elsewhere in the bladder (Van der Werf-
Messing et al. 1983a, b; Van der Werf-Messing and
van Putten 1989; Blank et al. 2007; Pernot et al. 1996;
Rozan et al. 1992; Mazeron et al. 1988; Gérard et al.
1985; van Onna et al. 2009; de Crevoisier et al. 2004).
Rozan et al. found that local recurrences elsewhere in
the bladder appear to occur after a longer interval time
(4–9 years), compared to true local recurrences that
originate often within 1 year after treatment (Rozan
et al. 1992). However, van Onna et al. could not con-
firm a difference in relapse time between true and
elsewhere recurrences in the bladder (van Onna et al.
2009). This underlines anyway the importance of long-
term cystoscopic evaluation in the case of bladder
conserving treatment.
Because of the lack of randomized studies com-
paring cystectomy with conservative treatment with
brachytherapy some investigators performed a retro-
spective study for comparison. No differences in
disease-free survival or overall survival were found in
these studies (Nieuwenhuizen et al. 2005; van der
Steen-Banasik et al. 2009). Five and 10 year overall
survival is 67–73% and 49–55% respectively,
reflecting to some extent the older age of the group of
conservatively treated patients (Blank et al. 2007;
Rozan et al. 1992; van Onna et al. 2009).
Few severe late complications are reported after
brachytherapy for bladder cancer. Blank et al. found in
a large cohort with a median follow-up of 5 years no
incidence of necrosis or fistula (Blank et al. 2007). Late
sequelae that are sometimes observed are painful
radiation cystitis and reduced bladder capacity (Blank
et al. 2007; van Onna et al. 2009). Blank et al. found,
822
in a series of 55 evaluable patients, a stable or increased
bladder capacity in 49 cases (Blank et al. 2007).
In many occasions a superficial ulcer can be detected
on cystoscopic evaluation up to several months after
brachytherapy with few or no clinical symptoms. The
treatment should be conservative, avoiding a biopsy
unless the lesion is suspect for recurrent tumor.
In general these radiation ulcers heal with time.
Pos et al. reported on their experience with high-
dose rate (HDR) brachytherapy for bladder cancer.
An inferior outcome on local control and an increase
in late toxicity were observed (Pos et al. 2004). HDR
brachytherapy for bladder cancer should therefore be
discouraged.
In a large retrospective study Rozan et al. found
that the majority of patients could preserve their
bladder function and that in only 14 of the 205 cases a
salvage cystectomy was performed (Rozan et al.
1992). In the van Onna’s study the bladder preser-
vation rate was 89% (van Onna et al. 2009).
In view of the good results obtained with brachy-
therapy for bladder cancer this conservative approach
should be encouraged for patients with a solitary
muscle-invasive T1-2 bladder tumor of less than 5 cm
who want to preserve their bladder function. Also
patients who are not fit for major surgical therapy can
be candidates for this treatment. Intensive collabora-
tion between urologists and radiation oncologists is of
utmost importance to perform this treatment for a
correctly selected group of patients.
9 Future Directions
Considerable advancements have been made in the
treatment of bladder cancer. With the development of
diagnostic tools utilizing molecular markers as prog-
nostic factors and for detection, treatment consisting of
possible combinations of intravesicular chemotherapy
or immunomodulators, various surgical procedures,
systemic therapy, and several forms of radiation ther-
apy might become individualized to the patient with
his/her specific tumor characteristics. The treatment of
bladder cancer needs a multidisciplinary approach to
optimize the treatment of the disease while maintain-
ing the best quality of life. For bladder-sparing pro-
cedures, the development of brachytherapy, IGRT,
IMRT, and the use of fiducial markers offers significant
promise to radiation treatment. However, further
P. Han et al.
investigations toward searching for optimal fraction-
ation schemes, techniques, and systemic agents remain
to be continued. As an example, RTOG is currently
accruing patients in a prospective trial utilizing a
hyperfractionated regimen with 5FU and CDDP or
once a day radiation treatment with gemcitabine
(RTOG 0712). In addition, targeted therapy has gained
significant promise in the treatment of other various
malignancies. Epidermal Growth Factor Receptors
(EGFR) have been reported to be overexpressed in
bladder cancers (Nguyen et al. 1994; Latif et al. 2003;
Neal et al. 1990). The use of trastuzumab has already
been reported for advanced bladder cancer with
concomitant chemotherapy (Hussain et al. 2007).
Elaborating on this, RTOG is currently conducting a
trial for muscle-invasive bladder cancer treated with
paclitaxel and external beam radiation therapy with or
without trastuzumab. In addition, the role of radiation
therapy in the management of T1 bladder cancer is
being further defined. RTOG is accruing patients for a
phase II trial for T1 bladder cancer using radiation
therapy with concurrent chemotherapy (cisplatin). The
evolving role of radiation therapy with concomitant
continuous 5FU infusion ± mitomycin ± targeted
therapy continues to grow for bladder cancer with
T1–T4 disease. Further development and research in
targeted therapies are awaiting which may continue to
improve oncological outcomes in the treatment of
bladder cancer.
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 Radiation Therapy for Cervical Cancer
Kathryn E. Dusenbery and Bruce J. Gerbi
Contents
1 Natural History of Cervical Cancer and Patterns
of Spread................................................................... 829
2 Workup and Staging ............................................... 830
3 General Management .............................................. 831
4 Radiotherapy Techniques ....................................... 832
4.1 General Description................................................... 832
5 Simulation/CT Simulation Procedures.................. 835
5.1 Target Volume and Organs at Risk.......................... 836
5.2 Dose Prescription....................................................... 836
6 LDR Brachytherapy ................................................ 838
6.1 Equipment .................................................................. 838
6.2 LDR Procedure .......................................................... 838
6.3 Milligram Hour.......................................................... 839
6.4 The Manchester System ............................................ 840
6.5 The International Commission on Radiographic
Units and Measurements ........................................... 842
6.6 University of Minnesota............................................ 845
6.7 Postoperative Radiotherapy....................................... 846
6.8 Dose to Bladder and Rectum .................................... 846
7 Sequelae .................................................................... 847
8 Results ....................................................................... 848
9 Quality Management Program .............................. 849
10 Conclusion ................................................................ 850
References.......................................................................... 850
K. E. Dusenbery (&)  B. J. Gerbi
Department of Therapeutic Radiology-Radiation
Oncology, University of Minnesota Medical School,
MMC 494420 Delaware St. S.E, Minneapolis,
MN 55455, USA
e-mail: dusen001@umn.edu
S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_279, Ó Springer-Verlag Berlin Heidelberg 2012
Abstract
Carcinoma of the uterine cervix is a highly curable
malignancy. Surgery is often used for early stages.
For patients with more advanced disease the
combination of external beam therapy with radio-
sensitizing chemotherapy combined with intracav-
itary radiotherapy offers excellent local control and
disease free survival but requires meticulous
attention to detail to ensure low complication rates
1 Natural History of Cervical Cancer
and Patterns of Spread
Cervical cancer is the third most common gynecological
malignancy after ovarian and uterine corpus cancers. In
the United States, in 2005, there were 12,200 new cases
and about 4,200 deaths (Greer et al. 2010). Worldwide, it
is an enormous health problem, with 500,000 women
dying each year. In the United States, largely because of
the widespread use of the Papanicolaou (Pap) smear,
often patients are diagnosed with early and pre-invasive
lesions and are reliably cured with surgery alone
(Herzog 2003; Waggoner 2003). The peak age at diag-
nosis is around 47 years; however, 50% of patients are
under the age of 35 years when diagnosed. Only 10% of
patients are older than 60 years (Herzog 2003; Wagg-
oner 2003). Cervical cancer is associated with known
risk factors including a higher number of sexual partners
([4), first intercourse at an early age (\16 years), his-
tory of genital warts, and lower social economic class
with poor access to health care (Mendenhall et al. 1984;
Chen et al. 1999; Karolewski et al. 1999; Gasinska et al.
2002; Dunst et al. 2003).
829
830
More than 90% of cervical squamous cell cancers
contain DNA evidence of human papilloma (HPV)
virus, acquired through sexual activity. Certain types
of HPV are particularly oncogenic; these include
types 16, 18, 31, 33 and 35, 68, 52, 59, 45, 53, 66,
73, mm4, mm8, and mm7 and are often associated
with moderate to severe dysplasia or carcinoma
in situ (Au et al. 2003; Hernandez-Hernandez
et al. 2003; Dunleavey 2004; Fey and Beal 2004).
High-risk subtypes of HPV produce viral proteins E6
and E7 thought to be important for malignant
transformation by binding and inactivating products
of the retinoblastoma gene, which ultimately allow
unchecked cell-cycle progression in cells infected
with HPV16 or 18 (Harima et al. 2002). Tobacco
smoking as well as possibly second hand exposure to
smoke is a independent risk factor for cervical dys-
plasia and cancer. Immunosuppression from any
cause [organ transplantation, acquired immunodefi-
ciency syndrome (AIDS), chronic steroid usage]
increases the risk of cervical cancer (Waggoner
2003).
2 Workup and Staging
The Pap smear is recommended for all sexually active
women or women after the age of 18 years. Pap
smears are generally reported as normal, ascus
(atypical squamous cells of uncertain significance),
ascus-h (atypical cells of uncertain significance:
cannot rule out high grade), low-grade squamous
intraepithelial lesion (lgsil), high grade squamous
intraepithelial lesion (hgsil) or carcinoma (Lieu 1996;
Mashburn and Scharbo-DeHaan 1997; Perlman
1999). Any Pap smear that is not normal requires
further evaluation, which can range from simply
repeating it, to testing for the presence of high-risk
HPV subtypes, or to colposcopy and directed biop-
sies, depending on the clinical situation.
If a visible lesion is identified by means of pelvic
examination, a Pap smear is not recommended and
these patients should have a biopsy. The most com-
mon invasive cancer by far will be a squamous cell
cancer, diagnosed in at least 80% of patients.
Adenocarcinomas make up about 20% of cervical
cancers, and less than 1% of patients have rare types
such as a true small cell (neuroendocrine), clear cell,
melanoma, or lymphoma.
K. E. Dusenbery and B. J. Gerbi
Table 1 Staging workup for cervical cancer
Physical examination
Lymph node assessment (supraclavicular, inguinal)
Pelvic examination
Radiographic studies
Chest X-ray
Intravenous pyelogram or CT scan of abdomen and pelvis
Barium enema
Laboratory evaluation
Creatinine
Hemoglobin
Procedures
Cervical biopsy
Cystoscopy
Proctoscopy
Other studies [not allowed for clinical (FIGO) staging]
CT scan or MRI
PET scan
Ultrasound
Bone scan
Extraperitoneal lymph node sampling
Once a biopsy reveals the diagnosis of invasive
cervical cancer, the staging workup follows (Table 1).
In general, cervical cancers are clinically staged. The
FIGO staging system (Table 2) is the most widely
used, and the cornerstone of the system is a thorough
careful pelvic examination, often done under general
anesthesia. Adjuncts to the pelvic examination
include either an intravenous pyelogram (IVP) or
computed tomography (CT) scan with intravenous
(IV) contrast to determine whether there is ureteral
obstruction and hydronephrosis. Additionally, a chest
X-ray is usually part of the initial workup.
If pelvic or para-aortic lymph nodes appear
enlarged, they should be investigated by means of fine-
needle aspiration or retroperitoneal node dissection. If
positive nodes are found, treatment can be individually
designed to encompass known sites of disease.
More recently, the use of PET imaging (Fig. 1) has
been shown to improve detection of pelvic and para-
aortic lymph node disease (Greven et al. 1999; Mutic
et al. 2003; Tsai et al. 2004). In a series of 32 patients
who underwent PET imaging prior to lymphadenec-
tomy, PET had a 75% sensitivity and 92% specificity
for predicting paraortic nodal metastasis and 100%
Radiation Therapy for Cervical Cancer
Table 2 FIGO staging
Stage 0 carcinoma in situ
Stage I confined to the cervix
IA microscopic tumor
IA1 no more than B3 mm of invasion, no wider than
7 mm
IA2 more than [3 mm but B5 mm of invasion, or wider
than 7 mm
IB visible tumor
IB1 tumor B4 cm
IB2 tumor greater than 4 cm
Stage II tumor beyond cervix, but not to pelvic side wall
IIA vaginal involvement but not to lower two-thirds of vagina
IIB parametrial involvement, but not to pelvic side wall
Stage III
IIIA vaginal involvement to lower third of vagina
IIIB extension to the pelvic side wall or hydronephrosis
Stage IV
IVA spread to bladder or rectum
IVB spread to distant organs
sensitivity and specificity in the pelvis (Rose et al.
1999). In a comparison of PET with MRI for lymph
node detection in 35 patients with stage IB/IIA
cervical cancer the sensitivity/specificity of PET was
91/100%, compared to 73/83% for MRI (Reinhardt
et al. 2001). Singh et al. (2003) demonstrated PET
imaging in the periaortic nodal chains in patients with
FIGO IIIB disease to correlate with survival. Addi-
tionally, persistence of PET positivity after comple-
tion of therapy may portend a worse prognosis and
may be useful in designing follow-up treatment for
high-risk patients (Grigsby et al. 2004).
There are many known prognostic factors in
cervical cancer. The FIGO stage and volume of tumor
are the most obvious. Other factors that affect the
prognosis include the depth of stromal invasion which
is associated with a higher incidence of metastasis to
pelvic lymph, higher grade of tumor, and whether
there is unilateral or bilateral hydronephrosis. At the
University of Minnesota we have routinely used
extraperitoneal lymph node sampling to determine the
extent and spread of cervical cancer. In our experi-
ence, the presence of grossly positive pelvic nodes
that are unresectable is a very poor prognostic factor,
whereas, patients who have only microscopic spread
831
to their pelvic nodes do as well as patients who have
grossly positive nodes that can be resected (Cosin
et al. 1998). Whether this reflects tumor biology or is
actually therapeutic is unknown. Other prognostic
factors include anemia at diagnosis, number of posi-
tive nodes, and patient age.
3 General Management
Once the diagnosis and staging workup are complete,
a management plan can be outlined. For asymp-
tomatic patients with normal appearing cervix, the
diagnosis is usually made after conization. If there is
less than 3 mm of invasion below the basement
membrane (stage IA1), the risk of pelvic nodal
spread is less than 1%. The treatment options include
a simple hysterectomy or, if preservation of fertility
is desired, cervical conization and careful follow-up.
If the focus of invasion extends 3 mm or more or if
there is lymph vascular space involvement (stage IA2),
the risk of nodal spread increases to 2–8% and most
oncologists recommend a (modified) radical hyster-
ectomy with pelvic lymphadenectomy or definitive
radiotherapy. The advantage of a surgical approach is
the possible preservation of ovarian function, the fact
that the entire uterus is removed for analysis, and the
lack of long-term radiation side effects. Alternatively,
patients with FIGO stage-I disease can be managed
with definitive radiotherapy. Advantages of this
approach include the lack of a need for prolonged
general anesthesia, especially if high-dose-rate (HDR)
brachytherapy is to be used. The only randomized trial
to address this issue was reported by Landoni et al
(1997). In their study, patients with FIGO stage IB or II
were randomized to either radical hysterectomy fol-
lowed by tailored radiotherapy or definitive radiother-
apy. In that trial of over 300 patients, the disease-free
survival and overall survival were equivalent. How-
ever, in the patients in the surgery arm, there was an
excessive complication rate of 20%. Critics of this
study have pointed to the high rate of needing postop-
erative radiotherapy in the surgical arm and the lack of
concomitant chemotherapy in the radiation therapy arm
as weaknesses of this study. It is however, the only
recent randomized study to look at this important
question.
For patients beyond stage I, the management is
generally definitive radiotherapy with both external
832
Fig. 1 a Coronal view PET CT scan demonstrating the extent of the tumor into the uterine corpus as well as pelvic and low periaortic
adenopathy. b Axial view PET CT demonstrating pelvic adenopathy on the right as well as abnormal PET activity in the cervix
beam and brachytherapy. Low-dose-rate (LDR)
brachytherapy has the longest experience record but
recently, HDR brachytherapy has become widely
available. There are advantages and disadvantages of
each (Table 3) and randomized trials comparing these
two modalities show that in trained hands the acute
and long-term side effects are roughly equivalent
(Table 4).
The addition of cis-platinum-based chemother-
apy during the course of definitive radiotherapy for
patients with IB2-IVA disease has been shown to
improve outcomes (Lukka et al. 2002; Nag et al.
2002). Five randomized trails have recently dem-
onstrated significant improvement in local control
and survival when concurrent chemotherapy was
added to radiation therapy in patients with early-
stage disease and high-risk for recurrence, as well
as in patients with advanced-stage disease (Keys
et al. 1999; Rose et al. 1999; Whitney et al. 1999).
Four of these studies evaluated concurrent chemo-
therapy combined with definitive radiotherapy
(Table 5).
K. E. Dusenbery and B. J. Gerbi
4 Radiotherapy Techniques
4.1 General Description
The design of the radiation treatment program
depends on the extent and volume of the tumor. Most
patients receive a combination of external beam
treatments (EBT) and brachytherapy, although very
early lesions may be treated with brachytherapy
alone. The number of external beam treatments rel-
ative to brachytherapy can be determined by general
guidelines, although experience provides optimal
treatment determinations. In general, advanced
tumors require more external beam therapy. This is
in part because the periphery of large tumors is
inadequately treated with brachytherapy due to the
rapid decrease in dose at a distance from the implant.
To treat advanced tumors, the majority of the
external beam therapy is given prior to initiating
brachytherapy to shrink the tumor. This leads to a
technically superior brachytherapy application and
Radiation Therapy for Cervical Cancer
Table 3 Advantages of low- and high-dose-rate brachytherapy
Low-dose-rate advantages
Long history of use
Ability to predict rate of late complications
Improves chances of catching tumors in sensitive phase of
cell-cycle
Longer treatment times allow for leisurely review of and
potential modifications to the treatment plan prior to the
delivery of a significant portion of treatment
Favorable dose rate effect on repair of normal tissues
Infrequent replacement and calibration of sources because
of long isotope half-life
High-dose-rate advantages
No short- or long-term confinement to bed
No indwelling bladder catheters and risk of bladder
infection
Not labeled ‘‘radiation risk zone’’ to relatives, visitors and
staff
Avoidance of several anesthesias (possibly)
Maintain position of the sources during the brief treatment
Ability to retract sensitive structures (rectum) during short
treatment time
Patient preparation simpler
Ability to treat greater patient loads (high output of
patients on each machine)
Ease of purchasing HDR iridium sources compared with
cesium sources
Short treatment times and minimal radiation protection
problems
Possibility of optimizing dose distribution by altering the
dwell times of the source at different locations
Between fractions, patient is not radioactive, allowing for
near continuous nursing care
Pulsed dose rate advantages
Complication rate profile more similar to that of LDR
More predic table time for removal of the applicator than
remote after-loading LDR where the sources are retracted
whenever someone enters the patient’s room
may result in radiobiological advantages, including the
possibility of better tumor oxygenation and, therefore,
more radio sensitivity as the tumor involutes.
The design of the external beam fields takes into
account the fact that cancer of the uterine cervix
spreads in a very predictable manner, first spreading
laterally to the para cervical nodes, then to the internal
common iliac and finally to the para-aortic nodes.
At the University of Minnesota, we historically
833
preferred extraperitoneal lymph node staging to
delineate the borders of the external beam fields
(Potish et al. 1984, 1989), but now rely more on PET
scans. Patients who do undergo lymph node dissec-
tion and have negative pelvic nodes receive treatment
in a small pelvic field with a superior border
approximately at the mid sacroiliac joint level.
Patients with involved pelvic nodes, but negative
common iliac, or periaortic nodes, receive radiother-
apy that encompasses what we call the ‘‘low peria-
ortic’’ area. The superior border of this field is
approximately at the L2–L3 interspace. For patients
with positive common iliac or periaortic nodes the
fields are extended to include the ‘‘high periaortic’’
areas and the field extends to the T9–T10 interspace
(Fig. 2).
PET imaging now precedes the decision to offer
extreaperitoneal lymph node sampling. For patients
without PET or CT evidence of spread to the nodes,
it is assumed that radiation can sterilize any occult
nodal metastasis and an extraperitoneal lymph node
dissection is not done, and the radiation field
encompasses the ‘‘whole pelvis’’ to approximately
the L4–L5 interspace. For patients with large
([2 cm) PET positive nodes, extraperitoneal lymph
node sampling is done, and the involved nodes are
removed. The radiation fields are then tailored to
the findings at surgery. If the PET scan reveals PET
positive nodes that are \2 cm in diameter lym-
phadenectomy is usually not offered, but the exter-
nal beam dose to the PET positive nodes is
augmented, usually with intensity modulated tech-
niques, so as to improve the odds of nodal tumor
control while sparing the nearby small bowel as
much as possible.
Alternatively, if extraperitoneal node sampling or
PET scans are not available, the extent of external
beam fields can be determined by combining CT or
MRI results with risk rates of pelvic nodal spread.
Approximately 15% of patients with FIGO stage-I
disease will be found to have positive pelvic nodes,
30% of those with stage II and up to 45% of those
with stage III. The risk of positive para-aortic nodes is
roughly half that of the pelvic node rate (6% in stage I,
12% in stage II and 24% in stage III). This informa-
tion can be used to plan the external beam fields.
For a small tumor, which is stage I, the pelvis alone
is usually an adequate external beam volume. For
patients with more advanced disease, one could
834 K. E. Dusenbery and B. J. Gerbi

Table 4 Cochrane Collaboration Review of high dose rate versus low dose rate brachytherapy for locally advanced uterine cervix
cancer (Wang 2010)
Studies Stage OS rate (%) Local control rate (%) Complications rate (%)
HDR LDR HDR LDR HDR LDR
Falkenberg (2006)a Total 55 60 76 78 3.5 4.8
III 33 45 83 72
Petereit (1999)a IB 86 82 85 91
II 65 58 80 78
IIIB 33 58 44 75
b
Ferrigno (2005) Total 55 69 65 74 56 73
III 36 46 50 58 37 49
Kucera (2001)a Total 58.2 51.3 3.8 9.0
I 84.6 68.3
II 78.9 58.1
III 53.8 37.3
IV 37.5 23.1
Sarkaria (1994)a Total 77 66 77 80 2.5 10
b
Kim (2001) Total 1.4 0
I 87.1 72.9
II 58.3 61.9
III 43.8 35.7
b
Okkan (2003) I 67.3 80 73 86
IIB 47.8 47.3 68 65
IIIB 31.6 33.3 45 53
el-Baradie (1997)a Total 62 68 67 74
b
Orton (1991) Total 60.8 59 9.05 20.66
III 47.2 42.6
a
3-year outcomes
b
5-year outcomes

consider treating extended fields to include either the
common iliac or para-aortic nodes. The RTOG
reported their 10-year results of prophylactic exten-
ded field radiotherapy in patients with stages-IIB and
bulky -1B and -IIA cervical cancers (Grigsby et al.
2001a, b). In that series, the extended radiotherapy
patients had an approximately 10% improvement in
10-year survival (44 vs. 55%).
The inferior border of the external beam field must
be tailored to the extent of the disease. A cervical gold
seed implanted at the time of the examination under
anesthesia is an excellent time to place gold seeds to
mark either the cervix or the inferior extent of vaginal
spread (Fig. 3). If there is vaginal extension of the
tumor, the inferior border should give at least a 2 cm
margin on the most inferior extent of the vaginal
extension. Additionally, for tumors that involve the
lower third of the vagina, the inguinal nodes are at
risk and should be included in the external beam
fields. Appropriate measures must be taken to ensure
that they receive adequate dose, such as using mixed
energy beams and ensuring that the field is wide
enough to include them.
In the past, bony landmarks were often used to
delineate the width of the pelvic field. On an AP
radiograph, if between 1.5 and 2 cm existed between
the widest point of the bony pelvis and the field edge,
it was thought that the pelvic nodes would easily be
included. With the advent of CT simulations it is
known that often these margins are not adequate and
it is better to perform a treatment planning CT with
both IV and oral contrast agents. The actual location
Radiation Therapy for Cervical Cancer 835

Table 5 Summary of results of chemoradiation therapy for definitive therapy for cervical cancers
Study FIGO Overall survival Progression-free survival Relative risk of
stage (%) (%) progression
Keys et al. (1999); GOG 123a IB2
XRT (control) 74 63
XRT plus weekly CDDP 83 79 0.51
Whitney et al. (1999); GOG IIB–IVAb
85
XRT ? H (control) 43 47
XRT plus CDDP/5FU 55 57 0.79
Rose et al. (1999); GOG 120 IIB–IVAb
XRT ? H (control) 50 41
XRT ? weekly CDDP 66 62 0.57
XRT ? H/5FU/CDDP 67 61 0.55
a
Also had adjuvant hysterectomy
b
Negative para-aortic nodes by extraperitoneal laparotomy
XRT definitive pelvic radiotherapy, H hydroxyurea, 5FU 5-flourouracil, CDDP cisplatin

of the vessels and surrounding nodes can then be

delineated and the field more accurately rendered.
The pelvis is usually treated with a four-field
external beam arrangement and care must be taken in
designing the lateral fields so that the entire uterus is
encompassed and the utero-sacral ligaments, which
attach at S1 and S2, are included. A common mistake
is to try to block large portions of the rectum and, in
doing so, shield the tumor extent posteriorly. Addi-
tionally, the uterus is often anteverted and a tight
anterior margin can block some of the uterus. For this
reason treatment planning CT scans have replaced
conventional simulation (Fig. 4).

5 Simulation/CT Simulation
Procedures

At the time of the simulation or CT simulation, the

Fig. 2 Anteroposterior radiograph showing the possible locations
for the superior border of the external beam field. Small pelvis field
is used if pelvic and periaortic nodes are free of metastasis at the
time of surgical staging. Low periaortic field is used if pelvic nodes
are involved with metastasis but periaortic nodes are negative. Note
that it does not include the inferior-most extent of the spinal cord.
Entire periaortic nodes are treated when shown to be involved by
metastasis either by surgical staging or needle biopsy
patient is usually placed supine with a full bladder
on the simulator or CT couch. Attempts have been
made to try to spare more small bowel with a prone
position on some type of false table-type device, but
with the location of the uterus, cervix, and nodal
spread, it is unclear whether the advantages of a
prone position are outweighed by the instability of
this position (Ghosh et al. 2001). The cervix is
marked either with a gold seed that has previously
been placed or with a vaginal marker (Fig. 3). Oral
contrast with the CT is highly useful, as is IV
836
Fig. 3 Gold seeds are placed at the most inferior extent of
vaginal involvement, if present, or in the cervix to act as a
marker for field placement. Lateral field posterior border set at
S2 so as to include the uterosacral ligament and presacral nodes
contrast, to delineate the vessel location. Alterna-
tively, a previously performed CT scan with oral and
IV contrast can be fused with the treatment planning
CT scan. The approximate field borders are set and
recorded, and the CT scan transferred to the treat-
ment planning computer.
5.1 Target Volume and Organs at Risk
The target volume is the cervix, uterus, uterosacral
ligaments, and nodes deemed at risk or known to
harbor metastatic disease. The uterus is easily seen by
means of CT scan or MRI. More difficult to visualize
are ligaments which that to be included, especially in
more advanced disease states. The bladder and rectum
are outlined, as is the small bowel and kidneys
(Fig. 4a). Usually a four-field 3D arrangement gives
excellent dose distributions and does allow for some
sparing of small bowel and bladder and possibly some
of the rectum, although IMRT techniques are gaining
K. E. Dusenbery and B. J. Gerbi
acceptance (Fig. 4f). As stated earlier, care must
be taken to not spare bowel at the extent of blocking
the uterosacral ligament. If extended fields are
used, the kidney location must be identified and
avoided. If a four-field arrangement is chosen, the
lateral fields may treat a large proportion of the
kidneys unless there is judicious use of blocking.
More recently, intensity modulated radiotherapy
has been utilized in an effort to dose escalate to sus-
picious or grossly involved nodes while sparing dose
to the small bowel, bone marrow, rectum, femoral
heads, or bladder (Fig. 4c, d, e). The irregular, elon-
gated shape of the target volume and proximity of
crucial normal structures (bladder, rectum, small
bowel) make IMRT especially appealing. However,
caution must be used as the organ motion in the pelvis
due to bladder and bowel filling and the inability to
image the sites of likely tumor spread along the
uterosacral and cardinal ligaments make a geographic
miss a high concern (Randall 2006).
IMRT has not been prospectively shown to be
superior to conventional three-dimensional RT tech-
niques when judged against criteria established in
advance, but many single institution feasibility reports
exist (Portelance et al. 2001; Mutic et al. 2003; Mundt
et al. 2002). Furthermore, there are many reasons to
consider the possibility that outcomes might be
compromised by IMRT techniques used to treat
gynecologic cancers, so caution should be used when
employing these techniques.
5.2 Dose Prescription
Patients with very early lesions can be treated with
brachytherapy alone, although often these patients
undergo radical hysterectomy and are referred for
definitive radiotherapy only if there are intermediate—
or high-risk pathological features. Everyone else
receives a combination of external beam treatment and
brachytherapy.
Table 6 gives the recommendations for treatment
regimens used at the University of Minnesota where we
continue to use mostly LDR brachytherapy for patients
with intact cervix cancer. For a patient treated with
brachytherapy alone, 10,000 mg h-1 in two applica-
tions is usually prescribed. As the FIGO stage and bulk
of disease increase, more external beam therapy is
delivered and less brachytherapy is delivered. At the
Radiation Therapy for Cervical Cancer
Fig. 4 a, b Digitally reconstructed radiographs with contours
of external and internal iliac vessels outlined as well as the
small bowel, bladder, and rectum. In general, a 2-cm margin on
the vessels will encompass the associated lymph nodes and can
be considered the clinical target volume. A margin placed
around this volume for day to day setup variation can be
considered the planning target volume. c Coronal view of
isodose distribution of a 7 field ‘‘step and shoot’’ IMRT plan.
This patient had FIGO stage II disease and the parametria
receive 210 cGy each day while the cervical tumor and
837
remaining pelvic nodes receive 175 cGy daily. The central
cervical tumor will be in the high dose region from the LDR
brachytherapy application. d Axial and e coronal views of
isodose distribution obtained using an IMRT plan. Two PTVs
are contoured and each receives a different daily dose ‘‘dose
painting’’. In this example the enlarged PET positive nodes
receive 5,600 cGy while the clinically uninvolved nodes
receive 4,500 cGy. f Coronal view of isodose distribution of
a 3D conformal plan generated using 4 fields
838
Table 6 ICRU reporting data
Description of technique
Source used (radionuclide, reference air kerma rate, shape
and size of source, and filtration)
Simulation of linear source for point or moving sources
Applicator geometry (rigidity, tandem curvature, vaginal
uterine connection, source geometry, shielding material
Total reference air kerma
Time dose pattern (application duration)
Description of reference volume
Reference isodose level
Isodose width, height, and thickness
Dose at reference points
Bladder
Rectum
Lymphatic trapezoid (lower periaortic, common iliac,
external iliac)
Pelvic wall
University of Minnesota, we generally deliver
175 cGy/day, but at most institutions between 180 cGy
and 200 cGy is the standard. The initial phase is given
with concurrent chemotherapy, usually cis-platinum
(40 mg/m2 per week.) The platinum is usually deliv-
ered early in the week so that there is maximum
potential for radiosensitization. After 4–5 weeks, the
first of two LDR brachytherapy applications is deliv-
ered. This is followed 2 weeks later by the second LDR
brachytherapy application. In the interval of time
between the two applications, external beam treatments
continue with blocking of the central area where the
high-dose brachytherapy application was concentrated.
This parametrial boost can be delivered to one or both
sides. At the University of Minnesota, our split pelvis
block is generally 4.5 cm wide at isocenter. At other
institutions, partial transmission blocks are designed
that correspond to the isodose lines of the brachyther-
apy application. The superior extent of the block is
determined by the superior extent of the tandem and
roughly corresponds to the location of the 30 cGy/h
isodose line from the brachytherapy application. It is
important to keep the treatment course to less than
8 weeks, as protraction has been associated with a
worse pelvic control rate (Erridge et al. 2002; Nag et al.
2002; Grinsky et al. 1993).
For patients with PET negative pelvic and peria-
ortic nodes, at the completion of external beam
K. E. Dusenbery and B. J. Gerbi
therapy the nodal areas will have received between
4,500 and 5,000 cGy.
If PET positive pelvic or periaortic lymph nodes
are present and a lymphadenectomy has not been
performed, IMRT is used to augment the dose to the
involved nodes. In this situation two different nodal
PTVs are contoured and each is prescribed a different
daily external beam dose (Fig. 4c, d). The nodes that
are PET positive usually receive 210 cGy/day
(sometimes more) and the ‘‘at risk’’ but PET negative
nodes receive 175 cGy/day. After 26 fractions the
cumulative dose to the PET positive nodes is
5,460 cGy while the remaining nodes will have
received 4,550 cGy.
6 LDR Brachytherapy
6.1 Equipment
Manual after-loading Fletcher-Suit-Delclos applica-
tors are used for the majority of cervical cancer
patients at the University of Minnesota (Fig. 5).
Over 100 other applicators are available worldwide.
LDR and pulse rate remote after-loading systems,
which minimize the exposure to medical personnel,
are available from manufacturers in several coun-
tries. For manual and remote after-loading, the
clinical, radiobiological, and physics principles of
LDR are the same. Only the size of the applicators,
radiation protection features and possibly the ability
to limit applicator movement during treatment
differs. Integral to the application is an implantation
system that has evolved around the use of those
applicators.
6.2 LDR Procedure
The LDR applicators are generally placed with the
patient in the operating room under general or spinal
anesthesia. HDR applicators can be placed under
general or regional anesthesia, or IV sedation. Once
the patient is anesthetized and an examination per-
formed, the cervical os is identified and the intra-
uterine canal serially dilated (often not required for
HDR). The appropriate length tandem is inserted into
the uterine canal and affixed to the cervix by suturing
it to the tandem through the collar. In order to
Radiation Therapy for Cervical Cancer
Fig. 5 a Fletcher-Suit-Delclos tandems no. 1 showing flange
that can be sutured to the cervix. The cesium sources are placed
in tandem in a straw which is placed in the metal tandem. A
‘‘pusher’’ ensures that the sources are snug at the tip of the
tandem. b A colpostat (also called ovoid) is shown. The
diameter of the bare metal colpostat is 2 cm. Caps can be
Fig. 6 Longitudinal ultrasound image through the uterus
demonstrating bladder (B), myometrium (M) and correct
position of tandem within the uterine cavity (T)
ascertain that the tandem is in the intrauterine canal,
an intraoperative transabdominal ultrasound is per-
formed (Fig. 6). The ovoids are then placed in each
fornix and affixed to the tandem. Packing with a
radio-opaque wire, is used to push the bladder and
rectum away from the applicators, taking care not to
let the packing extend superior to the ovoids. Foley
catheters with balloons are inflated with diluted con-
trast material and placed in both the bladder and
rectum for later determination of IRCU bladder and
rectal point doses. Intraoperative radiographs are
performed. The desired geometry of the tandem rel-
ative to the ovoids and relative to the pelvis is shown
in Fig. 7. Examples of poor implant geometry are
shown in Fig. 8. If a poor application is achieved, the
packing is removed and packing is repeated and re-
filmed until satisfactory. Figure 9 shows a radiograph
of the desired orientation of the tandem to ovoids and
839
placed over the metal colpostat increasing the diameter to either
2.5 or 3 cm. Caps effectively push the vaginal mucosa away
from the source and improve the ratio of dose at the vaginal
mucosal surface to the dose deeper below the vaginal surface.
The cesium source is placed into the metal device which slides
into the colpostat and locks in place
pelvis. Once this is achieved, the anesthesia is
reversed and the patient recovers in the recovery room
and is then transported to the radiotherapy department
for simulation.
6.3 Milligram Hour
In the pre-computer era when only radium sources
were available, gynecological brachytherapy appli-
cations were specified by the simple mathematical
product of the number of milligrams of radium times
the duration (number of hours) of the implant. Thus,
an implant of five 10-mg radium sources left in place
for 48 h would yield a ‘‘dose’’ of 2,400 mg h-1
(10 9 5 9 48). Since its initial use in the early 1900s
in Europe, the dose prescription system evolved and
was refined at M.D. Anderson Hospital by Dr. Gilbert
Fletcher and his colleagues. This system is still used
today. A 7% (8.25/7.71) correction factor is used to
convert the ‘‘Fletcher milligram’’ hours to ICRU
milligram hours, since the milligram hours recom-
mended by Dr. Fletcher are for implants with radium
and encapsulated with 1 mm of platinum (exposure
rate constant 7.71 R cm2 h-1 mg-1). The ICRU
specifies that a radium source with 0.5 mm of plati-
num filtration be used as the standard (exposure rate
constant 8.25 R cm2 h-1 mg-1).
Although the milligram hour system is easy to use, it
does not give any information about the dose distribu-
tion around the application. The reason the system
‘‘works’’ is because it specifies a particular geometry
840
Fig. 7 a Diagram illustrating the desired orientation of the tandem relative to the ovoids as seen on an anterior view. b Diagram
illustrating the desired orientation of the tandem relative to the ovoids as seen on a lateral view
between the tandem and ovoid and sources are loaded
in a rigidly prescribed manner. It is only applicable
when both the tandem and ovoid are implanted. For a
tandem loaded with a protruding vaginal source
(no ovoids), the milligram hour dose specification is not
applicable.
6.4 The Manchester System
The second dose prescription system that evolved
specifies the dose to four specific points in space
around the applicator—point A, point B, bladder, and
rectum. Originally developed in Manchester, Eng-
land, this system is widely used. Point A was initially
defined as the point 2 cm superior to the vaginal
fornix and 2 cm lateral to the cervical canal. Point B
was 3 cm lateral to point A. Points A and B were said
to represent critical anatomical structures, with point
A representing the site where the uterine vessels cross
the ureter and point B representing the location of the
more lateral pelvic nodes. Although most descriptions
of point A are 2 cm superior and 2 cm lateral to a
specified origin, the definition of the origin is not
standardized and there are at least six different origins
in the literature (Fig. 10). Depending on which origin
is chosen, the point A dose can vary widely, espe-
cially if the ovoids are displaced superiorly or infe-
riorly (Potish and Gerbi 1986). A relatively small
K. E. Dusenbery and B. J. Gerbi
displacement of the ovoid results in a large change in
the dose rate to point A. Since dose rate falls off
rapidly with distance from the brachytherapy sources,
any point surrounding the applicator will be expected
to be in a rapid fall off area, another disadvantage of
using the Manchester system. For small tumors, point
A may even lie outside the tumor volume, whereas for
larger tumors the tumor may extend significantly
more lateral than point A. Since some definitions of
point A are radiographic, point A may end up outside
the cervix altogether. Figure 11 is an isodose distri-
bution of a standard Fletcher-suit tandem and ovoid
application. Note that point ‘‘A’’ is in an area of sharp
dose fall off.
An association between point A, point B, and
milligram hours does exist. In a perfect Fletcher-suit
tandem loaded as described above, point A is almost
always between 50 and 60 cGy/hour. Point B usually
lies between 10 and 20 cGy/hour and is largely
dependent on the source strengths in the ovoids.
Because these dose rates for points A and B are
usually confined to a narrow range, as are implant
durations, it is not surprising that there is an asso-
ciation between these total point doses and milligram
hours. In an evaluation of almost 100 brachytherapy
applications performed at the University of Minne-
sota, a fairly high correlation between milligram
hours of radium and doses at point A and B was
reported, with correlation coefficients of 0.73 and
Radiation Therapy for Cervical Cancer
Fig. 8 Radiographic examples of poor geometry. a X-ray
demonstrating ovoids that are placed too inferior and posterior
relative to the tandem. Re-packing is indicated. b Radiograph
demonstrating ovoids that are too inferior and posterior relative
0.89, respectively. However, it was pointed out that
the point A dose was markedly affected by the
position of the colpostats relative to the tandem
collar and that there was considerable inter-patient
variability making the routine translation between
Fletcher and Manchester systems too unpredictable
841
to the tandem. If caps are on the ovoids, removing them might
improve the geometry. c The ovoids are superior relative to the
tandem. Note that the ovoids are widely spaced and placing
caps on the ovoids may help
for clinical use (Potish et al. 1982). Despite these
limitations, it is useful to translate milligram hours
into point A or point B doses. Bhatnagar et al.
(1980) has suggested a formula that roughly calcu-
lates the point A dose based on the milligrams of
radium loaded:
842 K. E. Dusenbery and B. J. Gerbi

Fig. 9 Radiographs of
desired orientation of the
tandem and ovoids

Fig. 10 a Possible origins of point A on anterior view. b Possible origins of point A on lateral view

Point A ðcGy=hÞ¼ 1:1ðmg in tandemÞ redefining and standardizing brachytherapy reporting

terminology (Table 6). This has not been widely
þ ðmg in ovoids/2ÞcGy=h
adopted in the US. Three reporting approaches were
Likewise, the following formula roughly converts proposed, the reference air kerma rate, the absorbed
milligram hours into the total point B dose: dose at certain reference points (Figs. 12, 13, 14, 15),
and the isodose reference volume.
Point B ðtotal dose in cGyÞ The reference air kerma rate was proposed to
¼ ðtotal milligram hours in two implantsÞ=4 introduce international units into brachytherapy
reporting. The reference air kerma rate is expressed in
lGy/h at 1 m. The total reference air kerma is,
6.5 The International Commission therefore, the sum of the products of the reference air
on Radiographic Units kerma rate and the duration of the application. The
and Measurements Fletcher milligram hours can easily be converted into
reference air kerma using the following formula:
In 1985, the ICRU recommended the system of LDR 1 mg h = 6.7 lGy at 1 m total reference air ker-
brachytherapy dose and volume specifications aimed at ma (for filtration of 1 mm of platinum). The total
Radiation Therapy for Cervical Cancer
Fig. 11 Brachytherapy
isodose plot. Note that point
‘‘A’’ is in an area where the
isodoses change rapidly and a
small variation in the location
of point ‘‘A’’ can make a big
difference in the resultant
dose rate
Fig. 12 Location of bladder and rectum points as specified by
the ICRU (ICRU 1985). From ICRU report no. 38. International
Commission on Radiation Units and Measurements, Bethesda,
MD, 1985. Used with permission
reference air kerma, therefore, has the same limita-
tions as milligram hour dose specification. The ICRU
recommended calculating the absorbed dose at certain
reference points (rectal, bladder, pelvic wall, trape-
zoid, node points but fell short of trying to standardize
the definitions for point A or B.
The most radical change proposed by the ICRU was
to specify reporting parameters for the pear-shaped
843
reference volume. The report states that ‘‘an absorbed
dose level of 60 Gy is widely accepted as the appro-
priate reference level for classical low-dose-rate
brachytherapy’’ and therefore the 60-Gy isodose ref-
erence volume was suggested. This reference volume is
determined by measuring the width, height, and
thickness of the tissue encompassed by the 60-Gy iso-
dose curve. The ICRU chose to subtract any external
beam therapy from this 60-Gy reference volume to
choose the relevant isodose. To choose the relevant
isodose surface, the EBRT is subtracted from the 60-Gy
volume, and the remainder is divided by the implant
duration to obtain the isodose surface by which to
calculate the reference volume. For example, if a
patient has received 40 Gy of external beam therapy
and 80 h of brachytherapy:
60 Gy  40 Gy ¼ 20 Gy
20 Gy=80 h ¼ 0:25 Gy=h
the 25-cGy/h isodose surface is chosen.
The attempt by the ICRU recommendation was
that this ‘‘reference volume’’ would further describe
the brachytherapy application and shed light on the
volume of tissue receiving a particular level of dose.
In recent years, image-guided brachytherapy for
cervical cancer has had some success. If the tumor
844 K. E. Dusenbery and B. J. Gerbi

Fig. 13 Determination of
reference points
corresponding to the
lymphatic trapezoid of
Fletcher. From ICRU report
no. 38. International
Commission on Radiation
Units and Measurements,
Bethesda, MD, 1985. Used
with permission

Fig. 14 Definition of pelvic

wall points. Position of right
pelvic wall (RPW) and left
pelvic wall (LPW) are
diagrammed. From ICRU
report no. 38. International
Commission on Radiation
Units and Measurements,
Bethesda, MD, 1985. Used
with permission

volume can be delineated with adequate imaging, the
ICRU concept of reference volume, especially if it is
the tumor reference volume, might be helpful.
The Image-Guided Brachytherapy Working Groups
(Nag et al. 2004; Haie-Meder et al. 2005) have made
recommendations for reporting dose, but it has not been
widely adopted. One concept that has been introduced
is that of an intermediate-dose clinical target volume
(ID-CTV), based on the extent of tumor noted on
imaging at the time of diagnosis, and a high-dose
clinical target volume (HD-CTV), based on extent of
tumor following EBRT, at the time of brachytherapy.
Two different dose prescriptions are applied to each
volume, a lower dose to the ID-CTV to eradicate
residual microscopic disease and a higher dose to the
HD-CTV to eradicate macroscopic residual disease.
Using MRI compatible applicators, T2 weighted MRI
is endorsed due to the superior soft tissue resolution it
offers. Other definitions in the era of IGRT include the
GTV((I)) defined as the gross tumor volume as seen
with MR imaging. The GTV is defined as the GTV((I))
plus any clinically visualized or palpable tumor
extensions, and GTV ? cx is defined as the GTV plus
the entire cervix. They also recommend calculating
dose–volume histograms (DVH) of the GTV,
GTV((I)), GTV ? cx, and reporting dose to 100, 95, or
90% of the GTV (D(100), D(95), and D(90), respec-
tively) as well as the percentage of the GTV covered by
Point A dose (V(100)). Similarly, the DVH calculations
of the bladder and rectum wall can be performed, and
the maximal dose at any point within the bladder and
rectal wall may be reported, along with the maximal
dose to a contiguous 1, 2, and 5 cm3 volume of the
bladder and rectum, respectively. Further work is
needed, but we are clearly moving away from merely
reporting dose to a single point or milligram hour2.
Radiation Therapy for Cervical Cancer
Fig. 15 ICRU reference volume is determined by finding the
reference isodose surface dimensions, dw (width) dh (height)
and dt (thickness). From ICRU dose–volume specification for
6.6 University of Minnesota
At the University of Minnesota, we rely heavily on
the Fletcher milligram hour dose specification system
(Fletcher 1973). When this is inappropriate (protrud-
ing vaginal source, vaginal cylinder), point A calcu-
lations is used (Table 7). The Manchester points are
calculated for all patients but are not routinely used to
specify dose. We find them useful as a double check
to assure ourselves that both an adequate tumor dose
has been achieved (remembering that point A may
have little relationship to the tumor) and that bladder
or rectal tolerances have not been exceeded
(remembering that a point dose to the rectum or
bladder provides no information about the dose to the
rest of the rectum or bladder received).
Microinvasive (FIGO IA) tumors are unlikely to
have spread to the pelvic lymph nodes. Patients with
these tumors may be treated with intracavitary ther-
apy alone. Doses of up to 10,000 mg h-1 in two
applications are used. For small (1–3 cm) IB tumors,
up to 3,000-cGy pelvis external beam whole pelvic
external beam therapy is given depending on the
extent of disease with up to 2,000 cGy of split pelvis
radiation. This is followed by LDR brachytherapy
applications of up to 7,000 mg h-1. For more
advanced tumors, 4,000-cGy whole pelvis EBRT is
used, and up to 6,500 mg h-1 of cesium may be used
845
reporting intracavitary therapy in gynecology. From ICRU
report no. 38. International Commission of Radiation Units and
Measurements, Bethesda, MD, 1985. Used with permission
in two implants. The parametrial areas may be
boosted with an additional 1,000-cGy EBRT using a
split pelvis field, either with a straight split pelvis
block (usually 4.5 cm in diameter) or with a step
wedge block. In the recent years we have begun to
boost the parametria with IMRT. For even larger
tumors, more whole pelvis (±periaortic nodal) EBRT
is given (4,500 cGy), and the two-brachytherapy
applications are shorter (5,000–6,000 mg h-1). Once
whole pelvis EBRT doses of over 4,500 EBRT are
exceeded, however, it is difficult to add significant
amounts of brachytherapy. Therefore, an examination
under anesthesia is performed at the 4,000-cGy dose
level. If there has been good tumor shrinkage, the first
implant is performed at that time. If the tumor is still
large after an initial 4,000-cGy whole pelvis EBRT
and there is concern that the implant will not have
good geometry, additional EBRT (with doses up to
1,000 cGy) may be given or an interstitial implant can
be considered. For tumors with significant vaginal
involvement, the implantation volume should include
the extent of disease in the vagina. Usually, the EBRT
leads to shrinkage of the vaginal involvement so that
at the time of the first brachytherapy application there
is little palpable tumor left. Often the previous tumor
is replaced with vague induration. If there is more
tumor than 0.5 cm of induration remaining, an inter-
stitial inplant of the vaginal component of the tumor
846 K. E. Dusenbery and B. J. Gerbi

Table 7 General guidelines used at University of MN for treatment of carcinoma of the intact cervix in surgically staged patients
FIGO Parametrial Tumor size Whole pelvis EBRT Maximum Point Ac Point Bd
stage extension (cm) dose (cGy) a mg h-1b (cGy) (cGy)
IB, IIA No 2–5 3,500–4,000 6,000–6,500 7,500+ 5,500–6,000
5+ 3,500–4,500 5,000–6,000 8,000–9,000 6,000
IIB Yes 2–5 3,500–4,000 6,000–6,500 8,000+ 6,000
6,000
5+ 3,500–4,500 6,000–6,500 8,000–9,000 6,000
III Yes 4,000–5,000 5,500–6,000 8,500–9,500 6,000
IV A Yes Individualize
EBRT external beam therapy given at 175 cGy/day
a
Dose to the whole pelvis (±periaortic nodes) given with EBRT given depends on bulk of tumor, FIGO stage, and amount of
regression at the time of the first brachytherapy application. If the periaortic nodes are included, periaortic nodal EBRT doses range
from 4,000 to 5,000 cGy
b
Given in 2 applications, with tandem and ovoids 2 weeks apart. Does not take into account 1.07-filtration factor correction for
cesium in 0.5 mm platinum
c
This maximum is when nominal strengths of cesium of 10, 15, 20 and 25 mgs are used. If cesium of lower activity is used, the
hours may be increased accordingly
d
Point ‘‘B’’ is boosted to 6,000 cGy for all patients with pathologically proved involvement of pelvic nodes or tumors larger than
2 cm in size. A split pelvis block is 4.5 cm wide with height determined by height of the tandem is used

should be considered. Tolerance of the vaginal wall to
high-doses of radiation probably depends on the
length of vagina treated as well as on the total dose
and dose rate. In general, the vaginal apex tolerates
more than the distal vagina, with the apex tolerating
doses of 10,000 cGy or more. More distal portions of
the vagina should probably not receive more than
7,000–8,000 cGy.
The American Brachytherapy Society has given
recommendations on the combination of external
beam irradiation and LDR brachytherapy (Nag et al.
2002). For completeness, the summary table has been
reproduced in Table 8.
6.7 Postoperative Radiotherapy
In cases of radical hysterectomy, recent randomized
trials have delineated patients who might be at greater
risk for recurrence and who benefit from postopera-
tive radiation therapy either alone (Sedlis et al. 1999)
or with concurrent chemotherapy (Peters et al. 2000).
In the first of these trials, patients with ‘‘intermediate’’
risk factors were randomized to either observation or
pelvic radiotherapy. The disease-free survival (DFS)
was better for the pelvic radiotherapy group
(Table 9). In the second trial, ‘‘high-risk’’ patients
were randomized to either pelvic radiation or pelvic
radiation and chemotherapy. The DFS was better for
the combined modality group. The risk of bowel or
bladder complications is high in this setting and care
must be taken to minimize the risk of a late radiation
complication as much as possible. The American
Brachytherapy Society has published guidelines for
postoperative radiation therapy for cervical cancer
(Nag et al. 2002), which is summarized in Table 10.
6.8 Dose to Bladder and Rectum
The ICRU suggests a method to choose which point
to calculate the rectal and bladder dose. These point
doses may have little relationship with the dose
received by other parts of the bladder or rectum and
may not be the highest dose area (Crook et al. 1987;
Esche et al. 1987; Katz and Eifel 2000). The locali-
zation of the bladder and rectum can be achieved by
either placing Hypaque in a Foley catheter, which has
been placed in the bladder or rectum, or by the use of
rectally inserted ionization chambers. This method,
however, is probably no more reliable than the point
calculation method.
Generally, the bladder can tolerate more radiation
than the rectum. No absolute point dose limit can be
set, but it is preferable to keep the maximum bladder
dose below 8,000 cGy and the maximum rectal dose
below 7,500 cGy. Therefore, it is optimal if the rectal
dose rate is lower than the bladder dose rate for the
Radiation Therapy for Cervical Cancer 847

Table 8 Carcinoma of the uterine cervix—the ABS suggested doses of external beam irradiation and low-dose-rate intracavitary
brachytherapy Modified from Nag et al. (2002)
Tumor Tumor extent External irradiation Parametrial LDR brachytherapy
stage (Gy) boost (Gy) (Gy)
Whole Pelvic Dose Total dose
pelvis wall to to point A
point (Gy)
A
IA1 0 0 0 50–60 50–60
1A2 Superficial ulceration; less than 1 cm in diameter 0 0 0 60–70 60–70
Selected or involving fewer than two quadrants
IB1
IB1 19.8 or 50.4 or 0 55 or 75 or
45 45 30–35 75–80
IB2, IIA,a 45 45 0 40 85
IIBa 45 45 9–15 40 85
a
III 45–50 45–50 9–15 40 85–90
IIB, IIIB, Poor pelvic anatomy; patient not readily treated 50 50 9–15 40 90
IV with intracavitary insertions (barrel-shaped cervix
not regressing; inability to locate external os)
Or interstitial 39.6–45 39.6–45 0–15 35–40b 75–85b
The panel making these recommendations acknowledge that a range of doses can be suitable depending on individual patient
circumstances
a
The alternative approach is to increase brachytherapy contribution to point A by giving whole pelvic EBRT of 19.8–30.6 Gy.
This is followed by whole pelvic EBRT with a step wedge midline shield for an additional 19.8–30.6 Gy and intracavitary
brachytherapy to bring point A dose to the recommended level described in the table
b
The interstitial brachytherapy dose is the ICRU external beam radiotherapy #58 reference dose and not the dose to Point A

Table 9 Randomized trials of postoperative irradiation after radical hysterectomy

Author Inclusion criteria Tx ARMS Outcome
Peters et al (2000)
High-risk (+) LN RT 64% 4-year PFS
(+) Margin or parametrial extension RT & CT 80% 4-year PFS
Sedlis et al. (1999)
Intermediate risk Lymph space invasion Observation 79% PFS at 2 years
Deep stromal invasion or large size RT 88% PFS at 2 years
PFS progression-free survival

brachytherapy application. Additionally, it is also
desirable for the dose rate to the bladder point to be
0.8 or less than that of the dose rate to point A.
7 Sequelae
Acute sequelae including diarrhea, cystitis, fatigue, and
lowered peripheral blood counts are common, but usu-
ally resolve within weeks after treatment. Ovarian
failure occurs in nearly all patients, unless ovarian
transposition outside the pelvis has been performed
(Belinson et al. 1984; Husseinzadeh et al. 1984).
Shrinkage of the vagina can be minimized by daily use of
a dilator during and after a course of radiation therapy.
The risk of developing a major complication
depends on multiple factors. Patient-related factors
include the stage and extent of the disease, weight, age
(Kucera et al. 1986), smoking history (Kucera et al.
1987), and number of previous abdominal surgical
848 K. E. Dusenbery and B. J. Gerbi

Table 10 The ABS general guidelines for postoperative radiation therapy for cervical cancer (Modified from Nag et al. 1999)
Tumor status Whole Pelvic Tumor Vaginal Total vaginal
pelvis wall boost brachytherapy mucosa dose
(Gy) (Gy) (Gy) dose (Gy) (Gy)
Radiation therapy after simple hysterectomy
[3-mm invasion, margin clear, nodal status unknown 45–50.4 45–50.4 – 0–15 45–60
Microscopically positive vaginal margins, or LVSI 45–50.4 45–50.4 – 20–30 70–75
Gross residual tumor or recurrent disease 45–50.4 45–50.4 – 30–35 80
Or with interstitial 45 45 – 30–35a 75–80a
Radiation therapy after radical hysterectomy
Positive pelvic lymph nodes 45–50.4 45–50.4 – 45–50.4
Deep stromal invasion (C10 mm or C70%, and 50 50 – 20 70
C4 cm tumor) microscopically positive vaginal
margins or positive LVSI
Microscopically positive parametrial or paravesical 45–50.4 50.4 9–15 0 45–60
margins
Gross residual tumor or recurrent disease 45–50.4 45–50.4 – 30–35 80
a
Or with interstitial 45 45 – 30–35 75–80a
a
The interstitial brachytherapy dose is the ICRU #38 reference dose and not the dose to vaginal mucosa

procedures (Potish et al. 1989; Coia et al. 1990).
Treatment-related factors include the volume of EBRT
field treated, fraction size, the dose of EBRT, the
brachytherapy used, and the technique of implantation
used (Unal et al. 1981; Hanks et al. 1983; Perez et al.
1984; Crook et al. 1987; Pourquier et al. 1987; Montana
and Fowler 1989; Deore et al. 1991).
The Patterns of Care study reported that from 8 to
15% of patients treated for cervical cancer with
definitive irradiation required hospitalization for a
complication, half of which required a surgical
intervention. Others have reported similar percent-
ages. In a review of 1,784 patients treated at M.D.
Anderson Hospital with FIGO stage IB cervical can-
cer, the risk of a major complication was 9.3% at
5 years and 14.4% at 20 years (Eifel et al. 1995). The
most common gastrointestinal complications include
proctitis, rectal ulceration, sigmoid structure, or small
bowel obstruction. Urinary complications include
cystitis or ureteral structure. Rectovaginal or vesico-
vaginal fistulas are uncommon.
In a review of M.D. Anderson Hospital data by
Jhingran et al. among the 4,043 patients who had been
treated with LDR intracavitary brachytherapy, only 11
(0.3%) had documented or suspected cases of throm-
boembolism resulting in four deaths (Jhingran and Eifel
2000). Other life-threatening perioperative complica-
tions included myocardial infarction (one death in five
patients), cerebrovascular accident (two patients), con-
gestive heart failure or atrial fibrillation (three patients),
and halothane liver toxicity (two deaths in two patients).
Intraoperative complications included uterine perfora-
tion (2.8%), and vaginal laceration (0.3%), which
occurred more frequently in patients older than 60 years.
Perez et al. (1999) reported the morbidity results of
1,456 patients treated with external radiotherapy plus
two LDR intracavitary insertions to deliver 70–90 Gy
to point A. In stage IB, the frequency of patients
developing grade-2 morbidity was 9% and grade-3
morbidity 5%; in stages IIA, IIB, III, and IVA, grade-2
morbidity was 10–12% and grade 3 was 10%. The most
frequent grade-2 sequelae were cystitis and proctitis
(0.7–3%). The most common grade-3 sequelae were
vesicovaginal fistula (0.6–2% in patients with stage I–
III tumors), rectovaginal fistula (0.8–3%), and intest-
inal obstruction (0.8–4%). In this study, multivariate
analysis showed that dose to the rectal point was the
only factor influencing rectosigmoid sequelae, and
dose to the bladder point affected bladder morbidity.
8 Results
The Patterns of Care Study reported 4-year disease-
free survivals of 87, 66, and 28% for FIGO stages I,
II, and III, respectively (Coia et al. 1990). Results
Radiation Therapy for Cervical Cancer 849

Table 11 Five-year disease- Authors Total number of Stage

free survival rates reported for patients
carcinoma of the cervix IB IIA IIB III IVA
a
Perez et al. (1998) 1,499 82 65 65 40 04
Coia et al. (1990) 0,565 74 – 56 33 –
Horiot et al. (1988) 1,383 09 85 75 50 20
Montana et al. (1985, 1986, 0,533 83 76 62 33 –
1987)
Potish et al. (1989) 0,153 67 71 70 – –
Leibel et al. (1987) 0,119 – – – – –
Gerbaulet et al. (1992) 0,441 89 78 – – –
Kramer et al. (1989) 0,048 – – – – 18
Mendenhall et al. (1984) 0,264 70a 71 70b – –
b c
68 43 – –
Kim et al. (1989) 0,569 82 78 65 48 27
Thoms et al. (1992) 0,371 56b 49c 53c – –
Willen et al. (1985) 0,168 88 77 68 – –
a
10-year survival
b
\6 cm
c
[6 cm

from other individual institutions are shown in
Table 11. Although results are often reported by
FIGO stage, other prognostic factors such as tumor
volume or extent of nodal spread may be more
important prognosticators of outcome, not currently
reflected in the clinical staging system of FIGO.
Patients with FIGO stage IA or small-IB disease have
an excellent prognosis with 5-year DFS estimates
from 80 to 100% (Mendenhall et al. 1984; Perez et al.
1984; Willen et al. 1985; Montana et al. 1987; Coia
et al. 1990; Gerbaulet et al. 1992). For larger IB
lesions, 5-year disease-free survival estimates range
from 75 to 90%. Stage IIB (DFS) results range from
60 to 75% (Montana et al. 1985; Horiot JC et al. 1988;
Kim et al. 1989) and for IIIB the 5-year disease-free
survival rates drop to 30–50% (Leibel et al. 1987;
Kim et al. 1989).
The in-field failure rate increases with increasing
initial FIGO stage (Table 12). For stage I patients, an
in-field recurrence rate of 5–9% has been reported
(Adcock et al. 1984; Kim et al. 1989; Potish et al.
1989; Sommers et al. 1989; Eifel et al. 1990; Montana
et al. 1991). For stage II patients, the in-field recur-
rences range between 10 and 23%, and for stage III
patients up to a 61% in-field recurrence rate has been
reported.
Most regional recurrences after definitive RT for
cervical cancer include a component of marginal
failure. Often this is immediately superior to the
radiation field (Beadle 2009) suggesting that better
delineation of target volumes might improve the
outcome.
9 Quality Management Program
A quality management program is crucial to the safe
functioning of a brachytherapy program. This cannot
be accomplished without dedicated physics support.
The various components of a quality management
program are covered in another chapter. However,
several issues relative to intracavitary cesium appli-
cations deserve emphasis. To assure accurate prepa-
ration of the sources that are to be loaded into the
patient, a series of checks should be in place. We use
color-coded cesium sources and check each source in
a well-ionization chamber. Two people must prepare
the sources to ensure that the proper strength sources
are loaded in the proper order and orientation. Sour-
ces must be logged in and out of the department
(along with a visual count of the remaining sources
left in the cesium safe) and the written directive
850 K. E. Dusenbery and B. J. Gerbi

Table 12 Percentage of in- Authors FIGO stage

field failure rates (expressed
as a percentage) I II III IV
Coia et al. (1990) 12 27 51 –
Kim et al. (1989) 11.2 8.2 (IIA), 30 (IIB) 52 69
Horiot et al. (1988) 8 12 (IIA), 20 (IIB) 37 (IIIA), 43 (IIIB) 82
Montana et al. (1983, 1986, 11 16 (IIA), 34 (IIB) 61 (IIIA), 47 (IIIB) –
1985)
Sasaoka et al. (2001) 5 9 17 –

Table 13 Quality assurance Test Frequency Tolerance

tests for intracavitary
brachytherapy applicators:
frequency of performance and
acceptable tolerance limits
Source location I, Y D
Coincidence of dummy and active sources I 1 mm
Location of shields I, Ya D
I initial use or following malfunction and repairs, Y yearly, D documented and correction applied
or noted in report of measurement when appropriate
a
Before each use the applicator may be shaken to listen for loose parts (Kutcher et al. 1994)

always accompanies all sources leaving the isotope
room. Regulations mandated by the Nuclear Regula-
tory Commission are followed.
Quality assurance tests for the brachytherapy
applicators need to be performed at specified intervals
(Table 13). A rattling noise when the ovoids are
gently shook suggests that the rectal or bladder
shields have dislodged and the applicator should be
radiographed immediately to verify this. Reports of
tandem tips coming off while implanted and remain-
ing within the uterine cavity make it prudent to check
the integrity of the tandem tip with each insertion.
The AAPM Task Group 40 recommended quality
assurance procedures for brachytherapy applicators
(Kutcher et al. 1994). In addition to these tests, we
radiograph the applicators yearly to confirm the cor-
rect position of the shields.
10 Conclusion
In the early-stages, cancer of the uterine cervix is
highly curable with either surgery or radiation ther-
apy. As the tumor advances, however, the best chance
of cure is with aggressive, definitive radiation therapy
consisting of a combination of external beam treat-
ments and brachytherapy applications. Both the
components are important; however, it is probably the
skilled use of intracavitary brachytherapy that is the
most crucial to a successful outcome. This skill is
achieved through experience as well as meticulous
attention to the details of the treatment outlined here.
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 Technical Aspects of Radiation Therapy
in Endometrial Carcinoma
Higinia R. Cárdenes, David L. Andolino, and Jennifer E. Zook

Contents 10 Palliative Radiotherapy........................................... 881

11 Uterine Papillary Serous and Clear Cell
1 Anatomy.................................................................... 856 Carcinoma ................................................................ 882

2 Clinical Presentation and Diagnostic 12 Intraperitoneal Radioactive Chromic Phosphate

Evaluation ................................................................. 856 Suspension [32P] Administration............................ 883

3 Histopathological Classification ............................. 856 References.......................................................................... 885

4 Clinical and Surgical Staging—FIGO

Pathological Staging System...................................
4.1 Clinical-Pathologic Prognostic Factors.....................
4.2 Adjuvant Therapy—Early Stage (FIGO I–II)
Endometrial Adenocarcinoma ...................................
4.3 Randomized Trials in Early Stage (I and occult II)
Endometrial Cancer ...................................................
4.4 Chemotherapy for High-Risk Early Stage
Endometrial Cancer ...................................................
5 Risk Groups in Early Stage
Endometrial Cancer ................................................ 863
6 Adjuvant Therapy—Advanced Stage
(FIGO III–IV) Endometrial Adenocarcinoma ..... 864
7 Radiation Therapy Techniques.............................. 866
7.1 Preoperative Irradiation ............................................. 866
7.2 Postoperative Irradiation ........................................... 869
8 Medically Inoperable Early Stage Endometrial
Cancer ....................................................................... 875
8.1 Recurrent Endometrial Cancer.................................. 877
8.2 Salvage Surgery for Recurrent
Endometrial Cancer ................................................... 879
9 Palliative Therapy in Endometrial Cancer .......... 881
9.1 Palliative Surgery ...................................................... 881
H. R. Cárdenes (&)
D. L. Andolino
J. E. Zook
Department of Radiation Oncology,
Indiana University School of Medicine,
535 Barnhill Drive, RT 041,
Indianapolis, IN 46202, USA
e-mail: hcardene@iupui.edu
857
Abstract
860
An estimated 43,470 new cases of EC are expected
860 in the US in 2010 with 7,950 estimated deaths
(American Cancer Society Cancer facts and fig-
860
ures 2010. American Cancer Society, Atlanta,
862 2010). Currently, EC is the fourth most common
cancer in females, ranking behind breast, bowel,
and lung cancer. In over 80% of the cases, the
disease is confined to the uterus and cervix at the
time of diagnosis, and uncorrected survival rates of
75% or greater are expected (Pecorelli Int J
Gynaecol Obstet 105(2):103–104, 2009). In the
last 25 years, the treatment of EC has evolved
from almost routine use of preoperative radiother-
apy (RT), generally intracavitary brachytherapy,
followed by hysterectomy, to upfront surgical
staging followed by tailored adjuvant therapy
based on histopathological findings, as recom-
mended by the International Federation of Gyne-
cology and Obstetrics (FIGO Int J Gynecol Obstet
28:189–193, 1989). The purpose of this chapter is
to review the role and technical aspects of external
beam RT (EBRT) and brachytherapy in the
management of EC as well as describing the
radiotherapeutic approach as definitive therapy for
medically inoperable patients and in the salvage
setting for recurrent disease.

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 855
DOI: 10.1007/174_2011_156, Ó Springer-Verlag Berlin Heidelberg 2012
856
1 Anatomy
The uterus, located in the pelvis between the rectum
and the bladder, is divided into the body (corpus) and
the cervix, separated by the isthmus. It is attached to
the pelvis primarily by the broad (lateral) and round
(antero-lateral) ligaments; in addition, the utero-sacral
ligaments at the lower uterine segment and the car-
dinal ligaments at the upper-lateral margin of the
cervix, contribute to its support.
The main artery supplying the uterus is the uterine
artery, a branch of the hypogastric artery. The uterus
has a rich lymphatic network: the lower and mid-third
of the uterus drain laterally along the parametrium into
the paracervical lymph nodes and from here to the
external iliac nodes (obturator nodes are the innermost
component) and hypogastric nodes; subsequently, the
pelvic lymphatics drain into the common iliac and
peri-aortic lymph nodes. However, the lymphatics
from the upper corpus and fundus pass laterally across
the broad ligaments continuous with those of the ovary
directly into the periaortic and upper abdominal lymph
nodes. Finally, there are lymphatic channels that drain
along the round ligaments to the femoral nodes.
Adequate knowledge of the anatomic distribution of
the lymphatics is crucial for accurate delineation of
volumes at risk and precise RT delivery.
2 Clinical Presentation
and Diagnostic Evaluation
The most common presentation of EC is abnormal
uterine bleeding, so the possibility of malignancy
deserves exclusion in any woman with postmeno-
pausal bleeding unrelated to hormonal therapy.
Patients may also present with vaginal discharge,
pelvic and lower back pain, or urinary or rectal
symptoms, depending upon the extent of the disease.
Peritoneal spread may present as abdominal disten-
tion, masses and/or ascites. Metastatic spread to the
lung can cause cough or hemoptysis.
Although the Papanicolaou (Pap) smear is not a
reliable screening test for EC, the presence of endo-
metrial cells or atypical glandular cell (AGUS) can
signify endometrial disease. More appropriately, the
diagnosis can be established by an office endometrial,
or pipelle, biopsy, as this does not require anesthesia
H. R. Cárdenes et al.
and is generally well tolerated. Hysteroscopy with
fractional dilation and curettage (D and C) remain the
gold standard when a pipelle is non-diagnostic and
suspicion remains high. However, the potential for
under grading by either of these methods can be
significant, with up to 30% of cases having higher
grade at the time of hysterectomy (Larson et al. 1995).
There is no recognized screening program for the
general population. Thin-Prep Pap smears have been
shown to have as high as 65% sensitivity for EC, but in
general are not viewed as an effective screening tool
(Schorge et al. 2002). Endometrial biopsy is relatively
uncomfortable and equivocal tests may lead to addi-
tional unnecessary evaluation. Transvaginal ultraso-
nography is useful in women who experience bleeding,
as an abnormal endometrial thickness is associated with
gradually increasing risk of neoplasia, but it is relatively
expensive and the positive predictive value is too low for
a screening tool. However, for those women carrying, or
related to carriers of the HNPCC mutation, the American
Cancer Society recommends annual endometrial biopsy
beginning at 30–35 years of age (Smith et al. 2010).
3 Histopathological Classification
Amongst the histopathological subtypes of EC, the
most prevalent types can be grouped together as
endometrioid adenocarcinomas (EAC), comprising
75–80%. They can be further subdivided and descri-
bed as shown in Table 1 (Silverberg and Kurman
1992). The differentiation of a carcinoma is expressed
as its grade. The FIGO grading system is shown in
Table 2. Well differentiated EAC is characterized
microscopically by a proliferation of back-to-back
endometrial glands without intervening stroma, but
there is no more than 5% solid growth. Moderately
differentiated EAC has between 6 and 50% solid
tumor without glands. Poorly differentiated EAC
contain more than 50% solid component. In addition,
nuclear atypia increases the grade of the lesion by one.
The non-EAC histopathological subtypes with
more aggressive behavior are shown in Table 1. The
most common types are UPSC and CCC. UPSC
accounts for 5–10% of EC and is hallmarked by a
papillary architecture rich with high grade, pleomor-
phic cells containing hyperchromatic nuclei with
prominent nucleoli and supported by a fibroblastic
stroma, not different from that seen in the ovarian
Technical Aspects of Radiation Therapy in Endometrial Carcinoma 857

Table 1 International Pathological subtypes Incidence

society of gynecologic
pathologists (ISGP) and the
WHO classification of uterine
tumors (Silverberg and
Kurman 1992)
Endometrioid Adenocarcinoma 75–80%
Papillary villoglandular
Secretory adenocarcinoma
Ciliated carcinoma
Adenocarcinoma with squamous differentiation
Adenoacanthoma
Adenosquamous carcinoma
Uterine papillary serous 10%
Clear cell carcinoma 4%
Mucinous carcinoma 1%
Squamous cell carcinoma \1%
Mixed cell type *10%
Undifferentiated carcinoma \1%
Glassy-cell carcinoma
Metastatic carcinoma to the endometrium

Table 2 Histopathology— Histological grade Definition

degree of differentiation.
FIGO and ISGP-WHO
definitions
G1: Well differentiated 5% or less of a nonsquamous or nonmorular solid growth pattern
G2: Moderately 6–50% of a nonsquamous or nonmorular solid growth pattern
differentiated
G3: Poorly differentiated More than 50% of a nonsquamous or nonmorular solid growth
pattern
Notes on pathologic grading
Notable nuclear atypia, inappropriate for the architectural grade, raises the grade to 3
Serous adenocarcinomas, clear-cell adenocarcinomas, and mixed mesodermal tumors are con-
sidered grade 3
Adenocarcinomas with benign squamous differentiation are graded according to the nuclear grade
of the glandular component
Rules related to staging
Because corpus cancer is now staged surgically, procedures previously used for determination of
stages are no longer applicable (e.g., findings from fractional D and C) to differentiate between
stage I and stage II
It is appreciated that there may be a small number of patients with corpus cancer who will be
treated primarily with radiation therapy. If that is the case, the clinical staging adopted by FIGO
(1971) would still apply, but designation of that staging system should be noted. Ideally, width of
the myometrium should be measured along with the width of tumor invasion

counterpart. The aggressiveness of this tumor is

manifested by its propensity for early spread to the
abdominal peritoneum. CCC accounts for 1–5% of
EC. The appearance can be described as cells with
clear cytoplasm that demonstrate a glandular, papil-
lary, or solid pattern of growth, and like the ovarian
counterpart, can be composed of cysts lined by flat-
tened epithelium. Like UPSC, this type of EC shows a
propensity for distant spread and failure, with series
showing 75% of failures outside of the pelvis, most
commonly to the upper abdomen, lungs, and liver.
4 Clinical and Surgical Staging—
FIGO Pathological Staging System
Once the diagnosis of EC has been established by
endometrial biopsy or curettage, the patient should
undergo a preoperative evaluation that includes a
thorough history and physical examination, paying
particular attention to the presence of medical
co-morbidities, in order to assess surgical fitness.
Routine laboratory studies and a chest X-ray (PA and
858
Table 3 FIGO surgical staging
Adequate abdominal incision (usually vertical)
Peritoneal/pelvic washings for cytology
Surgical exploration of all peritoneal surfaces with biopsies
and/or excision of any suspicious lesion
Total extrafascial abdominal hysterectomy and bilateral
salpingo-oopherectomy
The uterus should be bivalved in the operating room for gross
assessment of myometrial infiltration
Omental biopsies (omentectomy if PSC or CCC)
Pelvic and peri-aortic lymph node selective sampling versus
dissection in all patients except those with stage IA-B grade 1
disease
lateral) are recommended. Symptoms or exam find-
ings, suspicious for advanced disease or local organ
invasion can be further evaluated with colonoscopy or
cystoscopy. Serum levels of CA-125 are elevated in
most patients with advanced or metastatic EC or
unfavorable histologies. Preoperative levels greater
than 40 U/ml can be considered an indication for full
pelvic and peri-aortic lymphadenectomy at the time of
surgical staging (Hsieh et al. 2002).
The benefit of a more extensive radiologic work-up
remains debatable. Cross-sectional imaging in the
pretreatment evaluation can play an important role in
EC by assessment of morphologic prognostic factors,
including tumor size, depth of myometrial penetra-
tion, stage of disease, and lymph node status.
Diagnostic imaging may be helpful even in morbidly
obese patients or the elderly population with multiple
co-morbidities for which radiation therapy rather than
surgery might be advocated as primary treatment.
Imaging may also benefit young women with endo-
metrial carcinoma who wish to preserve fertility, in
which case hormonal therapy may be considered as
primary treatment rather than surgery.
When further imaging is warranted, several studies
have shown that MRI is not only more accurate than
trans-vaginal ultrasound with regard to the degree of
cervical involvement and depth of myometrial invasion,
but also equivalent to CT for assessment of pelvic and
para-aortic lymph nodes (DelMaschio et al. 1993; Kim
et al. 1995; Rockall et al. 2007; Torricelli et al. 2008;
Yahata et al. 2007). The reported overall accuracy of
contrast-enhanced MRI for the clinical staging of EC is
between 85 and 93% (Chung et al. 2007; Savelli et al.
2008). While PET has been shown to be useful for the
evaluation of lymph nodes, its role in the overall clinical
H. R. Cárdenes et al.
staging of EC remains complicated by the fact that up to
45% of grade 1 EC is non-FDG-avid (Horowitz et al.
2004; Kitajima et al. 2008; Suzuki et al. 2007).
Assuming the patient is a surgical candidate, and
there is no vaginal or bulky cervical involvement,
initial surgical management/staging is the recom-
mended approach [International Federation of
Gynecology and Obstetrics (FIGO 1989)]. The fun-
damentals of FIGO surgical staging (Table 3) include
total-abdominal hysterectomy and bi-lateral salpingo-
oophorectomy (TAH-BSO) as well as peritoneal
washings and omental sampling. The utility of pelvic
and para-aortic lymph node dissection, while histori-
cally included as part of the staging procedure, is
currently a topic of much debate and is discussed fur-
ther below. The result of surgical staging is the cate-
gorization of the stage of the disease as per the FIGO
Pecorelli (2009) update (Table 4). Note should be
made of changes in the 2009 update compared to the
original FIGO surgical staging system released in
FIGO (1989). Stage IC is no longer a category, with
disease limited to the endometrium or less than 50%
myometrial invasion being classified as IA, and disease
involving greater or equal to 50% of the myometrium
classified as IB. Furthermore, endocervical glandular
involvement by itself no longer qualifies as stage II
disease, and peritoneal washings are no longer a factor
in stage classification. The other area of note is that
pelvic and para-aortic node involvement has been
separated rather than combining them in a single sub-
stage. This seems to be reasonable since data would
suggest that the prognosis is worse if the para-aortic
nodes are involved. As a result, stage IIIC is now cat-
egorized as IIIC1 (indicating positive pelvic nodes)
and IIIC2 (indicating positive para-aortic nodes with or
without positive pelvic nodes) (Pecorelli 2009).
The prognostic utility of surgical-pathological stage
has been confirmed by multiple studies, being the single
strongest predictor of outcome in patients with EC
(Boronow et al. 1984; Creasman et al. 1987; Morrow
et al. 1991) For those patients who are not surgical
candidates, the clinical staging system adopted by FIGO
(1971) (Table 5) would still apply (FIGO 1971), keep-
ing in mind that approximately 15–20% of the patients
would be upstaged with complete surgical staging.
Subsequent to the FIGO endorsed change in FIGO
(1989) which led to wider, but not universal, adoption
of extended surgical staging (ESS), Morrow et al.
(1991) reported that of 895 surgically staged patients
Technical Aspects of Radiation Therapy in Endometrial Carcinoma 859

Table 4 Endometrial cancer surgical staging system. Pecorelli 2009

Stages Definition
Stage I Tumor limited to corpus uteri
IA Limited to endometrium or invasion to \50% of the myometrium
IB Invasion to C50% of the myometrium
Stage II Extension to the stromal connective tissue of cervix but not beyond the uterus
Stage III Extension outside of the uterus/cervi±regional metastasis
IIIA Tumor invades serosa and/or adnexae
IIIB Vaginal or parametrial involvement
IIIC 1 Metastasis to pelvic lymph nodes
IIIC 2 Metastasis to para-aortic lymph nodes, with or without pelvic lymph node involvement
Stage IV
IVA Tumor invades bladder and/or bowel mucosa
IVB Distant metastasis including intra-abdominal and/or inguinal lymph nodes
Notes on updated staging system (1) Stage IC designation no longer exists. Tumor limited to endometrium and tumor limited to
\50% of myometrium now grouped together as IA, and tumor involving C50% of myometrium now IB rather than IC. (2)
Endocervical glandular involvement no longer stage II, but rather stage I. (3) Positive peritoneal cytology no longer accounted for
in updated system. (4) Differentiation made between involvement of pelvic nodes only (IIIC1) versus involvement of para-aortic
nodes with or without involved pelvic nodes (IIIC2)

Table 5 Endometrial cancer Stages/ Definition

clinical staging system FIGO
(1971)
grades
Stage I Tumor confined to the uterus
IA Length of the uterine cavity B8 cm
IB Length of the uterine cavity [8 cm
Histological Subtypes of Adenocarcinoma
G1 Highly differentiated adenomatous carcinoma
G2 Differentiated adenomatous carcinoma with partly solid areas
G3 Predominantly solid or entirely undifferentiated carcinoma
Stage II Extension to the cervix but not beyond the uterus
Stage III Extension outside of the uterus/cervix but not outside of the true pelvis
Stage IV Extension outside of the true pelvis or involvement of the bladder and/or
rectum
Tumor invades bladder and/or bowel mucosa
Distant metastasis including intra-abdominal and/or inguinal lymph nodes

only 48 were found to have positive para-aortic nodes
and 47/48 had either suspicious para-aortic nodes,
grossly positive pelvic nodes, involved adnexa or
deep myometrial invasion. It was concluded that ‘‘it is
logical to limit the surgical evaluation of aortic nodes
to those patients with suspicious aortic nodes on
palpation or high risk factors such as grossly positive
pelvic nodes, gross adnexal masses or outer-third
myometrial invasion’’. Such high risk factors were
seen in only 25% of patients, but accounted for 98%
of those with positive paraortic nodes (Morrow et al.
1991). In the previous GOG 33 study (Creasman et al.
1987) of 621 clinical stages FIGO I and occult stage II
patients, 11% had metastasis to pelvic and peri-aortic
nodes. The main prognostic factor related with the
presence of positive nodes was the depth of myome-
trial invasion. Regardless of grade, only 1% of
patients with endometrial involvement were found to
860
have metastasis to either pelvic or peri-aortic nodes;
however, the relative frequency of pelvic or peri-
aortic nodal involvement increased to 23 and 17%,
respectively, for deep myometrial invasion (Creasman
et al. 1987).
Retrospective evaluations have demonstrated the
superiority of extensive surgical staging (ESS) in
predicting outcome and allowing more accurate
assessment of the extent of disease and individuali-
zation of adjuvant therapy. However, the impact of
ESS compared with total abdominal hysterectomy
and bilateral salpingo-oophorectomy (TAH-BSO)
without nodal dissection, on the ultimate outcome of
patients with early-stage EC has been questioned.
Benedetti Panici et al. (2008) randomized 514
patients with clinical stage I EC to either TAH/BSO
alone or with systemic pelvic lymphadenectomy, and
found no difference in 5 year disease free or overall
survival (Benedetti Panici et al. 2008). In a similar
trial [MRC-ASTEC trial] randomizing 1,408 women
with clinical stage I disease, (ASTEC Study Group
et al. 2009) Kitchener et al. likewise found no
advantage for systemic pelvic lymphadenectomy in
terms of recurrence free or overall survival.
The Society of Gynecologic Oncology (SGO)
Practice Guidelines, however, has recommended ESS
for those with high risk histologies (e.g., CCC and
UPSC), high grade endometrioid lesions (grade 2–3),
deep myometrial invasion ([50%), clinically evident
extrauterine disease, suspicious nodes, or cervical
involvement (Chen et al. 1999).
4.1 Clinical-Pathologic Prognostic
Factors
Prognostic factors identified in EC include (1) Patient
related factors such as age and medical co-morbidities
and (2) Tumor-related factors, in particular, patho-
logical stage, depth of myometrial invasion, histo-
logical grade and ploidy, cell type (endometrioid vs
non-endometrioid tumors i.e., UPSC and CCC) and
presence of lymphovascular space invasion (LVSI).
The pathological stage is the most significant pre-
dictor of outcome (Morrow et al. 1991).
Zaino et al. (1996), analyzing more than 1,000
patients entered on a GOG protocol, developed two
models of survival for patients with clinical and
pathological stages I–II endometrial cancer. For
H. R. Cárdenes et al.
clinical stage I–II tumors, the cell type, histological
grade, depth of myometrial invasion, peritoneal
cytology, age, and LVSI were all found to be inde-
pendent prognostic factors for survival. However, in
patients with pathological stages I–II, the only two
significant independent prognostic factors for survival
were age and depth of myometrial invasion.
4.2 Adjuvant Therapy—Early Stage
(FIGO I–II) Endometrial
Adenocarcinoma
For the past decade, there existed two prevailing
therapeutic paradigms: 1 TAH-BSO, without exten-
ded surgical staging (ESS), followed by a more liberal
use of post-operative radiotherapy (RT) based upon
histopathological factors noted in the uterine speci-
men and, 2 TAH-BSO with ESS followed by a more
restricted use of post-operative RT. However, given
the results of the PORTEC-2 and ASTEC trials,
which will be discussed in greater detail below, a
more uniform approach is developing for early stage
disease, one that places less emphasis on ESS and
withholds pelvic EBRT for only the highest risk
cases. At the same time, there is continued investi-
gation into the value of adjuvant chemotherapy for the
management of high-risk early stage disease.
4.3 Randomized Trials in Early Stage
(I and occult II) Endometrial Cancer
Aalders et al. (1980) enrolled 540 patients with
endometrial cancer with stages IB–IC undergoing
TAH-BSO without lymph node dissection to receive
adjuvant vaginal brachytherapy, after which the
patients were randomized to observation versus
EBRT. A significant reduction on local recurrence
rates was observed with the addition of pelvic RT, 1.9
versus 6.9%, respectively. There was no difference in
survival between the two groups, although in the
group of patients with IC grade 3 disease there was a
cancer-specific survival advantage with the addition
of pelvic RT (Aalders et al. 1980).
The post-operative therapy in endometrial carci-
noma (PORTEC) trial (which did not require lymph
node sampling), randomized 715 patients with: grade
1, greater or equal to 50% myometrial invasion; grade
Technical Aspects of Radiation Therapy in Endometrial Carcinoma
Table 6 GOG-99 and PORTEC
PORTEC trials. 5 year
cumulative incidence of LRR—RT 4.2%
recurrence and death LRR—no RT 13.7%
DM—RT 7.9%
DM—no RT 7%
Any—RT 9.4%
Any—no RT 17.2%
Death—RT 19.3%
Death—no RT 14.9%
HR high-intermediate risk group
LR low risk group
2, with any myometrial invasion and, grade 3 with
less than 50% myometrial invasion to receive adju-
vant pelvic RT or no further treatment (NFT) (Cre-
utzberg et al. 2000). PORTEC investigators felt that
patients with greater than 50% invasion and grade 3
histology represent a ‘‘higher risk’’ subgroup pre-
sumed to benefit from pelvic radiotherapy, and these
patients were excluded from the trial.
The Gynecologic Oncology Group (GOG-99)
conducted a similar trial in 448 patients with ‘‘inter-
mediate-risk’’ endometrial cancer, defined as stages
IB–IC and occult II disease, after complete surgical
staging, which, as per protocol design, was considered
satisfactory even if only one lymph node was con-
tained in the surgical specimen. The investigators
subsequently defined a ‘‘high-intermediate-risk’’
group (HIRG), which included 132 patients (about
one-third of the study population), based on the pres-
ence of grade 2–3 disease, presence of LVSI and/or
deep myometrial involvement. Patients younger than
50 years of age with the three risk factors, 51–69 years
of age with two factors or greater than 70 years of age
with any of those risk factors were included in the
HIRG and analyzed separately (Keys et al. 2004).
It is important to notice that in each one of these
trials the most significant prognostic factors for loco-
regional recurrence were age, depth of myometrial
infiltration, histological grade and in the GOG study,
LVSI (Aalders et al. 1980; Scholten et al. 2005;
Creutzberg et al. 2000; Kelly et al. 2004).
These trials demonstrated the ability of adjuvant
pelvic RT to decrease pelvic and vaginal recurrences.
Eight-year actuarial local–regional relapse (LRR) was
15 versus 4% in the RT versus NFT patients in the
PORTEC trial (Creutzberg et al. 2003). In GOG-99,
the 5 year LRR was 8% (RT) versus 2% (NFT) with the
861
GOG 99 ALL GOG 99 HR GOG 99 LR
2% 5% 0%
8% 13% 5%
6% 10% 4%
8% 19% 9%
7% 13% 4%
14% 27% 7%
9% 13% 7%
15% 27% 8%
largest difference being in the HIRG with a LRR of 6%
in the RT arm and 26% in the observation arm (Kelly
et al. 2004). Overall survival, however, was not
statistically improved with the addition of pelvic RT.
In the PORTEC trial, 8 year actuarial overall survival
was 71% for RT and 77% for NFT. In GOG-99, despite
a longer recurrence-free interval for those receiving
pelvic RT, the estimated 2 year survival was 92% in
the RT arm and 86% in the observation arm. The HIRG
accounted for nearly two-thirds of the recurrences and
cancer-related deaths. A comparison of the 5 year
cumulative incidence of recurrence/death for the
PORTEC and GOG-99 trials is shown in Table 6.
In both trials, the majority of the recurrences in the
observation arm (up to 75% in the PORTEC trial and
around 70% in the GOG-99 trial) were in the vagina.
In the PORTEC trial, 35 of the 39 patients with iso-
lated vaginal recurrence received salvage treatment
with curative intent (Creutzberg et al. 2003) Thirty-
one of the 35 (89%) patients who received treatment
with curative intent obtained a complete remission,
and 24 of these 31 patients remained disease-free after
a median follow-up of 44 months post-relapse.
In contrast, only four of ten patients with pelvic
relapse obtained a complete remission following sal-
vage treatment. Similar differences were observed for
rates of 3 year post-relapse overall survival: 73%
after vaginal relapse alone versus 8% after pelvic
relapse versus 14% after distant relapse. While based
on a small number of patients, these findings suggest
that many women with vaginal-only relapse can be
salvaged and achieve extended periods of disease-free
survival, while the prognosis for those with pelvic or
distant relapse is likely much worse. Importantly, the
PORTEC authors note that patients randomized to
observation, despite suffering higher rates of vaginal
862
relapse, were no more likely to experience distant
relapse compared to those randomized to adjuvant
EBRT (Creutzberg et al. 2003).
Considering that the HIRG population accounted
for the majority of LRR, and that the majority of LRR
occurred in the vagina, Dutch investigators initiated
PORTEC-2, a randomized multi-institution trial
comparing adjuvant vaginal brachytherapy (VB)
alone versus adjuvant pelvic EBRT for patients with
high-intermediate risk endometrial cancer. ESS was
not required, and patients were eligible if they ful-
filled any of the following high-intermediate risk
criteria; (1) stage IC grade 1 or 2 and age 60 or over,
(2) stage IB grade 3 and age 60 or over, (3) stage 2A,
any age, grade 1 or 2, and (4) stage 2A, any age, grade
3 with less than 50% myometrial invasion.
Four hundred twenty-seven patients were enrolled.
With a median follow-up of 45 months (range 18–
78 months), there was no difference in 5 year actuarial
rates of vaginal recurrence between the VB and EBRT
arms, 1.8 versus 1.6%, respectively, (p = 0.74). The
5 year rates of locoregional relapse (vaginal or pelvic
recurrence, or both) were 5.1% for VB and 2.1% for
EBRT (p = 0.17). There was a significantly higher
rate of pelvic recurrence in the VB arm, 3.8%, com-
pared to 0.5% in the EBRT arm (p = 0.02). Rates of
distant metastases were similar between the two groups
(8.3 vs. 5.7%, p = 0.46). There was also no difference
between the VB and EBRT arms in regards to disease
free survival, 82.7 versus 78.1%, or overall survival,
84.8 versus 79.6%, respectively (Nout et al. 2010).
Finally, when weighing the benefits of adjuvant
RT for early-stage EAC, one must be mindful of its
associated toxicities and how these toxicities vary
between modalities. The toxicity from pelvic EBRT
will be primarily gastrointestinal, genitourinary, and
hematological. The majority of acute toxicity is self-
limited, and treatment interruptions are relatively rare.
The PORTEC-1 investigators found that pelvic RT
was associated with a higher risk of grade 1–2 late
intestinal (17 vs. 1%) and genitourinary (8 vs. 4%)
toxicity when compared to no further treatment.
Grade 3–4 toxicity was rare in both arms, but all
grade 3–4 toxicity occurred in the RT arm (3% of
patients) (Creutzberg et al. 2000). The GOG study
(Kelly et al. 2004) reported results similar to POR-
TEC-1, with statistically significant differences in
intestinal, genitourinary, hematologic, and cutaneous
toxicities between treatment arms. PORTEC-2
H. R. Cárdenes et al.
investigators reported on the difference in toxicity
profiles between pelvic RT and VB. The prevalence
of acute G1-2 GI toxicity was worse for the pelvic RT
arm, 53.8%, compared to 12.6% in the VB arm; this
difference decreased with further follow-up and lost
statistical significance after 24 months. Late grade 3
gastrointestinal toxicity was reported in four (2%)
patients receiving EBRT and in one (\1%) receiving
VB, requiring surgery for bowel obstruction due to
adhesions or fibrosis. No treatment related deaths
occurred (Nout et al. 2010).
In the PORTEC-2 trial, patients in the VB group
reported better social functioning (p = 0.002) and
lower symptom scores for diarrhea, fecal leakage, the
need to stay close to the toilet, and limitation in daily
activities because of bowel symptoms (p = 0.001).
Sexual functioning and symptoms did not differ
between the treatment groups although rates of long-
term vaginal mucosal atrophy were higher among
those receiving VB (Nout et al. 2009). It should be
noted that surgical staging did change the toxicity
profile in the GOG study; patients in both the surgery
alone and radiation therapy arms were noted to have
lymphatic complications (primarily chronic lymphe-
dema, occurring in 2.5% of the control patients and
5% of the radiotherapy patients). This complication
was not noted in patients from the PORTEC studies,
where lymph node dissection was not utilized.
In view of these results, it seems that the use of
postoperative RT should be limited to those patients
with sufficiently high risk of LRR (C15%), and whereas
for the majority of patients with early-stage disease,
vaginal brachytherapy alone should be sufficient.
4.4 Chemotherapy for High-Risk Early
Stage Endometrial Cancer
Neither patients with both C50% myometrial invasion
and grade 3 histology, nor patients with cervical
stromal invasion, are well represented in the above
described trials. The PORTEC authors, echoing the
general consensus, believed that this population was
at a much higher risk for both local and distant
relapse, and thus it was not ethical to randomize these
patients to no further therapy following surgery. This
was confirmed through a separate, non-randomized
arm of PORTEC-1 that enrolled patients with stage IC
grade 3 disease to receive adjuvant pelvic RT.
Technical Aspects of Radiation Therapy in Endometrial Carcinoma
The 5 year rates of pelvic relapse, distant relapse, and
overall survival were 14, 31, and 58%, respectively
(Creutzberg et al. 2004).
As this cohort of patients is clearly at a higher risk
for distant metastases relative to their low- and inter-
mediate-risk counterparts, they have rightfully been
enrolled on a number of trials investigating the value of
adjuvant chemotherapy. The NSGO-EC-9501/EO-
RTC-55991 trial randomized 383 patients, FIGO
(1989) stages IC G3, IIA G3 ([50% myometrial inva-
sion), IIIA, and IIIC, to adjuvant pelvic RT alone versus
adjuvant sequential RT followed by chemotherapy
(various regimens allowed). A similar trial, ILIADE-
III, randomized 153 patients, FIGO (1989) stages IIB–
IIIC, to adjuvant pelvic RT versus adjuvant sequential
doxorubicin and cisplatin followed by RT. Serous and
clear cell histologies were eligible on NSGO-EC-9501/
EORTC-55991 but excluded from ILIADE-III. These
trials, published as a pooled analysis, show a significant
37% reduction in the risk of relapse or death with the
addition of chemotherapy (HR 0.63, CI 0.44–0.89;
p = 0.009). Neither study alone showed significant
differences in overall survival. In the pooled analysis,
overall survival approached statistical significance (HR
0.69, CI 0.46–1.03; p = 0.07) and cancer-specific
survival (CSS) was significantly improved with the
addition of chemotherapy (HR 0.55, CI 0.35–0.88;
p = 0.01). The authors concluded that the addition of
adjuvant chemotherapy to radiation improves progres-
sion-free survival in operated endometrial cancer
patients with no residual tumor and a high-risk profile
(Hogberg et al. 2010).
RTOG 9708 was a phase II trial that investigated
the feasibility of adding concurrent as well as
sequential chemotherapy to adjuvant RT. Forty-six
patients with grade 2 or 3 endometrial adenocarci-
noma with more than 50% myometrial invasion,
cervical stromal invasion, or pelvic-confined extra-
uterine disease received 45 Gy pelvic RT with con-
current cisplatin, 50 mg/m2 on days 1 and 28. Patients
also received IVB, followed by four cycles of
sequential cisplatin and paclitaxel. Maximum late
toxicity was grade 3 in 16% and grade 4 in 5%. At
4 years pelvic, regional, and distant recurrence rates
were 2, 2, and 19%, respectively. Overall survival and
disease-free survival (DFS) rates at 4 years were 85
and 81%, respectively (Greven et al. 2006). Based on
these encouraging results, PORTEC-III is an ongoing
phase III trial comparing adjuvant RT alone to a
863
regimen of concurrent and sequential chemo-RT
similar to RTOG 9708 [PORTEC-3].
Multiple groups have attempted to remove radiation
therapy altogether from first-line treatment for patients
with early-stage high-risk EC. Maggi et al. (2006)
randomized 345 patients with stages IC-G3, II-G3 with
myometrial invasion greater than 50%, and stage III
patients to adjuvant pelvic RT versus five cycles of
adjuvant cyclophosphamide, doxorubicin, and cis-
platin (CAP). Similarly, Susumu et al. (2008) ran-
domized 385 patients with stages IC–IIIC with more
than 50% myometrial invasion to adjuvant pelvic RT
versus at least three cycles of CAP. Neither trial
showed any difference in overall survival or progres-
sion free survival, nor did they show any significant
difference in patterns of recurrence between the two
arms. Currently the GOG is conducting a phase III trial,
GOG-0249, comparing pelvic radiation therapy ±
vaginal cuff boost (standard arm) to vaginal brachy-
therapy followed by Paclitaxel and Carboplatin
chemotherapy (investigational arm) in patients with
high-risk early stage endometrial cancer.
5 Risk Groups in Early Stage
Endometrial Cancer
As the majority of available data regarding risk group
stratification and treatment recommendations are
based on the 1989 FIGO surgical staging system rather
than the 2009 update, the following guidelines refer to
the 1989 stage designations. Please refer to Table 4 for
a list of changes in the 2009 update (Table 7).
1 Low-Risk Group
a Stage IA disease, grade 1–2, without evidence
of LVSI, has a recurrence rate of less than 10%
(Morrow et al. 1991). The risk of positive pel-
vic nodes for this group is also very low, less
than 5% (Creasman et al. 1987). These patients
can be managed with surgery alone, even
without ESS (Mariani et al. 2000), without
adjuvant therapy.
2 Low-Intermediate Risk Group
a Stage IA, grade 3, represents a small subgroup
(only eight patients in GOG 33) for which
potential options in the adjuvant setting, with or
without surgical staging, may include observation
versus vaginal brachytherapy alone depending on
the absence or presence of other risk factors.
864
Table 7 Prognostic groups in early stage endometrial cancer
Low risk Intermediate-low risk
Stage IA, Stage IA, G3
G1
Negative LVSI
Stage IA, Stage IB, G1
G2 Stage IB, G2, negative LVSI
Stage IIA, grade 1, \50% MI, negative
LVSI
b Stage IB, grade 1–2, have excellent outcome
with recurrence rates between 2 and 4% after
ESS (Straughn et al. 2002) or with adjuvant
vaginal brachytherapy without routine lymph
node staging (Alektiar et al. 2005).
i In the absence of LVSI, patients with stage
IB grade 1 disease could be observed,
whereas patients with IB grade 2 could be
offered vaginal brachytherapy alone (mainly
in older women) versus observation.
3 High-Intermediate Risk Group
a Stage IB, grade 3, stage IC, grade 1 and 2, and
stage IIA (apart from grade 3 with greater than
50% myometrial invasion). Based on PORTEC-
2, VB alone is appropriate, regardless of sur-
gical staging.
b Stage IC, grade 3, and stage IIA, grade 3 with
deep myometrial invasion. Five year rates of
pelvic relapse, distant relapse, and overall
survival with adjuvant pelvic RT alone are 14,
31, and 58%, respectively (Creutzberg et al.
2003). Options include pelvic RT versus pelvic
RT + concurrent/sequential chemotherapy as
per NSGO-EC-9501/EORTC-55991 and RTOG
9708. May consider VB alone if young age, no
LVSI, and complete ESS.
4 High-Risk Group
a Stage IIB disease, any grade. Options include
pelvic RT ± VB versus pelvic RT + concurrent/
sequential chemotherapy ± VB as per NSGO-
EC-9501/EORTC-55991 and RTOG 9708.
b Patients with unfavorable histologies, UPSC
and CCC should also be considered High-risk
patients requiring adjuvant therapy. These will
be discussed later in the chapter.
H. R. Cárdenes et al.
Intermediate-high risk High risk
Stage IB, G3 Stage IIB, any
grade
Stage IC, any grade
Stage IIA, grade 2–3, [50%
MI ? LVSI
1/3 above w/age 370 Papillary or
2/3 above w/age 350 Clear cell
3/3 above w/age \50 carcinoma
6 Adjuvant Therapy—Advanced
Stage (FIGO III–IV) Endometrial
Adenocarcinoma
Even with positive cytology no longer factoring into
the updated FIGO staging, patients with advanced EC
still represent a very heterogeneous group with sur-
vival ranging from about 15% for patients with stage
IVB to nearly 60% for those with stage IIIA (National
Cancer Data Base 2004). Within the stage III classi-
fication, it is possible to distinguish a ‘‘favorable’’
group that includes patients with isolated adnexal
involvement (Connell et al. 1999) or positive pelvic
nodes with negative retroperitoneal sampling/dissec-
tion (Nelson et al. 1999). These patients generally do
quite well with adjuvant pelvic RT, with survival
rates between 65 and 85%. However, patients with
uterine serosal involvement have a worse prognosis
with a high rate of distant relapse (around 50%) and
5 year disease-free survival of less than 50% in some
series (Ashman et al. 2001).
Patients with stage IIIC disease also represent a
heterogeneous group with very different outcomes
depending upon the presence of isolated pelvic nodes
without any other significant risk factors, positive peri-
aortic nodes, or presence of multiple sites of extra-
uterine disease. Patients with positive pelvic nodes
only, without any other site of extrauterine disease
have 5 year disease-free survival between 55 and
70%, whereas in the presence of other extrauterine
disease the survival drops dramatically to around 30%
(Mariani et al. 2002). The prognostic significance of
the presence of peri-aortic nodes has been recognized
in the Pecorelli (2009) FIGO staging system.
Technical Aspects of Radiation Therapy in Endometrial Carcinoma
Patients with advanced EC have been treated with
different approaches in the adjuvant setting including
pelvic RT, extended field RT (pelvic + peri-aortic
RT), whole abdominal irradiation (WAI), and che-
motherapy. Currently, the prevailing paradigm for
patients with surgically staged extra-uterine disease
entails adjuvant chemotherapy with cisplatin and
doxorubicin, withholding RT for patients who are
believed to have an especially high risk of pelvic
failure. The popularity of this approach arises pri-
marily from GOG-122, one of the few randomized
trials conducted in this patient population (Randall
et al. 2006). This trial randomized patients with stages
III–IV disease (without evidence of distant metasta-
sis) after surgical staging and optimal surgical deb-
ulking, to receive WAI versus adjuvant chemotherapy
(doxorubicin and cisplatin), and demonstrated the
superiority of chemotherapy over WAI in terms of
progression-free survival and overall survival.
Since the publication of GOG-122, two other ran-
domized studies, one from Japan (Susumu et al. 2008)
and the other from Italy (Maggi et al. 2006), have
addressed the same question but in a more heteroge-
neous population including patients with uterine-con-
fined disease. Neither study found a significant
difference between adjuvant chemotherapy compared
to adjuvant RT in terms of disease free or overall sur-
vival. It should be noted, however, that upon perform-
ing an unplanned subset analysis, the Japanese study
(Susumu et al. 2008) did report an overall and disease
free survival benefit for chemotherapy among patients
with intermediate-high risk disease, defined as (1) stage
IC and age greater than 70 or grade 3 histology, or (2)
stage II or IIIA disease (positive cytology) with greater
than 50% myometrial invasion. However, in the high
risk group [defined as stage IIIA other than peritoneal
cytology, IIIB and IIIC] there was no difference in the
5 year overall survival (RT 76%, CT 71%) or disease-
free survival (RT 79%, CT 64%) (Susumu et al. 2008).
Despite the current trend of treating patients with
advanced EC with chemotherapy alone, there remains
active investigation into the value of combined
modality therapy. This interest arises from the
increased rates of local failure observed in the che-
motherapy alone arms of the above-mentioned trials,
as high as 18% in GOG-122. In a Canadian phase II
study, (Lupe et al. 2009) enrolled 43 patients with
stage III/IV EC to receive adjuvant Carboplatin and
Paclitaxel, four cycles every 3 weeks, followed by
865
EBRT to 45 Gy followed by another two cycles of the
same chemotherapy. They observed three local
recurrences, with 3 year rates of DFS and OS of 53
and 68%, respectively. RTOG 9708 used a concurrent
approach to treat 46 patients with surgically staged
IB—IIIC disease (66% of the patients had stage III
disease). Patients received adjuvant EBRT to 45 Gy
concurrently with cisplatin, 50 mg/m2, on days 1 and
28. Vaginal brachytherapy was performed after
EBRT. All patients then received a further four
courses of Cisplatin and Paclitaxel given every
4 weeks. The rate of pelvic recurrence was 2% for all
patients, and 4 year rates of DFS and OS for patients
with stage III disease were 72 and 77%, respectively.
More than 90% of the patients were able to complete
treatment as planned, and rates of acute and long-term
toxicity were deemed acceptable (Greven et al. 2006).
Homesley et al. 2009 reported the results of the
GOG-184 trial in which after surgical debulking and
volume-directed irradiation of the pelvis/para-aortic
lymph nodes, 552 eligible patients with advanced stage
EC were randomized between six cycles of Cisplatin
(50 mg/m2) and Doxorubicin (45 mg/m2) [CD] with or
without Paclitaxel (160 mg/m2) [CDP]. Accrual closed
to stage IV patients in June, 2003. Approximately 80%
completed six cycles of chemotherapy. Hematologic
adverse events, sensory neuropathy, and myalgia, were
more frequent and severe in the Paclitaxel arm
(p \ 0.01) which was confirmed by quality of life
assessments. Percentage of patients alive and recur-
rence-free at 36 months was 62% for CD versus 64%
for CDP. The hazard of recurrence or death relative to
the CD arm stratified by stage is 0.90 (95% CI is 0.69–
1.17, p = 0.21, one-tail). However, in subgroup anal-
ysis, CDP was associated with a 50% reduction in the
risk of recurrence or death among patients with gross
residual disease (95% CI: 0.26–0.92). Stage, residual
disease, histology/grade, positive para-aortic node and
cytology, pelvic metastases, and age were significantly
associated with RFS. Interestingly, volume directed
radiation therapy was well tolerated among patients
receiving either the two or three chemotherapy drug
combinations. The authors concluded that the addition
of Paclitaxel to Cisplatin and Doxorubicin following
surgery and radiation was not associated with a sig-
nificant improvement in RFS but was associated with
increased toxicity (Homesley et al. 2009). The ongoing
GOG 0258 is a phase III trial comparing adjuvant
chemotherapy alone (Carboplatin + Paclitaxel 9 6) to
866
adjuvant chemoradiation in patients with stage III/IVA
EC. The investigational arm is similar to the regimen
utilized in RTOG 9708.
7 Radiation Therapy Techniques
There are two types of RT that can be used either alone
or in combination in the management of endometrial
cancer. These are intracavitary brachytherapy (ICB)
and external beam radiotherapy (EBRT). Over the last
four decades there has been a shift from preoperative
RT (EBRT ± ICB) to postoperative EBRT ± intrav-
aginal brachytherapy (Aalders et al. 1980), to EBRT
alone in the 1990s (Creutzberg et al. 2000; Keys et al.
2004). Over the past decade, especially since the
publication of PORTEC II, ICB alone has become the
focus of what is now a more tailored adjuvant treatment
paradigm based on the histopathological features of the
surgical specimen (Nout et al. 2010).
7.1 Preoperative Irradiation
Although it is less commonly used now than in the past,
it is still advocated for some patients such as those with
gross involvement of the cervix (FIGO clinical stage
II) or vagina (FIGO clinical stage IIIB). Preoperative
irradiation generally involves the use of ICB alone or in
combination with pelvic EBRT. Patients undergoing
ICB only in the preoperative setting can undergo extra-
fascial hysterectomy as soon as 1–3 days from com-
pletion of the implant. If EBRT is required, surgery
should be done no sooner than 4–6 weeks after com-
pletion of therapy when most of the radiation-associ-
ated inflammation has subsided.
Although uncommon, patients may present with
gross pelvic or retroperitoneal nodal disease, in the
absence of distant metastasis. These patients could be
considered for preoperative extended field RT and
brachytherapy to be followed by surgical staging.
7.1.1 Preoperative Intracavitary
Brachytherapy
7.1.1.1 Low-Dose-Rate Brachytherapy
For preoperative intracavitary insertions, in addition
to afterloading tandem and vaginal ovoids, it is the
practice at Mallinckrodt Institute of Radiology (MIR)
H. R. Cárdenes et al.
to pack the uterine cavity with afterloading Heyman–
Simon capsules. The implant is performed in the
operating room with the patient under general or
spinal anesthesia. Following the exam under anes-
thesia (EUA), a Foley catheter is placed in the bladder
and the bulb is inflated with 7 cc of contrast material.
Subsequently, a D and C is performed with or without
cervical biopsies if they had not been previously
obtained. Radio-opaque seed markers are placed on
the cervix at 12 and 6 o’clock positions. The Simon–
Heyman capsules have diameters of 6, 8, and 10 mm.
The capsules are numbered on their distal end and the
order of capsule placement is recorded at the time of
placement since they are to be removed in reverse
order of their placement. Simon–Heyman capsules are
placed through the cervical os into the uterine fundus
to fill the body of the uterus. Depending upon the
uterine cavity sounding, small capsules (i.e., 6 mm)
are to be used for patients with hysterometry between
6 and 8 cm and large capsules (i.e., 8–10 mm) for
those with sounding of 8–12 cm. The number of
capsules placed in the uterus would depend on its
size, generally 5–7 although large uterine cavities
could potentially accommodate as many as 16. The
intrauterine tandem is placed into the uterus such that
the tip of the tandem abuts the lowest Simon–Heyman
capsule, generally at the lower uterine segment with
the flange at 4–6 cm. Vaginal ovoids are then placed
in the vaginal fornices. The size of the ovoids should
always be the largest diameter that fills the lateral
fornices (usually 2 or 2.5 cm). Once all the applica-
tors are in adequate position, the vagina is packed
with Ray-tack vaginal packing soaked in AVC cream.
Vulvar labial sutures are sometimes placed to prevent
the implant from sliding down. Localization radio-
graphs (AP and Lateral orthogonal films) are obtained
in the conventional simulator, after the procedure is
completed, for dosimetry purposes (Fig. 1a, b).
In the absence of Simon–Heyman capsules, one or
two intrauterine tandems can be used in combination
with vaginal ovoids (Fig. 2a, b). If there is tumor
extension into the vagina, the entire length of the
vagina should be treated with Delclos vaginal cylin-
ders, if tumor infiltration is less than 5 mm in thick-
ness, or Syed-Nebblett interstitial implant, depending
on tumor bulk.
When using low-dose-rate brachytherapy, the
implant remains in place for 48–72 h. During that
time, the patients are kept in the hospital on radiation
Technical Aspects of Radiation Therapy in Endometrial Carcinoma 867

Fig. 1 a AP radiograph tandem + novoids + heyman capsules. Preoperative brachytherapy. b Lateral radiograph tandem + ovoids
+ heyman capsules. Preoperative brachytherapy

Fig. 2 a AP radiograph, preoperative tandem and ovoids. b Lateral radiograph, preoperative tandem and ovoids

precautions. While inpatient it is important to obtain paid to deep venous thrombosis prophylaxis by using
adequate pain control, for which we use a patient LovenoxÒ and sequential compression devices
controlled anesthesia (PCA) machine with Morphine (SCDs) as well as encouraging patients to do leg
or Fentanyl. In addition, careful attention should be exercises. Finally, patients are kept on a low residue
868
diet and loperamide while in bed, and they are
encouraged to do incentive spirometry to minimize the
risk of atelectasis and subsequent respiratory infec-
tions. Prophylactic use of antibiotics is not recom-
mended unless if at the time of the D and C the patient
is found to have a pyometra or if uterine perforation is
suspected. Once the implant time is completed the
radioactive sources will be removed in the patient’s
room and returned to storage. Subsequently, the vag-
inal packing, ovoids, tandem, and Simon–Heyman
capsules are removed (the latter ones in reverse order
of their placement). Generally, patients are given a
‘‘bolus’’ of the pain medication while on the PCA,
approximately 30 min before implant removal. Care-
ful attention should be paid to potential vaginal
bleeding after removal of the implant. The patients
will be discharged home once they are able to void
without difficulties, and have had a bowel movement
and are able to ambulate without assistance.
The typical prescription, empirically established, is
of 3,500–4,000 mghRaEq to be delivered to the
uterus and 6,500 cGy surface dose to the vagina. The
Simon–Heyman capsules are loaded with 10 mgRaEq
each; the tandem is loaded generally with three
sources (for 6 cm long tandem), 10-20-20 mgRaEq
(adequate dose to the lower uterine segment); each
one of the ovoids loaded with 20 mgRaEq (2 cm
ovoids) or 25 mgRaEq (2.5 cm ovoids). Classical
point A dose rates will be calculated as for cervical
cancer brachytherapy implants, as well as points B, P,
rectal and bladder doses.
7.1.1.2 High-Dose-Rate Brachytherapy
The procedure for an HDR preoperative implant is
similar to an LDR implant, although many centers
will perform the procedure in an HDR suite as
opposed to a formal operating room. CT-based
treatment planning is preferred, but if image-guidance
is not available, the ABS recommends placement of
the dose point 2 cm from the central axis at the
midpoint of the intra-uterine applicator. If delivering
HDR brachytherapy alone, in the absence of EBRT,
the ABS recommends 4 fractions of 8.5 Gy at a depth
of 2 cm to the above described dose point. If deliv-
ering HDR in addition to 45 Gy EBRT, only two
fractions of 8.5 Gy at a depth of 2 cm are required. As
detailed by Nag et al. (2000) there are in fact multiple,
more protracted regimens also appropriate for the pre-
operative setting.
H. R. Cárdenes et al.
7.1.2 Preoperative External Beam Radiation
Therapy
Patients with gross cervical involvement or more
advanced disease could potentially benefit from
EBRT to the pelvis in addition to ICB. Generally,
patients will receive a dose between 20 and 40 Gy
(180 cGy/fraction), using photon energies greater
than 10 MV with a four field technique (AP/PA and
lateral fields). Computerized tomography (CT) scan
simulation is encouraged, and oral contrast should be
used to opacify the small bowel. A vaginal marker
should be placed in the vagina in addition to seed
markers at the most distal tumor extent in the vagina,
to be able to adequately encompass the gross tumor
volume (GTV). This includes the entire uterus and
cervix as well as any gross regional lymphadenopa-
thy. The clinical target volume (CTV) includes the
GTV as well as the pelvic lymph node areas poten-
tially harboring microscopic disease; this is the
obturator, external, and internal iliacs as well as the
lower common iliacs. Careful attention should be paid
to include the external iliacs anteriorly as well as the
presacral nodes posteriorly (S2–S3 level), in the lat-
eral fields, since these nodal areas are at high risk in
the presence of gross cervical involvement.
Every attempt should be made to minimize the
volume of small bowel included in the radiation fields
by using bladder distension, or placing the patient in
the prone position. Similarly, as much as possible of
bladder and rectum volume should be spared without
compromising the coverage of the clinical target
volume.
At our institution, for those selected patients with
clinical Stage II uterine cancer with gross cervical
infiltration, we have used a combination of EBRT,
3,960–4,500 cGy in 22–25 fractions, followed by a
single ICB implant using intrauterine tandem and
vaginal ovoids to deliver a dose of 3,000–3,500 cGy
to classical point A. After completion of the implant,
the split fields, using a central customized block, will
receive a boost of 540 cGy to deliver a total pelvic
side wall dose of 4,500 cGy.
Grigsby et al. 1992 reported on 858 patients with
clinical stage I endometrial cancer treated with
preoperative LDR intracavitary brachytherapy
(2,500–4,000 mghRaEq to the uterus with Heyman
capsules and intrauterine tandem, and 6,500 cGy
surface dose to the upper vagina) followed by TAH-
BSO done within 3 days to 6 weeks following
Technical Aspects of Radiation Therapy in Endometrial Carcinoma
completion of the RT. When deep myometrial inva-
sion was present, patients received postoperative
EBRT, 2,000 cGy to the whole pelvis and an addi-
tional 3,000 cGy to the parametrium with a midline
step wedge. The 5 year survival rate for all patients
was 84%, with a 5 year PFS of 92 and 86% for FIGO
clinical stages IA and IB, respectively.
7.2 Postoperative Irradiation
While the application of adjuvant radiation therapy
has become increasingly tailored to the specific
prognostic factors of each individual patient, the
overwhelming trend in early stage EC has been
towards the use of intracavitary brachytherapy alone.
This trend was initially based on the findings of two
prospective randomized trials investigating the role of
adjuvant EBRT in early stage EC, either after TAH-
BSO alone or after ESS (Creutzberg et al. 2000; Keys
et al. 2004). Both GOG-99 and PORTEC-1 found that
adjuvant EBRT in early stage intermediate-risk EC
significantly improved loco-regional control and DFS,
without a significant impact on overall survival.
On further analysis, both trials also suggested that
adjuvant RT may be unnecessary for patients with
low-intermediate risk disease, and for those with
high-intermediate risk disease, the majority of local–
regional recurrences were solely within the vagina,
thus vaginal brachytherapy alone was adequate. These
findings were confirmed in PORTEC-2, which found
adjuvant ICB alone to be equivalent to adjuvant
EBRT for this population (Nout et al. 2010). The use
of EBRT is still recommended in those patients with
deeply invasive tumors (stage IC), poorly differenti-
ated histologies –including unfavorable types such as
UPSC and CCC, and patients with pathological stage
IIB without ESS, mainly if there is evidence of LVSI
in the surgical specimen. Whether some of these
high-risk patients can be managed with vaginal
brachytherapy alone is unknown.
As discussed above, patients with stages III—IVA
disease may receive adjuvant chemotherapy alone, or
in combination with sequential and/or concurrent RT,
involving pelvic RT ± extended field RT (EFRT) to
cover the peri-aortic nodes in patients with positive
nodes. Based on the results of GOG-122, WAI is no
longer an accepted adequate therapy in patients with
advanced EC.
869
7.2.1 Postoperative Intracavitary
Brachytherapy
7.2.1.1 Low-Dose-Rate Intracavitary
Brachytherapy
(LDR-IVB) is generally performed in the operating
room with the patient under anesthesia. After the
EUA, a Foley catheter is placed in the bladder and the
bulb is inflated with 7 cc of radiopaque contrast
material. A radiopaque seed marker is placed in the
center of the colpectomy scar. Fletcher–Suit after-
loading colpostats are placed in contact with the
suture line; always using the largest diameter ovoids
that can be comfortably accommodated by the
patient’s anatomy. Subsequently, the applicators are
kept in place by carefully packing in front and behind
the ovoids, to improve separation from the recto-
vaginal and vesico-vaginal septum. The packing of
the entire vagina is completed and often two labial
sutures are placed in the vulva to further avoid dis-
placement of the applicators. After the implant is
completed in the operating room, a set of orthogonal
radiographs (AP and lateral) are obtained to document
applicator placement and obtain dosimetry (Fig. 3a,
b). Generally, a dose of 6,500 cGy is prescribed to the
vaginal surface. Point doses to the rectum and bladder
should be calculated and documented as well.
7.2.1.2 High-Dose-Rate Intracavitary
Brachytherapy
High-dose-rate intracavitary brachytherapy (HDR-
IVB) has become quite popular primarily due to
patients’ convenience, as it is an outpatient procedure
with much shorter treatment times. Generally, 2–3
procedures are performed at 1 week intervals. Vagi-
nal ovoids or more commonly vaginal cylinders are
used. These are commercially available with design
similar to the LDR applicators, with diameters rang-
ing from 1.5 to 4 cm (Fig. 4). For patients with a
more retracted vaginal cuff (‘‘dog-ear’’ shaped),
vaginal ovoids are preferred since they allow better
contact with the vaginal cuff surface. It is imperative
for the vaginal mucosa to be in contact with the
applicator surface in order to obtain an effective dose
distribution and, therefore, the largest diameter cyl-
inder or ovoids that can comfortably fit in the vagina
should be used. The position of the applicator should
be rechecked before each treatment and adjusted
as necessary. It is important to avoid backward
870
Fig. 3 a AP radiograph of LDR postoperative vaginal ovoids. b Lateral radiograph of LDR postoperative vaginal ovoids
Fig. 4 HDR vaginal cylinders
placement of the applicators since this would
contribute to higher doses to the rectum.
Localization radiographs for each insertion should
be obtained in the treatment position for dosimetry
purposes (Fig. 5a–c). Although this is not a generalized
practice when using vaginal cylinders, we strongly
recommend doing it for documentation. In addition,
although it would be ideal to obtain a customized plan
prior to each fraction, the films and dosimetry are gen-
erally obtained only prior to the first application, since
they are time consuming and when using an applicator
with a fixed geometry, repeating the plan prior to each
fraction seems unnecessary (assuming the geometry of
the implant remains the same for each fraction).
Generally, the proximal 3–5 cm of the vagina is
treated. At our institution, we treat the entire length of
the vagina only in those patients with unfavorable
H. R. Cárdenes et al.
histologies, such as UPSC and CCC. In those situa-
tions, special attention should be paid to avoid a
protruding source at the introitus. The last active
source position should be placed at least 1 cm prox-
imal to the introitus. Placement of a radiopaque
marker at the introitus as well as at the vaginal cuff is
highly recommended.
The HDR dose depends on the specification point
and whether EBRT is used as well. We strongly
recommend reviewing the ‘‘American Brachytherapy
Society (ABS) recommendations for HDR Brachy-
therapy for Carcinoma of the Endometrium’’ pub-
lished by Dr. Nag et al. (2000). The most commonly
used regimen when using HDR-IVB alone is 650–
700 cGy per fraction, per week, prescribed to a depth
of 0.5 cm from the vaginal surface. The dose distri-
bution should be optimized to deliver the prescribed
dose to the points of interest. Optimization points
should be placed not only along the lateral vaginal
surface but also at the apex (or 0.5 cm depth,
depending upon prescription point), and along the
curved portion of the vaginal cylinder to assure ade-
quate distribution (Fig. 5c).
When patients have received external beam, the
most common fractionation used at our institution is
two fractions of 500–550 cGy prescribed at a depth of
0.5 cm or three fractions of 600 cGy prescribed to the
surface of the vagina. We generally use this second
regimen in higher risk patients such as stage IIB or in
the presence of LVSI. Table 8 shows some of the
Technical Aspects of Radiation Therapy in Endometrial Carcinoma 871

b Fig. 5 a AP radiograph. postoperative vaginal cylinders, 3 cm

diameter. b Lateral radiograph. postoperative vaginal cylinders,
3 cm diameter. c Optimization and dose distribution of 3 cm
vaginal cylinders. 700 cGy prescribed to 0.5 cm from the
vaginal surface

ABS recommended schedules for HDR-ICB when

used as the only adjuvant therapy or after whole
pelvic RT. For additional information regarding other
potential schedules please refer to Dr. Nag’s publi-
cation (Nag et al. 2000).
Occasionally, patients with stage III disease are
given HDR-IVB after EBRT. At our institution we
limit the use of IVB in advanced disease to those
patients with lower uterine segment or cervical
involvement, positive vaginal margins, or LVSI.
Patients with Stage III disease, optimally debulked,
will receive a single fraction of HDR-IVB delivering a
dose of 700 cGy prescribed to a depth of 0.5 cm from
the vaginal surface after an EBRT dose of 5,040 cGy.
Imaged guided brachytherapy (IGBT) using HDR-
CT compatible applicators have been incorporated as
a routine practice at our institution. Advantages of
IGBT include better delineation of the high risk
clinical target volume, three-dimensional reconstruc-
tion of the surrounding structures, in particular the
small bowel, rectum and bladder, obtaining dose-
volume histograms of the reconstructed volumes, and
subsequent optimization of the dose distribution to
minimize acute and long term toxicity (Fig. 6a–c).

7.2.2 Postoperative External Beam

Radiation Therapy Techniques
CT simulation is encouraged for better delineation of
target volumes and sparing normal tissues, primarily
small bowel, rectum, and bladder. The four field
technique is the most commonly used, with treatment
delivered using a linear accelerator with a peak pho-
ton energy of 10 MV or greater.
Whole Pelvis EBRT fields in patients with negative
pelvic and peri-aortic nodes, or positive pelvic nodes
with negative sampled peri-aortic nodes, should
encompass all the potential nodal areas of micro-
scopic involvement, with adequate margins, as well as
the proximal half to two-thirds of the vagina. At the
time of simulation, a vaginal marker should be used
as well as oral contrast to opacify the small bowel. If
possible, maneuvers such as full bladder or the use of
‘‘belly boards’’ may be explored, to exclude as much
as possible of small bowel in the radiation fields.
872
Table 8 ABS recommendations for adjuvant HDR vaginal brachytherapy in endometrial cancer. Modified from Nag et al. (2000)
# Of fractions HDR Dose/Fx (Gy) Dose-specific point
Adjuvant HDR Vaginal Brachytherapy Alone
3 7.0 0.5 cm depth
4 5.5 0.5 cm depth
3 10.5 Vaginal surface
Adjuvant EBRT–4,500 cGy- and HDR Vaginal Brachytherapy
2 5.5 0.5 cm depth
3 6 Vaginal surface
Definitive EBRT–4,500 cGy- and HDR Vaginal Brachytherapy for Recurrent Disease
3 7 0.5 cm depth
4 6 0.5 cm depth
The AP/PA pelvic fields superior border will be
through the L4-5 interspace unless the target volume
(e.g., need for inclusion of common iliac nodes in
patients with positive pelvic nodes) would not be
encompassed adequately in a cephalad direction. In the
latter case, a 2 cm margin should be added to
the highest level of pathologic abnormality, but should
not be cephalad to the L-3/L-4 interspace. The lateral
border will be 2 cm beyond the lateral margins of the
bony pelvis. The inferior border will be inferior to the
obturator foramen or the lowest extension of vaginal
disease with at least a 3 cm margin. The inferior aspect
of any potential vaginal extension should be marked so
that the inferior border of disease can be documented
and treated with at least 3 cm margins.
Lateral Pelvis Fields anterior border should be
determined by the location of the external iliac vessels
as drawn at the time of the CT simulation with a
minimum margin of 1.5 cm (generally anterior to the
symphysis pubis). The posterior border should be
placed at least 1.5 cm behind the anterior surface of
the sacrum to adequately include the sacral nodes, at
risk in those patients with lower uterine and cervical
tumor extension. Attention should be paid to exclude
as much as possible of the sacral plexus. The posterior
wall of the rectum should be excluded provided that
the vagina is adequately covered (as delineated by
vaginal marker) with a 2–3 cm margin. Superior and
inferior borders will be the same as for the anterior and
posterior fields. If clips are present from the lymph
node dissection to document the position of the lymph
nodes, then these should be used as a guide when
anterior blocks are designed to shield small bowel.
There should be at least a 3 cm margin on the anterior
H. R. Cárdenes et al.
Equivalent of tumor dose (Gy) Equivalent of late effect dose
29.8 23.2
28.4 21.1
53.8 45.6
58.5 53.7
68.3 61.3
74.0 66.4
76.3 67.4
edge of the L-5 vertebral body, and the anterior two-
thirds of the vertebral body should be included in the
field in order to adequately cover the common iliac
nodes with a 1.5–2 cm margin (Fig. 7a, b).
More recently intensity modulated radiation therapy
(IMRT) is being incorporated in the adjuvant treatment
of EC, for those patients requiring EBRT, in an attempt
to minimize acute and long-term gastrointestinal and
genitourinary toxicity (Ahamad et al. 2005; Mundt
et al. 2003) (Fig. 8a, b). In addition, IMRT or Intensity
Modulated Arc Therapy (IMAT) allows significant
reduction in dose to the bone marrow, which could
potentially result in better hematological tolerance in
high risk patients undergoing pelvic with/without para-
aortic irradiation in combination with systemic che-
motherapy (Brixey et al. 2002; Lujan et al. 2003; Wong
et al. 2005). However, it has been well recognized that
this technique requires accurate target delineation (CT
simulation with IV and gastrointestinal contrast
required), highly reproducible patient immobilization,
and a clear understanding of internal-organ motion in
order to achieve optimal advantage in the use of IMRT
over conventional methods of post-hysterectomy pelvic
radiation therapy (Ahamad et al. 2005; Mundt et al.
2003; Wong et al. 2005).
Extended Pelvic and Peri-aortic Fields should be
treated in patients found to have positive peri-aortic
nodes, when pelvic nodes are positive and no peri-
aortic lymph node sampling has been performed or
patients without ESS with positive pelvic nodes by CT
scan. The use of CT simulation is crucial when treating
extended fields, since this allows an accurate delinea-
tion of the kidneys, small bowel, and liver as well the
clinical target volume, which should encompass the
Technical Aspects of Radiation Therapy in Endometrial Carcinoma
Fig. 6 a Axial CT with dose distribution for postoperative
HDR vaginal cylinders, 3 cm diameter, 500 cGy prescribed to
0.3 cm from the vaginal surface. b Sagittal CT with dose
distribution for postoperative HDR vaginal cylinders, 3 cm
diameter, 500 cGy prescribed to 0.3 cm from the vaginal
surface. c Coronal CT with dose distribution for postoperative
HDR vaginal cylinders, 3 cm diameter, 500 cGy prescribed to
0.3 cm from the vaginal surface
peri-caval, inter aorto-cava and para-aortic areas with a
minimum margin of 1.5 cm for microscopic disease or
2–2.5 cm for gross residual disease.
AP/PA Extended Fields superior border will be at
T11-T12 or L1-L2 interspace, depending upon the
extent of the nodal disease, inferior border as the
inferior border of the pelvic fields described above.
873
Fig. 7 a AP postoperative whole pelvis field. b Lateral
postoperative whole pelvis field
Lateral borders should include the entire peri-aortic
region as delineated by CT scan simulation, including
any potential gross lymphadenopathy with a margin
between 1.5 and 2 cm (in uninvolved areas) and 2–
2.5 cm if gross disease present. A minimum width of
5 cm is required. Attention should be paid to exclude
as much as possible of the kidney volume. At the
level of the pelvis, the lateral borders should be as
described above with a margin between 2 and 2.5 cm
beyond any grossly involved pelvic nodes and
1.5–2 cm for microscopic disease only.
874
Fig. 8 a Axial CT with dose distribution of postoperative
pelvic IMRT, prone position on belly board. b Sagittal CT with
dose distribution of postoperative pelvic IMRT, prone position
on belly board, vaginal marker in place
Lateral Extended Fields superior and inferior bor-
ders are the same as in the AP/PA fields. The anterior
border should cover the entire peri-aortic regions as
delineated by CT scan with a 1.5 cm margin in unin-
volved areas and 2–2.5 cm margins around any
grossly involved pelvic or peri-aortic nodes. The
posterior border should be anterior to the spinal canal
in order to protect the spinal cord and lumbo-sacral
plexus. At least the anterior 1/2–2/3 of the vertebral
body should be included in the field in order to ade-
quately encompass the peri-aortic region (Fig. 9).
Patients treated with extended fields will receive
4,500 cGy delivered to the pelvic and peri-aortic
fields at 150 cGy per fraction, using a four field
technique, in 29 fractions. The pelvis will receive a
total dose of 5,040 cGy in 28 fractions at 180 cGy/
fraction. Therefore, a daily boost to the pelvis of
30 cGy, via AP/PA fields (superior edge of the pelvic
field at L5-S1 or L4-L5) will be required in order to
deliver 180 cGy/fraction to the pelvis while the peri-
aortic region would receive 150 cGy/fraction. It is
H. R. Cárdenes et al.
important to deliver the boost dose with AP/PA fields
rather than lateral fields in order to preserve some of
the bone marrow in the iliac bones. After 28 fractions,
the peri-aortic region treatment should receive one
additional fraction to complete a total dose of
4,500 cGy. In the case of pathologically confirmed
peri-aortic nodes, an additional boost of 500 cGy
could be delivered to the high-risk area, generally
using four field techniques. The placement of intra-
operative vascular clips in the areas of gross disease
could be very helpful in delineating the boost volume.
It should be noted that IMRT is especially suited
for irradiation of the para-aortic lymphatics, with a
greater ability to spare small bowel, kidneys, and
spinal cord compared to standard three-dimensional
techniques (Lian et al. 2008). As suggested by the
preliminary findings of Salama et al. 2006, this
greater ability to spare normal tissues can result in an
improved toxicity profile for those patients requiring
extended-field RT.
Whole Abdominal Irradiation has been used for the
adjuvant treatment of advanced EC, pathological
stages III–IVA, as well as unfavorable histologies
such as UPSC and CCC known to have a pattern of
spread similar to ovarian cancer with a greater inci-
dence of intra-abdominal failures (Martinez et al.
2003). However, since the presentation of the results
of GOG 122 (Randall et al. 2006), demonstrating the
superiority of systemic chemotherapy (Doxorubicin
and Cisplatin) over WAI, this modality has fallen out
of favor.
The ability of WAI to alter failure patterns by
decreasing upper abdominal relapse is determined by
the adequacy of the technique, emphasizing the
necessity of covering the diaphragm with adequate
margin during all phases of normal respiration. This
requires that liver shielding be limited or absent.
Appropriate kidney localization and blocking should
be undertaken to keep total doses within tolerance.
CT simulation and possibly intensity modulated RT
may more precisely shield the liver and kidneys
(Fig. 10a–f).
Whole abdominal irradiation dose is generally
2,500–3,000 cGy (at 150 cGy/fraction). The peri-aortic
region generally receives a boost to 4,200–4,500 cGy
and the pelvis is treated to 5,040–5,100 cGy. The kid-
ney dose should be limited to B2,000 cGy via a 100%
posterior transmission block. Martinez et al. (2003)
advocate the use of a liver transmission block to
Technical Aspects of Radiation Therapy in Endometrial Carcinoma
Fig. 9 a–d Isodose distributions for pelvic and peri-aortic fields
keep the total liver dose to 2250 cGy. This is not
universally accepted and it was not required in the
GOG-122 trial.
Most of the toxicity encountered with WAI is
gastrointestinal, up to 10–15% grade 3–4 in some
series (Martinez et al. 2003; Randall et al. 2006). In
addition, grade 3 renal and/or liver toxicity has been
reported in about 2% of patients (Martinez et al. 2003;
Sutton et al. 2005). Hematological toxicity was
reported in 4% of patients undergoing WAI in GOG
122 (Randall et al. 2006).
8 Medically Inoperable Early Stage
Endometrial Cancer
Although surgery is the definitive treatment of choice
for most patients with EC, in approximately 10–20% of
cases, patients are morbidly obese, are very advanced
875
in age, and have severe co-morbid cardiovascular or
other diseases which contraindicate extirpative
abdominal surgery (Fishman et al. 1996). In these non-
operable cases, primary RT has been used with success
varying with the stage of disease and the individual
experience of the treating institution, using a combi-
nation of brachytherapy with or without external beam
pelvic irradiation.
Patients with stage IA, and some selected stage IB,
well or moderately differentiated tumors, without evi-
dence of deep myometrial infiltration or lymph node
metastasis by CT or MRI scan, can be treated with ICB
alone, as described previously. The loading of the
tandem(s) is different from cervical cancer, in order to
provide adequate dose distribution laterally and supe-
riorly. Image-based brachytherapy can potentially
provide a more accurate understanding of the dose
received by the gross tumor (as delineated by MRI) and
clinical target volumes (defined as the entire uterus,
876 H. R. Cárdenes et al.

Fig. 10 a AP—WAI DRR. a AP-PA WAI. b PA—WAI DRR. c AP Peri-aortic and diaphragmatic DRR. d Lateral peri-aortic and
diaphragmatic DRR. e AP lateral pelvic boost DRR. f Isodose distribution WAI

cervix and proximal 2–3 cm of the vagina), as well as
the various organs at risk (Beriwal et al. 2006).
There is not a consensus regarding optimal dose or
prescription points. When using LDR-ICB alone,
many institutions will perform one or two applica-
tions designed to deliver a dose of 7,000–7,500 cGy
to point A. The ABS recommends prescribing the
dose at a point 2 cm from the central axis at the
midpoint along the intrauterine sources, when using
HDR (Nag et al. 2000). In the MIR system the
prescription dose is made such that the total activity/
exposure from the intrauterine sources (generally
Simon–Heyman capsules and intrauterine tandem)
would be around 5,000 mghrRaEq, and from the
vaginal ovoids approximately 3,000 mghrRaEq, with
pelvic control rates of 100% for patients with stage IA
with ICB alone, and 88% for patients with stage IB
disease, generally with a combination of EBRT and
ICB (Chao et al. 1996; Grigsby et al. 1987). Chao
et al. (1996) demonstrated a reasonable mortality of
Technical Aspects of Radiation Therapy in Endometrial Carcinoma
2.1% and life-threatening complication rate of 4.2%
with this approach. For patients with high risk stage I
or stage II disease, EBRT (4,500–5,000 cGy) and ICB
(3,000–3,500 cGy to point A) are often used in
combination, bringing the total point A dose to 7,500–
8,500 cGy.
HDR-ICB is also employed in the management of
clinically inoperable early-stage EC, with comparable
rates of disease control. While HDR techniques may
be desirable in the medically inoperable patient pop-
ulation due to concerns regarding prolonged immo-
bilization, one must keep in mind the morbidity
associated with multiple procedures and rounds of
anesthesia as required by HDR-ICB. In a series of 41
medically inoperable patients with early stage EC,
Petereit et al. (1998) reported a 30 day mortality of
9.8% following a course of fractionated HDR-ICB
using multiple insertions. The ABS recommendations
regarding HDR-ICB alone or in combination with
EBRT in terms of prescription points, number of
fractions, dose per fraction and optimization have
been extensively reviewed by Nag et al. (2000). A
careful review of their guidelines is strongly recom-
mended prior to implementation of such approach.
Patients with stage I disease, poorly differentiated
or deeply invasive tumors, as well as patients with
inoperable stage II disease, should be treated with a
combination of EBRT (45–50 Gy) and ICB. When
there is clinical involvement of the uterine cervix,
FIGO clinical stage II, most series show disease free
survival outcomes with definitive radiotherapy to be
10–20% worse than those for clinical stage I disease
(Taghian et al. 1988). The combination and technique
for EBRT and ICB are similar to that described for
higher risk clinical stage I cancer outlined above.
Considering the above described results of RTOG
9708, NSGO-EC-9501/EORTC-55991, and ILIADE-
III, the addition of concurrent or sequential chemo-
therapy may be appropriate as performance status
allows.
Advanced stage EC is more difficult to definitively
control with RT alone, as the risk for systemic spread
dramatically increases, and the local bulk of disease is
usually significant. However, multiple series have
shown long-term freedom from EC relapse in a sig-
nificant proportion of patients, with disease specific
survivals in up to 50% of patients at 5 years (Kup-
elian et al. 1993). Indeed, many clinical stage III
patients are so-staged on the basis of small vaginal
877
nodules, which can be adequately treated with the
ICB. In these patients the entire vaginal surface
should be treated with Delclos vaginal cylinders.
Patients with inoperable stage III disease could
potentially be treated to the pelvis only followed by
ICB in the absence of nodal pelvic or retroperitoneal
metastasis, or with EFRT and ICB in those patients
with nodal disease, followed by chemotherapy or
enrollment in a clinical trial if the patient has ade-
quate performance status. This situation is very
uncommon and generally patients with advanced
pelvic and retroperitoneal disease present with mul-
tiple co-morbidities that preclude them from such an
aggressive approach, being, often times, considered
for palliative therapy only.
8.1 Recurrent Endometrial Cancer
The rates of pelvic recurrence in patients with early
stage disease after surgery alone range between 5 and
15%, most of which are isolated vaginal recurrences
(Creutzberg et al. 2000; Creutzberg et al. 2003; Kelly
et al. 2004). The reported salvage rate with definitive
irradiation is 65–80% in patients with isolated vaginal
relapses (as high as 80–90% in patients with lesions
confined to the vaginal mucosa) compared with 25–
60% salvage rate in patients with pelvic and/or
regional recurrences (Creutzberg et al. 2003; Hasbini
et al. 2002; Petignat et al. 2006). However, the 5 year
survival rate is only 30–60%, given the high inci-
dence of regional recurrences and/or distant failures,
indicating the need for more aggressive salvage
therapy, probably using a combined modality
approach (Creutzberg et al. 2003; Hasbini et al. 2002;
Petignat et al. 2006).
The treatment of recurrent EC after surgery alone
generally requires a combination of EBRT and brach-
ytherapy. Unfortunately, much higher doses of RT are
often required for the successful treatment of LRR in
EC compared with the doses delivered in the adjuvant
setting, when IVB alone is used, which translates into
higher toxicity (15–20% grade 3–4) (Petignat et al.
2006; Jhingran et al. 2003; Lin et al. 2005).
8.1.1 External Beam Radiotherapy
for Recurrent Disease
The volume irradiated will include the totality of the
gross disease locally and regionally, as visualized by
878
Fig. 11 a AP, b PA, c R Lateral, and d L Lateral, fields for recurrent endometrial cancer
CT scan, in addition to the lymphatic regions including
the obturator, hypogastric, external and internal iliac
lymph nodes. A margin of 2–3 cm should be given
around the gross disease and 1.5–2 cm around unin-
volved lymph nodes. Generally, the pelvis is treated to
a dose of 4,500–5,000 cGy (Fig. 11). CT simulation
is encouraged in order to more adequately delineate
the gross tumor volume (GTV) and clinical target
volume (CTV). Prior to the simulation, placement of
radiopaque markers delineating the gross tumor vol-
ume or at least the most inferior extent of the disease in
the vagina, are very helpful to assure adequate cover-
age. In general, it is recommended to treat the entire
length of the vagina. Those lesions involving the distal
third of the vagina are to be treated with at least 2–3 cm
distal margin, which often times require the inclusion
of vulva or perineum in the external beam fields. In that
particular situation, inclusion of the inguino-femoral
lymph node regions is highly recommended (please
H. R. Cárdenes et al.
refer to the Vaginal Cancer chapter for details
regarding the technique for treating inguino-femoral
nodes).
Patients with pelvic/regional recurrences non-
amenable to brachytherapy implant should receive
additional boost using conformal techniques (we
prefer the use of multiple coplanar or non-coplanar
beam arrangement) in order to deliver a total dose to
the gross disease around 6,500 cGy, providing the
small bowel can be spared doses over 4,500 cGy.
Patients with extensive pelvic lymphadenopathy
extending to the common iliacs and/or peri-aortic
nodal disease, in the absence of systemic failure as
documented by CT scan of the chest, abdomen and
pelvis, should be considered for EFRT with or with-
out brachytherapy, if associated with vaginal recur-
rence. These patients are at very high risk for distant
failures. Although there are no data to support the use
of adjuvant chemotherapy in this setting, patients with
Technical Aspects of Radiation Therapy in Endometrial Carcinoma
residual disease after completion of EFRT should be
considered for enrollment into clinical trials for
advanced/recurrent disease, rather than waiting until
progression. An alternative approach would be a
combination of ‘‘tailored EBRT’’ with concurrent
and/or sequential chemotherapy similar to that
investigated in the above-described RTOG 9708 and
EORTC-55991 trials.
8.1.2 Brachytherapy in Recurrent
Endometrial Cancer
Following the completion of external beam RT, the
patient will receive one or two implants, using a
combination of interstitial ± intracavitary techniques.
At our institution, the entire surface of the vagina
receives a dose of 6,000 cGy. The GTV as defined by
physical exam and/or CT scan will receive a dose
between 7,500 and 8,000 cGy, including the contri-
bution of the EBRT and the intracavitary and inter-
stitial implants, depending upon the size and depth of
infiltration of the recurrence.
Intracavitary brachytherapy alone will be used in
patients with vaginal lesions less than 5 mm thick.
The dose should be prescribed to a depth of 0.5 cm
unless only superficial mucosal infiltration is present.
We mostly use LDR-ICB in this setting at Indiana
University. However, HDR-ICB has been used in
combination with EBRT for patients with small
vaginal cuff recurrences amenable to ICB alone. See
Dr. Nag’s publication regarding American Brachy-
therapy Society recommendations (Nag et al. 2000)
(Table 8).
Interstitial brachytherapy (ITB) should be used
for lesions C5 mm thickness. The interstitial tech-
niques used in the management of isolated vaginal
recurrences from EC are similar to those described in
the Vaginal Cancer chapter. Essentially, the first step
in designing an interstitial implant is adequate target
volume delineation primarily by performing a
detailed examination under anesthesia (EUA) and
acquisition of CT imaging data. Once the target
volume has been defined, a preoperative plan is
created to determine the position, number and
strength of the radioactive sources to obtain
the desired dose rate. Generally, a dose rate of
40–50 cGy/hour is calculated to the periphery of the
implant. When performing an interstitial procedure,
the flexiguides or funnel needles are placed into the
tumor in a 1 9 1 cm matrix. It is important to pass
879
Fig. 12 Modified templates for interstitial brachytherapy
the catheters beyond the most superior extension of
the tumor, which often times is possible by careful
rectal examination at the time of the procedure, to
assure an adequate cephalad margin of minimum
1 cm. The catheters are secured in place with the aide
of a template, which also helps to assure adequate
separation between the catheters. We often use the
modified Syed–Neblett (Disaia et al. 1990) applicator
which consists of a perineal template, vaginal obtu-
rator, and 17-gauge hollow guides of various lengths.
The vaginal obturator is 2 cm in diameter, and 12 or
15 cm in length. The vaginal obturator has seven
grooves on its surface for the placement of guide
needles, and is centrally drilled as to allow the
placement of a tandem loaded with 137Cs sources.
This makes it possible to combine an interstitial and
intracavitary application simultaneously (Fig. 12).
Generally, one implant is performed, delivering a
dose around 2,000–2,500 cGy after EBRT, in order
to achieve a total tumor dose of 7,000–7,500 cGy.
Those patients with bulky residual disease after
external beam (larger than 2 cm), would require
doses in the range of 3,000–3,500 cGy, for which
two implants may be necessary, 2 weeks apart
(Fig. 13a–c).
8.2 Salvage Surgery for Recurrent
Endometrial Cancer
Isolated pelvic recurrences after surgery and adjuvant
RT are rare and generally associated with distant fail-
ures. Early recurrences are especially associated with a
poor prognosis, and the role of additional surgery is
880 H. R. Cárdenes et al.

Fig. 13 a AP radiograph interstitial implant in recurrent endometrial cancer. b Lateral radiograph interstitial implant in recurrent
endometrial cancer. c Isodose distribution for the interstitial implant

generally limited. Patients without evidence of distant However, the benefit is unclear and the toxicity can be
metastatic disease, with recurrences limited to the quite significant. While median survival time for these
central pelvis, without extent to the pelvic side wall, patients is thought to be in the order of months, some
may be considered for exenterative surgical salvage. select series do report 20–45% survival at 5 years
Technical Aspects of Radiation Therapy in Endometrial Carcinoma
(Barakat et al. 1999). There are also those who advocate
aggressive surgical debulking of recurrent extrapelvic
disease. While the perioperative mortality risk approa-
ches 10%, there are reports of improved local control
with 5 year survival rates of 60% if the patients can be
completely debulked. Although some women clearly
benefit from such drastic interventions, the identifica-
tion of this very specific subset remains challenging.
9 Palliative Therapy in Endometrial
Cancer
9.1 Palliative Surgery
The role of surgery in the palliative setting in EC
involves primarily: (1) Debulking large masses in an
attempt to improve patients’ symptoms and quality of
life. (2) An attempt to relieve intestinal obstruction
generally related to a mechanical obstruction from
recurrent masses. Careful preoperative evaluation is
indicated before any surgical intervention, including
assessment of patient’s performance and nutritional
status and history of prior radiation therapy. Imaging
studies may help to delineate the number and location
of obstructions as well as the extent of intra-abdom-
inal disease, in order to guide the surgical decision
making process. Patients with recurrent disease and
short life expectancy are unlikely to benefit from
exploration. In patients in whom surgery may be
indicated, the procedure to be performed needs to be
carefully evaluated. It is important to exercise good
judgment and expertise to maximize outcome for
these patients with short life expectancy in order to
improve their quality of life.
10 Palliative Radiotherapy
Patients with grossly recurrent and metastatic EC
following surgery and radiation therapy often have
symptoms unresponsive to further systemic therapy,
generally related to pelvic recurrent disease causing
pain and/or bleeding. Distant recurrence in the brain,
chest, groins, and other areas may require palliation as
well.
There are not curative options for patients who
present with stage IVB disease. Many of these
patients suffer from severe pelvic pain or bleeding.
881
Patients with large volume disease in the pelvis with
limited metastatic disease and good performance
status with an estimated survival around 1 year or
longer, could potentially benefit from a more pro-
tracted course of EBRT (4,500–5,000 cGy) with or
without brachytherapy, to be followed by systemic
therapy. The techniques of EBRT to the pelvis have
been previously described.
However, patients with poor performance status
and/or extensive distant disease, who present with
local symptoms such as bleeding or pain, should be
treated using shorter RT regimens. If vaginal bleeding
is the main concern, brachytherapy, using endocav-
itary and/or interstitial techniques, when feasible,
often offers good symptomatic control with relatively
low morbidity. For patients who have received prior
RT, intracavitary doses in the range of 35–40 Gy
tumor dose, may suffice to palliate symptoms.
For those patients that may not be candidates for
brachytherapy, a short course of EBRT using high
dose fractionation schedules have been used. Spanos
et al. (1989) reported on a phase II study (RTOG
85-02) of daily multifraction split-course EBRT in
patients with recurrent or metastatic disease. The
regimen consisted of 370 cGy per fraction given
twice daily for two consecutive days and repeated at
2–6 week intervals, for a total of three courses (tumor
dose, 4,440 cGy). Occasionally, this regimen was
combined with an ICI (4,500 mgh), with a midline
block in the last 1,440 cGy. In patients completing
three courses of irradiation (59%), the rate of com-
plete or partial response was 45%. Twenty-seven
patients survived longer than 1 year. Late complica-
tions were relatively rare, with a projected actuarial
rate of 5% at 12 months (Spanos et al. 1989). The
same investigators (Spanos et al. 1993) have shown
that using a 2 week interval between courses
improved the response rates mainly because more
patients would complete all three courses of therapy.
This schedule offers significant logistic benefits, and
has been shown to result in good tumor regression and
excellent palliation of symptoms. Spanos et al. (1994)
reported a trend toward increased acute toxicity in
patients with shorter rest periods, but late toxicity was
not significantly different in the two groups. With this
regimen it is important to use CT simulation, allowing
for better target delineation and improved confor-
mality, in an attempt to reduce both acute and long-
term toxicity (Fig. 14).
882
Fig. 14 5-Fields coplanar beam arrangement for palliative EBRT
11 Uterine Papillary Serous and Clear
Cell Carcinoma
As previously mentioned, UPSC and CCC are
aggressive histological subtypes that differ from typi-
cal endometrial cancers by their poor prognosis, even
in early stage disease, and a propensity for peritoneal as
well as lymphatic and systemic spread. Therefore, it is
imperative to perform complete surgical staging
because of the expected high rate of surgical upstaging.
The rarity of these subtypes makes prospective studies,
and thus definitive treatment recommendations, diffi-
cult. Published adjuvant therapeutic approaches in
patients with stage I and II disease, after complete
surgical staging, include observation (Craighead et al.
2000; Huh et al. 2003; Kwon et al. 2008), systemic
chemotherapy and vaginal cuff brachytherapy
(Kelly et al. 2004; Turner et al. 1998), limited-field
H. R. Cárdenes et al.
EBRT with or without systemic chemotherapy (Mehta
et al. 2003; Fields et al. 2008), and intraperitoneal 32P
in combination with IVB (Fakiris et al. 2010). Most
clinicians will recommend some form of adjuvant
therapy for these patients who have not undergone
comprehensive staging, but at present there is not a
standardized approach based on level I evidence.
The incidence of abdominal recurrences has led
some investigators to study the impact of adjuvant
WAI on these subtypes, with mixed results in single
institution series. In a relatively large retrospective
series of patients treated in the British Columbia
Cancer Agency, 78 patients underwent hysterectomy
and were found to have uterine confined disease or
positive washings only (stages I–IIIA). Fifty-eight
patients were treated with adjuvant WAI with a 5 year
disease-specific survival of 74.9%, compared with
41.3% in 20 patients receiving less than WAI (Lim
et al. 2001). Martinez et al. (2003) have reported
Technical Aspects of Radiation Therapy in Endometrial Carcinoma
similar results using ‘‘high dose WAI’’ in patients
with UPSC and CCC, with encouraging 5 year cause-
specific survival of 80%, but 5 year disease-free sur-
vival of only 49% secondary to high rates of both
intra-abdominal and distant failures.
The GOG did conduct a prospective trial (GOG
94), in which all stages of UPSC and CCC underwent
surgical staging with optimal cytoreduction to less
than 2 cm residual disease. All patients then received
adjuvant WAI (30 Gy) followed by a peri-aortic boost
to 45 and 49.8 Gy boost to the pelvis. The 5 year PFS
for patients with stages I–II was 38% for patients with
UPSC and 54% for patients with CCC, respectively;
more than half of the treatment failures were within
the radiation field (Sutton et al. 2006). In a separate
report pertaining to only those patients with stage III–
IV disease, the 3 year recurrence-free survival and
overall survival was 27 and 35%, respectively
(Axelrod et al. 1995; Sutton et al. 2005).
In addition to these sub-optimal results and the
potential toxicities associated with this technique, the
findings of GOG 122 have contributed to a decrease
in the use of WAI for the treatment of advanced stage
UPSC and CCC (Randall et al. 2006). As described
above, this trial prospectively compared WAI to AP
chemotherapy for patients with stage III/IV disease,
including those with UPSC and CCC histologies, and
found improved overall survival in the chemotherapy
arm. However, outcomes with chemotherapy alone
are still undesirable, and volume directed RT with
concurrent and/or sequential chemotherapy may lead
to improved results.
Fields et al. (2008) investigated the use of adjuvant
pelvic RT (45 Gy) or EFRT for patients with more
than two pelvic nodes or peri-aortic positive nodes,
with three cycles of Paclitaxel + Platinum (Cisplati-
num or Carboplatin) chemotherapy both before and
after RT in 30 women with UPSC, surgically staged
and without evidence of gross residual disease. Three-
year DFS and OS were 69 and 75% for stage I/II
disease and 54 and 52% for stage III/IV disease,
respectively. Grade III/IV toxicity was primarily
hematologic, and all but one patient completed the
full course of therapy.
However, the benefit of chemotherapy in patients
with these high risk histologies remains unclear.
In both of the above described GOG 122 and EORTC
55991 trials, unplanned subset analyses failed to show
any benefit for the use of chemotherapy in place of or
883
in addition to RT for patients with UPSC or CCC
histologies.
In patients with negative nodes, comprehensively
staged, without residual disease, the potential risk for
peritoneal spread can be addressed with less toxicity
using intraperitoneal (IP) treatment with radioactive
colloids. IP radioactive [32P] phosphorus has been
used for similar adjuvant therapy in the ovarian
counterpart of UPSC with low morbidity (Young
et al. 1990). Likewise, the vaginal cuff recurrence
pattern can be addressed with IVB with acceptably
low toxicity (Alektiar et al. 2005).
Such a combined approach has been prospectively
studied at Indiana University School of Medicine by
the Hoosier Oncology Group (Fakiris et al. 2010).
In this study, 22 patients were treated with upfront
TAH-BSO, including ESS with lymph node dissec-
tion, omentectomy or omental biopsies, and perito-
neal/pelvic washings. Maximal surgical debulking
was required with patients having no residual disease
[3 mm, no positive lymph nodes, and no evidence of
disease outside of the abdomen. The surgical stages
ranged from IA to IVB, with the majority (17) having
stage I or II disease. Treatment consisted of IP
administration of 15 mCi of 32P followed by three
HDR-vaginal brachytherapy procedures. The results
from this experience were encouraging as acute tox-
icity was limited to grade 1, and no late toxicity was
observed. In addition, with a median follow-up of
39.6 months, the disease free survival data compares
favorably with only five patients (20.3%) suffering
recurrence (Fakiris et al. 2005). Of note, two recur-
rences were in the distal vagina early in the experi-
ence when we routinely treated the proximal vagina
only. After these recurrences, the protocol was altered
to treat the entire vaginal length, and thereafter no
vaginal recurrences have been seen. Therefore, we
recommend treating the entire vaginal length for these
patients when considering adjuvant IVB.
12 Intraperitoneal Radioactive
Chromic Phosphate Suspension
[32P] Administration
Radioactive [32P] phosphorous seem to be the most
attractive radiocolloid for IP administration because it
is a pure b-emitter which avoids the hazards of c
radiation. 32P has a half life of 14.3 days, average
884
Fig. 15 Distribution study prior to administration of intraperi-
toneal P-32. HDR high-dose rate, DRR digitally reconstructed
radiograph, AP antero-posterior, PA postero-anterior
tissue penetration of 1.4–3.0 mm, and maximum and
average b energies of 1.71 and 0.69 MeV, respec-
tively. Chromic 32P is a blue-green, chemically inert
colloidal form of 32P, used for intracavitary instilla-
tion. Unfortunately the precise distribution and dose
delivered by 32P to the peritoneal surface is unknown
and often unpredictable. The IP isotope distribution
should be tested prior to instillation with radioactive
technetium sulfur colloid (Tc99m) or after radiocolloid
administration with scintigraphic imaging of brems-
strahlung photons.
The best available data supporting that 10–15 mCi
of 32P delivers superficial but therapeutic dosages to
the peritoneal surfaces, is from (Currie et al. 1981).
There appears to be predominantly an abdominal
distribution with much smaller systemic absorption.
The majority of the 32P is either absorbed by the
peritoneal surface, by the macrophages lining the
peritoneal cavity, or phagocytized by free-floating
macrophages. The rest of the 32P is carried by the
abdominal current to the right hemidiaphragm where
it passes through the diaphragmatic lymphatics and
enters the mediastinal lymphatics. It then passes to the
right subclavian vein via the right thoracic trunk and
enters the general circulation where it is rapidly
cleared by the liver and deposited to a lesser extent in
other tissues (spleen and bone marrow). Pelvic and
para-aortic lymph nodes receive relatively low non-
therapeutic doses. Several studies using imaging
techniques confirm that the distribution of chromic
32
P is dynamic for the first 6–24 h but thereafter is
fixed. Boye et al. (1984) reported that the estimated
peritoneal surface dose from 10 mCi of 32P is
approximately 30 Gy, although the uptake and dis-
tribution of 32P in the peritoneal cavity often shows
H. R. Cárdenes et al.
32
Table 9 Procedure for administration of intraperitoneal P at
Indiana University
1. Patient admitted to the Hospital the day prior to or the same
day of the administration. Patient needs to be NPO after
midnight.
2. One multi-perforated peritoneal dialysis catheter
(Tenckoff’s catheter) to be placed in the right or left lower
quadrants.
3. Transportation to the Nuclear Medicine Department where
approximately 2 mCi of Tc99m is inserted into the right
catheter, followed by approximately 100 cc of normal saline.
4. Patient instructed to roll from side to side and preferably, to
lie on the abdomen in order to distribute the radioisotope. A
small detectable external marker should be placed on the
patient’s skin to identify the xiphoid process and the pubic
symphysis.
5. The abdomen is then scanned, AP and lateral, following the
right side injection.
6. If the distribution is poor, the procedure is terminated and
no 32P is administered.
7. 15 mCi of 32P will be dissolved in 250 cc of normal saline
(NS) and injected into the abdominal cavity using an IV line
(running full flow) through the catheter.
8. Approximately 1,000–1,500 cc of NS in then injected into
the peritoneal cavity following the radioisotope
administration.
9. Intraperitoneal catheter is removed at the completion of the
procedure. The catheter insertion site should be closed with a
purse-string suture.
10. The patient is transported to her room and instructed to
turn to her left side, onto her back in Trendelenburg and
reverse Trendelenburg positions, onto her right side and her
abdomen every 10 min for about 2 h.
11. IM Compazine may be given routinely for the first 24 h to
prevent the occurrence of nausea and vomiting.
12. The patient can be discharged home with adequate
radiation precautions once the rotational schedule is
completed.
13. Radiation precautions are recommended within the area of
administration and patient’s room regarding linens saved and
room decontamination procedures.
significant inhomogeneity. They noted an increase in
measurable levels of 32P in the blood for 7 days fol-
lowing which it declined; the estimated maximum
dose to the peripheral blood even at its peak was
1.2 cGy. The dose to the bone marrow was higher by
2–5 times, but the maximum dose was still very low,
in the order of 6 cGy.
The protocol of instillation and distribution of 32P at
Indiana University is outlined in Table 9. Generally,
the administration takes place within 3 weeks of
Technical Aspects of Radiation Therapy in Endometrial Carcinoma
surgery, although occasionally we have treated
patients up to 8 weeks from the surgical staging. Ide-
ally, the catheter for IP administration should be placed
at the time of the surgery, before adhesions are formed.
However, the practical matter is that a decision
regarding therapy is not completely made until a full
pathological evaluation of the specimen is submitted.
At our institution, following placement of an IP
catheter, generally within 3 weeks from surgery, a
distribution study is performed using Tc99m to ensure
that there are no adhesions causing loculations, which
could result in an uneven distribution of the radio-
isotope throughout the peritoneal surfaces (Fig. 15).
In our experience, only 1/22 patients had a loculation
preventing peritoneal therapy. Subsequently, the IP
administration of 15 mCi of 32P dissolved in 1,500 cc
of normal saline is performed, as indicted in Table 9.
One week after the IP administration we proceed
with IVB, using either HDR, 2,100 cGy in three
fractions prescribed to 0.5 cm depth, or LDR,
6,500 cGy in 1–2 fractions prescribed to the vaginal
surface.
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 Vulva
Carlos A. Perez and Imran Zoberi
Contents
1 Anatomy.................................................................... 889
2 Natural History ........................................................ 890
3 Diagnostic Workup.................................................. 892
3.1 Lymph Node Evaluation ........................................... 892
4 Staging....................................................................... 892
5 Pathological Classification ...................................... 893
6 Prognostic Factors ................................................... 895
6.1 Capillary Lymphatic Space Involvement and Lymph
Node Metastasis......................................................... 896
6.2 Extracapsular Extension of Metastatic
Lymph Nodes ............................................................ 897
7 General Management .............................................. 897
7.1 Stage III and IV Tumors........................................... 898
7.2 Management of Patients with Positive Nodes.......... 899
8 Radiation Therapy Techniques..............................
8.1 Irradiation Alone .......................................................
8.2 Regional Lymphatics.................................................
8.3 Preoperative Radiation Therapy................................
8.4 Postoperative Radiation Therapy ..............................
8.5 Treatment for Recurrent Lesions ..............................
8.6 Patient Positioning and Simulation...........................
8.7 Beams and Energies ..................................................
8.8 Lymphatic Irradiation................................................
C. A. Perez (&)
Department of Radiation Oncology,
Washington University Medical Center,
4511 Forest Park Boulevard,
Suite 200, St. Louis, MO 63108, USA
e-mail: cperez@radonc.wustl.edu
I. Zoberi
Department of Radiation Oncology,
Washington University School of Medicine,
Campus Box 8224, 4921 Parkview Place,
St. Louis, MO 63110, USA
S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_363, Ó Springer-Verlag Berlin Heidelberg 2012
8.9 Brachytherapy ............................................................ 905
8.10 Three-Dimensional Conformal
(3D-CRT) and Intensity Modulated Radiation
Therapy (IMRT) ........................................................ 906
8.11 Patterns of Failure after Treatment........................... 906
9 Sequelae of Treatment ............................................ 908
10 Carcinoma of the Vulva and Pregnancy .............. 909
11 Clinical Trials........................................................... 909
12 Treatment of Other Vulvar Malignant
Neoplasias ................................................................. 909
12.1 Adenocarcinoma ........................................................ 909
12.2 Vulvar Sarcoma ......................................................... 910
12.3 Malignant Melanoma................................................. 910
13 Chemotherapy .......................................................... 910
13.1 Combination of Chemotherapy and Irradiation........ 910
References.......................................................................... 912
899
900 Abstract
901 This chapter summarizes prognostic factors affecting
901 therapeutic decisions, management guidelines and
901
901 describes in detail techniques of irradiation for the
901 treatment of patients with carcinoma of the vulva.
902
903
1 Anatomy
The vulva consists of the mons pubis, clitoris, labia
majora and minora, vaginal vestibule, and their sup-
porting subcutaneous tissues and blends with the urinary
meatus anteriorly and with the perineum and anus pos-
teriorly. The mons pubis is a prominent mound of sub-
cutaneous connective and adipose tissue located anterior
to the pubic symphysis; after puberty it is covered with
pubic hair. The labia majora are two elongated skin folds
889
890 C. A. Perez and I. Zoberi

that course posteriorly from the mons pubis and blend

into the perineal body. The skin of the labia majora is
pigmented and contains both hair follicles and seba-
ceous glands. The labia minora are a smaller pair of skin
folds located between the labia majora; they extend
posteriorly to form the margin of the vaginal vestibule.
Anteriorly, the labia minora separate into two compo-
nents that course above and below the clitoris, fusing
with those of the opposite side to form the prepuce and
frenulum, respectively. The skin of the minora contains
numerous sebaceous glands but no hair follicles and has
no underlying adipose tissue. The clitoris is supported by
the fusion of the labia minora and is about 2–3 cm
anterior to the urethral meatus. It is composed of erectile
tissue organized into the glans, body, and two crura,
which course laterally, covered by the ischiocavernosus
muscles, and attach to the ischial rami.
The vaginal vestibule is in the center of the vulva
and is demarcated laterally by the labia minora and
posteriorly by the perineal body. Anteriorly, numerous
small vestibular glands are located beneath the mucosa
and open onto its surface adjacent to the urethral
meatus. The Bartholin’s glands, two small mucous-
secreting glands situated within the subcutaneous tis-
sue of the posterior labia majora, have ducts that open
onto the posterolateral portion of the vestibule. The
perineal body is a 3–4 cm band of skin, located between
the posterior extension of the labia majora, which
separates the vaginal vestibule from the anus and forms
the posterior margin of the vulva (Burke et al. 1996).
Fig. 1 a The lymphatic drainage of the vulva initially flows to
Lymphatics of the labia drain into the superficial the superficial inguinal nodes, then to the deep femoral and iliac
inguinal and femoral lymph nodes, located anterior to groups. Drainage from midline structures may flow directly
the cribriform plate and fascia lata. The lymphatics beneath the symphysis to the pelvic nodes (Plentl and Friedman
subsequently penetrate the cribriform fascia and reach 1971). b The superficial inguinal lymph nodes comprise eight
to ten subcutaneous nodes located between Camper’s fascia and
the deep femoral nodes. Lymphatics of the fourchette, the cribriform fascia. These nodes are immediately adjacent to
perineum, and prepuce follow the lymphatics of the the saphenous vein and its branches (DiSaia et al. 1979)
labia. The lymph from the glans clitoris, on the other
hand, can drain not only to the inguinal nodes but also (Fig. 1b). There are usually three to five deep nodes, the
to deep femoral nodes and pelvic lymph nodes. Some most superior of which, located under the inguinal
lymphatics originating in the clitoris may enter the ligament, is known as Cloquet’s node (Burke et al.
pelvis directly, connecting with the obturator and 1996). From these, the lymph drains into the pelvic
external iliac lymph nodes, bypassing the femoral area lymphatics (external and common iliac lymph nodes).
(Fig. 1a). About ten superficial inguinal lymph nodes
lie along the saphenous vein and its branches between
Camper’s fascia and the cribriform fascia overlying the 2 Natural History
femoral vessels. The superficial nodes are located
within the triangle formed by the inguinal ligament Over 70% of vulvar malignancies arise in the labia
superiorly, the border of the sartorius muscle laterally, majora and minora, 10–15% in the clitoris, and
and the border of the adductor longus muscle medially 4–5% in the perineum and fourchette. The vestibule,
Vulva 891

Table 1 Incidence of lymph node involvement correlated with primary tumor size and extent
Primary tumor size or depth of invasion No. of patients Number of patients with positive lymph nodes (%)
Depth
B1 mm 120 00 (0)
1.1–2 mm 121 08 (6.6)
2.1–3 mm 097 08 (8.2)
3.1–4 mm 050 11 (22)
4.1–5 mm 040 10 (25)
Size
[5 mm 032 12 (37.5)
[2 cm 168 77 (45.8)
Any size primary tumor extending beyond vulva 070 38 (54.2)
Data from Rutledge et al. (1970), Boutselis (1972), Parker et al. (1975), Krupp and Bohm (1978), Donaldson et al. (1981), Hacker
et al. (1981), Hoffman et al. (1988), and Perez et al. (1997)

Table 2 Relationship between laterality of primary tumor and laterality of inguino-femoral lymph node metastases (n = 180)
(Burger et al. 1996)
Laterality of primary tumor
Laterality of inguino-femoral metastases Unilateral left Unilateral right Central or bilateral
No metastases 44 37 43
Unilateral left 10 1 12
Unilateral right 11 9
Bilateral 1 12

Bartholin’s gland, and the clitoral prepuce are unusual
primary sites, each accounting for less than 1% of
vulvar cancers (Plentl and Friedman 1971).
Carcinomas arising in the vulvar area ordinarily
follow a predictable pattern of spread to the regional
lymph nodes. Superficial inguino-femoral lymph
nodes are involved first, followed by the deep ingui-
no-femoral nodes. Metastasis to the contralateral
inguinal or pelvic lymph nodes is very unusual in the
absence of ipsilateral inguino-femoral node metasta-
sis. Although lesions arising in or involving the glans
clitoris or urethra theoretically can spread to pelvic
lymph nodes through the channels that bypass the
inguinal areas, such metastases without inguinal
node involvement occur infrequently (Franklin and
Rutledge 1971; Krupp and Bohm 1978).
The incidence of inguinal lymph node metastasis
in surgically staged patients varies from 6–50%,
depending on tumor invasion (Table 1) (Rutledge
et al. 1970; Boutselis 1972; Parker et al. 1975;
Donaldson et al. 1981; Hacker et al. 1981; Hoffman
et al. 1988; Wang et al. 1996). Plentl and Friedman
(1971) reported a 62% incidence of lymph node
metastases in patients with clinically palpable ade-
nopathy and 35% without clinically palpable lymph
nodes. Franklin (1972) noted that approximately 75%
of patients with clinically suspicious lymph nodes had
nodal metastasis, and nodes that were clinically neg-
ative were found to be positive for metastasis in
11–43% of cases. In women with T1 or T2 carcinoma
of the vulva who underwent radical vulvectomy and
bilateral inguino-femoral lymphadenectomy, 23 of
104 (22.1%) with unilateral tumor had lymph node
metastases; 21 (91%) had unilateral, one contralateral,
and one bilateral metastases (Table 2); the contralat-
eral node may have been from a previously treated
endometrial carcinoma (Burger et al. 1996). In a study
of 320 patients with vulvar cancer operated on, 226
had clinically negative inguinal nodes, of which 180
(79%) were found to be negative and 40 (20%) had
palpable nodes not suspected of having metastatic
spread. Occult groin node metastasis were detected in
892
15.2% of patients with T1, 30% with T2, 24% with
T3 and 0% with T4 tumors. Eighty-six patients
underwent pelvic node dissection, 24 (28%) had
positive inguinal nodes and four positive pelvic
nodes. Of 62 patients with negative inguinal nodes
who underwent pelvic node dissection only one had
pelvic node metastasis (Gonzalez Bosquet et al.
2003). Approximately 20% of patients with histo-
logically proven involvement of femoral nodes show
deep pelvic lymph node involvement if pelvic lym-
phadenectomy is performed (Boutselis 1972).
Hematogenous dissemination is unusual and is a
manifestation of late disease (Stern and Kaplan 1969).
The most common metastatic sites are lung, liver, and
bone.
3 Diagnostic Workup
Clinical history and a complete physical examination
are essential. In addition to the vulvar and anal area
and perineum, physical examination should include
the vagina and cervix, which should be thoroughly
inspected. Careful bimanual pelvic examination is
mandatory. Besides careful determination of the
extent and depth of the primary lesion (size, fixation,
etc.), essential in physical examination is assessment
of the regional lymph nodes; although, because of
inflammatory lymphadenopathy in the inguinal area,
lymph node assessment in vulvar tumors has a sub-
stantial rate of error. A Papanicolaou smear of the
cervix and vagina should be performed.
Chest radiographs should be routinely obtained.
Other studies include cystoscopy, proctosigmoidos-
copy, barium enema, and intravenous pyelogram
when indicated. Computed tomography (CT) or
magnetic resonance imaging (MRI) aid in the defi-
nition of tumor extent and in evaluating the inguinal
and pelvic/periaortic lymph nodes. Radiographic
evaluation of regional lymphatics in carcinoma
of the vulva is of limited value and is rarely used.
Preoperative lymphography was evaluated at the
Mallinckrodt Institute of Radiology in 32 patients
with vulvar carcinoma; correlation with the surgical
specimens showed an overall accuracy of 54.5%, with
a sensitivity of 15.7% and a specificity of 66.1%
(Weiner et al. 1986). The standard workup for these
patients is described in Table 3.
C. A. Perez and I. Zoberi
3.1 Lymph Node Evaluation
Positron emission tomography (PET) was used to
detect inguinal node metastasis is 15 patients prior to
exploration of 29 groins (Cohn et al. 2002). Of these
patients, six had positive scans, suggesting nodal
metastasis in eight groins. On pathological exam, five
patients had metastasis in nine groins; PET demon-
strated the metastasis in four of the patients and in six
groins. The positive predictive value of PET was 80%
and negative predictive value 90%. The authors
concluded that PET was relatively insensitive in
predicting groin lymph node metastases, but the high
specificity (90%) made it useful in planning radiation
therapy.
Surgical assessment of superficial femoral (ingui-
nal) lymph nodes continues to be a widely accepted
procedure for determination of therapeutic strategy,
since survival is closely correlated with the patho-
logical status of the inguinal nodes (at 5 years,
80–85% for patients with negative nodes and 40–50%
with positive nodes). It is generally agreed that pelvic
lymph nodes do not need to be treated in patients
without femoral lymph node involvement, yet the
identification of patients with involved inguinal nodes
for therapeutic management directed at the pelvis is
of obvious importance. Many surgeons routinely
dissect the pelvis in patients with positive inguinal
nodes; however, Curry et al. (1980) noted that none of
their patients with three or fewer unilaterally positive
groin nodes had positive deep pelvic nodes. Similar
findings have been observed by Hacker et al. (1983).
Although deep pelvic node involvement is an omi-
nous sign, one-quarter to one-third of the patients are
still salvageable, particularly if only a few nodes are
involved (Franklin and Rutledge 1971; Boutselis
1972; Curry et al. 1980).
4 Staging
The international federation of gynaecology and
obstetrics (FIGO) adopted a modified surgical staging
system for vulvar cancer in 1989 (Shepherd 1989;
Creasman 1990). Staging errors led to acceptance of
the current surgical evaluation of the inguinal lymph
nodes. Tumor assessment is based on physical
examination with endoscopy in cases of bulky
Vulva
Table 3 Diagnostic workup for vulva tumors (Perez et al.
1997)
General
History
Physical examination, including careful bimanual pelvic
examination
Special studies
Exfoliative cytology of cervix and vagina
Colposcopy and directed biopsies (including Schiller‘s test)
Biopsies and examination under anesthesia to determine
tumor extent
Cytoscopy
Proctosigmoidoscopy (as indicated)
Radiographic studies
Standard
Chest radiographs
Intravenous pyelogram
Complementary
Barium enema
Lymphangiogram
Computed tomography or magnetic resonance imaging of
pelvis and abdomen
Laboratory studies
Complete blood count
Blood chemistry
Urinalysis
disease. Nodal status is determined by the surgical
evaluation of the groins.
A micro invasive substage (IA) was defined by
FIGO for tumors less than 2 cm in diameter with
depth of invasion less than 1 mm, confined to the
vulva or perineum (Parker et al. 1975).
The stages correlate well with treatment results.
The use of 2.0 cm as the size to determine assignment
of the primary lesion to T1 or T2 has been adopted.
T2 and T3 tumors are classified according to the
extent of involvement of the adjacent structures
(vagina, urethra, anus). Degree of tumor differentia-
tion is generally expressed from GX (grade cannot be
assessed) to G4 (Undifferentiated).
Lymph nodes are staged according to the number
of pathologically involved and size (5 mm or greater).
The American Joint Committee (Edge et al. 2010)
and FIGO staging systems are shown in Table 4 and
Fig. 2 (DuBeshter et al. 1993).
893
5 Pathological Classification
Preinvasive forms of vulvar malignancy include car-
cinoma in situ (Bowen’s disease or erythroplasia of
Queyrat and Paget’s disease). Paget’s disease is
equivalent to the same entity in the breast and is
associated with invasive apocrine carcinoma in
approximately 20–30% of cases (Helwig and Graham
1963; Kaufman and Gardner 1965; Ulbright et al.
1983; Barnhill et al. 1988; Hoskins and Perez 1989).
Unsuspected invasion in patients with intraepithelial
vulva neoplasia was described in 13 of 69 patients
(18.8%) and superficial invasion in eight patients
(Chafe et al. 1988).
Squamous cell carcinoma comprises over 90% of
invasive lesions of the vulva. Histologically, most of
these tumors are well differentiated with keratin for-
mation; 5–10% are anaplastic (Gosling et al. 1961).
Two variants of squamous cell carcinoma infre-
quently described are adenosquamous (Lasser et al.
1974) and basaloid carcinoma (Lucas et al. 1974).
Verrucous carcinoma of the vulva is extremely
rare. Until 1988, the number of cases involving the
female genital tract was 89 (Anderson and Sorenson
1988). Verrucous carcinoma is a slowly growing,
nonaggressive tumor with pushing margins and a
rather benign histological appearance. The incidence
of lymph node metastasis is very low. The preferred
treatment is wide surgical excision.
Basal cell carcinoma of the vulva is occasionally
reported (Breen et al. 1975; Perrone et al. 1987;
Hoffman et al. 1988).
Adenoid cystic carcinoma of the Bartholin’s gland
constitutes about 10% of all carcinomas of this gland
and approximately 0.1% of all vulvar malignancies.
Small numbers of patients with this tumor have been
treated with a combination of surgery (wide local
excision or hemivulvectomy) combined with postop-
erative irradiation with doses ranging from 40–54 Gy.
About 75% of the patients are alive and well, with
follow-up ranging from 2 years to over 13 years. Late
distant metastases may occur (Rosenberg et al. 1989;
Lelle et al. 1994).
Adenocarcinoma usually originates either in
Bartholin’s gland or from bulboadnexal structures,
although it rarely arises from the periurethral Skene’s
glands (Leuchter et al. 1982). Occasionally Bartholin’s
gland carcinoma may be squamous cell when it
894 C. A. Perez and I. Zoberi

Table 4 TNM and staging classifications for carcinoma of the vulva

TNM (AJCC) 2010 Staging (FIGO) 1989
T primary tumor
Tis Preinvasive carcinoma (carcinoma in situ) Stage Tis Carcinoma in situ; intraepithelial carcinoma
0
T1a Tumor confined to the vulva and/or Stage T1 N0 M0 Tumor confined to the vulva and/or perineum
perineum – 2 cm or less in diameter, I – 2 cm or less in greatest dimension. No nodal
with stromal invasion 1 mm or less metastases
T1b Tumor more than 2 cm or any size with
stromal invasion more than 1 mm, confined
to vulva or perineum
T2 Tumor of any size with extension to adjacent Stage T2 N0 M0 Tumor confined to the vulva and/or perineum
structures (distal 1/3 urethra, distal 1/3 II – more than 2 cm in greatest dimension. No
vagina, anal involvement nodal metastases
T3 Tumor of any size with extension to any of Stage T3 N0 M0, Tumor of any size with the following: (1)
the following:proximal 2/3 of urethra, III T3 N1 M0, adjacent spread to the lower urethra, the
proximal 2/3 vagina, bladder mucosa rectal T1 N1 M0 vagina, the anus, and/or (2) unilateral
mucosa or fixed to pelvic bone regional lymph node metastases
N regional lymph nodes Stage T1 N2 M0 Tumor invades any of the following:
IVA
N0 No nodes palpable T2 N2 M0 Upper urethra, bladder mucosa, rectal
N1 Unilateral regional lymph node metastases T3 N2 M0 mucosa, pelvic bone, and/or bilateral regional
node metastases
N2 Bilateral regional lymph node metastases T4 any
N M0
M distant metastases Stage IVB Any T, any Any distant metastases, including pelvic
N, M1 lymph nodes
M0 No clinical metastases
M1 Distant metastases (including pelvic lymph
node metastases)
AJCC TNM FIGO
NX Regional lymph nodes cannot be assessed
NO No regional lymph node metastasis
N1 One or two regional nodes with following features
N1a IIIA One lymph node metastasis each 5 mm or less
N1b IIIA One lymph node metastasis 5 mm or greater
N2 IIIB Regional node metastasis with following features
N2a IIIB Three or more node metastasis each less than 5 mm
N2b IIIB Two or more node metastasis 5 mm or greater
N2c IIIC Lymph node metastasis with extracapsular spread
N3 IVA Fixed or ulcerated regional lymph nodes
TNM tumor-node-metastasis, FIGO International Federation of Gynaecology and Obstetrics (Edge et al. 2010)

originates near the orifice of the duct, papillary if it
arises from the transitional epithelium of the duct, or
adenocarcinoma when it arises from the gland itself.
Cardosi et al. (2001) treated twelve women with
Bartholin’s gland carcinoma; eleven patients were
reported. Squamous cell carcinoma was most common.
Of the patients, ten were treated with primary surgery,
followed by adjuvant radiation in seven for inadequate
resection margins or lymphatic metastases; one patient
was treated with primary chemoirradiation. Recur-
rence was seen in 54.5% during a mean follow-up time
of 73.5 months. Overall survival was 58.3%.
Vulva
Fig. 2 Anatomic staging for vulva cancer (DuBeshter et al. 1993)
In contrast to this, Balat et al. (2001) analyzed 18
patients with advanced primary carcinoma of the
Bartholin’s gland (median follow-up was nine years):
seven were treated with wide local excision followed
by radiation therapy, nine had radical vulvectomy
followed by radiation therapy to the vulvar and
inguino-femoral and pelvic node areas, and two were
treated with radiation therapy alone after biopsy of the
tumor. The 5-year disease-free survival rates were 86,
78, and 50%, respectively. Of two patients treated
with radiation therapy alone, one lived for six years
with no evidence of disease, and the other lived for 20
months. The rate of local tumor control was 100% for
all three treatment groups. There were no significant
differences among the treatment groups in rate of
primary tumor control or 5-year disease-free survival
rate (P = 0.1300).
Melanoma represents 2–9% of vulva malignancies;
two varieties, nodular and superficial spreading mel-
anoma, are described. As in other locations, the depth
of invasion correlates with the patterns of spread and
895
prognosis (Chung et al. 1975; Baltzer et al. 1986;
Benda et al. 1986; Woolcott et al. 1988; Brand et al.
1989; Hoskins and Perez 1989).
Sarcomas of the vulva are extremely rare;
leiomyosarcoma is the most common. Neurofibro-
sarcoma, rhabdomyosarcoma, fibrosarcoma, and
angiosarcoma have been reported (Tavassoli and
Norris 1979; Ulbright et al. 1983; Barnhill et al.
1988).
Metastatic carcinoma to the vulva from the uterine
cervix (most common), the endometrium, or the ovary
and extension or metastases from the urethra or the
vagina have been described (Dehner 1973).
6 Prognostic Factors
Tumor size, depth of invasion, and histological sub-
type of the primary tumor, as well as degree of
lymphatic and vascular invasion, correlate closely
with the incidence of regional lymph node
896
involvement and prognosis (Rutledge et al. 1970;
Donaldson et al. 1981; Malfetano et al. 1985; Shimm
et al. 1986; Sedlis et al. 1987; Rutledge 1991).
Local recurrence is related to the adequacy of the
surgical resection margins. Heaps et al. (1990), in an
analysis of formalin-fixed tissue specimens, demon-
strated a sharp rise in the incidence of local recurrence
for tumors with microscopic margins less than 8 mm.
They suggested that this would correspond to a mini-
mum margin of 1 cm in fresh, unfixed tissue. Inadequate
resection margins are an important consideration when
planning treatment for large tumors and those involving
midline structures such as the urethra, vagina, and anus.
Rosén and Malstrom (1997) reported a retrospective
analysis of 328 patients with primary invasive vulvar
cancer, 277 of whom were treated primarily with sur-
gery and 189 with the addition of irradiation. Of the
328, 18 were treated primarily with irradiation and 5 of
these in combination with chemotherapy. The most
important prognostic factors were tumor stage, histo-
logical differentiation, and patient age (69 years).
Kurzl and Messerer (1989) carried out a multi-
variate analysis of 124 patients with various stages of
vulvar carcinoma treated with simple vulvectomy and
local/inguinal irradiation (40 Gy). No inguinal lym-
phadenectomy was performed. They found that age,
disassociated growth, lymphatic spread, tumor thick-
ness, and ulceration were relevant prognostic factors.
Jhingran et al. (2003), in a review of 139 patients
with vulvar cancer treated with surgery and pre- or
post-operative RT (49 and 22%, respectively), found
that patients with tumors less than 3 cm had a vulvar
recurrence rate (VRR) of 13% and with larger lesions
30% (P = 0.02); in 32 patients with negative groin
nodes the incidence of VRR was 10%, compared to
32% in patients with positive nodes and 27% in those
with unbiopsied nodes.
In a study of 178 patients with vulvar cancer (Wo
et al. 2008) treated with surgery alone (104), RT
alone, median dose 45 Gy (36), chemoradiation (10)
or chemotherapy alone (2), with 31 months median
follow up, the incidence of vulvar failures was
24–29% for stages I, II, III, and 40% for stage IV.
In 106 patients treated without radiation the failure
rate was 20% (11/55) in patients with negative, 28%
(12/43) with close and 50% (3/6) with positive sur-
gical margins. Actuarial 5-year overall survival was
65% for negative, 66% for close, and 43% for positive
margin patients (P = 0.47). Of 27 patients receiving
C. A. Perez and I. Zoberi
RT the VRR was 20% (2/10) with negative, 31%
(5/16) with close and 0/1 with positive margins.
Tumor size, depth of invasion, lymphovascular inva-
sion or nodal status were not predictors of risk for
vulvar failure.
Extension of the primary tumor to the urethra,
vagina, and anal area is associated with an increased
incidence of nodal involvement and worsening of
prognosis. Treatment usually involves either exen-
terative surgery or a combination of surgery and
irradiation.
The incidence of lymph node involvement corre-
lates well with the FIGO clinical stage. In the expe-
rience of Donaldson et al. (1981), 15% of patients
with clinical stage I disease, 40% with stage II, 80%
with stage III, and 100% of patients with stage IV
disease had confirmed regional lymph node involve-
ment. Similar involvement was noted by Sedlis et al.
(1987), who found regional node involvement with
stages I, II, III, and IV to be 8.9, 25.3, 31.1, and
62.5%, respectively.
Lymph node metastasis is the single most impor-
tant prognostic factor in women with vulvar cancer.
The presence of inguinal node metastases routinely
results in a 50% reduction in long-term survival
(Figge et al. 1985; Farias-Eisner et al. 1994).
6.1 Capillary Lymphatic Space
Involvement and Lymph Node
Metastasis
In analysis of gynaecologic oncology group (GOG)
protocol no. 36, two significant risk factors were
identified for recurrence in the vulva: (1) tumor size
greater than 4 cm and (2) capillary lymphatic space
involvement. If either of these factors was present, the
risk of vulva recurrence after radical vulvectomy was
20.7% (30 of 184); but, if neither factor was present,
the risk was only 9.2% (37 of 404). The depth of
invasion did not add significantly to the prediction of
vulvar failure.
However, in another study, depth of invasion
of 1, 2, and 3 mm corresponded to 4.3, 7.8, and
17% incidence of nodal involvement, respectively.
Perineural invasion was strongly associated with
lymph node metastasis (Rowley et al. 1988).
Wharton et al. (1974) proposed eliminating groin
dissection for patients with small tumors that invaded
Vulva
less than 5 mm. Later reports showed that 10–20% of
these patients had occult groin metastases, making the
elimination of some form of inguinal lymphadenec-
tomy or irradiation undesirable (Parker et al. 1975;
Donaldson et al. 1981; Hacker et al. 1984b; Binder et al.
1990). The current consensus is that only tumors with
less than 1 mm invasion fulfill this criterion (Sedlis
et al. 1987; Berman et al. 1989; Kelley et al. 1991); this
is reflected in FIGO’s recent decision to classify tumors
invading less than 1 mm into substage IA.
GOG protocol no. 37 demonstrated that two major
poor prognostic factors were clinically suspicious or
fixed ulcerated groin nodes and more than one positive
groin node. Nodal metastases did not influence the
probability of vulvar relapse, but did increase the risk of
relapse in the groin, pelvis, or other sites. The irradiated
group had statistically fewer groin recurrences (3 of 59,
51%) than the patients who received no postoperative
irradiation (13 of 55, 23.6%). The difference in survival
for 114 evaluable patients significantly favored the
adjuvant radiation therapy group (P = 0.03).
6.2 Extracapsular Extension
of Metastatic Lymph Nodes
For patients with vulvar carcinoma, Origoni et al.
(1992) noted that extracapsular tumor extension was of
prognostic value, even in those with a single positive
lymph node. This observation was confirmed by the
study of van der Velden et al. (1995), in which this
variable was the only independent predictive factor for
survival. It suggested that extra nodal extension is an
indication for adjuvant radiation therapy even in
patients with single-node metastatic disease.
7 General Management
In the current treatment of women with vulvar cancer,
greater emphasis is placed on prognostic factors and
organ preservation. The preinvasive forms of vulvar
malignancies (carcinoma in situ and Paget’s disease)
and micro invasive tumors can be treated with topical
chemotherapy, cryosurgery, or surgical resection. The
preferred method of treatment for invasive carcinoma
is surgery, which varies from wide local excision to
partial vulvectomy (Hacker et al. 1984a; Fiorica et al.
1988; Husseinzadeh et al. 1989; Burke et al. 1996;
897
Moore et al. 2009), depending on extent and multi-
plicity of intraepithelial lesions and the patient’s wish
to preserve the vulva.
The traditional management of patients with
invasive stage I and II carcinomas of the vulva con-
sisted of radical vulvectomy with inguino-femoral
lymphadenectomy (Kurzl and Messerer 1989; Moore
et al. 2009), which involved removal of the entire
vulva from the perineum to the upper margin of the
mons pubis and bilateral excision of the tissues in the
femoral triangle and those overlying the inguinal
ligament. The urethral meatus is generally left in situ.
Many gynaecologists have proposed limited
resections for smaller invasive vulvar tumours con-
sidered to represent early or low-risk disease (DiSaia
et al. 1979; Berman et al. 1989; Burke et al. 1990).
DiSaia et al. (1979) described conservative resection
in 18 of 20 cancers measuring 1 cm or less with
invasion of less than 5 mm. Others include patients
with larger lesions and more significant invasion
(Wharton et al. 1974; Berman et al. 1989; Burke et al.
1990; Stehman et al. 1992a).
While many surgeons have performed pelvic lym-
phadenectomy, the current policies at some institutions
reserve this procedure only for patients with clinically
positive inguino-femoral lymph nodes. Attempts are
being made to refine patient selection, omitting
inguinal lymphadenectomy in patients with small,
low-grade primary lesions and omitting pelvic lym-
phadenectomy in patients with three or fewer involved
inguinal nodes, provided the primary lesion does not
invade the clitoris, urethra, vagina, or anal region.
Because of the morbidity associated with radical
vulvectomy and to enhance psychosexual rehabilita-
tion and based on the biological and therapeutic
principles already validated in the head and neck,
breast, and soft-tissue sarcomas, there is increasing
use of wide local excision or partial vulvectomy to
remove the primary tumor (usually T1) and, if nec-
essary, an inguino-femoral lymph node dissection in
patients with clinically positive nodes combined with
moderate doses of radiation therapy to the remaining
vulva and regional lymph node-bearing areas (50 Gy
for subclinical disease with a boost of 10–15 Gy
through reduced portals or brachytherapy for micro-
scopically involved areas).
Resection of the primary lesion with a 1–2 cm
margin of normal tissue and carrying the dissection to
the deep perineal fascia are recommended. This is
898 C. A. Perez and I. Zoberi

Fig. 3 Algorithm illustrating Operable vulva lesions

the various therapeutic
options for patients with
favorable or unfavorable
operable carcinoma of the
vulva (Perez et al. 1997)
Favorable tumor Unfavorable tumor
Lateralized T1, T2 tumor Advanced T3 tumor
Selected T3 tumor Clitoris, perineum involved
Sphincter preservation (+) Multiple enlarged nodes
Movable inguinal nodes

Clinically N+ Clinically N– Sphincter preservation desired

Tumor approaching Tumor not approaching
midline midline

Vulvectomy SIND Vulvectomy UIND No Yes

Margins < 1 cm Surgery Pre-operative RT

or capillary lymphatic space positive (45–50 Gy / 5–6 weeks)
or > 1 node (+) or chemoradiotherapy
or extracapsular extension of LN

Yes No Post-OP RT Surgery

(?) Post-OP RT boost
Post-OP RT Observation
(50 Gy / 5–6 weeks)

combined with a more conservative surgical approach
to the groin, the ipsilateral superficial groin nodes
being used as the sentinel group for lymphatic
metastases (Morris 1977; DiSaia et al. 1979; Stehman
et al. 1992a). Bilateral superficial dissections are
performed in patients whose tumors involve midline
structures (clitoris or perineal body) (Burke et al.
1995). Recently, sentinel lymph node biopsies have
been introduced to decrease treatment morbidity (de
Hullu et al. 2004). In patients with pathologically
negative inguinal nodes, no further dissection or
postoperative therapy is used. Patients with positive
nodes can undergo additional nodal dissection of the
deep nodes and the contralateral groin or be treated
with postoperative irradiation, or both. In a review of
67 patients with clinically suspicious and 160 with
clinically negative inguinal lymph nodes, Katz et al.
(2003) noted that 119 were treated with lymph node
dissection alone, 57 with lymph node dissection and
radiation therapy, and 51 with radiation therapy alone.
Treatment guidelines for lateralized or central oper-
able tumors are summarized in Fig. 3.
Busch et al. (2000) described results in 92 patients
treated for vulvar cancer with simple vulvectomy,
electrocoagulation, or local excision and radiation
therapy to the vulva (0–90 Gy). All patients received
irradiation to the inguinal lymph nodes, ranging from
30 to 60 Gy. In T1 patients, 5-year survival rates were
71% and in T2 patients 43%. Post-operative doses of
45 Gy or higher to the vulva were sufficient to increase
the 5-year cause-specific survival rate from 55–88%.
7.1 Stage III and IV Tumors
Some of these more extensive tumors can be com-
pletely resected by radical vulvectomy or some vari-
ation of pelvic exenteration and vulvectomy. Radical
surgery is frequently ineffective in curing patients
with bulky tumors or positive groin nodes. However,
most recent therapeutic efforts have focused on pre-
operative multimodality treatment that combines
radiation therapy or chemoirradiation with less-radi-
cal surgery (Burke et al. 1996). Management options
are illustrated in Fig. 4. Vulvar cancers are radiore-
sponsive, and function-sparing operations are feasible
in some patients with advanced disease (Fig. 5).
The role of radiation therapy alone in the primary
management of carcinoma of the vulva remains con-
troversial, primarily because of lack of long-term data
on the results of treatment with modern techniques and
because of the traditional belief that vulvar tissues could
not tolerate high doses of irradiation (over 60 Gy).
However, this misconception has been corrected in
recent reports (Perez et al. 1993) and, with reduced
fields, doses of 65–70 Gy in 7–8 weeks are delivered to
gross tumor volumes (Helgason et al. 1972; Kuipers
1975). Radiation therapy is often used for palliation or
Vulva 899

Fig. 4 Algorithm illustrating Inoperable vulva lesions

therapeutic options for
patients with locally advanced
or inoperable carcinoma of Locally advanced tumor Medically inoperable
the vulva (Perez et al. 1997) Fixed to surrounding tissues
or T4 tumors
or fixed inguinal nodes

Pre-operative RT
(45–50 Gy / 5–6 weeks) Definitive RT
or chemoradiotherapy (45–50 Gy / 5–6 weeks)
or chemoradiotherapy

Inoperable Operable

RT boost Surgery
(15–20 Gy) (?) RT boost

Fig. 5 a Patient with a 4-cm epidermoid carcinoma in the right
labia and clitoris and a 4 9 4 9 3-cm right inguinal lymph
node. Wide local excision of the primary tumor was carried out.
b Portal used to deliver external irradiation to treat pelvic and
vulvar areas to 50 Gy. Bolus (2 cm thick) was used over right
inguinal areas. Additional 15 Gy was delivered with 12-MeV
electrons to right tumor volume. c Posttreatment photograph
3 years later showing excellent cosmetic results. Patient is
tumor free (Perez et al. 1997)

for treatment of patients who are not amenable to radical
surgical resection. Table 5 summarizes treatment
guidelines at Washington University.
Misonidazole was used as a radiosensitizer
combined with high-dose radiation therapy (usually
48–58 Gy) in ten patients with advanced vulvovagi-
nal carcinoma. Nine patients had tumor control and
five were tumor free 9–30 months after diagnosis.
Toxicity was minimal, with only one patient devel-
oping peripheral neuropathy (Nori et al. 1983).
femoral lymphadenectomy as initial therapy and are
found to have positive nodes—particularly more than
one positive node—will benefit from postoperative
irradiation to the groins and pelvis (Homesley et al.
1986). Treatment algorithms are shown in Figs. 3 and 4.
Radiation therapy is superior to surgery in the manage-
ment of patients with positive pelvic nodes as docu-
mented by Homesley et al. (1986). The morbidity
(primarily lymphedema) of combining superficial and
deep inguinal lymphadenectomy with irradiation is
significant.

7.2 Management of Patients

with Positive Nodes
Patients with clinically positive inguinal nodes may
benefit from a course of preoperative irradiation
(45–50 Gy) as suggested by Boronow (1982), Boronow
et al. (1987) or, in a clinical trial, combined with che-
motherapy. Patients who undergo bilateral inguino-
8 Radiation Therapy Techniques
In general, irradiation will encompass the vulvar area and
the inguino-femoral and, in some patients, the pelvic
lymph nodes, while minimizing the dose to the femoral
heads.
900 C. A. Perez and I. Zoberi

Table 5 Carcinoma of the vulva: recommended treatment guidelines

Surgical therapy has been the standard in vulvar carcinoma.
Carcinoma in situ or microinvasion (B5 mm): wide local excision
Invasive carcinoma
Stage I (superficial, \2 cm in diameter): wide local excision or hemi/simple vulvectomy
Other stage I or stage II: Modified radical vulvectomy with inguinal lymph node dissection
If clinically negative nodes, a reasonable alternative is no lymph node dissection, elective node irradiation
Radiation therapy doses:
Negative lymph nodes, simple vulvectomy: 50 Gy with 6- to 18-MV photons and appropriate bolus or IMRT
Wide local excision, pathologically negative margins: as above. Perineal electron beam boost to bring vulva excision site dose to
60 Gy or IMRT
Pathologically positive margins: after 60 Gy, additional boost to positive margins or positive lymph nodes (5 Gy) with electrons
or IMRT or interstitial implant
Stage III: after radical vulvectomy and lymphadenectomy, indications for postoperative irradiation
a. Primary tumor C4 cm
b. Positive surgical margins
c. Three or more positive lymph nodes
Dose: 50 Gy to vulva and inguinal areas; boost to positive margins (10–15 Gy) via perineal portal or interstitial implant; boost to
inguinal region via anteroposterior (AP) field (10–15 Gy) or IMRT.
Stage IV: pelvic exenteration
Preoperative irradiation: 45 Gy to pelvis and inguinal areas with radical vulvectomy and complete inguinal lymph node
dissection. *Postoperative boost to primary (10–15 Gy) via interstitial and/or intracavitary and/or appositional electrons, when
indicated or IMRT
*In patients with palpable inguinal nodes, superficial inguinal node dissection and inguinal/pelvic irradiation may be an acceptable,
less-mutilating alternative (Perez et al. 1997)

8.1 Irradiation Alone
In the occasional medically inoperable patient, small
superficial lesions may be controlled with 60–65 Gy.
For larger tumors, the primary lesion needs to be
irradiated with reduced fields (after 50 Gy) to a dose
of approximately 70 Gy. It is important to use daily
fractionation of 1.6–1.8 Gy in five weekly fractions to
enhance tolerance to treatment. Usually parallel
opposed anterior and posterior portals are used,
preferentially loaded anteriorly (or a high-energy
photon single anterior beam with bolus), that cover
the vulva and the regional lymphatics to deliver
45–50 Gy to an appropriate depth (Perez et al. 1998).
Bolus material over the areas of the skin (vulva) at
risk for tumor involvement is essential (Pao et al.
1988). Interruption of the irradiation course is fre-
quently necessary in the third or fourth week of
treatment to prevent severe moist desquamation and
maceration of the perineal skin. Because of the
decreasing thickness of the perineum/vulvar area,
with resulting higher dose with AP-PA fields, it is
necessary to use wedges to achieve a more homoge-
neous dose distribution.
After a dose of 45–50 Gy is delivered to the vulvar
area, a 6–9 MeV electron beam or low-energy photon
beam (4–6 MV) aimed directly at the vulva is used to
deliver an additional 10–20 Gy to gross or micro-
scopic tumor volumes. An interstitial implant may
also be considered to deliver the boost dose to the
primary tumor (Miyazawa et al. 1983; Carlino et al.
1984). In patients treated without tumor excision,
Jhingran et al. (2003) noted a vulvar recurrence rate
of 65% in 15 patients receiving less than 54 Gy ver-
sus 15% in 35 patients treated to higher doses
(P = 0.0005).
Palpable metastatic inguino-femoral lymph nodes
receive an additional dose (15–20 Gy), preferably
with electrons to decrease the dose to the underly-
ing bones. The energy (12–20 MeV) is determined
with CT scans to define the depth of the lymph
nodes.
Vulva
8.2 Regional Lymphatics
In patients with primary lesions less than 2 cm in
diameter, the probability of nodal involvement is low,
and irradiation of the pelvic lymph nodes may be
omitted if only the inguino-femoral nodes are being
treated (Fig. 5a).
In patients with primary tumors larger than 2 cm
and no clinical evidence of regional lymphatic
involvement, the inguinal and pelvic lymph nodes
may be treated electively to a dose of 45–50 Gy in
1.8–2 Gy fractions per day in lieu of lymph node
dissection (Fig. 5b).
If palpable inguinal lymph nodes are present, the
dose to the inguino-femoral lymph nodes needs to be
65–70 Gy (with reduced fields after 50 Gy), depending
on the size of the involved nodes. When there is evi-
dence of spread to the pelvic nodes, the dose must be
increased to 60 Gy. Because some patients with
involved pelvic lymph nodes are potentially curable,
irradiation of the lower periaortic chain in the presence
of pelvic lymph node involvement might be appropriate.
In patients in whom the pelvic nodes must be trea-
ted, anterior and posterior portals covering the vulvar
and regional lymphatic volumes are required (Fig. 5c).
8.3 Preoperative Radiation Therapy
Patients with advanced primary lesions involving sur-
rounding structures, either of questionable resectability
or clearly unresectable, are sometimes treated with
preoperative irradiation (Boronow et al. 1987), which
may allow the surgeon to obtain negative margins
without sacrificing important structures (clitoris,
urethra, anus) (Moore et al. 2009). Moderate doses of
45–50 Gy in 5–6 weeks may increase the resectability
rate and also avoid mutilating procedures such as
exenteration (Boronow 1982; Boronow et al. 1987).
8.4 Postoperative Radiation Therapy
Increasingly, radiation therapy is used in combina-
tion with surgery. Postoperative irradiation consist-
ing of 50 Gy (1.75–1.8 Gy daily) is indicated in
patients who have undergone radical resection of
the primary lesion and inguino-femoral lymph
nodes and are considered at high risk of recurrence
901
because of inadequate resection margins; in patients
with positive inguinal nodes (in lieu of pelvic
lymph node dissection); or in patients treated with
wide local tumor excision. If the resection margins
are microscopically involved or if there is gross
residual tumor, an additional dose of 15–20 Gy
needs to be administered with reduced portals or an
interstitial implant.
When an inguinal lymph node dissection is per-
formed and only superficial node involvement (three
or more) is detected, postoperative irradiation is given
only to the inguino-femoral lymph nodes (50 Gy at
4–6 cm); a boost of 5–10 Gy may be administered
with electron beam, depending on the number of
nodes, size, or extracapsular extension of the tumor
(Fig. 6a).
Patients with metastatic deep inguino-femoral
nodes found at node dissection may benefit from
postoperative irradiation, including the pelvic
lymphatics, consisting of 50 Gy at the midplane of the
pelvis in 5–6 weeks (Fig. 6b, c).
8.5 Treatment for Recurrent Lesions
Some recurrent lesions may be treated surgically
(Burke et al. 1996). Recurrences after surgical
resection remain potentially curable and must be
treated aggressively in the manner described earlier to
deliver tumor doses of 65–70 Gy with reducing fields.
Hruby et al. (2000) treated 26 women with recurrent
vulvar cancer (16 had surgical excision and 2 debul-
king) with radiation therapy. Fields and doses varied
according to the site of the recurrence, from 30–60 Gy
(Mean 46.8 Gy). In 20 patients treated with radical
intent the mean dose was 50 Gy. The local tumor
control was 34.6% and the 5-year survival 22%.
Women with recurrences confined to the vulva
have a significantly higher 5-year survival (46%)
compared with those with more extensive lesions.
Brachytherapy, usually interstitial, has been
used in some patients with recurrent vulvar lesions
(Hoffman et al. 1990).
8.6 Patient Positioning and Simulation
The patient is usually treated in the supine ‘‘frog-leg’’
position, with the knees apart and the feet together
902
Fig. 6 a Portal for elective irradiation of regional lymphatics
in patients with no clinical evidence of inguinal lymph
node involvement. b Portal for irradiation of pelvic and
inguino-femoral lymph nodes and vulvar area. The groins are
subsequently boosted to a total of 60–65 Gy. A final boost of
Fig. 7 a Supine frog-leg
position for irradiation of
vulva and inguinal pelvic
lymph nodes. The patient’s
thighs are abducted and
outwardly rotated so that the
inguinal folds are stretched
flat. b Example of portal used
for irradiation of vulva and
inguino-femoral lymph nodes
with patient in treatment
position (Pao et al. 1988)
(Fig. 7). A cast or alpha cradle in the treatment
position facilitates everyday repositioning.
When the patient is simulated, wires should be
used to identify surgical scars or palpable or visible
lesions. If the vagina or perineum is involved, a
radiopaque marker should be placed to identify the
tumor margins on the radiographs. For tumors
involving the urethra, a urethral catheter, if tolerated
by the patient, may aid in tumor localization.
During simulation, strong consideration should
be given to designing and constructing compensat-
ing filters to achieve a more homogeneous dose in
the entire target volume, to compensate for the
sloping surface and decreased diameter of the
perineum.
C. A. Perez and I. Zoberi
5–10 Gy to the positive inguinal lymph nodes may be given
with further field reduction, bringing the total dose to that
area to approximately 70 Gy. c Simulation film of portal
covering pelvic and inguino-femoral lymph nodes and vulva
(Perez et al. 1997)
8.7 Beams and Energies
Depending on the available equipment, either an
anteroposterior (AP) beam or differentially loaded
parallel opposed AP–posteroanterior (PA) beams or
electron beam (for part of the treatment) can be
used. Helpful in the design of portals covering the
inguinal regions is a mapping of distribution of
gross inguinal lymph nodes marked with radiopaque
lead wire in patients with various tumors of the
anus, low rectum, and gynaecologic organs (Fig. 8).
If only the vulva and inguino-femoral lymph nodes
are treated, 60Co or 4–6 MV X-rays through an
anterior portal and high-energy ([10 MV) X-rays
through a posterior portal may be adequate. Care
Vulva
Fig. 8 Topographic distribution of inguinal lymph node
metastases in patients with carcinoma of the vulva–vagina–
cervix (triangles), urethra (squares), or anus–low rectum
(circles) (Wang et al. 1996)
should be taken to deliver adequate doses not only
to the primary tumor area and superficial inguinal
nodes but also to the femoral and deep pelvic nodes
(Fig. 9).
Higher energy photon beams (15–18 MV) with
unequal loading (AP3:PA2) and bolus on the anterior
portal can be used. An alternative is to treat the
anterior portal with 60Co or 4–6 MV X-rays and
the posterior portal with a high-energy photon beam
(15–18 MV).
Kalnicki et al. (1987) and King et al. (1993) descri-
bed a technique using a partial transmission block that
reduces the dose to the femoral heads. CT is very helpful
both for evaluation of size and depth of tumor and
regional lymph nodes and for treatment planning.
Gross tumor in the vulva or nodal areas may be
boosted with en face electron fields; the energy for
the vulva is 6–9 MeV using a 1–1.5 cm bolus. The
electron-beam energy used to irradiate lymph nodes,
which are usually 4–6 cm or even 8 cm deep (Koh
903
et al. 1993a; McCall et al. 1995), depends on the depth
of the inguinal nodes, which must be determined by CT
scanning. In some cases, interstitial implants or en face
electron fields may be used to boost the dose to the
primary site (Carlino et al. 1984; Miyazawa et al.
1983). Because of the sloping surface of the perineum,
higher doses may be delivered to this area when the
tumor dose is calculated at the central axis of the portal,
and no compensators are used (Fig. 10).
Although dry and moist desquamation are fre-
quently observed, we still favor the use of bolus
limited to areas potentially involved with tumor.
8.8 Lymphatic Irradiation
The value of elective irradiation of the pelvic lymph
nodes was demonstrated by Homesley et al. (1986),
who reported on a randomized study involving
114 patients with invasive squamous carcinoma of the
vulva and positive inguinal lymph nodes treated with
radical vulvectomy and bilateral groin lymphadenec-
tomy. Patients were randomized to receive irradiation
of 45–50 Gy to the pelvic and inguinal regions over a
5–6 week period or pelvic lymph node dissection.
No irradiation was given to the central vulvar area.
Of 59 patients randomized to irradiation, the 53 who
were treated had a 68% 2-year survival rate. In con-
trast, the nonirradiated group had a 54% survival rate.
The benefit of radiation therapy was noted only in the
patients with N2 or N3 lymphadenectomy. Regional
lymph node recurrences were noted in 7 of 59 patients
(11.9%) allocated to irradiation in contrast to 14 of
55 patients (25.4%) treated with surgery only.
Stehman et al. (1992b) published results of a GOG
protocol that randomized 58 patients with squamous
carcinoma of the vulva and nonsuspicious (N0 or N1)
inguinal nodes to receive either groin dissection or
groin irradiation, each in conjunction with radical
vulvectomy. Radiation therapy consisted of 50 Gy
given in daily 2-Gy fractions to a depth of 3 cm below
the anterior skin surface. The study was closed pre-
maturely because of an excessive number of groin
relapses in the irradiation group. In the groin dissec-
tion group, 5 of 25 patients (20%) had positive groin
nodes; these patients received postoperative irradia-
tion. There were five groin relapses (18.5%) among
the 27 patients on the groin-irradiation regimen and
none on the groin-dissection regimen. The groin-
904
Fig. 9 Representative treatment plans for irradiation of vulvar
region and regional lymphatics. a Parallel opposed 18-MV
photon beams, preferentially loaded anteriorly (27 Gy anteri-
orly, 18 Gy posteriorly); bolus is added over the inguinal areas
dissection regimen had a significantly better pro-
gression-free interval (P = 0.03) and survival
(P = 0.04). This study has been vehemently criti-
cized because the protocol prescription required that
50% of the tumor dose be delivered with 9-MeV
electrons, which are grossly inadequate to treat the
deep inguinal lymph nodes (90% depth dose at
3.1 cm).
Noteworthy McCall et al. (1995) evaluated the
depth of inguinal lymph nodes with CT scans in
100 women without palpable inguinal adenopathy or
prior inguinal surgery. The tumor doses the patients
would have received were determined using isodose
curves constructed according to the guidelines in
GOG protocol no. 88. Only 18% of women had all
inguinal lymph nodes measured at a depth of 3 cm or
C. A. Perez and I. Zoberi
to improve dose distribution in subcutaneous tissues in that
area. A 15-Gy boost using 16-MeV electrons (without bolus) is
added to the groin. b–d Alternative setups with different beam
energies and loadings (Perez et al. 1997)
less. More than half of all women would have
received less than 60% of the prescribed irradiation
dose because their inguinal lymph nodes were deeper
than 5 cm.
Koh et al. (1993a) also quantified inguino-femoral
node depths using pre-treatment CT scans in
50 patients with gynaecological cancer. The distance
of each femoral vessel beneath the overlying skin
surface was determined as an indicator of groin nodal
depth. Correlative data regarding height and weight
were used to calculate the Quetelet index, defined as
(weight in kg)/(height in m)2. Individual femoral
vessel depths ranged from 2.0 to 18.5 cm. When the
depths of all four femoral vessels were averaged in
each patient, the mean ‘‘four-vessel average’’ nodal
depth was 6.1 cm. Recalculation of doses provided to
Vulva
Fig. 10 Sagittal isodose contours on a patient. Note the
relative underdosage of the posterior vulvar region, thereby
requiring a supplemental en face perineal electron beam field
(Pao et al. 1988)
five patients failing prophylactic groin irradiation in
the GOG study showed that all had received nodal
tumor doses of less than 47 Gy, with three patients
being under dosed by more than 30%.
Petereit et al. (1993) updated a study that com-
pared inguino-femoral irradiation to lymphadenec-
tomy for N0 and N1 vulvar carcinomas. Because of
the skin reaction and possible under-dosing of deep
femoral nodes with electrons, as used in the GOG
study, opposed AP–PA photon fields to 50 Gy were
used; 48 patients underwent radical vulvectomy fol-
lowed by either lymphadenectomy (25 patients) or
inguino-femoral irradiation (23 patients). Actuarial
nodal tumor control was 100% in the first group and
91% in the latter (P = 0.14). In addition, there was
no difference in cause-specific survival at 3 years
(96 and 90%, respectively) (P = 0.47). The mor-
bidity of lymphadenectomy included lymphedema
(16%), seroma (16%), infection (44%), and wound
separation (68%). In the irradiated patients, 16%
developed lymphedema, and only 9% had a signifi-
cant skin reaction. Thus, irradiation of the N0 or N1
inguino-femoral nodes is an alternative to lym-
phadenectomy for squamous cell carcinoma of the
vulva if the proper irradiation technique and dose are
used. The acute and late morbidity are less than with
lymphadenectomy.
905
Van der Velden and Ansink (2001) carried out a
literature search using the criteria set by the coch-
rane gynaecological cancer group. Of nine reviewed
papers, only three met the selection criteria. From
these studies, it became clear that the incidence of
groin recurrences after primary radiation therapy was
higher than after surgery, and survival was also
worse in the radiation therapy group. Morbidity after
primary irradiation was lower than with surgery. The
conclusion was criticized, on the grounds that the
depth of 3 cm used in the radiation therapy is too
shallow to administer an optimal dose to the deeper
groin nodes (Koh et al. 1993a). This means that
surgery ought still to be considered the cornerstone
of therapy for the groin nodes in women with vulvar
cancer. Individual patients not fit enough to with-
stand surgery can be treated with primary radiation
therapy, using CT scans to determine the depth of
the inguino-femoral nodes and adequate techniques
of irradiation.
8.9 Brachytherapy
A few reports have described the use of interstitial
irradiation in vulvar cancer. Pohar et al. (1995)
reported on 34 patients treated with 192Ir brachy-
therapy for vulvar cancer (21 at first presentation
when surgery was contraindicated or declined); 12
patients had FIGO stage III or IV disease, 8 had stage
II, 1 had stage I, and 1 had stage 0. Of these patients,
13 were treated for recurrent disease. Paris system
brachytherapy rules were followed; the median ref-
erence dose was 60 Gy (range, 53–88 Gy). With a
median follow-up of 31 months, 10 of 34 patients
(29%) were alive. Actuarial 5-year local tumor con-
trol was 47%, and locoregional tumor control was
45%; 5-year disease-specific survival was 56% and
overall survival 29%. Subset analysis disclosed
higher actuarial 5-year locoregional tumor control in
patients treated at first presentation (80 vs. 16%)
(P = 0.01).
At Washington University, 20 patients had an
interstitial implant as part of therapy, usually as a
boost at the primary tumor site, occasionally for
positive lymph nodes. The loco regional tumor con-
trol was 100% for T1 or T2 (4 patients), 80% for T3
(10 patients), and 50% for 6 patients with T4 or
recurrent tumors. None of the 5 patients receiving a
906
Fig. 11 Example of 3-D conformal treatment planning for a
patient with carcinoma of the vulva treated with anteroposte-
rior–posteroanterior (AP–PA) pelvic portals including regional
lymphatics. A total of 50.40 cGy was delivered to the planning
target volume (PTV) in 1.8-Gy daily fractions using 18-MV
photons and 15° dynamic wedges. a Inguino-femoral and pelvic
common iliac lymphatic volumes are outlined. b Low pelvis
cross-section dose distribution. c Sagittal dose distribution
total dose of 60 Gy or less had significant sequelae, in
contrast to 8 of 15 (53%) treated with higher doses.
Patients treated with external irradiation only had
11–26% moderate or severe sequelae (P = 0.16).
C. A. Perez and I. Zoberi
8.10 Three-Dimensional Conformal
(3D-CRT) and Intensity Modulated
Radiation Therapy (IMRT)
With the advent of new technology an increasing
number of patients have been treated with 3-D con-
formal radiation therapy to minimize irradiation to
normal tissues, including the bone marrow in the
pelvic bones (Harper et al. 2004). An example of
target delineation, including iliac and inguinal
lymphatics, portals defined by MLC, and dose dis-
tributions are illustrated in Fig. 11 for a patient with
primary vulvar cancer.
Beriwal et al. (2006) treated 15 patients with
IMRT, 7 with pre-operative chemoradiation (46 Gy)
and 8 with post-operative RT (50 Gy). Treatment
position was supine, patient immobilized with a
vacuum-evacuated Vac-Lok bag (MEDTEC, Orange
City IA). GTV was expanded by 1 cm to be included
in the CTV, which was delineated to include the
vulva, bilateral inguino-femoral, external and internal
iliac lymph nodes p to L5-S1. The pelvic blood ves-
sels were used as guide, with 1 cm margins, to
delineate the lymph node volumes.
We use PTV margins of 1 cm. All pelvic organs at
risk (bladder, small bowel, and rectum) as well as the
femoral head and necks are delineated. Figure 12 illus-
trates the dose distribution with IMRT at various levels
of the pelvis. Beriwal et al. (2006) used bolus in the
vulvar region, but we have not used, as with IMRT there
is minimal skin sparing. They noted two recurrence in
the irradiated volumes and no grade three toxicity.
Comparison of 3D-CRT and IMRT pelvic irradi-
ation has shown satisfactory target volume coverage
and significantly less volume of organs at risk with
IMRT (Ahmad et al. 2004; Beriwal et al. 2006).
8.11 Patterns of Failure after Treatment
The experience of Princess Margaret Hospital
demonstrated that 80–95% of relapses after radical
vulvectomy and bilateral groin node dissection were
locoregional and could be encompassed in the loco-
regional irradiation fields (Bryon et al. 1991).
Perez et al. (1993) updated the results on
50 patients with primary invasive and 17 with recur-
rent histologically confirmed vulvar carcinoma trea-
ted with radiation therapy for loco regional disease.
Vulva
Fig. 12 Dose distributions with IMRT in patient with vulvar cancer stage III, at levels: a pelvic nodes, b inguinal nodes, c Vulva.
Courtesy of Dr. Wu-Jin Koh, Seattle, WA, USA
Results in 68 patients with primary and 18 with
recurrent tumors (unpublished data) are further
updated in this chapter. Of the patients with primary
tumors, 18 were treated with biopsy and irradiation
alone, 13 with wide excision plus radiation therapy,
11 with partial or simple vulvectomy, and 24 with
radical vulvectomy followed by irradiation to the
operative fields and inguino-femoral/pelvic lymph
nodes. In patients with primary tumors treated with
biopsy or local excision, local tumor control was
92–100% for T1-3N0 disease, 40% for similar stages
with N1-3, and 27% for recurrent tumors. Among
patients treated with partial or radical vulvectomy and
radiation therapy, primary tumor control was 90% in
those with T1-3 tumors and any nodal stage, 33% in
those with any T stage and N3 lymph nodes, and 66%
in patients with recurrent tumors. The actuarial 5-year
disease-free survival rates were 87% for patients with
T1N0 disease, 62% for those with T2-3N0 disease,
30% for those with T1-3N1 disease, and 11% for
patients with recurrent tumors. There was no signifi-
cant impact of type of vulvectomy on outcome. There
were no long-term survivors with T4 or N2-3 disease.
Of 17 patients treated for postvulvectomy recurrent
disease, four remain disease-free after local tumor
excision and radiation therapy. In patients with T1 or
T2 tumors treated with biopsy or wide tumor excision
and irradiation with doses less than 50 Gy, the local
tumor control rate was 75% (3 of 4 patients), in
contrast to 100% (13 patients) with 50.01–65 Gy.
With T3 or T4 tumors treated with local excision and
radiation therapy, tumor control occurred in none of
three patients with doses less than 50 Gy and in 66%
(6 of 9) with 50.01–65 Gy. In patients with T1 or T2
907
tumors treated with partial or radical vulvectomy and
irradiation, local tumor control was 75% (6 of 8),
regardless of dose level; in T3 and T4 tumors, it was
67% (4 of 6 patients) with 50–60 Gy and 86% (6 of 7)
with 65–70 Gy. Differences were not statistically
significant. There was no significant dose response for
tumor control in the inguino-femoral lymph nodes
with doses of 50–60 Gy for elective treatment of
nonpalpable lymph nodes, yielding 91.6% tumor
control (33 of 36), and 60–70 Gy controlling tumor
growth in 75–80% of patients with positive nodes
when administered postoperatively after partial or
radical lymph node dissection.
Dusenbery et al. (1994) reported on 27 patients
irradiated postoperatively after radical vulvectomy and
bilateral lymphadenectomy (25 patients), radical vul-
vectomy and unilateral lymphadenectomy (1), or
hemivulvectomy and bilateral lymphadenectomy (1).
There were 14 FIGO stage III, 8 stage IVA, and 5 stage
IVB patients. Inguinal lymph nodes were involved with
tumor in all patients. Postoperative irradiation was
directed at the bilateral groin and pelvic nodes
(19 patients), unilateral groin and pelvic nodes (six
patients), or unilateral groin only (one patient); the
midline area was blocked in all patients. One patient
received irradiation to the entire pelvis and perineum.
Doses ranged from 10.8 to 50.7 Gy (median, 45.5 Gy).
Actuarial 5-year overall and disease-free survival rates
were 40 and 35%, respectively. Recurrences developed
in 63% (17 of 27 patients) (median of nine months from
surgery), and 15 of these died; two patients with
recurrences were surviving at 24 and 96 months after
further surgery and radiation therapy. Central recur-
rences (under the midline block) were present in 13 of
908
Fig. 13 Patterns of failure in 27 patients irradiated after
radical vulvectomy in whom the vulva was shielded with a
central block. Dots represent a single patient. If relapsing in two
or more sites, dots are connected by lines. a Isolated central
these 17 patients (76%), either as central only (eight
patients), central and regional (four patients), or central
and distant (one patient) (Fig. 13). Additionally, three
patients developed regional recurrences, and one
patient developed a concurrent regional and distant
relapse. Use of a midline block resulted in a 48% central
recurrence rate (13 of 27), much higher than the 8.5%
rate previously reported using this technique. Routine
use of the midline block should be abandoned, and
postoperative irradiation volumes should be tailored to
the tumor in each patient.
In 86 patients treated at Washington University,
with either irradiation alone or combined with local
excision or a partial or radical vulvectomy (always
irradiating the vulvar area), the incidence of recur-
rence was about 38% at the primary site, 10% in the
inguino-femoral lymph node region, and 23% distant
metastases (Perez et al. 1993).
9 Sequelae of Treatment
Common sequelae associated with radical surgery are
those related to wound problems, primarily infection
and necrosis. The reported incidence of wound
C. A. Perez and I. Zoberi
(under the midline block) recurrences. b Combined central and
regional (inguinal or thigh) recurrences. c Remainder of first
recurrences consisted of either isolated regional recurrences or
regional and distant recurrences (Dusenbery et al. 1994)
infection varies greatly. Iversen et al. (1980) observed
it in 5.7% of patients and Boutselis (1972) in 50% of
patients. The incidence of wound dehiscence and
necrosis varies in most reports from 30–50%
(Rutledge et al. 1970; Boutselis 1972). Leg edema is a
serious complication of nodal dissection. Transient
edema occurred in approximately 14% of patients
reported on by Boutselis (1972) and Rutledge et al.
(1970). Chronic (persistent) edema was reported in
71% of patients reported on by Boutselis (1972) and
in 20% of those reported on by Rutledge et al. (1970).
Operative mortality in most series varies from 3–6%.
With a tumor at the skin or mucosal surface, which
requires that the peak dose be at the surface, it is to be
expected that literally all patients will have a signif-
icant acute cutaneous and mucosal reaction. Of more
concern, however, is the incidence of late (chronic)
sequelae, some of which can be attributed to the
fractionation scheme used. Schulz et al. (1980), for
example, reported a very high incidence of compli-
cations with 5-Gy fractions. The rate has been con-
sistently low in patients treated with 2 Gy per day or
similar fractionation schemes (Backstrom et al. 1972;
Nobler 1972). Significant treatment morbidity in 86
patients treated at Washington University included
Vulva
one rectovaginal fistula, one case of proctitis, one
rectal stricture, four bone or skin necroses, five vag-
inal necroses, and one groin abscess. Occasionally,
necrosis and fracture of the femoral head/neck may be
observed; Grigsby et al. (1995) reported a 5% actu-
arial 5-year incidence of fractures in patients receiv-
ing doses of 50 Gy or greater. Cosmetic results with
conservation surgery and irradiation may be very
rewarding if appropriate surgical and irradiation
techniques are applied.
In a review of 73 patients, Balat et al. (2000)
compared complications with wide local excision plus
postoperative radiation therapy or radical vulvectomy
and bilateral lymphadenectomy plus pre- or postop-
erative radiation therapy. There were no significant
differences among these treatments in terms of pri-
mary tumor control, 5-year disease-year survival, or
overall survival. The best treatment for advanced
vulvar cancer was wide local excision plus radiation
therapy, as this method retained a high survival with
less morbidity.
Edema of lower extremities after nodal irradiation
alone is very low (Petereit et al. 1993; Katz et al.
2003).
In patients with gynaecological tumors treated
with irradiation including the hips Grigsby et al.
(1995) reported an incidence of 4.8% femoral neck
fractures, which occurred with doses of 45–63 Gy.
No fractures were observed in patients receiving
less than 42 Gy.
10 Carcinoma of the Vulva
and Pregnancy
Extremely infrequently encountered is the associa-
tion of pregnancy and vulvar carcinoma. Gitsch
et al. (1995) reported on two women with stage II
and III disease; the first patient, who had a
5 9 2 cm ulcerated lesion under the clitoris, was
treated by radical anterior vulvectomy and bilateral
groin dissection when 22 weeks pregnant. She had
an uneventful pregnancy; a Cesarean section was
performed, and she was free of disease 29 months
after initial surgery. The second patient, who had
multifocal lesions with a maximal depth of 1.9 mm
of tumor invasion, underwent modified radical vul-
vectomy with bilateral groin dissection when
17 weeks pregnant. Because of a grossly positive
909
groin lymph node, she underwent radiation therapy
after Cesarean section. She was alive without
invasive cancer 28 months after diagnosis. Early
histological diagnosis and treatment are mandatory
in the management of suspicious vulvar lesions
during pregnancy, delaying irradiation until the
pregnancy is terminated.
11 Clinical Trials
Only a small number of clinical trials are available for
the treatment of vulvar carcinoma. A phase II trial to
document the rates and patterns of recurrence in early
stage I patients, all treated with ipsilateral superficial
inguinal lymphadenectomy and modified radical
hemivulvectomy, is in progress by the Gynaecologic
Oncology Group (GOG-74). These patients must have
pathologically negative ipsilateral superficial inguinal
lymph nodes and resection margins at the dermis of
greater than 5 mm.
Patients with advanced or recurrent vulvar cancer
that is refractory to curative therapy or established
treatments are eligible for GOG no. 26. This phase II
protocol screens new agents and drug combinations
for activity in patients with advanced or recurrent
pelvic malignancies.
12 Treatment of Other Vulvar
Malignant Neoplasias
12.1 Adenocarcinoma
Most primary adenocarcinomas of the vulva arise in
the Bartholin’s gland (Leuchter et al. 1982; Copeland
et al. 1986; Burke et al. 1996). Other potential tissues
of origin include skin appendages or ectopic breast
tissue.
Radical wide excision, hemivulvectomy, or radi-
cal vulvectomy has been used to treat these patients
(Copeland et al. 1986). The incidence of groin node
metastases is about 30% (Leuchter et al. 1982), thus
inguinal lymphadenectomy should be included in
primary surgical resection. Radiation therapy may
have a role in enhancing local tumor control for
women with large primary tumors or inguinal node
metastases (Copeland et al. 1986).
910
12.2 Vulvar Sarcoma
Primary sarcomas are rare tumors that can arise
from any mesenchymal tissues of the vulva; leio-
myosarcoma and rhabdomyosarcoma predominate
(Hays et al. 1988; Tavassoli and Norris 1979).
Usual treatment consists of aggressive resection of
either primary or locally recurrent disease; postop-
erative irradiation may decrease the incidence of
local recurrence. Rhabdomyosarcoma may be
responsive to both chemotherapy and irradiation;
the current treatment of choice is to combine
chemoirradiation (using vincristine, dactinomycin,
cyclophosphamide, and doxorubicin and 50–55 Gy
in 1.6–1.8 Gy fractions) with limited surgical
resection of residual tumor (Boronow 1973; Krupp
et al. 1975).
12.3 Malignant Melanoma
Superficial malignant melanoma of the vulva can be
treated with wide local excision. The current
accepted management for more invasive vulvar
melanoma is radical vulvectomy and bilateral
inguinal lymph node dissection for levels of inva-
sion greater than Clark’s level 2. Although some
gynaecology oncologists recommend ipsilateral
inguinal lymph node dissection, Chung et al. (1975)
found no lymph node metastases in eight patients
with level-2 malignant melanoma, and none of
these patients died of the disease. Survival was
closely related to depth of invasion; only 2 patients
of 25 with Clark levels 3 through 5 melanoma
survived 5 years. The most common sites of
recurrence were the groin.
(Nine patients), perineum, vagina, and urethra (two
cases in each location), and cervix and rectum (one
each). All patients who died of melanoma had wide-
spread metastases to lungs, adrenals, brain, liver,
kidneys, or retroperitoneal lymph nodes.
Woolcott et al. (1988) reported on 50 patients with
primary melanoma of the vulva, 42 of whom were
treated with definitive therapy: 16 with wide local
excision, two with unilateral inguino-femoral and two
with bilateral inguino-femoral lymphadenectomy, two
with hemivulvectomy and inguino-femoral lymph
node dissection, and 1 with simple vulvectomy alone.
Twenty-three patients were treated with radical
C. A. Perez and I. Zoberi
vulvectomy, combined with bilateral inguino-femoral
lymphadenectomy in 22 patients. Two patients also
had pelvic lymphadenectomy. Of 42 patients treated
with curative intent, three received adjuvant radiation
therapy. Of 50 patients, 17 (34%) were alive and free
of disease at the last follow-up. The 5-year survival
rate for 32 eligible patients was 43.8%. Depth of
melanocytic penetration was the main prognostic
factor. Local recurrence developed in seven of the
23 patients treated with radical vulvectomy; four had
inguino-femoral nodal recurrences, and eight devel-
oped distant metastases. Of 16 patients treated with
wide local excision, three developed local recurrence,
four had inguino-femoral recurrences, and two had
distant metastases.
13 Chemotherapy
Topical chemotherapy has been used for treatment of
selected patients with vulvar or vaginal intraepithelial
neoplasia; 5-fluorouracil (5-FU) has been the most
commonly used agent (Sillman et al. 1985). All
25 patients treated in this manner were free of disease
for 3 months to more than 40 months after treatment,
although three required retreatment at 3, 9, and
11 months (Calgar et al. 1981).
Several drug regimens have been used in squa-
mous cell vulvar cancer, most frequently incorporat-
ing bleomycin, vincristine, cisplatin, mitomycin-C, or
methotrexate in various three- or four-agent combi-
nations with limited activity in phase II studies (Burke
et al. 1996).
13.1 Combination of Chemotherapy
and Irradiation
Thomas et al. (1989) described results in 33 patients
with vulvar cancer treated with a combination of
5-FU and/or mitomycin-C; 32 had squamous cell
carcinoma. Of 18 patients with primary disease, nine
were treated in an adjuvant setting (five after radical
vulvectomy and inguinal node dissection; four had
local excision only). Several patients had positive
surgical margins; 6 of 9 received vulvar irradiation
(40–64 Gy in daily fractions of 1.6–1.8 Gy), and 5 of
6, in addition, received inguinal lymph node irradia-
tion. Of nine patients, three were treated to inguinal
Vulva
nodes only. At 5–45 months, 6 of 9 patients remained
disease-free. Of the other patients with primary dis-
ease, nine received chemotherapy and irradiation to
the vulva, and 4 of 5 with positive nodes also
underwent treatment to the inguinal areas. After a
follow-up of 5–43 months, 6 of the 9 patients were
disease-free. Of six patients with residual or recurrent
vulvar carcinoma after initial chemoirradiation, five
had salvage surgery (local excision in four and radical
vulvectomy in one). Of nine patients, seven had
vulvar primary tumor control after salvage therapy.
No patient developed nodal or distant metastases.
After initial surgery, 15 patients were treated for
recurrence; ten had a previous radical vulvectomy and
bilateral node dissection. At 5–45 months, seven of
these patients remain alive without disease. Of
11 patients treated for recurrence in the vulva only,
six were alive without disease. Four patients who
developed pulmonary metastases died.
Combined therapy was well tolerated, except for the
expected oropharyngeal mucositis and haematological
toxicity of 5-FU. One patient developed severe proc-
titis after receiving 55 Gy in 35 fractions with electrons
to the vulva, and one patient developed a vascular hip
necrosis after a dose of 47 Gy in 27 fractions.
The experience from Princess Margaret Hospital
(Thomas et al. 1989) using concurrent chemoirradia-
tion for vulvar cancer showed that late vulvar fibrosis,
atrophy, telangiectasia, and necrosis can be almost
totally avoided if the irradiation fraction size is kept
below 1.6–1.8 Gy and excessive total dose is not
used; disease recurred in two of six patients receiving
less than 50 Gy, and in two of seven patients with
doses greater than 50 Gy. Dose exceeding 60 Gy may
substantially increase treatment morbidity, particu-
larly if surgical salvage is required. If residual disease
persists after 60 Gy, an attempt should be made to
remove it surgically. The irradiation volume is tai-
lored to the extent of disease.
Of patients with advanced squamous cell carci-
noma of the vulva, 42 were treated with a combina-
tion regimen of bleomycin (180 mg) and external
irradiation (30–45 Gy) (Scheistroen and Trope 1993);
22 patients had primary and 22 had recurrent disease.
Of 15 patients with primary disease, five showed
complete and ten partial response; four underwent
surgery. Of these, one was alive after 60 months with
no evidence of disease, two died of unrelated causes
without signs of recurrence, and 17 relapsed and died
911
of carcinoma of the vulva. Of 22 patients treated for
recurrence, 2 had complete and 11 had partial
responses; none underwent surgery. All of these
patients died of carcinoma of the vulva; median sur-
vival was 6.5 months. Toxicity was acceptable, and
there were no treatment-related deaths Increased
irradiation dose beyond 45 Gy and more aggressive
surgery might have improved the results.
Russell et al. (1992) observed 16 complete
responses in 25 women with locally advanced or
recurrent squamous cell carcinoma of the vulva
treated with 5-FU continuous infusion for 96 h (in
11 patients combined with three doses of cisplatin at
100 mg/m2) and pelvic irradiation (median dose
54 Gy). Of 18 previously untreated patients, 12 were
cancer-free at 2–52 months; three patients developed
intermittent urinary incontinence and four developed
leg edema.
Wahlen et al. (1995) described 19 patients with
locally advanced vulvar cancer (4 stage II and 15
stage III) The patients received 45–50 Gy to the
pelvis and inguinal nodes with concurrent chemo-
therapy (5-FU in a 96-h continuous infusion,
1000 mg/m2 per day, during week 1 and week 5 of
radiation therapy). Boosts with implants or electrons
were received by ten patients, and six others under-
went local excision. With median follow-up of 34
months, combined therapy resulted in a local tumor
control rate of 75% (14 of 19); all five failures
occurred within six months of treatment. Of these
patients, four were rendered disease free by radical
vulvectomy and/or exenteration, for an overall local
control rate of 95% (18 of 19).
Han et al. (2000) published results in 54 patients
with locally advanced vulvar cancer treated with
radiation therapy, among which 20 received chemo-
therapy (5-FU and mitomycin-C) and radiation
therapy, while 34 patients received radiation therapy
alone. Of the 20 patients, 14 were treated for primary
or recurrent disease, and after vulvectomy for high-
risk disease. Of the 34 patients, 12 were treated
primarily and 22 received adjuvant treatment.
Six patients received cisplatin in place of mitomycin-
C. In the chemoirradiation groups, radiation was
administered to the vulva, pelvic, and inguinal lymph
nodes to a median dose of 45 Gy, with an additional
6–17 Gy to gross disease. In radiation therapy groups,
the median dose to the microscopic disease was
45 Gy. Nine patients received external beam boost
912 C. A. Perez and I. Zoberi

Table 6 Results of chemotherapy and irradiation in locally advanced or recurrent vulvar cancer
Author No. of Chemotherapy Irradiation Complete Partial Locoregional Disease- DFS
patients (Gy) response response tumor control free time
(%) (%) survival (months)
Eifel et al. 12 5-FU, C 90 90 6/12 17–30
(1995)
Iversen 15 Bleo 36–40 15 4/15 15% 48
(1982)
Koh et al. 20 5-FU, C, M 40–54 50 40 10/20 59% 60
(1993b)
Montana 46 C, 5-FU 47.6 76 – 29/38 50%
et al. (2000)
Russell et al. 25 5-FU, C 36–72 64 – 16/18 67%
(1992) primary
4/7 recurrent 29% 2–52
Scheistroen 42 Bleo 30–45 33 40 5/22 5% 60
and Trope
(1993)
Thomas et al. 33 5-FU, M 40–64 7/9 primary, 5–45
(1989) 7/10 post-RV
5-FU 5-fluorouracil, Bleo bleomycin, C cisplatin, M mitomycin-C, RV radical vulvectomy, DFS disease-free survival. Modified
from Perez et al. (1997)

and 16 patients received supplementary brachyther-
apy. Overall survival was superior in the patients
treated with chemoirradiation versus irradiation alone
(P = 0.04). There was also a statistically significant
improvement in disease-specific (P = 0.03) and
relapse-free (P = 0.01) survival, favoring chemoir-
radiation. No statistically significant trends of
improved survival rates favoring chemoirradiation
over adjuvant radiation therapy were observed.
Montana et al. (2000) reported on a GOG study of
46 patients with vulvar cancer and N2-3 lymph nodes.
Patients underwent a split course of radiation ther-
apy—4760 cGy to the primary and lymph nodes with
concurrent chemotherapy, cisplatin/5-FU followed by
surgery. Following chemoirradiation, the disease in
the lymph nodes became resectable in 38 of
40 patients. Because of pulmonary metastasis, two
patients who completed chemoirradiation did not
undergo surgery as per protocol. One underwent
radical vulvectomy and unilateral node dissection and
the other radical vulvectomy only. The lymph nodes
were histologically negative in 15 of 37 patients
(40%). Recurrent and/or metastatic disease developed
in 19 patients. The sites of failure were as follows:
primary area only, 9; lymph node area only, 1; pri-
mary area and distant metastasis, 1; distant metastasis
only, 8. Local control of the disease in the lymph
nodes was achieved in 36 of 37 and in the primary
area in 29 of 38 patients. Of the patients, 20 are alive
and disease-free, and 5 have died without evidence of
recurrence or metastasis; two patients died of treat-
ment-related complications.
Preliminary results of chemotherapy and irradia-
tion, summarized in Table 6, are promising and sug-
gest that patients in high-risk groups can be treated
effectively with combinations of surgery, irradiation,
and systemic chemotherapy. Further assessment of
long-term results is in progress, and prospective
clinical trials are strongly encouraged.
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 Carcinoma of the Vagina
Higinia R. Cardenes, Jennifer E. Zook, and David L. Andolino
Contents
1 Anatomy.................................................................... 917
2 Pathology .................................................................. 918
3 Natural History ........................................................ 919
4 Clinical Presentation ............................................... 919
5 Diagnostic Workup.................................................. 919
6 Staging....................................................................... 920
7 Prognostic Factors Influencing Choice
of Treatment............................................................. 922
8 General Management: Treatment Options .......... 923
9 Radiation Therapy Techniques.............................. 924
9.1 External Beam Radiotherapy .................................... 924
9.2 Low Dose Rate Intracavitary Brachytherapy ........... 927
9.3 High Dose Rate Intracavitary Brachytherapy
and Interstitial Brachytherapy................................... 929
9.4 Interstitial Brachytherapy .......................................... 930
10 Squamous Cell Carcinoma: Treatment Options
and Outcome by Figo Stages.................................. 932
10.1 FIGO Stage 0: VAIN-CIS....................................... 932
10.2 Invasive Squamous Cell Carcinoma ....................... 932
11 Chemotherapy and Radiation ................................ 934
12 Hyperthermia and Radiation ................................. 937
13 Salvage Therapy ...................................................... 937
14 Treatment Complications and Their
Management ............................................................. 939
H. R. Cardenes (&)
J. E. Zook
D. L. Andolino
Department of Radiation Oncology,
Indiana University School of Medicine,
535 Barnhill Drive, RT 041,
Indianapolis, IN 46202, USA
e-mail: hcardene@iupui.edu
S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology,
DOI: 10.1007/174_2011_157, Ó Springer-Verlag Berlin Heidelberg 2012
15 Palliative Radiotherapy........................................... 940
References.......................................................................... 941
Abstract
Primary vaginal cancer is a rare entity representing
about 2% of all female genital neoplasias and only
0.1–0.2% of all cancers (Jemal et al. 59(4):225–249,
2009). Most carcinomas found in the vagina repre-
sent direct extension or metastasis from other
primary gynecologic (cervix or vulva) and non-
gynecologic sites, most commonly breast and
gastrointestinal tract. There are a number of contro-
versies in terms of epidemiology, staging, and
diagnostic evaluation as well as in the management
of vaginal cancer. Because of its rarity, there is a
lack of prospective, randomized studies in patients
with vaginal cancer, and therefore it is difficult to
establish strong, evidence based-recommendations.
Decisions regarding therapeutic options are for the
most part, based on retrospective data and individual
assessment using general principles derived from
clinical experience in the cancer management in
other sites. Most of the available data refer to the
treatment of primary invasive SCC of the vagina,
since this represents the most common histology.
1 Anatomy
The vagina is a dilatable tubular structure averaging
7.5 cm in length, lined by non-keratinizing, stratified,
squamous epithelium extending from the vestibule to
the cervix of the uterus. It lies dorsal to the base of
917
918
the bladder and urethra, and ventral to the rectum. The
upper fourth of the posterior wall is separated from the
rectum by a reflection of peritoneum, the pouch of
Douglas. The vaginal wall is composed of three layers:
the mucosa, muscularis, and adventitia. Beneath the
mucosa lies a submucosal layer of elastin and a double
muscularis layer, highly vascularized with a rich
innervation and lymphatic drainage. The muscularis
layer is composed of smooth muscle fibers, arranged
circularly on the inner portion and longitudinally in the
outer portion. The adventitia is a thin, outer connective
tissue layer that merges with that of adjacent organs.
The proximal vagina is supplied by the vaginal
artery branch from the uterine or cervical branch of
the uterine artery. It runs along the lateral wall of the
vagina and anastomoses with the inferior vesical and
middle rectal arteries from the surrounding viscera
(Sedlis and Robboy 1987). The accompanying venous
plexus, running parallel to the arteries, ultimately
drains to the internal iliac vein. The lumbar plexus
and pudendal nerve, with branches from the sacral
roots 2–4, provide innervation to the vaginal vault.
The lymphatic drainage of the vagina is complex,
consisting of an extensive inter-communicating net-
work. Fine lymphatic vessels coursing through the
submucosa and muscularis, coalesce into small trunks
running laterally along the walls of the vagina. The
upper anterior vagina drains along cervical channels
to the interiliac chain; the posterior vagina drains into
the inferior gluteal, presacral, and anorectal nodes.
The distal vagina lymphatics drain into the inguinal
and femoral nodes and from there to the pelvic nodes.
Lymphatic flow from lesions in the mid-vagina
may drain either way (Plentl and Friedman 1971).
However, because of the presence of inter-commu-
nicating lymphatics along the terminal branches of the
vaginal artery and near the vaginal wall, the external
iliac nodes are at high risk, even in lesions of the
lower third of the vagina. Such a complex lymphatic
drainage pattern has significant implications for
therapeutic planning. Therefore, bilateral pelvic nodes
should be considered at risk in any invasive vaginal
carcinoma, and bilateral groin nodes considered at
risk in those lesions involving the distal third of the
vagina. Although these drainage patterns serve as a
general rule, recent data utilizing lymphatic mapping
in women with vaginal cancer challenges the estab-
lished drainage patterns (Frumovitz et al. 2008).
Frumovitz et al. found unexpected lymphatic drainage
H. R. Cardenes et al.
from primary lesions in the vagina, including in 3 of
5 women with lesions located at the introitus that
were found to have a sentinel node in the pelvis on
pretreatment lymphoscintigraphy, when anatomic
site would predict drainage to the inguinal triangle.
Conversely, 2 of 4 women who had lesions in the
upper third of the vagina were found to have a
sentinel node in the inguino-femoral region when
anatomic site would predict for involvement of
pelvic lymph nodes.
2 Pathology
Squamous Cell Carcinoma (SCC) represents about
80–90% of primary vaginal cancers (Zaino et al.
2002). Histologically, keratinizing, non-keratinizing,
basaloid, warty, and verrucous variants have been
described. Tumors may also be graded as, moderately,
or poorly differentiated, most cases being moderately
differentiated and non-keratinizing. Vaginal intraepi-
thelial neoplasia (VAIN) is a precursor of SCC, and is
graded from I to III, depending upon the degree of
nuclear atypia and crowding, and the proportion of
the epithelium involved. The true incidence of VAIN
and its rate of progression to invasive carcinoma are
unknown, ranging in several series from 5 to 28%
(Boonlikit and Noinual 2010; Aho et al. 1991;
Hoffman et al. 1991; Brinton et al. 1990). It is thought
that human papillomavirus (HPV) plays a central role
in the development of squamous cell vaginal cancer
(Daling et al. 2002).
Clear-Cell Adenocarcinoma (CCA) is associated to
intrauterine Diethylstilbestrol (DES) exposure
(Kaufman et al. 1982; Maassen et al. 1993; Robboy
et al. 1977, 1982, 1984; Antonioli and Burke 1975).
These tumors have a predilection for the upper third
of the vagina and the exocervix. Most are exophytic
and superficially invasive (Herbst et al. 1974). Other
Adenocarcinomas that could involve the vagina
include: mucinous type (Ebrahim et al. 2001; Hiroi
et al. 2001; Munkarah et al. 1994), endometrioid
adenocarcinoma—usually arising in endometriosis
(Haskel et al. 1989), mesonephric (Hinchey et al.
1983) and papillary serous adenocarcinoma (Riva
et al. 1997). Frank et al. (2007) proposed that there
is a different natural history when comparing
DES-associated adenocarcinoma of the vagina com-
pared to non-DES-associated adenocarcinomas of the
Carcinoma of the Vagina
vagina and that the latter subgroup has a worse
prognosis (Frank et al. 2007).
Creasman et al. (1998) published in 1998 the
National Cancer Data Base (NCDB) report on 4885
patients with primary diagnosis of vaginal cancer
registered from 1985 to 1994 (Creasman et al. 1998).
Approximately 92% of the patients were diagnosed
with in situ or invasive SCC or adenocarcinomas; 4%
with melanomas; 3% with sarcomas; and 1% with
other or unspecified types of cancer. In the NCDB
report, invasive carcinomas accounted for 72% of the
carcinoma cases, or 66% of all vaginal cancers. In situ
carcinomas accounted for 28%; SCC represented 79%
of invasive vaginal carcinomas; and adenocarcinomas
represented 14% (Creasman et al. 1998). In a more
recent Surveillance, Epidemiology and End Results
program (SEER) study by Shah et al. (2009), 2,149
women with primary vaginal cancer were diagnosed
between 1990 and 2004. Squamous cell histology
represented 65% of all cases, followed by adenocar-
cinomas, 14%, melanoma, 6%, and the other category
representing the remaining 15% (Shah et al. 2009).
3 Natural History
The majority (57–83%) of vaginal primaries occurs in
the upper third or at the apex of the vault, most
commonly in the posterior wall; the lower third may
be involved in as many as 31% of patients (Gallup
et al. 1987a; Rubin et al. 1985; Stock et al. 1995).
Lesions confined to the middle third are uncommon.
Vaginal tumors may spread along the vaginal walls to
involve the cervix or the vulva. A lesion on the
anterior wall may infiltrate the vesico-vaginal septum
and/or the urethra; those on the posterior wall may
eventually involve the recto-vaginal septum, and
subsequently infiltrate the rectal mucosa. Vaginal
cancer may invade the parametrium and paracolpal
tissues, extending into the obturator fossa, cardinal
ligaments, lateral pelvic walls and the uterosacro
ligaments.
The issue of regional nodal metastasis, both the
incidence of occult nodal disease and the anatomic
pathways of lymphatic spread, are somewhat contro-
versial. The incidence of positive pelvic nodes at
diagnosis varies with the stage and location of the
lesion. Although data on staging lymphadenectomy
are sparse, two studies reported a significant incidence
919
of nodal disease in early stage vaginal carcinoma.
In Al-Kurdi’s series (Al-Kurdi and Monaghan
1981), the incidence of pelvic nodal metastasis was
14% and 32% for stage I and II, respectively,
whereas in Davis’s series (Davis et al. 1991) the
incidence was 6% and 26% for stage I and II,
respectively. The incidence is expected to be higher
for stage III, although no substantial data are
available. Involvement of inguinal nodes is most
common when the lesion is located in the lower
third of the vagina.
Distant metastasis may occur, primarily in patients
with advanced disease at presentation, or those who
recur after primary therapy. In Perez series (Perez
et al. 1988), the overall incidence of distant metastasis
was 16% in Stage I, 31% in Stage IIA, 46% in Stage
IIB, 62% in Stage III, and 50% in Stage IV. In the
largest series reported to date by Hellman et al.
(2006), distant metastases at diagnosis was rare at 2%.
In five of the seven patients with distant metastases,
the tumor involved the entire vagina (Hellman et al.
2006).
4 Clinical Presentation
VAIN most often is asymptomatic (Lenehan et al.
1986), and is usually detected by cytology. In patients
with invasive disease, irregular vaginal bleeding and/
or discharge, often post-coital, is the most common
presenting symptom, followed by vaginal discharge
and dysuria. Pelvic pain is a relatively late symptom,
generally related to tumor extent beyond the vagina
(Gallup et al. 1987b; Rubin et al. 1985; Tjalma et al.
2001).
5 Diagnostic Workup
In general, in patients with suspected vaginal malig-
nancy, thorough physical exam with detailed specu-
lum inspection, digital palpation, colposcopic and
cytologic evaluation, and biopsy constitute the most
effective procedure for diagnosing primary, meta-
static, or recurrent carcinoma of the vagina. In
symptomatic patients, biopsy of any abnormal exo-
phytic or endophytic lesion noted at the time of the
exam is indicated. Examination under anesthesia is
recommended for the thoroughness of evaluation of
920 H. R. Cardenes et al.

Table 1 FIGO staging system for carcinoma of the vagina

Stage Description
Stage I Limited to the vaginal wall
Stage II Involvement of the subvaginal tissue but without extension to the pelvic side wall
Stage III Extension to the pelvic side wall
Stage IV Extension beyond the true pelvis or involvement of the bladder or rectal mucosa.
Bullous edema as such does not permit a case to be allotted to Stage IV
IVA Spread to adjacent organs and/or direct extension beyond the true pelvis
IVB Spread to distant organs
From FIGO Committee on Gynecologic Oncology (2009)

all of the vaginal walls and local extent of the disease,
primarily if the patient is in great discomfort because
of advanced disease, in order to obtain a biopsy.
Biopsies of the cervix, if present, are recommended to
rule out primary cervical tumor. It is important that
the speculum is slowly withdrawn from the vaginal
fornix so that the total vaginal mucosa may be
visualized.
The patients with a history of pre-invasive or
invasive carcinoma of the cervix, found to have
abnormal cytology following prior hysterectomy or
RT should be offered colposcopy with application of
acetic acid to the entire vault, followed by biopsies as
indicated by areas of white epithelium, mosaicism,
punctation, or atypical vascularity. It can be very
helpful for the menopausal patient or the patient
previously irradiated to use a short course of topical
estrogen (PremarinÒ) into the vault once or twice a
week for one month prior to the colposcopy, in order
to foster epithelial maturation. Another method of
identifying the area(s) most in need of biopsy would
be, after application of the acetic acid, to place half-
strength Schiller’s iodine, to determine if the Schiller
positive (non-staining) areas correspond with the
involved areas identified after acetic acid application.
6 Staging
The two commonly used staging systems for carci-
noma of the vagina are the International Federation of
Gynecology and Obstetrics (FIGO) (Table 1) (FIGO
Committee on Gynecologic Oncology 2009) and
the American Joint Commission on Cancer (TNM)
classifications (Table 2) (American Joint Committee
on Cancer 2010). According to FIGO and AJCC
guidelines, cases should be classified as vaginal car-
cinomas only when ‘‘the primary site of the growth is
in the vagina’’. A tumor of the vagina that involves
the cervix or vulva should be classified as a primary
cervical or vulvar cancer, respectively. Additionally,
in the setting of a prior gynecologic malignancy, a
neoplasm would be classified as primary carcinoma of
the vagina if the current vaginal tumor occurred 5 or
more years after the initial cancer diagnosis and if
there is no other clinical evidence of recurrence of the
initial gynecologic lesion (Zaino et al. 2002). It may
be difficult or impossible histologically to distinguish
a primary vaginal SCC from recurrent cervical or
vulvar disease. In this setting, it is unclear whether the
vaginal lesion represents a new carcinoma of the
vagina, recurrent cervical cancer, or a HPV-related
field effect in these patients.
Perez et al. (1973) proposed that FIGO stage II
vaginal cancer should be subdivided into stage IIa
(tumor infiltrating the subvaginal tissues but not
extending into the parametrium) and stage IIb (tumor
infiltrating the parametrium but not extending to
pelvic side walls) (Perez et al. 1973). However, most
authors do not use this classification, and there is
limited published data to support the prognostic sig-
nificance of this subclassification (Perez et al. 1988;
Prempree and Amornmarn 1985). In addition, FIGO
does not assign a specific stage for those patients with
inguino-femoral lymphadenopathy. Some authors
assign these patients to stage III, whereas others
consider them stage IVB. In the AJCC staging sys-
tem, patients with T1-3 and positive nodes (pelvic or
inguinal) are assigned to stage III (American Joint
Committee on Cancer 2010).
Carcinoma of the Vagina 921

Table 2 American Joint Commission on Cancer (AJCC) Staging of Vaginal Cancer

Primary tumor(T)/FIGO
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ (preinvasive carcinoma)
T1/I Tumor confined to the vagina
T2/II Tumor invades paravaginal tissues but not the pelvic wall
T3/III Tumor extends to the pelvic wall
T4/IVA Tumor invades mucosa of the bladder or rectum and/or extends beyond
the pelvis (Bullous edema is not sufficient to classify a tumor as T4)
Regional lymph nodes (N)
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph nodes
N1/III Pelvic or inguinal lymph node metastasis
Distant metastasis (M)
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1/IVB Distant metastasis
AJCC stage groupings
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T1-3 N1 M0, T3 N0 M0
Stage IVA T4, any N, M0
Stage IVB Any T, any N, M1
American Joint Committee on Cancer (2010)

At present, primary malignancies of the vagina are
all staged clinically. In addition to a complete history
and physical examination, routine laboratory evalua-
tions including CBC with differential and platelets,
and assessment of renal and hepatic function should
be undertaken. In order to determine the extent of
disease, the following tests are allowed by the FIGO
criteria: chest X-ray, a thorough bimanual and recto-
vaginal exam, cystoscopy, proctoscopy, and intrave-
nous pyelogram. If the patient is in significant
discomfort, the exam should be conducted under
anesthesia, preferably by a radiation oncologist and a
gynecologic oncologist. However, it can be difficult
even for the experienced examiner to differentiate
between disease confined to the mucosa (stage I) and
disease spread to the submucosa (stage II) (Ball and
Berman 1982; Rubin et al. 1985; Frank et al. 2005).
Cystoscopy and proctoscopy are generally performed
on patients with symptoms or clinical findings sus-
picious for bladder or rectal infiltration, respectively.
Pelvic CT scan is generally performed to evaluate
inguino-femoral and/or pelvic lymph nodes, as well as
extent of local disease. In patients with vaginal mel-
anoma or sarcoma, chest, abdomen, and pelvis CT
scans are often part of the work-up. PET/CT has also
been studied in a prospective registry study in 23
patients comparing the results of CT and whole-body
FDG-PET (Lamoreaux et al. 2005). CT visualized the
intact primary tumor in 43% of patients as compared
to PET which visualized 100% of all intact primary
tumors.
Furthermore, all abnormal lymph nodes visualized
by CT were also detected by PET, with the addition of
four additional foci consistent with nodal metastasis
922
found on PET imaging (Lamoreaux et al. 2005).
Magnetic resonance imaging (MRI) has emerged as a
potentially important imaging modality in the evalu-
ation of vaginal cancers, predominantly intermediate
signal intensity on T1-weighted images and high
signal intensity on T2-weighted images (Taylor et al.
2007). Taylor et al. (2007) concluded that MRI
identified over 95% of primary vaginal tumors and
enabled radiologic staging, which correlated with
outcomes. Additionally, MRI can provide useful
information during treatment planning. MRI also
allows a distinction of tumor from fibrotic tissue in
patients with suspected recurrent vaginal carcinoma
(Chang et al. 1988).
7 Prognostic Factors Influencing
Choice of Treatment
As with most primaries, stage of disease is the
dominant prognostic factor in terms of ultimate
outcome (Chu and Beechinor 1984; Chyle et al.
1996; Dancuart et al. 1988; Dixit et al. 1993; Eddy
et al. 1991; Kirkbride et al. 1995; Lee et al. 1994;
Leung and Sexton 1993; Perez et al. 1988, 1999;
Peters et al. 1985; Hellman et al. 2006; de Crevoisier
et al. 2007; Tran et al. 2007; Sinha et al. 2009;
Delclos 1984; MacNaught et al. 1986). In Perez
series, including 212 patients with primary vaginal
carcinomas treated with definitive RT, the 10-year
actuarial disease-free survival was 94% for Stage 0,
80% for Stage I, 55% for Stage IIA, 35% for Stage
IIB, 38% for Stage III, and 0% for those with Stage
IV (Perez et al. 1999). In a recent SEER analysis of
over 2000 patients by Shah et al. (2009), the 5-year
disease-specific survival was 84% for stage I, 75%
for stage II tumors, and 57% for women with
advanced disease (Shah et al. 2009).
The impact of lesion location has been contro-
versial. Several authors (Ali et al. 1996; Chyle et al.
1996; Kucera and Vavra 1991; Tarraza et al. 1991;
Urbanski et al. 1996) have shown better survival and
decreased recurrence rates for patients with cancers
involving the proximal half of the vagina when
compared with those in the distal half, or those
involving the entire length of the vagina. Chyle et al.
(1996) observed a 17% pelvic relapse in patients with
upper vagina lesions, 36% with mid- or lower vagina
tumors, and 42% with whole vaginal involvement. In
H. R. Cardenes et al.
addition, lesions of the posterior wall have worse
prognosis than those involving other vaginal walls
(10-year recurrence rates of 32% and 19%, respec-
tively), which probably reflects the greater difficulty
of performing adequate brachytherapy procedures in
this location.
The prognostic importance of lesion size has been
controversial, with an adverse impact noted with
increasing size on multivariate analysis in several
series (Kirkbride et al. 1995; Tjalma et al. 2001;
Chyle et al. 1996; Hellman et al. 2006; Shah et al.
2009) contrary to Perez et al. findings (Perez et al.
1999). In the Perez series (Perez et al. 1999) stage
was an important predictor of pelvic tumor control
and 5-year DFS, but the size of the tumor in stage I
patients was not a significant prognostic factor.
However, in stage IIA disease, lower pelvic tumor
control and survival were noted with tumors larger
than 4 cm. In stages IIB-III, tumor size was not a
significant prognostic factor, probably related to the
difficulty in assessing size, and the fact that higher
doses of RT were delivered for larger tumors. Stock
et al. (1995) reported that disease volume, a likely
surrogate for stage or lesion size, adversely impacted
survival, as well as local tumor control (Stock et al.
1995).
Age has also been reported as a significant prog-
nostic factor with increasing age correlating with
poorer survival (Hellman et al. 2006; Tjalma et al.
2001; Urbanski et al. 1996). Similar findings were
reported by Eddy et al. (1991) and in the NCDB of the
American College of Surgeons (Creasman et al. 1998)
with better survival in younger patients (90 vs. 30%,
respectively). However, most of these series do not
correct for death secondary to intercurrent disease in
the elderly population. No statistical significance of
age to survival was found in the series of Dixit et al.
(1993) and Perez et al. (1999).
With regard to the histological type and grade,
several series (Otton et al. 2004; Kirkbride et al. 1995;
Kucera and Vavra 1991; Urbanski et al. 1996) have
shown the histological grade to be an independent,
significant predictor of survival. However, the his-
tology of the tumor (SCC vs. other) has not been
found to be a prognostic factor for NED survival
among the patients with invasive tumors. Chyle et al.
(1996) noted a higher incidence of local recurrences
in adenocarcinomas when compared with SCC (52
and 20%, respectively, at 10 years), higher distant
Carcinoma of the Vagina
metastasis rate (48 and 10%, respectively) and lower
10-year survival (20 vs. 50%, respectively). A report
by Frank et al. (2007) compared outcome of patients
with non-diethylstilbestrol (DES) associated adeno-
carcinoma of the vagina to that of patients with
squamous cell carcinomas. They found a 5-year
overall survival rate of 34% in the adenocarcinoma
group compared to 58% for the patients with squa-
mous cell carcinoma (P [ 0.01) (Frank et al. 2007).
An increased propensity for distant metastases to the
lung and supraclavicular nodes has been reported in
patients with CCA (Robboy et al. 1974). It has been
reported that patients with vaginal melanoma (Reid
et al. 1989) and malignant mesenchymal tumors
(Tavassoli and Norris 1979) have a worse prognosis
than patients with SCC due to a higher propensity for
development of local recurrence and distant metas-
tases. However in a SEER analysis by Shah et al.
(2009) there was no difference in 5-year disease
specific survival between all histologic types,
although vaginal melanoma was associated with an
increased risk of mortality in their multivariate model
(HR 1.51).
Lymph node metastasis at diagnosis portends a
poor prognosis. However, this has not been exten-
sively evaluated in vaginal cancer. The only report of
outcome based on lymph node status is by Pingley
et al. (Pingley et al. 2000). They reported a 56% DFS
for patients without lymph node involvement and
33% for those with metastatic lymphadenopathy at
presentation.
In a recent series by Tran et al., which included
only invasive SCC, prior hysterectomy as well as
normal pretreatment/treatment Hg levels were
favorable prognostic factors on multivariate analysis
in the treatment of vaginal cancer (Tran et al. 2007).
In their review, it is recommended to consider trans-
fusion with packed red blood cells to maintain normal
hemoglobin levels as this approach has had some
success in cervical cancer patients. Possible expla-
nations for improved outcomes in women with pre-
vious hysterectomies included possible increased
surveillance with detecting vaginal cancer at an ear-
lier stage, or simply less vaginal substrate for
tumorigenesis to occur within (Tran et al. 2007).
Chyle et al. (1996) and Hellman et al. (2006) also
found that previous hysterectomy had more favorable
outcomes, however this result did not hold up on
multivariate analysis.
923
8 General Management: Treatment
Options
Most of the current literature in terms of radiothera-
peutic and surgical techniques refers to primary SCC
of the vagina, with the majority of the patients having
been treated with radiation therapy (RT). However,
several surgical series have reported acceptable to
excellent outcomes in well-selected patients, with
survival rates after radical surgery for stage I disease
ranging from 75 to 100% (Ball and Berman 1982;
Creasman et al. 1998; Davis et al. 1991; Rubin et al.
1985; Tjalma et al. 2001), although few studies
directly compare the two treatment modalities. The
SEER analysis by Shah et al. (2009) showed that
among women with stage I disease, those treated with
RT only or RT and limited surgery or no treatment,
had worse outcome that those treated with surgery
alone [generally involving radical or exanterative
procedures]. However, only women with stage I dis-
ease who received no treatment had a statistically
significant increased risk of mortality (HR 2.23; 95%
CI 1.01–5.03).
Cases in which surgery may be the preferred
treatment include selected stage I–II patients, with
lesions at the apex and upper-third of the posterior or
lateral vagina that could be approached with radical
hysterectomy, upper vaginectomy, and pelvic lym-
phadenectomy providing adequate margins (Ball and
Berman 1982; Davis et al. 1991; Gallup et al. 1987b;
Rubin et al. 1985; Stock et al. 1995) and very
superficial lesions which may be removed with wide
local excision. If the margins are found to be close or
positive after resection, adjuvant RT is recommended.
However, for lesions at other sites, and those cases
requiring more extensive resection, definitive RT is
the treatment of choice, in order to maximize cure and
improve quality of life, with isolated central failures
offering exenteration (Rubin et al. 1985).
Furthermore, most patients are elderly, and a
radical surgical approach is often not feasible. In
younger patients with early stage disease, treatment
can also depend on the desire to preserve a func-
tional vagina as well as ovarian function. Radical
surgery in the past precluded vaginal function, but
this situation has been improved significantly by the
use of split-thickness grafts, intestinal segments, and
myocutaneous flap reconstruction (Magrina and
924
Masterson 1981). Creasman noted superior survival
in patients undergoing surgery (Creasman et al.
1998). However, he and Tjalma (Tjalma et al. 2001)
recognized that there may be bias in surgical series.
Younger, healthier patients with better performance
status are more likely to be offered radical surgery,
whereas older patients with multiple co-morbid
medical conditions are offered RT.
In most patients, the primary treatment modality is
RT, as noted by the Society of Gynecologist Oncol-
ogists in practice guidelines published in 1998
(Creasman et al. 1998). RT provides excellent tumor
control in early and superficial lesions, with satis-
factory functional results, making imperative that
optimal RT techniques be used. Conclusions from
Frank et al. (2005), suggest that radiation treatment be
individualized with the optimal treatment approach
selected according to the tumor size, tumor site,
extent of disease, and response to initial EBRT.
Intracavitary and interstitial irradiation is used in
small superficial Stage I disease. A combination of
external beam RT (EBRT), intracavitary, and/or
interstitial brachytherapy with or without chemo-
therapy is used in more extensive Stages II–IV
disease.
9 Radiation Therapy Techniques
Radiation prescription and technique varies according
to stage, tumor volume, and anatomic location. In the
recent years several series have reported improved
outcomes with techniques emphasizing the higher
radiation doses that can be achieved when all or part
of the therapy is accomplished with interstitial tech-
nique (Leung and Sexton 1993; Perez et al. 1999;
Pingley et al. 2000; Puthawala et al. 1983).
9.1 External Beam Radiotherapy
External beam radiotherapy (EBRT) is advisable in
patients with deeply infiltrating or poorly differentiated
stage I lesions, and in all patients with stage II–IVA
disease. The treatment generally has been delivered
using opposed anterior and posterior fields (AP/PA),
covering the pelvis and in patients with mid- to lower-
third tumors, the inguinal nodes. The pelvis receives
between 20 and 45 Gy, depending on the stage of the
H. R. Cardenes et al.
disease. This will be followed, in some cases, by
bilateral pelvic side wall boosts to 50–55 Gy, after
brachytherapy to treat the central disease. High-
energy photons are usually preferred, and often times,
a mix of photon energies is used (6 and 15–18 MV) to
improve target coverage with optimal dose distribu-
tion. Treatment portals cover at least the true pelvis
with 1.5–2 cm margin beyond the pelvic rim. Supe-
riorly, the field extends to either L4-L5 or L5-S1 to
cover the pelvic lymph nodes up to the common iliacs,
and distally extending to the introitus to include the
entire vagina. Lateral fields, if used, should extend
anteriorly to adequately include the external iliac
nodes, anterior to the pubic symphysis, and at least to
the junction of S2-S3 posteriorly to adequately cover
the presacral nodes (Fig. 1). In patients with tumors
involving the middle and lower vagina with clinically
negative groins, the bilateral inguino-femoral lymph
node regions should be treated electively to 45–50 Gy.
Planning CT is recommended to adequately determine
the depth of the inguino-femoral nodes. In patients
with distal vaginal lesions, it is often necessary to treat
the vulva in order to achieve adequate tumor cover-
ages, in which case the patient should be placed in
open-leg position to reduce the vulvar skin reaction
(Frank et al. 2005).
In patients with clinically palpable inguinal nodes,
additional doses of 15–20 Gy (calculated at a depth
determined by CT scan) are necessary with reduced
portals. This is generally achieved by using low
energy photons or electron beam (12–18 MeV). For
patients with positive pelvic nodes, or those patients
with advanced disease not amenable to interstitial
implant, additional boost to the areas of gross disease,
as defined by CT scan, should be given using con-
formal therapy to deliver a total dose between 65 and
70 Gy with high energy photons.
A number of techniques have been used to treat the
areas at risk without over-treating the femoral necks.
Some of the most commonly used techniques include
the use of unequal loading (2:1, AP/PA), a combi-
nation of low and high energy photons (4–6 MV, AP,
and 15–18 MV, PA), or equally weighted beams with
a transmission block in the central AP field, utilizing
small AP photon or electron beams to deliver a daily
boost to the inguino-femoral nodes. While these
techniques decrease the dose to the femoral heads,
they also have disadvantages such as higher dose
inhomogeneity at the match line or the need to
Carcinoma of the Vagina
Fig. 1 Proximal third vaginal cancer, invasive Squamous cell
carcinoma, with mid-third of the vagina Squamous cell
carcinoma in situ, without involvement of inguino-femoral
nodes. Digital Reconstructed Radiographs (DRRs): a AP/PA
fabricate transmission blocks that must be installed
daily during the time of treatment. A technique pre-
viously developed and implemented at Indiana
University uses a narrow PA field to treat the pelvis,
and a wider AP field encompassing the pelvis and
925
whole pelvis fields, b Right/Left Lateral whole pelvis fields,
intended to treat the entire length of the vagina, c Axial,
Sagittal, and Coronal isodose distributions
inguino-femoral nodes, with daily AP photon boost to
the inguinal nodes being delivered using the asym-
metric collimator jaws (Dittmer and Randall 2001).
Advantages of this technique include simplicity of
set-up and treatment (single isocenter, no need for
926 H. R. Cardenes et al.

Fig. 2 Vaginal cancer with distal third vaginal involvement, intended to treat the pelvis only, in order to decrease the dose to
squamous cell carcinoma. Technique for Pelvic and Inguino- the femoral heads; small AP photon field for additional daily
Femoral nodal irradiation. a Digital Reconstructed Radiographs boost to the inguino-femoral nodes. b Axial, Sagittal, and
(DRRs). AP field intended to treat pelvis and groins; PA field Coronal isodose distributions
Carcinoma of the Vagina
transmission block), dose homogeneity, reduced dose
to the femoral necks, low potential risk of nodal un-
derdose, and elimination of dosimetric difficulties
inherent in electron boosts (Fig. 2).
The above technique was initially set up and
planned using a conventional simulator. With the
advent of more modern CT based simulation and 3D
treatment planning software, the technique described
above is being replaced by a similar technique
described by Moran et al. (2010) with some modifi-
cations. In their technique called modified segmental
boost technique (MSBT), Moran et al. (2010) uses CT
simulation and 3D treatment planning software that
incorporate multileaf collimators (MLCs) to shape the
desired fields. Relevant anatomic areas such as fem-
oral vessels, involved nodes etc. are outlined on the
CT scan to help create the appropriate field borders.
The field arrangements are similar to the Indiana
University technique including a wide AP photon
field, a narrow PA pelvic field, and a bilateral (or
unilateral) inguinal boost field(s). The inguinal fields
are angled slightly to align with the divergence of the
PA field and are shaped using MLCs. They found that
this technique significantly improved homogeneity
throughout the treatment volume in comparison with
other traditional techniques (Moran et al. 2010).
Intensity modulated radiation therapy (IMRT) is
another potential therapeutic option in pelvic tumors
which require the treatment of the inguinofemoral
region (Salama et al. 2007; Milano et al. 2005;
Menkarios et al. 2007; Moran et al. 2010; Pepek et al.
2010). It is postulated that the use of IMRT may
reduce acute and long-term toxicity by minimizing
the dose to organs at risk (OAR). This is a topic
of current investigation in a phase II RTOG trial
(05–29), in which IMRT to the pelvic and inguinal
nodes is being combined with chemotherapy for anal
cancer in a multi-institutional setting. Moran et al.
(2010) performed a dosimetric comparison of the
MSBT technique to IMRT for treatment of pelvic/
inguinal nodes in a variety of patients, including those
with the diagnoses of primary vaginal cancers (Moran
et al. 2010). The doses to the bladder, rectum, small
bowel, and bone marrow were higher using the MSBT
technique compared to IMRT plan, however the
treatment planning process (including contouring)
was 40 min for the MSBT plan compared to
approximately 6 h for the IMRT plan (Moran et al.
2010). At this time there is no sufficient data on
927
outcomes to routinely recommend the use of IMRT
for the treatment of primary vaginal cancer when the
inguinofemoral nodes must be irradiated. Certain
clinical scenarios may warrant the use of IMRT, such
as those patients who require doses [50.4 Gy to the
pelvis or inguinofemoral region or when radiation
must be delivered to an area that has previously been
irradiated.
9.2 Low Dose Rate Intracavitary
Brachytherapy
VAIN and small T1 lesions with less than 0.5 cm
depth can be adequately treated with ICB alone. Low
dose rate intracavitary brachytherapy (LDR-ICB) is
performed using vaginal cylinders such as Burnett
et al. (Delclos et al. 1980), or MIRALVA (Perez et al.
1990) loaded with Cesium-137 (137Cs) radioactive
sources. Delclos afterloading vaginal cylinders, have
a central hollow metallic cylinder in which the sour-
ces are placed, and plastic rings of varying diameter
(2.5–4 cm), 2.5 cm in length, which are inserted over
the cylinder. Domed cylinders are used to irradiate the
vaginal cuff homogeneously, when indicated. Delclos
(Delclos et al. 1980), recommended a short Cesium-
137 source to be used at the top to obtain a uniform
dose around the dome, because a lower dose occurs at
the end of the linear celium source. Some cylinders
have a lead shielding to protect selected portions of
the vagina, the bladder, and/or the rectum. The largest
possible diameter that can be comfortably accom-
modated by the patient should be used to improve the
ratio of mucosa to tumor dose, and eliminate vaginal
rotations. The cylinders can be mounted in the vaginal
component of an intrauterine tandem, or along the
stem of a dome cylinder. Before the cylinders are
mounted over the vaginal component of an intra-
uterine tandem, this is inserted into the uterus (when
present) and the cylinders are fitted along the pro-
truding tandem. To minimize the rotation of the tan-
dem, a flat, round flange with keel is placed below the
last cylinder and is kept in position with some packing
if required. In general, the vulva is sutured-closed
with praline or silk for the duration of the implant in
order to secure the position of the applicators (Fig. 3).
In patients with upper vagina lesions with less
than 0.5 cm depth of invasion, vaginal colpostats
alone (after hysterectomy) or in combination with
928 H. R. Cardenes et al.

Fig. 3 a AP and b lateral views of vaginal cylinders only. c AP and d lateral views of intrauterine tandem and vaginal cylinders

intrauterine tandem, loaded with 137Cs sources similar
to that used in treatment of cervical cancer, can be
used to treat the proximal vagina to a minimum dose
of 65–70 Gy, estimated at 0.5 cm depth, including
the contribution of EBRT if given. When indicated,
the remainder of the vagina can be treated by per-
forming a subsequent implant using vaginal cylinders
(generally 50–60 Gy, prescribed to the vaginal sur-
face). It is important to avoid the placement of a
protruding source over the vulva, with the subsequent
increased risk of complications. The use of LDR
remote control afterloading technology allows the
reduction of radiation exposure to hospital per-
sonnel and optimization of the isodose distribution.
Carcinoma of the Vagina 929

When appropriate dose specification points are cho-

sen, a very uniform dose distribution over the entire
length of the vagina can be obtained.

9.3 High Dose Rate Intracavitary

Brachytherapy and Interstitial
Brachytherapy

Little information regarding high dose rate (HDR)

brachytherapy in the treatment of primary carcinoma
of the vagina is available (Nanavati et al. 1993; Stock
et al. 1992; Kucera et al. 2001; Kushner et al. 2003;
Mock et al. 2003; Beriwal et al. 2006; Beriwal et al.
2008). Few patients have been treated, follow-up is
short, publication bias is likely, and there is no
agreement upon treatment regimen. With HDR, there
is a need to adjust the total dose and additional
fractionation is necessary, compared with LDR
brachytherapy, because of the biologically equivalent
dose considerations. Generally, the number of inser-
tions ranges from 1 to 6 (median 3), with the dose per
fraction ranging from 300 to 800 cGy (median
700 cGy). High dose rate intracavitary brachytherapy
(HDR-ICB) is typically performed with a 10 Ci single
Iridium-192 (192Ir) source (Micro-Selectron HDR,
Nucletron). The applicators are similar to those
described for LDR, consisting of vaginal cylinders of Fig. 4 a M.A.C. HDR-GYN Contour Template. b HDR CT
2.5–4 cm in diameter. High dose rate interstitial Miami Multi-Channel Vaginal Applicator. Reprinted with
brachytherapy (HDR-ITB) has also been reported by permission from Mick Radio-Nuclear Instruments, Inc
Kushner et al. (2003) in which the Syed Template
Applicators were used (Kushner et al. 2003). Newer
HDR compatible interstitial systems are available increased fractionation, the planned dose was changed
including the M.A.C. (Mick-Alektiar-Cohen) HDR- to 2000 cGy in four equal fractions. They did not
GYN Contour Template, compatible with ultrasound observe any acute or chronic intestinal or bladder
stabilizing devices, and the Miami Multi-Channel grade 3 or 4 toxicity. However, moderate to severe
Vaginal Applicator (Mick Radio-Nuclear Instruments vaginal stenosis occurred in 46% of the patients. The
Inc., Mount Vernon, NY) (Fig. 4). authors recognize that ‘‘late-occurring toxicity could
Nanavati et al. (1993) reported 13 patients with be missed at a medium follow-up of 2.6 years’’. In
primary vaginal cancer (5 St I, 4 St IIA and 4 St IIB) another report Mock et al. (2003) showed similar
treated with external beam RT (45 Gy) and HDR-ICB outcome and toxicity rate, stage by stage, in 86
(20–28 Gy in 3–4 fractions, calculated at 0.5 cm patients with primary vaginal cancer treated with a
from the surface of the applicator) (Nanavati et al. variety of external beam and HDR brachytherapy
1993). All 13 patients had a complete response, and (Mock et al. 2003). However, Kushner et al. (2003)
local control was achieved in 92% of the patients found a 15.8% rate of serious late complications
with a median follow-up of only 2.6 years (range (ureteral stenosis, painful vaginal necrosis, and small
0.7–5.2 years). Originally the planned dose was bowel obstruction) in 19 patients treated with a
2100 cGy in 3 fractions, 700 cGy/fraction, but combination of HDR-ICB and HDR-ITB (Kushner
because of reports of decreased complications with et al. 2003).
930
Many aspects remain unknown or not well-
understood in the use of HDR brachytherapy. These
include the radiobiologic equivalency of HDR to
LDR, fractionation schedule, total dose, specification
of dose prescription, and how to combine HDR with
EBRT and/or LDR brachytherapy. In addition, opti-
mization approaches and methods of dose calculation,
such as the inclusion of anisotropic corrections, are
not well-described in the sparse literature available to
date (Gore et al. 1995; Li et al. 1998). Li et al. (1998)
have shown that when optimized dose distribution at a
distance from the cylinder surface is calculated using
an accurate dose calculation model, the vaginal
mucosa dose becomes significantly higher than cal-
culated, and therefore should be carefully monitored.
These factors could result in an increased incidence of
severe complications, such as vaginal necrosis, and
recto-vaginal or vesico-vaginal fistulas (Rutkowski
et al. 2002; Tyree et al. 2002).
In the opinion of the authors, until further data
are available with longer follow-up, as well as a
better understanding of the physical and radiobio-
logical principles involved in HDR brachytherapy,
this should not be routinely used in the radiother-
apeutic management of primary vaginal carcinoma.
We strongly encourage the continued use of LDR
brachytherapy, given its excellent results and widely
documented long-term outcome and complications
(Chyle et al. 1996; Kirkbride et al. 1995; Perez
et al. 1988, 1999; Frank et al. 2005; Sinha et al.
2009).
9.4 Interstitial Brachytherapy
Interstitial brachytherapy (ITB) is an important
component in the treatment of more advanced pri-
mary vaginal carcinomas, typically in combination
with EBRT and/or ICB. In the first place, a careful
definition of the ‘‘target volume’’, that is gross tumor
volume (based on clinical, radiological, and operative
findings) and a margin of adjoining normal tissue, is
required. Other considerations include whether a
permanent (198Gold or 125Iodine) or temporary
implant (192Ir) is optimal, the geometry of the implant
(e.g., single or double plane or volume implant),
source distribution, dose rate, and total dose, based
upon tumor size, location, local extent, and proximity
of normal structures (Hilaris et al. 1987). The
H. R. Cardenes et al.
principal advantages of temporary implants are
readily controlled distribution of the radioactive
sources and easier modification of the dose distribu-
tion. The main advantages of a permanent seed
implant include relative safety/simplicity, easy
applicability, cost-effectiveness, and ability, in most
cases, to be performed using local anesthesia. As a
general rule, temporary implants are more commonly
used in the curative treatment of larger gynecological
malignancies, whereas permanent implants are usu-
ally performed for smaller volume disease.
The number and strength of the radioactive sources
and their intended distribution within the target vol-
ume are determined pre-operatively, making use of
available guidelines such as nomograms, tables, and
computer-assisted optimization techniques. Following
this, it is necessary to specify an approximate dose
rate to the target volume, which requires careful
localization of the sources and computer calculation
of the three-dimensional radiation dose distribution.
Finally, a dose prescription, based upon the treatment
volume, tumor sensitivity, dose rate, prior treatments,
and tolerance of normal surrounding tissues is
required (Hilaris et al. 1987).
When performing an interstitial procedure, free-
hand implants or template systems designed to assist
in pre-planning and to guide and secure the position
of the needles in the target volume, can be employed.
Popular commercially available templates include the
Syed-Neblett device (SNIT) (Alpha Omega Services,
Bellflower, CA) (Syed et al. 1987), the modified
Syed-Neblett (Disaia et al. 1990), and the ‘‘MUPIT’’
(Martinez Universal Perineal Interstitial Template)
(Martinez et al. 1984). All rely on pelvic examination
to help guide the location and depth of needle
placement.
The Syed-Neblett device consists of two identical
superimposed Lucite plates, each about 1 cm thick,
held together by six screws. Both plates are drilled in
an identical pattern of predetermined needle positions
that can be afterloaded with Iridium-192 (192Ir)
sources (Syed et al. 1987). The modified Syed-Neblett
(Disaia et al. 1990) applicator consists of a perineal
template, vaginal obturator, and 17-gauge hollow
guides of various lengths. The vaginal obturator is
2 cm in diameter, and 12 or 15 cm in length. The
vaginal obturator has 7 grooves on its surface for the
placement of guide needles, and is centrally drilled so
that it can allow the placement of a tandem to be
Carcinoma of the Vagina
Fig. 5 Syed-Neblett and modified templates
Fig. 6 MUPIT template structure. Reprinted with permission
from Martinez et al. (1984)
loaded with 137Cs sources. This makes it possible to
combine an interstitial and intracavitary application
simultaneously (Fig. 5).
A similar afterloading applicator, referred to as
‘‘MUPIT’’ (Fig. 6) was developed by Martinez et al.
(1984). The device basically consists of two acrylic
cylinders, an acrylic template with predrilled holes
that serve as guides for trocars, and a cover plate.
Some of the guide holes on the template are angled
outward to permit a wide lateral coverage without
danger of striking the ischium. The cylinders have an
axial hole large enough to pass a central tandem or
suction tube for drainage of secretions. Thus, the
device allows for the interstitial placement of 192Ir
ribbons as well as the intracavitary placement of
either 137Cs tubes or 192Ir ribbons. In use, the cylin-
ders are placed in the vagina and rectum and then
931
fastened to the template, so that a fixed geometric
relationship among the tumor volume, normal struc-
tures and source placement is preserved throughout
the course of implantation.
The major advantage of these systems is greater
control of the placement of the sources relative to
tumor volume and critical structures, due to the fixed
geometry provided by the template and cylinders.
In addition, improved dose-rate distributions are
obtained by means of computer-assisted optimization
of the source placement and strength during the
planning and loading phase. Due to the inaccuracies
of pelvic examination and close proximity of the
rectum and bladder to the target volume, there exists a
serious risk of either underdosing the target volume,
or causing bladder and rectal morbidity. In order to
improve the accuracy of target localization and needle
placement, several investigators have explored per-
forming ITI under trans-rectal ultrasound (TRUS)
(Stock et al. 1997), computed tomography (CT),
magnetic resonance imaging (MRI)-planned implants
with endorectal coil (Corn et al. 1995), laparotomy,
and laparoscopic guidance (Childers and Surwit 1993;
Corn et al. 1995). While laparotomy facilitates the
displacement of bowel during the procedure by using
slings or tissue expanders and/or lysis of adherent
bowel, there is some degree of associated morbidity,
such as ileus, bleeding, and increased operative time.
Laparoscopy is a shorter and less invasive procedure.
Real time TRUS-guided Syed-Neblett template
implantation technique was reported by Stock et al.
(1997). TRUS allows the ultrasound (US) probe to be
in closer proximity to the pelvic structures (cervix,
parametria, and vagina) than trans-abdominal US and
can more accurately guide needle placement into
tumor and avoid needle insertion into critical sur-
rounding normal tissues. Transverse US imaging is
used to assure that the needles cover the target area
and do not enter the bladder, rectum, or small bowel.
The longitudinal mode of the US probe is equally
important in the implant procedure due to its ability to
guide the optimum depth of needle insertion. With
this technique, invasive laparotomy and/or laparos-
copy can often be avoided, providing an interactive,
non-invasive technique allowing for highly accurate
needle placement (Stock et al. 1997). Shah et al.
(2010) reported on toxicity after needle puncture of
visceral organs during interstitial brachytherapy
without assistance of image guidance during the
932
placement (Shah et al. 2010). They imaged 36
patients after needle placement with a postoperative
CT scan and found bowel puncture in 26 patients and
bladder puncture in 19 patients; however they found
no relationship between visceral puncture and the
incidence of acute or late GI or GU toxicity. They did
note that needles that perforated the bowel or bladder
were not loaded or the dwell times were minimized in
these areas and concluded that toxicity may be related
to the dose received by the normal structures rather
than the occurrence of visceral puncture (Shah et al.
2010).
10 Squamous Cell Carcinoma:
Treatment Options and Outcome
by Figo Stages
10.1 FIGO Stage 0: VAIN-CIS
VAIN has been approached both surgically and
medically by multiple investigators. Treatment
options include local excision, partial or complete
vaginectomy, laser vaporization, topical 5% fluoro-
uracil (5-FU) administration, or ICB alone. Overall,
the reported control rates are very similar among the
different approaches, ranging from 48 to 100% for
laser (Diakomanolis et al. 2002; Hoffman et al. 1991;
Jobson and Homesley 1983; Julian et al. 1992; Stafl
et al. 1977; Townsend et al. 1982), 52–100% for
colpectomy (Creasman et al. 1998; Fanning et al.
1999; Hoffman et al. 1992; Robinson et al. 2000),
75–100% for topical 5-FU (Krebs 1989; Petrilli et al.
1980; Piver et al. 1979; Woodruff et al. 1975) and
83–100% for RT (Chyle et al. 1996; Kirkbride et al.
1995; Perez et al. 1977). The degree of VAIN and the
age and general health of the patient are important
treatment considerations.
Radiation therapy has a long history of docu-
mented efficacy, and has a significantly better thera-
peutic ratio than other modalities (Chyle et al. 1996;
Kirkbride et al. 1995; Perez et al. 1977; Prempree and
Amornmarn 1985). Using conventional LDR-ICB
techniques, the entire vaginal mucosa should receive
between 60 and 70 Gy in one or two implants (Perez
et al. 1977). Perez et al. (1977) reported only one
local failure in the 20 patients treated for CIS. This
recurrence developed distally to the vaginal vault in a
patient inadequately treated with vaginal ovoids only.
H. R. Cardenes et al.
There have been some reports in the literature
regarding the use of HDR-ICB for patients with
VAIN-3. Ogino et al. (1998) reported 6 patients
treated with HDR to a mean dose of 23.3 Gy (range
15–30 Gy), none of whom developed recurrent dis-
ease. Limited rectal bleeding and moderate to severe
vaginal mucosa reactions were noted in patients
treated to the entire length of the vagina (Ogino et al.
1998). MacLeod et al. (1997) used HDR-ICB to treat
14 patients with VAIN 3, with a dose of 34–45 Gy in
4.5–8.5 Gy fractions, with a local control of 78.5%
(MacLeod et al. 1997). With a median follow-up of
46 months, two patients developed grade 3 vaginal
toxicity. At the present, no definite conclusions can be
drawn from the limited data published in the literature
regarding the use of HDR-ICB. Based on the excel-
lent local control and functional results obtained with
LDR-ICB, this remains, in the authors’ opinion, the
treatment of choice when definitive RT is used.
10.2 Invasive Squamous Cell Carcinoma
Most authors emphasize that brachytherapy alone is
adequate for superficial FIGO stage I patients, for
whom 95–100% local tumor control has been
achieved with intracavitary and interstitial techniques
(Chu and Beechinor 1984; Kucera and Vavra 1991;
Leung and Sexton 1993; Perez et al. 1988; Peters
et al. 1985; Reddy et al. 1991; Stock et al. 1995;
Urbanski et al. 1996). Superficial lesions with less
than 3 mm invasion can be adequately treated with
ICB alone using afterloading vaginal cylinders.
Mucosal doses of 80–100 Gy are typically delivered,
depending on the diameter of the cylinders, when
prescribing 65–70 Gy to the tumor area, at 0.5 cm
depth beyond the vaginal surface (Perez et al. 1977).
For lesions thicker than 0.5 cm at the time of
implantation, it is advisable to combine ICB and ITB
in order to deliver tumor dose in the range of
65–70 Gy, calculated to the base of the lesion, lim-
iting the proximal and distal vaginal mucosal doses to
140 Gy and 98 Gy, respectively.
There are no well-established criteria regarding the
use of EBRT in patients with stage I disease. Perez et al.
(1988, 1999) did not find a significant correlation
between the technique of irradiation used and the
probability of local or pelvic recurrence, probably since
the treatment technique varied based on tumor-related
Carcinoma of the Vagina 933

Fig. 7 a AP and b Lateral radiographs of an interstitial and intracavitary implant in carcinoma of the vagina using the modified
Syed-Neblett template. c Three-dimensional isodose distribution, Ir192 only; d Ir192 plus Cs137

factors (Perez et al. 1988, 1999). There is a general
consensus that EBRT (20–50 Gy) is advisable for lar-
ger, more infiltrating, or poorly differentiated tumors
that may have a higher risk of lymph node metastasis.
Chyle et al. (1996) recommended EBRT in addition to
brachytherapy for stage I disease to cover at least the
paravaginal nodes and, in larger lesions, to cover the
external and internal iliac nodes. The 5-year survival
for patients with stage I disease treated with RT alone
ranges from 70 to 95%.
Patients with FIGO stage II disease are uniformly
treated with EBRT, followed either by ICB and/or
ITB (Fig. 7). Perez et al. (1999) showed that in stage
IIA, the local tumor control was 70% (37/53) in
patients receiving brachytherapy combined with
EBRT, compared with 40% (4/10) in patients treated
with either brachytherapy or EBRT alone. In stage
IIB, the local–regional control was also superior with
combined EBRT and brachytherapy (61 vs. 50%,
respectively). Generally, 40–50 Gy is delivered to the
934
Fig. 8 Interstitial brachytherapy boost in a patient with locally advanced vaginal cancer. a Left anterior oblique and b Right
anterior oblique radiographs of the implant. c Placement of funnel needles using the modified Syed-Neblett template
whole pelvis, followed by an additional boost of
30–35 Gy given with brachytherapy. Patients with
lesions limited to the upper third of the vagina can be
treated with an intrauterine tandem and vaginal ovoids
or cylinders. In patients with parametrial infiltration,
a ‘‘boost’’ with EBRT and/or an interstitial implant
is advisable to deliver a minimum tumor dose of
70–75 Gy and 55–60 Gy to the pelvic side wall (Fig. 8).
The 5-year survival for patients with stage II disease
treated with RT alone ranges between 35–70% for stage
IIA, and 35–60% for stage IIB. The results of several
series published in the literature using radiation therapy
with or without limited surgical resection for the treat-
ment of stage I and II vaginal cancer are shown in
Table 3 (Chyle et al. 1996; Creasman et al. 1998; Davis
et al. 1991; Kirkbride et al. 1995; Kucera and Vavra
1991; Perez et al. 1999; Stock et al. 1995; Urbanski et al.
1996; Hellman et al. 2006; de Crevoisier et al. 2007;
Sinha et al. 2009; Frank et al. 2005; Lian et al. 2008;
Otton et al. 2004; Tabata et al. 2002; Tran et al. 2007).
Generally, patients with FIGO stages III–IV dis-
ease will receive 45–50 Gy EBRT to the pelvis, and
in some cases, additional parametrial dose with mid-
line shielding to deliver up to 60 Gy to the pelvic side
walls. Ideally, ITB brachytherapy boost is performed,
if technically feasible, to deliver a minimum tumor
dose of 75–80 Gy (Fig. 8). If brachytherapy is not
feasible, a shrinking-field technique can be used, with
fields defined using the three-dimensional treatment
planning capabilities to deliver a tumor dose around
65–70 Gy. The overall cure rate for patients with
H. R. Cardenes et al.
stage III disease is 30–50%. Stage IVA includes
patients with rectal or bladder mucosa involvement,
or in most series, positive inguinal nodes. Although
some patients with stage IVA disease are curable,
many patients are treated palliatively with EBRT
only. Pelvic exenteration can also be curative in
highly selected stage IV patients with small volume
central disease. Table 4 (Chyle et al. 1996; Creasman
et al. 1998; Kirkbride et al. 1995; Kucera and Vavra
1991; Perez et al. 1999; Stock et al. 1995; Urbanski
et al. 1996; Tran et al. 2007; de Crevoisier et al. 2007;
Frank et al. 2005; Sinha et al. 2009; Lian et al. 2008;
Tabata et al. 2002) shows the treatment results in
patients with advanced disease. However, each of
these series reported a greater number of patients with
similar stage disease treated with RT, which repre-
sents the preferred approach in contemporary practice
(Perez et al. 1988; Prempree and Amornmarn 1985).
11 Chemotherapy and Radiation
The control rate in the pelvis for stages III–IV patients
is relatively low, and about 70–80% of the patients
have persistent or recurrent disease in the pelvis, in
spite of high doses of external beam RT and brach-
ytherapy. Failure in distant sites does occur in about
25–30% of the patients with locally advanced tumors,
much less than pelvic recurrences. Therefore, there is
a need for better approaches to the management of
advanced disease, such as the use of concomitant
Carcinoma of the Vagina 935

Table 3 FIGO stage I–II vaginal cancer: treatment outcomes

Authors Treatment modality No patients Outcome-survival
Chyle et al. (1996) RT 59 St I 10 year 76%
104 St II 10 year 69%
Creasman (NCDB) (1998) RT 169 St I 5 year surv: 73%; 79% S ? RT (47), 63% RT (122)
± surgery 175 St II 5 year surv: 58%; 58% S ? RT (39), 57% RT (136)
Davis et al. (1991) RT 19 St I 5 year surv: 100% S ? RT (5), 65% RT (14)
± surgery 18 St II 5 year surv: 69% S ? RT (9), 50% RT (9)
de Crevoisier et al. (2007) RT 26 St I 5 year 65%
35 St II 5 year 62%
Frank et al. (2005) RT 50 St I 5 year 85% (DSS)
± surgery 97 St II 5 year 78% (DSS)
Hellman et al. (2006) RT 104 St I 5 year 75%
± surgery ± chemo 29 St IIA 5 year 36%
Kirkbride et al. (1995) RT 40 St I 5 year 72%
± surgery ± chemo 38 St II 5 year 70%
Kucera and Vavra (1991) RT 16 St I 5 year 81%
23 St II 5 year 43.5%
Lian et al. (2008) RT 14 St I 5 year 90% (DSS)
± surgery 28 St II 5 year 87% (DSS)
Otton et al. (2004) RT 40 St I 5 year 71%
± surgery 30 St II 5 year 48%
Perez et al. (1999) RT 59 St I 10 year 80%
63 St IIA 10 year 55%
34 St IIB 10 year 35%
Sinha et al. (2009) RT 13 St I 5 year 92%
± surgery ± chemo 20 St II 5 year 82%
Stock et al. (1995) RT 8 St I 5 year 100% S ? RT, 80% RT
± surgery 35 St II 5 year 69% S ? RT, 31% RT
Tabata et al. (2002) RT 11 St I 5 year 82%
± surgery 23 St II 5 year 70%
Tran et al. (2007) RT 33 St I 5 year 92% (DSS)
± surgery ± chemo 23 St II 5 year 68% (DSS)
Urbanski et al. (1996) RT 33 St I 5 year 73%
37 St II 5 year 54%

chemo-radiotherapy. Agents such as 5-FU, mitomy-
cin, and cisplatin have shown promise when com-
bined with RT, with complete response rate as high
as 60–85% (Evans et al. 1988; Roberts et al. 1991)
but long-term results of such therapy have been
variable. Evans et al. (1988) found no local recur-
rences, however, among patients achieving a com-
plete response with RT and 5-FU plus Mitomycin-C
(12 of 25 patients), with a median follow-up of
28 months. The survival for the entire population
was 56% (66% for patients with primary vaginal
cancer). Only 2 patients had severe complications.
More sobering are the data from Roberts et al.
(1991) who reported 67 patients with advanced
cancers of the vagina, cervix, and vulva treated with
concurrent 5-FU, cisplatin and RT. Although 85%
936 H. R. Cardenes et al.

Table 4 FIGO stage III–IV vaginal cancer

Authors Treatment modality No patients Outcome-survival
Chyle et al. (1996) RT 55 St III 10 year 47%
16 St IV 10 year 27%
Creasman (NCDB) RT St III–IV, 180 5 year surv: 36%; 60%-S ? RT (36), 35%-RT
(1998) ± surgery (144)
de Crevoisier et al. (2007) RT 26 St III 5 year 42%
4 St IV 5 year 2%
Frank et al. (2005) RT 46 St III & IVA 5 year 58% (DSS)
± surgery
Kirkbride et al. (1995) RT ± surgery ± chemo 42 St III–IV 5 year 53%
Kucera and Vavra (1991) RT 46 St III 5 year 35%
19 St IVA 5 year 32%
Lian et al. (2008) RT 9 St III 5 year 32% (DSS)
± surgery 4 St IV 5 year 26% (DSS)
Perez et al. (1999) RT 20 St III 10 year 38%
15 St IV 0%
Sinha et al. (2009) RT 11 St III & IVA 5 year 20%
± surgery ± chemo
Stock et al. (1995) RT 9 St III 5 year 0%
± surgery 8 St IV 0%
Tabata et al. (2002) RT 5 St III 5 year 0%
± surgery 7 Stage IV 5 year 14%
Tran et al. (2007) RT 13 St III 5 year 44% (DSS)
± surgery 9 St IV 5 year 13% (DSS)
± chemo
Urbanski et al. (1996) RT 40 St III 5 year 22.5%
15 St IVA 0%

experienced a complete response, 61% of them
recurred, with a median time to recurrence of only
6 months, and an overall survival at 5 years of 22%.
Further, 9 of 67 patients (13%) developed severe
late complications of which 8 required surgeries.
No randomized trials comparing radiation with or
without chemotherapy have been reported.
Dalrymple et al. (2004) published recently a small
study including 14 patients, primarily stages I and II
SCC of the vagina treated with reduced doses of RT
(median 63 Gy) concurrently with different 5-FU based
chemotherapeutic regimens (Dalrymple et al. 2004).
They report a 93% control rate, probably reflecting a
more favorable stage distribution. Interestingly, none
of the patients required interstitial implants and no
patients developed fistulas. The authors indicate that
this approach, similar to the one used in the manage-
ment of anal and vulvar cancer would allow reducing
the RT dose with the subsequent improvement in organ
function and late toxicity.
Samant et al. (2007) reviewed institutional data on
12 patients (50% FIGO St III or IVa) treated with
concurrent radiation and weekly cis-platinum chemo-
therapy (40 mg/m2 for 5 weeks). At a median follow-
up of 50 months, the 5-year overall, progression-free,
and local relapse-free survival rates were 66, 75, and
92% respectively. Sinha et al. (2009) reported on 11 of
45 patients that received concurrent cisplatin with
radiation that failed to show a benefit in disease control
with the addition of chemotherapy; however these
patients had more advanced FIGO stages which has
shown to be a major determinant of failure and survival.
Carcinoma of the Vagina
In a study by Benedetti Panici et al. (2008), 11 patients
received neoadjuvant chemotherapy with paclitaxel and
cisplatin for three courses followed by radical surgery for
patients with FIGO stage II vaginal cancer. They found
complete clinical responses in 3 (27%) patients, partial
clinical responses in 7 (64%) patients, and one patient
with stable disease (9%). At a median follow-up of
75 months, 91% are alive and 73% are disease free.
Further investigation is needed, given the limited data
available, to determine the role of neoadjuvant chemo-
therapy, the therapeutic efficacy of combined chemora-
diotherapy as well as the optimal chemotherapy regimen
in patients with vaginal cancer. Published data on
cervical cancer have demonstrated an advantage in
loco-regional control, overall survival, and disease-free
survival for patients receiving cisplatin-based chemo-
therapy concurrently with RT (Keys et al. 1999; Morris
et al. 1999; Rose et al. 1999; Whitney et al. 1999). Based
on these data, as well as data on loco-regionally
advanced vulvar cancer (Moore et al. 1998), consider-
ation should be given to a similar approach in patients
with advanced vaginal cancer. Also, in a recent SEER
analysis for vaginal cancer, using the year 2000 as a
surrogate for the introduction of chemoradiation in cer-
vical cancer, a trend toward lower risk of death after 2000
in their multivariate model was found, as compared with
women diagnosed between 1990 and 1994 (HR 0.83,
P = 0.07) (Shah et al. 2009). Randomized trials com-
paring radiation therapy alone to chemoradiation ther-
apy, however, are unlikely due to small patient numbers.
12 Hyperthermia and Radiation
Hyperthermia, intratumoral temperature elevation to
39–43°C in combination with radiation and/or che-
motherapy has been utilized to improve clinical
results in various tumors (Franckena et al. 2008).
More recently, hyperthermia was tested in vaginal
cancer in a cohort study with a tumor size greater than
4 cm in diameter for FIGO stage III disease (Aktas et al.
2007). Seven patients out 39 received hyperthermia and
RT, 29 received RT alone and 3 received concurrent
chemotherapy and RT. They found when irradiation
was used as a monotherapy in FIGO stage II and III in
tumors \4 cm, the 5-year survival rate was 57% and
when hyperthermia was added to RT (in tumors[4 cm)
the 5-year survival rate was 68% (Aktas et al. 2007).
A prospective registration study has been initiated
937
examining hyperthermia in the treatment of vaginal
cancer in order gain a better understanding of how to
achieve optimal results (Van der Zee et al. 2008).
13 Salvage Therapy
In general, the patient with recurrent cancer of the lower
female genital tract presents a difficult clinical dilemma.
It must be determined if the disease is amenable to
curative salvage therapy, implying some reasonable
chance of cure, or whether palliation is the primary goal.
Treatment selection factors include primary therapy,
extent of the disease at presentation, site of recurrence,
extent of the recurrence, disease-free interval, evidence
of metastatic disease, patient age, performance status,
and co-existing medical conditions.
In most cases, only patients with small volume local
recurrences and no metastatic disease are curable.
Therefore, careful work-up to establish the extent of
disease is crucial. When salvage therapies are contem-
plated, local recurrences should be confirmed by biopsy,
and, when possible, parametrial recurrences should be
documented pathologically. Pelvic side wall involve-
ment can almost always be diagnosed in the presence of
a symptom triad of sciatic pain, leg edema, and hydro-
nephrosis. It is important to evaluate for regional and/or
distant metastasis by physical examination and imaging
studies such as CT or MRI scans. More recently, PET
scan has been used to document the extent of recurrent
disease (Sun et al. 2001) but both false positive and false
negative results have been reported.
Generally, patients with isolated pelvic or regional
recurrences after definitive surgery who have not
received prior RT are managed with EBRT, often in
conjunction with brachytherapy (Davis et al. 1991;
Kirkbride et al. 1995; Stock et al. 1995). Concurrent
cisplatin-based chemotherapy may also be recom-
mended (Urbanski et al. 1996). Salvage options for
patients with central recurrence after definitive or
adjuvant RT are limited to radical surgery, usually
exenterative (Davis et al. 1991; Kirkbride et al. 1995;
Stock et al. 1995; Urbanski et al. 1996). In selected
patients, with small-volume disease, re-irradiation
using interstitial radiation implants or highly conformal
three-dimensional EBRT. Response rates with che-
motherapy are low, and the impact on survival limited.
Further, response to chemotherapy in central pelvic
recurrences following radiation therapy tends to be less
938
common than response at distant sites. Additionally,
prior high dose radiation therapy compromises bone
marrow tolerance of many agents which are active in
this tumor (e.g., ifosfamide and doxorubicin). How-
ever, chemotherapy-responsive patients can obtain
meaningful palliation in many cases.
Those patients who have not received prior RT
should be treated with whole-pelvis EBRT followed
when feasible by brachytherapy. Generally, the whole
pelvis receives a dose of 40–50 Gy. Inguino-femoral
lymph node regions should be included in patients with
involvement of the distal third of the vagina or with
vulvar recurrences. The gross tumor volume in the
vagina, paravaginal tissues, and/or parametrium should
receive an additional boost, preferably with an intersti-
tial implant, to bring the total tumor dose to 75–80 Gy.
Re-irradiation in previously irradiated patients must be
undertaken with extreme caution. However, selected
patients who are medically inoperable, technically un-
resectable, or refuse to undergo exenterative surgery are
appropriately considered for re-irradiation to limited
volumes. A variety of techniques are available, and the
choice is based on patient and tumor-related factors, as
well as the experience of the radiation oncologist. When
using EBRT, multiple beam arrangements utilizing
three-dimensional treatment planning is favored. Only
limited doses are possible, and the physician might
consider a hyper-fractionated regimen in an attempt to
decrease the incidence of late toxicity.
In patients with small, well-defined vulvo-vaginal
or pelvic recurrences, re-irradiation using primarily
interstitial techniques has been attempted with control
rates between 50 and 75%, and grade 3 or higher
complication rates between 7 and 15% (Charra et al.
1998; Gupta et al. 1999; Randall et al. 1993; Russell
et al. 1987; Epstein et al. 2001; Xiang et al. 1998). The
rationale, logistics, and selection of implant technique
when performing an ITI have been reviewed earlier in
the chapter. Permanent radioactive seed implants (e.g.,
198
Gold) in patients with small vaginal recurrences
often provides long-lasting tumor control in elderly or
medically debilitated patients previously treated with
definitive doses of RT. In a series by Brabham and
Cardenes (2009), 19 patients with low volume recur-
rent gynecologic malignancies (4 vaginal primaries)
were treated with permanent interstitial implants using
198
Gold. Complete response was observed in almost
95% of patients and local control was achieved in 63%,
however the authors emphasize that these results are in
H. R. Cardenes et al.
a selected patient population with small volume
recurrences no thicker than 1 cm (Brabham and
Cardenes 2009). Advantages and disadvantages of
surgery and re-irradiation as salvage therapies are
shown in Table 5 (Randall et al. 1993).
Other potential treatment options include the use
of surgery and Intraoperative RT (IORT). The loco-
regional recurrence and distant metastasis rates after
IORT vary between 20–60% and 20–58%, respec-
tively. The 3–5 year actuarial survival is poor, rang-
ing from 8 to 25%. Grade 3 or higher toxicity has
been reported in about 28–35% of patients (Garton
et al. 1997; Tran et al. 2007; Haddock et al. 1999). In
the Memorial Sloan-Kettering Cancer Center experi-
ence using radical surgical resection and HDR-IORT,
patients with complete gross resection had a 3-year
local control rate of 83%, compared to 25% in
patients with gross residual disease. Interestingly,
most of the failures in the microscopic group were
distant, perhaps indicating a potential role for adju-
vant chemotherapy (Gemignani et al. 2001).
Stereotactic body radiotherapy (SBRT), also known
as extracranial stereotactic radioablation (ESR), is a
novel treatment paradigm that delivers a small number
of high-dose fractions to extracranial targets using a
linear accelerator with highly precise, accurate, and
reproducible target localization, based on the same
principles as that of the Gamma-knife therapy. By
means of better target localization and patient immo-
bilization, smaller margins or normal tissue surround-
ing the gross tumor volume are required, which allow
treatment complications to be minimized. Three
reports in the literature describe using SBRT for pri-
mary or recurrent gynecological malignancies (Deo-
dato et al. 2009; Molla et al. 2005; Guckenberger et al.
2010). Molla et al. (2005) used SBRT in place of a
brachytherapy boost in 16 patients (14 primary and 2
patients with recurrent disease). SBRT doses of 2
fractions of 7 Gy or 4 fractions of 5 Gy were used and
the authors report high rates of local control with only
one local failure. One patient in their series had late
rectal complications with grade 3 rectal bleeding
18 months after reirradiation for a vaginal vault
relapse. Guckenberger et al. (2010) reported on 19
patients that were treated with stereotactic body
radiotherapy for a local boost in unfavorable locally
recurrent gynecological cancers (12 recurrent cervical
cancers and 7 recurrent endometrial). The majority of
patients were treated with conventionally fractionated
Carcinoma of the Vagina
Table 5 Advantages and disadvantages of salvage surgery and interstitial re-irradiation
Salvage therapy Advantages
Surgery Ability to assess the extent of disease and act
accordingly
Applicable to larger volume recurrences
Re-Irradiation Little perioperative morbidity or mortality
Little or no hospitalization for permanent
implants unless laparotomy is required
Relative inexpensive
Preserves structure and function in most patients
Applicable to patients who are medically infirmed
or aged
Reprinted with permission from Randall et al. (1993)
EBRT followed by a stereotactic boost, because the
large volume and/or peripheral location of the recur-
rence made vaginal brachytherapy inappropriate as a
sole boost technique. Three patients received SBRT
only. The mean dose delivered with EBRT was 50 Gy
and the mean stereotactic dose was 3 fractions of 5 Gy
prescribed to the 65% isodose line. The local control
rate for these recurrences was 81% after two and three
years. The rate of late toxicity greater than grade 2 was
25%, with two patients suffering from intestinovaginal
fistula and one patient from small bowel ileus.
14 Treatment Complications and Their
Management
Clearly, the knowledge of common acute and late
complications with standard RT and consideration of
risk factors may improve the therapeutic ratio of RT
for gynecological malignancies in general and for
vaginal cancer in particular (Cardenes et al. 2001).
The acute and chronic pathophysiology of vaginal
RT has been well described (Grigsby et al. 1995).
Chemotherapy concurrently with RT enhances the
acute mucosal response to both EBRT and brachy-
therapy. The effects of chemotherapy on the incidence
of late complications, if any, are unclear. Vaginal
narrowing, shortening, paravaginal fibrosis, loss of
elasticity, and reduced lubrication often result in
dyspareunia. More severe complications include
necrosis, with ulceration that can progress to fistula
939
Disadvantages
Perioperative morbidity and mortality, particularly
after previous RT
Prolonged hospitalization
High rate of re-operation
Expense
Applicable only to selected patients with good
performance status/good general condition
Detrimental to patient self-image
Extent of disease difficult to assess in some cases
Risk of late radiation injury
Applicable only to small-volume recurrences
if excessive complication rate is to be avoided
formation (rectovaginal, vesicovaginal, urethrovagi-
nal). MRI may be useful in evaluating complications
of the disease and treatment, such as vesicovaginal or
rectovaginal fistulas (Parikh et al. 2008).
The RT tolerance limits of the entire vagina are ill-
defined, given the variety of techniques employed for
the treatment of vaginal cancers. An irradiation tol-
erance level of the proximal vagina was suggested by
Hintz et al. (1980) based on a study of 16 patients
who received a maximum surface dose of 140 Gy,
none of whom developed severe complications or
necrosis of the upper vagina (Hintz et al. 1980). Based
on their previous observation of a patient who
developed a vesico-vaginal fistula after receiving a
dose of 150 Gy mucosal dose to the anterior vaginal
wall, they recommended a tolerance dose level of
150 Gy (direct summation of EBRT dose and ICB) to
the anterior upper vaginal mucosa. They also rec-
ommended keeping the total dose to the distal vagina
less than 98 Gy. In addition, it was also observed that
the posterior wall of the vagina is more prone to
radiation injury than the anterior or lateral walls, and
that the dose should be kept below 80 Gy in order to
minimize the risk of recto-vaginal fistula. Rubin and
Casarett (1968) suggested that the tolerance of the
vaginal mucosa (TD 5/5: 5% necrosis within 5 years)
is around 90 Gy for ulceration, and more than 100 Gy
for fistula formation. This tolerance limit has been
specified as a direct summation of dosage given by
LDR-ICB and EBRT in the treatment of cervical
cancer. Within the low dose-rate range, whether a
940
correction for brachytherapy dose rate is necessary
remains controversial. In a more recent series from
Washington University, the traditional LDR tolerance
dose of 150 Gy to the mucosa of the proximal vagina
was shown to yield a nominal 11 and 4% grades 1–2
and 3 sequela, respectively (Au and Grigsby 2003).
The incidence of greater or equal to grade 2
complications has been reported to be 14–25%,
(Chyle et al. 1996; Kirkbride et al. 1995; Kucera and
Vavra 1991; Perez et al. 1999; Peters et al. 1985;
Rubin et al. 1985; Stock et al. 1995; Urbanski et al.
1996; de Crevoisier et al. 2007; Frank et al. 2005;
Sinha et al. 2009) with the average of severe com-
plications (those requiring surgery for correction or
necessitating hospitalization) around 8–17% cumula-
tive risk (Frank et al. 2005; Sinha et al. 2009).
In a series by de Crevoisier et al. (2007), anterior
tumor location was associated with increased bladder
toxicity (P = 0.01) and decreased rectal toxicity
(P = 0.08). Vaginal toxicity was associated with the
extent of vaginal involvement (P = 0.02) and FIGO
stage (P = 0.03); the total reference air kerma was
significantly higher in the group of patients who
experienced grade 2–3 urinary or intestinal toxicity
(P = 0.03) (de Crevoisier et al. 2007).
Host factors that may increase the risk of com-
plications include prior pelvic surgery, pelvis
inflammatory disease, immunosuppression status,
collagen vascular disease, low body weight, patient
age, significant smoking history, and co-morbid ill-
ness (e.g., diabetes, hypertension, and cardiovascular
disease) (Perez et al. 1988, 1999). In Frank et al.
(2005) series, major complications at 5 years were
found in 25% of current smokers compared to 18%
in patients who claimed to quit more than 6 months
prior to radiation therapy, compared to only 5% in
patients who had no smoking history (P \ 0.01).
Other factors such as diabetes and hypertension were
not found to be significant in their series (Frank
et al. 2005).
Lee et al. (1994) showed that the total dose to the
primary site was the most significant factor predicting
the development of a severe complication (9% in
patients receiving B80 Gy as compared with 25% in
those receiving higher doses) (Lee et al. 1994). Perez
et al. (1988) reported an increase in the rate of severe
complications with higher clinical stage, probably
reflecting the higher doses delivered with EBRT and
brachytherapy.
H. R. Cardenes et al.
Treatment options for acute radiation vaginitis
include daily vaginal douching with a diluted hydro-
gen peroxide/water mixture. This should continue for
2–3 months, or until the mucosal reactions have
subsided. Patients are then advised to continue
douching once or twice per week for several months.
Regular vaginal dilation is recommended as a way for
patients to maintain vaginal health and good sexual
function, although the compliance rate is low. The
lack of resolution of vaginal ulceration or necrosis
after several months of adequate therapy must be
appropriately evaluated, considering the possibility
of recurrent tumor. The use of topical estrogens
following completion of RT appears to stimulate
epithelial regeneration more than systemic estrogens.
Some patients with severe radiation sequelae, such
as fistula formation, will respond to conservative
treatment with antibiotics and periodic limited
debridement of necrotic tissue. More recently, Dela-
nian et al. (2003) published a randomized trial dem-
onstrating the effectiveness of the combination of
Pentoxifylline and Vitamin E in the regression of
radiation-induced fibrosis (Delanian et al. 2003).
Patients with more severe gastro-intestinal or uri-
nary late effects will require urinary or fecal diversion
with possible delayed re-anastomosis. Occasionally,
repair of the fistula may be attempted by employing a
myocutaneous graft, in which the skin, subcutaneous
fat, and muscle are mobilized using a vascular pedicle
to maintain the blood supply to the pedicled graft
(martius flap), or by excision of the necrotic tissue
with reestablishment of organ continuity (such as in
the treatment of high rectovaginal fistula).
15 Palliative Radiotherapy
At the present time, there is no curative option for
patients who present with stage IVB disease. Many of
these patients suffer from severe pelvic pain or
bleeding. If vaginal bleeding is the main concern,
intracavitary brachytherapy, if feasible, often offers a
good symptom control with relatively low morbidity.
For patients who have received prior RT, intracavitary
doses in the range of 35–40 Gy to point A should be
prescribed.
Short course of EBRT using high dose fraction-
ation schedules have been used, including single
doses of 10 Gy per fraction, times three, with an
Carcinoma of the Vagina
Fig. 9 Palliative course of external beam irradiation using the
RTOG 85-02 regimen. a CT scan prior to initiation of therapy.
b AP and c lateral DRRs of the initial fields. d CT scan after
two split courses of hypofractionated irradiation (2950 cGy) in
interval of 4–6 weeks between courses, combined
with misonidazole, RTOG clinical trial 79-05,
resulting in significant palliation in selected patients
with advanced gynecological malignancies. The
overall response rate was 41% for patients completing
the 3 courses; however, the actuarial 45% incidence
of grade 3–4 late gastrointestinal toxicity was unac-
ceptable (Spanos et al. 1994).
Spanos et al. (1989) reported on a phase II study
(RTOG 85-02) of daily multifraction split-course
EBRT in patients with recurrent or metastatic disease
(Spanos et al. 1989). The regimen consisted of 3.7 Gy
per fraction given twice daily for two consecutive
days and repeated at 3–6 week intervals, for a total of
three courses (tumor dose, 44.4 Gy). Occasionally,
this regimen was combined with an ICI (4500 mgh),
with a midline block in the last 14.4 Gy. Complete
tumor response was noted in 15 patients (10.5%), and
partial response in 32 (22.5%) (Fig. 9). In patients
completing three courses of irradiation (59%), the rate
of complete or partial response was 45%. Twenty-
seven patients survived longer than one year. Late
complications were significantly less, with a projected
actuarial rate of 5% at 12 months.
941
one week. e AP and f lateral DRRs of the conedown fields prior
to a brachytherapy boost. g AP and h lateral radiographs of the
brachytherapy implant
In a subsequent Phase III Study (Spanos et al.
1993), 136 patients were randomized between rest
intervals of 2 versus 4 weeks between the split
courses of RT. Decreasing the interval between
courses did not result in a significant improvement in
tumor response (34 vs. 26%). More patients in the
2-week rest group completed the three courses of
therapy, and not surprisingly, patients completing all
three courses had a higher overall response rate than
patients completing less than three courses (42 vs.
5%), and a higher complete response rate (17 vs. 1%).
This schedule offers significant logistic benefits, and
has been shown to result in good tumor regression and
excellent palliation of symptoms. Spanos et al. (1994)
reported a trend toward increased acute toxicity in
patients with shorter rest periods, but late toxicity was
not significantly different in the two groups.
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 Prostate
Jeff M. Michalski and Thomas Wiegel

Contents 5.4 Supplemental Therapies .......................................... 1000

5.5 PSA Bounce............................................................. 1001
5.6 Approaches to Minimize Morbidity ....................... 1001
1 Anatomy.................................................................. 950
6 High-Dose-Rate Brachytherapy ........................... 1004
2 Natural History...................................................... 951 6.1 Introduction.............................................................. 1004
2.1 Local Growth Patterns ............................................ 951 6.2 Technological Aspects ............................................ 1005
2.2 Regional Lymph Node Involvement ...................... 952 6.3 Radiobiological and Dose Fractionation Aspects ... 1006
2.3 Distant Metastases ................................................... 954 6.4 Clinical Outcome Data From
2.4 Diagnostic and Staging Work-Up........................... 954 HDR-BT Plus EBRT............................................... 1006
6.5 The Role of Neoadjuvant and Concomitant
3 Prognostic Factors ................................................. 956
Endocrine Therapy .................................................. 1009
3.1 Tumor Stage, Pretreatment PSA, and Histological
6.6 Discussion/Future Aspects ...................................... 1010
Features.................................................................... 956
References.......................................................................... 1010
4 Radiation Therapy Techniques............................ 959
4.1 General Treatment Guidelines ................................ 959
4.2 External Irradiation.................................................. 961
4.3 Conventional Radiation Therapy Techniques ........ 961 Abstract
4.4 Conformal Radiation Therapy Simulation Given the high global incidence of prostate cancer,
and Treatment Planning .......................................... 964 it represents one of the most common diseases
4.5 Intensity-Modulated Radiation Therapy ................. 976
4.6 Dose Prescription for 3D CRT or IMRT ............... 976 treated in radiation oncology and urological clinics.
4.7 Normal Tissue Constraints...................................... 980 It also represents a disease where technological
4.8 Hypofractionation and Stereotactic Radiation innovations are often introduced and evaluated
Therapy .................................................................... 983 before they are advanced to other disease sites. In
4.9 Proton Beam Radiation Therapy ............................ 985
4.10 Considerations for Postoperative Radiation ........... 986 this chapter we describe an array of acceptable
4.11 Postoperative Radiation Therapy Techniques ........ 989 methods for the curative treatment of prostate
cancer, from conventional radiation therapy tech-
5 Prostate Brachytherapy ........................................ 992
5.1 Introduction.............................................................. 992 niques, intensity modulated radiation therapy, ste-
5.2 Brachytherapy Planning .......................................... 996 reotactic body radiation therapy, brachytherapy,
5.3 Post-Implant Evaluation .......................................... 998 and proton therapy. The choice of modalities used in
any given clinical situation is often determined by
its technical availability, as no ‘‘level one’’ evidence
J. M. Michalski (&) exists to demonstrate clinical outcome superiority
Department of Radiation Oncology, of one technique to another. We also discuss the
Washington University School of Medicine,
definitive management of patients with brachyther-
4921 Parkview Place, St. Louis, MO 63110, USA
e-mail: jmichalski@radonc.wustl.edu apy and the post-operative management of patients
who have adverse pathologic factors or have failed
T. Wiegel
Department of Radiation Oncology, University Hospital, radical prostatectomy. Discussions on appropriate
Ulm, Germany immobilization and localization techniques are

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 949
DOI: 10.1007/174_2011_398, Ó Springer-Verlag Berlin Heidelberg 2012
950
Fig. 1 Coronal CT (a), coronal MR (b), sagittal CT (c), and sagittal MR (d) images of the pelvis illustrating anatomic
relationships of the prostate
provided. Finally, prescription methods and normal
organ dose constraints for the various techniques of
radiation therapy are given.
1 Anatomy
The prostate gland is a walnut-shaped solid organ that
surrounds the male urethra between the base of the
bladder and the urogenital diaphragm, and weighs
J. M. Michalski and T. Wiegel
about 20 g. The prostate is attached anteriorly to the
pubic symphysis by the puboprostatic ligament. It is
separated from the rectum posteriorly by Denonvil-
liers’ fascia (retrovesical septum), which attaches
above to the peritoneum and below to the urogenital
diaphragm. The seminal vesicles and the vas deferens
pierce the posterosuperior aspect of the gland and enter
the urethra at the verumontanum. The lateral margins
of the prostate, usually delineated against the levator
ani muscles, form the lateral prostatic sulci (Fig. 1).
Prostate
In young men the prostate gland can be divided
into three distinct zones (McLaughlin et al. 2005).
The central zone (CZ) surrounds the ejaculatory
ducts. The transition zone (TZ) is the central com-
ponent of the prostate that tends to hypertrophy with
age. The hypertrophied TZ will compress the CZ and
periurethral glandular tissue, making it nearly
impossible to identify these zones on ultrasound, CT,
or MRI. The hypertrophied TZ is often called the
central gland and is readily recognized on MRI
(Villeirs et al. 2005). While in young men the
peripheral zone (PZ) may make up 70% of the pros-
tate tissue, it becomes condensed by an enlarged TZ
in men with benign prostatic hypertrophy.
Myers et al. (1987), in a study of 64 gross pro-
statectomy specimens, noted variations in the shape
and exact location of the prostatic apex and pointed
out that the configuration of the external striated
urethral sphincter was related to the shape of the
prostatic apex. Two basic prostatic shapes were rec-
ognized and distinguished by the presence or absence
of an anterior apical notch, depending on the degree
of lateral lobe development and the position of its
anterior commissure. Observations by these authors
that the urethral sphincter is a striated muscle in
contact with the urethra from the base of the bladder
to the perineal membrane corroborates the previous
description by Oelrich (1980), who pointed out that
there is no distinct superior fascia of the so-called
urogenital diaphragm separating the sphincter muscle
from the prostate.
The lymphatics of the prostate and the seminal
vesicles were detailed through anatomic dissections
described by Rouvière. Lymphatic drainage of the
prostate originates in an extensive intraprostatic net-
work that coalesces to form a subcapsular system and
then to a periprostatic lymphatic network with four
pedicles: the external iliac, hypogastric (or internal
iliac), and posterior and inferior pedicles that termi-
nate in the external iliac (including the obturator),
presacral, and hypogastric lymph nodes, respectively.
The lymphatics of the seminal vesicle originate in the
mucous and muscular networks and drain to the
lymph nodes of the external iliac system. Modern
surgical series of extended pelvic lymph node dis-
sections report involved lymph nodes commonly in
the obturator fossa, external and internal iliac regions
(Heidenreich et al. 2002; Weckermann et al. 2007).
These sites account for nearly 85% of lymph node
951
metastases in prostate cancer (Weckermann et al.
2007). Another 15% of involved nodes can be iden-
tified in the presacral, paravesicular, and pararectal
sites (Weckermann et al. 2007).
2 Natural History
2.1 Local Growth Patterns
Most clinically significant prostatic carcinomas
develop in the peripheral zone of the prostate,
whereas benign prostatic hyperplasia arises predomi-
nantly from the central (periurethral) portions
(McNeal 1969). Peripheral zone cancers can be
detected by digital rectal exam or by standard trans-
rectal ultrasound guided biopsies. Transition zone
(TZ) cancers can grow relatively large before
extending beyond the confines of the fibromuscular
stroma. TZ tumors can produce substantial elevations
of prostate-specific antigen (PSA). In a series of 148
cases of TZ prostate cancer, 70% were clinical stage
T1c with a preoperative PSA of greater than 10 ng/ml
in nearly two-thirds of the patients (Noguchi et al.
2000).
Breslow et al. (1977) found that 64% of 350 car-
cinoma were present in a slice taken 5 mm from the
distal end of the prostate; therefore, the urethra must
be transected distal to the prostate to avoid leaving
prostatic cancer behind. The apex is the most com-
mon site of positive surgical margins following radi-
cal prostatectomy, accounting for nearly half of
involved margins following radical prostatectomy
(Blute 1998; Smith et al. 2007). This is an important
detail in the design of external irradiation portals or in
brachytherapy of prostate cancer.
Jewett (1980) reported that multiple foci of tumor
were found throughout the prostate in 77% of pro-
statectomy specimens. In a series of 486 patients,
Wise et al. (2002) reported that 83% of the cancers
were multifocal; therefore, the entire gland needs to
be considered at risk of harboring cancer.
As the tumor grows, it may extend into and
through the capsule of the gland, invade seminal
vesicles and periprostatic tissues, and later involve the
bladder neck or the rectum. Tumor may invade the
perineural spaces, the lymphatics, and the blood
vessels producing lymphatic or distant metastases.
The incidence of microscopic extraprostatic
952
extenstion (EPE) beyond the capsule of the gland (at
time of radical prostatectomy) in patients with clinical
stages T1 or T2 ranges from 18 to 57% (Villeirs et al.
2005; Catalona 1994; Kattan et al. 1997; Makarov
et al. 2007; Partin et al. 2001). EPE is a pathologic
feature that is associated with a worse outcome
(Trapasso et al. 1994; Wheeler et al. 1998; Epstein
et al. 1993; Lowe and Lieberman 1997; Pruthi et al.
1997). Several pretherapy tumor-related factors are
associated with EPE, and these include clinical tumor
stage (Partin et al. 2001), pretherapy serum PSA value
(Partin et al. 2001), biopsy tumor grade (Partin et al.
2001), and percent of biopsy containing cancer
(Bostwick et al. 1996). Although any of these factors
may be individually used to estimate the likelihood
for EPE, the accuracy of such estimates is enhanced
by combining those factors that independently con-
tribute to the predictive model (Kattan et al. 1997;
Makarov et al. 2007; Partin et al. 2001).
In the PSA era, Partin et al. (1993) were among the
first to use multivariate statistical analysis to identify
pretherapy variables associated with EPE in patients
who underwent RP and demonstrated that clinical
tumor stage, Gleason score of the diagnostic biopsy,
and serum PSA level independently correlate with
this finding. The combination of these factors was
used to develop probability estimates. Kattan and
associates (Kattan et al. 1997) conducted a separate
validation study that confirmed that the nomogram
discriminated well between men with organ-confined
disease and those in whom the disease extended
beyond the prostate gland.
Stone et al. (1995) reported none of 13 patients
with prostate-specific antigen (PSA) \4 ng/ml, 11 of
99 patients (11%) with PSA of 4.1–20 ng/ml, and 12
of 45 patients (27%) with PSA [20 ng/ml having
positive seminal vesicle biopsy. None of the patients
with stages T1a–T1c had positive seminal vesicle
biopsies, compared with 2 of 33 (6%) with stage T2a,
14 of 80 (17.5%) with stage T2b, and 7 of 23 (30%)
with stage T2c tumors. Seminal vesicle involvement
has been observed in 10% of patients with stage-A2
tumors to 30% of patients with stage-B2 lesions
(Catalona and Bigg 1990).
Seminal vesicle invasion (SVI) occurs when tumor
extends into the region where vas deferens and seminal
vesicles converge at the prostatic base (Villers et al.
1990). Direct tumor growth from this location along the
ejaculatory duct complex or through the prostatic
J. M. Michalski and T. Wiegel
capsule may result in seminal vesicle invasion. This
mechanism accounts for the observations that tumor
volume is often greatest at the prostatic end of the
seminal vesicle in the vicinity of the vas deferens
(Villers et al. 1990), that involvement of both seminal
vesicles is a common finding (Ohori et al. 1993), and
that isolated deposits of prostate cancer remote from the
ejaculatory duct complex are observed in only one-
eighth of seminal vesicle specimens involved with
tumor (Ohori et al. 1993). Just as the accuracy of esti-
mating EPE is enhanced by combining clinical factors
in predictive models, the use of PSA, biopsy Gleason
Score, and clinical stage help predict the risk of SVI in
patients undergoing radical prostatectomy (Kattan
et al. 1997; Makarov et al. 2007; Partin et al. 2001).
Roach (1993) proposed the following formula based on
analysis of radical prostatectomy specimens to estimate
the probability of seminal vesicle involvement:
SVI ¼ PSA þ ðGleason score minus 6Þ  10
2.2 Regional Lymph Node Involvement
Tumor volume and grade affect the tendency of
prostatic carcinoma to metastasize to regional
lymphatics. The incidence of lymph node metastases
was as high as 12–28% in clinical stage-T2 disease in
the pre-PSA era (Middleton 1988). Fowler and
Whitmore (1981) reported that 40% of 300 patients
with apparently localized prostate cancer had pelvic
lymph node metastases upon surgery. In the era of
PSA screening, there has been a dramatic decrease in
the incidence of pelvic lymph node metastases.
Modern series report a less than 10% incidence of
lymph node involvement at radical prostatectomy
(Kattan et al. 1997; Makarov et al. 2007; Partin et al.
2001).
Ohori et al. (1995), in 478 patients treated with
radical prostatectomy, reported no pelvic lymph node
metastases in 70 patients with stages T1a, b, 1 of 43
(2%) in patients with stage T1c, 5 of 96 (5%) with
stage T2a, and 19 of 269 (7%) with stages T2b, c. The
incidence of seminal vesicle invasion was 6, 11, 5,
and 17%, respectively.
In a review of 2,439 patients treated with radical
prostatectomy, Pisansky et al. (1996a) reported posi-
tive pelvic nodes in 12 of 457 (2.6%) with stages
Prostate 953

Table 1 Correlation of PSA levels, Gleason score, clinical [20 ng/ml had positive nodes. When correlated with
stage, and status of positive seminal vesicle biopsy specimen clinical stage, none of the patients with stage T1b, c,
with incidence of positive pelvic lymph nodes (from Stock
et al. 1995a) or stage T2a had positive nodes, compared with 10 of
69 (15%) with T2b and 4 of 17 (24%) with T2c
Parameter No. of positive p value
pelvic lymph nodes
tumors. Eleven of 23 patients (48%) with positive
seminal vesicles also had positive nodes, compared
PSA B 10 2 (6)
with 3 of 107 (3%) with negative seminal vesicle
PSA [ 10 7 (15) 0.3
biopsy.
PSA B 20 2 (3) Makarov et al. (2007), Partin et al. (2001, 1997)
PSA [ 20 7 (24) 0.003 analyzed surgical data from three academic institu-
Grade \ 7 1 (2) tions to develop validated nomograms that predict
Grade C 7 8 (35) \0.0001 lymph node involvement based on clinical stage,
T1a–T2a 0 (0) preoperative PSA, and Gleason score. Several groups
T2b–T2c 9 (18) 0.03
have adapted these predictive models to graphical or
online risk calculators (Cagiannos et al. 2003; Ohori
Positive seminal vesicle 9 (50)
biopsy specimen et al. 2004; Stephenson et al. 2006). Risks of lymph
Negative seminal vesicle 0 (0) \0.0001
node metastases, extracapsular extension, and seminal
biopsy specimen vesicle invasion can be estimated by entering pre-
Values in parentheses are percentages
treatment clinical factors such as the PSA, clinical
stage, and Gleason score at www.nomograms.org
(URL, MSKCC Cancer Information/Prediction Tools)
or www.nomogram.org. (URL, Nomogram Chal-
lange) These nomograms are useful in predicting the
T1a–c, 15 of 456 (3.3%) with stage T2a, 130 of 1,206 risk of lymph node involvement and aid in the deci-
(10.8%) with stage T2b, c, and 81 of 320 (25%) with sion to use elective seminal vesicle or pelvic lymph
stage-T3 tumors. node radiation.
Stock et al. (1995b), in 99 patients who underwent Roach (1993) suggested a revised formula based
laparoscopic lymph node dissection (Table 1), corre- on pathological findings in prostatectomy specimens
lated incidence of positive nodes with PSA, Gleason incorporating clinical stage, to estimate the incidence
score, stage, and involvement of seminal vesicles. of metastatic pelvic lymph nodes:
None of the patients with a Gleason score of 4 or
lower, even with PSA [20 ng/ml, had positive pelvic Risk of node positive ¼ 2=3 PSA
lymph nodes, and 8% in the group with Gleason þ ½ðGS  6Þ þ TG  1:5
scores of 5 or 6 and PSA levels of 4–10 ng/ml had  10;
positive nodes; however, the incidence of positive
lymph nodes increased significantly (24%) in patients where GS is Gleason score and TG is clinical tumor
with PSA [20 ng/ml. group; TG is as follows: TG 1 (stages T1c and T2a) is
Bluestein et al. (1994), Narayan et al. (1994), assigned a value of 1, TG 2 (T1b and T2b) is given a
Makarov et al. (2007), Partin et al. (2001, 1993, value of 2, and TG 3 (T2c and T3) is assigned a value
1997), and Spevack et al. (1996) have offered com- of 3.
parable models based on pathological data that may Modern European series of extended lymph node
predict risk for lymph node metastases, to decide dissection did discover a significantly increased
whether the patient should be subjected to a staging number of men with lymph node metastases, com-
lymphadenectomy (including laparoscopic technique) pared with a similar group who had undergone stan-
or considered for irradiation of the pelvic lymph dard lymph node dissection (Heidenreich et al. 2002;
nodes. Weckermann et al. 2007; Wawroschek et al. 2003). In
Stone et al. (1995) reported that none of these series, PSA screening was not prevalent in the
11 patients with PSA \4 ng/ml, 4 of 77 (9%) with patient population. The incidence of lymph node
PSA of 4–20 ng/ml, and 10 of 42 (24%) with PSA metastases discovered by the extended pelvic lymph
954
Table 2 Percentage of node-positive patients who would have
been detected if only lymph nodes from different regions had
been histologically investigated (based on the results of sentinel
lymphadenectomy in 207 patients with or without additional
pelvic lymphadenectomy and with serial sections and immu-
nohistochemistry of all sentinel lymph nodes) (from
Weckermann et al. 2007)
Regions of lymphadenectomy Node-positive
patients (%)
Obturator fossa, external and internal 207 (100)
iliac region, presacral, pararectal,
paravesical
Obturator fossa, external and internal 176 (85)
iliac region
Obturator fossa, internal iliac region 94 (45)
Obturator fossa, external iliac region 76 (37)
Obturator fossa 32 (16)
node dissection was 26.2–26.8%. This finding raises
the question as to whether or not the incidence of
lymph node metastases is underestimated in modern
series.
Clark et al. (2003) performed a randomized trial of
standard lymph node dissection versus an extended
lymph node dissection in a series of 123 patients. In
that trial each patient served as his own control, with
one side having a standard dissection and the other
side an extended dissection. There was no difference
in the rate of lymph node metastases discovered with
the extended dissection. The patient population was
generally low risk with 72% clinical stage T1c, 84.6%
having a PSA of \10 ng/ml, and 67% with cancers of
Gleason score 6 or less (Clark et al. 2003).
The pattern of lymph node metastases has been
described by well-known series. Periprostatic and
obturator nodes are involved first, followed by
external, internal, and common iliac, and eventually
the periaortic nodes (Pistenma et al. 1979). While the
incidence of metastases is less than in the past, the
pattern of involvement is unchanged. Weckerman
reported a series of 207 patients who underwent an
extended pelvic lymph node dissection. The overall
rate of lymph node involvement was 19.6%. Table 2
demonstrates the number of node-positive patients
who would have been detected, provided only that
lymph nodes from different regions had been histo-
logically investigated. These data suggest that more
than 85% of the involved lymph nodes would be
covered by fields that encompassed the obturator,
J. M. Michalski and T. Wiegel
external, and internal iliac chains. Only 15% of lymph
nodes would be missed if the presacral, pararectal,
and paravesical nodes were omitted (Weckermann
et al. 2007).
In the pre-PSA era, metastases to the peri-aortic
nodes were identified in 5–25% of patients, depending
on tumor stage and histological differentiation
(Pistenma et al. 1979). They are associated with a
higher incidence of distant metastases and lower
survival (Lawton et al. 1997). Peri-aortic metastases
are rare in PSA screened patients and represent distant
metastases according to AJCC staging.
2.3 Distant Metastases
Prostatic carcinoma can metastasize to the skeleton,
liver, lungs, and occasionally to the brain or other
sites. In the pre-PSA era, Perez et al. (1988) reported
an overall incidence of distant metastases of 20% in
stage B, 40% in stage C, and 65% in stage D1. In the
modern era, distant metastases are uncommon at the
time of diagnosis and rare in men diagnosed through
PSA screening.
2.4 Diagnostic and Staging Work-Up
Transrectal ultrasound (TRUS) is an important tool in
prostate cancer diagnosis. The typical sonographic
appearance of prostate cancer is an area of diminished
echogenicity (hypoechoic) in the peripheral zone of
the gland. However, 14–29% of prostate cancers have
an isoechoic tumor that cannot be reliably distin-
guished from normal prostate tissue and up to one-
third of hypoechoic nodules do not have cancer by
needle biopsy (Brawer and 1992; Flanigan 1994;
Mettlin et al. 1996). TRUS is very insensitive in the
detection of extrprostatic extension or seminal vesicle
invasion. The Radiology Diagnostic Oncology Group
prospectively evaluated preoperative TRUS in 219
patients (Rifkin et al. 1990). Among 85 patients
considered to have disease confined to the prostate
gland, 43 (51%) had extraprostatic tumor extension,
whereas 50 of 134 patients (37%) with suspected
extraprostatic disease did not have this confirmed by
final pathology. Overall, the sensitivity and specificity
of TRUS in identifying extraprostatic disease were 66
and 46%, respectively, and the test accuracy was only
Prostate
58%. In a prospective, multi-institutional study of
263 patients who underwent radical prostatectomy,
preoperative clinical staging by TRUS and DRE was
compared with pathologic staging (Smith et al. 1997).
Overall, TRUS was not significantly better than DRE
was, in predicting ECE.
Pelvic CT is not particularly sensitive in the
evaluation of local prostate cancer extension. Prostate
cancer has similar attenuation as the surrounding
structures and intraprostatic disease is not visualized.
In the presence of EPE, deformity of the bladder base
or indistinct fat planes may be present but they may
also be related to distension of the bladder or rectum.
Diagnostic CT scanning of the abdomen and pelvis
for lymph node staging of diagnosed cancer infre-
quently yields valuable information. CT imaging can
detect only abnormalities in lymph node size that may
result from extensive tumor involvement. As a result,
the diagnostic sensitivity of this procedure with
respect to lymph node assessment is poor (*25%)
(Engeler et al. 1992; Flanigan et al. 1996), and the
routine use of CT is of little value in evaluating the
regional node stage in low-risk patients (Hanks et al.
1992).
Body-coil 1.5T MRI for prostate cancer staging
has been prospectively evaluated in a multi-
institutional trial by the Radiology Diagnostic
Oncology Group in the late 1980s (Rifkin et al. 1990).
Based upon a low sensitivity, specificity, and accu-
racy they concluded that body-coil MRI was not an
accurate method for prostate cancer staging. Over the
past decade technologic advances have allowed for
higher MRI resolution and improved staging accu-
racy. Endorectal coil MRI of the prostate has superior
spatial resolution and contrast compared to 1.5T body
coil images. In a prospective study of 82 patients, an
endorectal–pelvic-phased array coil significantly
improved anatomical details, staging accuracy, and
specificity. Local staging accuracy, sensitivity, and
specificity using a pelvic-phased array coil alone were
59, 54, and 62%, respectively, while using a com-
bined endorectal–pelvic-phased array coil, local
staging accuracy, sensitivity, and specificity were 83,
65, and 98%, respectively (Futterer et al. 2007). In
addition, the simultaneous use of other clinical
information in pretreatment nomograms enhances the
value of MRI in predicting seminal vesicle invasion
and organ confined disease (Wang et al. 2007).High
955
field (3T) MRI may further improve the sensitivity
and specificity for the staging of localized prostate
cancer (Futterer et al. 2006). In a prospective study of
32 patients undergoing 3T endorectal MRI prior to
radical prostatectomy the accuracy, sensitivity, and
specificity of local staging were 94, 88, and 96%,
respectively, for two experienced radiologists, and 81,
50, and 92%, respectively, for a less experienced
radiologist.
MR spectroscopy (Kurhanewicz et al. 2000) and
dynamic contrast enhanced MR (Bloch et al. 2007;
Padhani et al. 2000) may also improve the sensitivity
and specificity of MR to detect intraprostatic tumor
and enhance the diagnostic accuracy and staging of
prostate cancer. Additional research is evaluating the
role of intravenous iron oxide lymphotropic super-
paramagnetic nanoparticles to enhance MRI imaging
of lymph nodes. (Harisinghani et al. 2003).
Clinically apparent metastatic disease is limited to
bone in 80–85% of patients with prostate cancer
metastases and is observed in a pattern that correlates
with the distribution of hematopoietic marrow in the
adult. Radionuclide bone scan appearance of metas-
tases may range from a solitary focus of radionuclide
uptake to the ‘‘super scan,’’ wherein the entire skel-
eton shows intense diffuse activity with diminished
renal and soft tissue uptake. Chybowski evaluated the
utility of routine bone scan in the pretherapy evalu-
ation of the patient with newly diagnosed prostate
cancer (Chybowski et al. 1991). This retrospective
evaluation of 521 randomly selected patients corre-
lated clinical tumor stage, tumor grade, acid phos-
phatase, and PSA serum levels with bone scan
findings. The probability of a bone scan showing
metastatic disease was most strongly associated with
and was directly proportional to the serum PSA level.
Only 0.3% of patients with a pretherapy PSA of
20 ng/ml or lower had a positive bone scan at pre-
sentation (Chybowski et al. 1991).
The role of monoclonal antibody imaging with 111
In-labeled Capromab pendetide (ProstaScint) is
unclear. In the setting of a rising PSA following
prostatectomy, Prostascint imaging has been used to
evaluate patients for the presence of local or lymph
node recurrence of disease following prostatectomy.
The reported value of Prostascint imaging has been
inconsistent with some investigators reporting
improved patient selection and outcomes for salvage
956
Fig. 2 Diagnostic Algorithm Guidelines for the initial staging
workup. The National Comprehensive Cancer Network
(NCCN) guidelines constitute a statement of evidence and
consensus by its authors on the accepted approaches to
treatment. Any clinician seeking to apply or consult any
NCCN guideline is expected to use independent medical
judgment in the context of individual clinical circumstances to
determine any patient’s care or treatment. The NCCN makes no
warranties of any kind regarding the guidelines’ content, use, or
application and disclaims any responsibility for their applica-
tion or use in any way. Adapted with permission from The
therapy of a presumed localized recurrence whereas
others have reported no difference in outcome in
patients with localized versus distant tracer uptake
(Koontz et al. 2008; Liauw et al. 2008; Nagda et al.
2007). Positron Emission Tomography (PET) imag-
ing with 18F Fluorodeoxyglucose (FDG) has been
disappointing with poor sensitivity and specificity for
staging local and regional disease due to poor uptake
of FDG in slowly proliferating prostate cancer as well
as urinary excretion causing bladder uptake to
obscure pelvic disease (Sanz et al. 1999; Shreve et al.
1996). Newer PET imaging agents using 11C labeled
methionine, acetate, or choline may show promise in
the staging of high-risk prostate cancers (Nunez et al.
2002).
The American College of Radiology (ACR) (Israel
and ACR Appropriateness criteria 2009) and the
National Comprehensive Cancer Network (NCCN)
have established guidelines for the pretreatment
staging of prostate cancer. The scheme proposed by
the NCCN is displayed in Fig. 2 (NCCN 2010).
J. M. Michalski and T. Wiegel
NCCN Clinical Practice Guidelines in OncologyTM for Prostate
Cancer V.4.2011. Ó 2011 National Comprehensive Cancer
Network, Inc. All rights reserved. These Guidelines and
illustrations herein may not be reproduced in any form for
any purpose without the express written permission of the
NCCN. To view the most recent and complete version of the
guideline, go online to www.nccn.org. NATIONAL COM-
PREHENSIVE CANCER NETWORKÒ, NCCNÒ, NCCN
GUIDELINESTM, and all other NCCN Content are trademarks
owned by the National Comprehensive Cancer Network, Inc
3 Prognostic Factors
3.1 Tumor Stage, Pretreatment PSA,
and Histological Features
The strongest prognostic indicators in carcinoma of the
prostate are clinical stage, pretreatment PSA level, and
tumor grade (Perez 1998). This is a consequence of the
more aggressive behavior and greater incidence of
local extension as well as lymphatic and distant
metastases in the larger and less-differentiated tumors.
The AJCC staging system accounts for local tumor size,
bilaterality, extraprostatic extension, and metastases to
the lymph nodes and/or distant sites. The criteria for
assigning pathologic classification and stage were
developed by the American Joint Commission on
Cancer (AJCC) and the International Union Against
Cancer (Table 3) (AJCC 2009; Sobin et al. 2009).
The local extent of prostate cancer is an important
factor predictive of patient outcome. Studies
Prostate 957

Table 3 American joint commission on cancer TNM staging classification (from AJCC Cancer Staging Manual 2009)
Classification Definition Classification Definition
Primary tumor (T) Primary tumor (T)
Clinical Pathologic
(pT)c
Tx Primary tumor cannot be assessed pT2 Organ confined
T0 No evidence of primary tumor pT2a Unilateral, one-half of one side
or less
T1 Clinically inapparent tumor neither palpable nor visible by pT2b Unilateral, involving more than
imaging one-half of side but not both
sides
T1a Tumor incidental histologic finding in 5% or less of tissue pT2c Bilateral disease
resected
T1b Tumor incidental histologic finding in more than 5% of pT3 Extraprostatic extension
tissue resected
T1c Tumor identified by needle biopsy (for example, because of pT3a Extraprostatic extension or
elevated PSA) microscopic invasion of
bladder neckd
T2 Tumor confined within prostatea pT3b Seminal vesicle invasion
T2a Tumor involves one-half of one lobe or less Regional lymph nodes (N)
T2b Tumor involves more than one-half of one lobe but not both Clinical
lobes
T2c Tumor involves both lobes Nx Regional lymph nodes were not
assessed
T3 Tumor extends through the prostate capsuleb N0 No regional lymph node
metastasis
T3a Extracapsular extension (unilateral or bilateral) N1 Metastasis in regional lymph
node(s)
T3b Tumor invades seminal vesicle(s) Pathologic
T4 Tumor is fixed or invades adjacent structures other than pNx Regional nodes not sampled
seminal vesicles, such as external sphincter, rectum, pN0 No positive regional nodes
bladder, levator muscles, and/or pelvic wall
T4 Tumor is fixed or invades adjacent structures other than pNx Regional nodes not sampled
seminal vesicles, such as external sphincter, rectum, pN0 No positive regional nodes
bladder, levator muscles, and/or pelvic wall
pN1 Metastases in regional node(s)
Distant metastasis (M)e
M0 No distant metastasis
M1 Distant metastasis
M1a Nonregional lymph node(s)
M1b Bone(s)
M1c Other site(s) with or without
bone disease
a
Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c
b
Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3 but as T2
c
There is no pathologic T1 classification
d
Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease)
e
When more than one site of metastasis is present, the most advanced category is used. pM1c is most advanced
958
demonstrate an association of primary tumor stage
with several endpoints in patients with localized dis-
ease. Cause-specific and overall survival are directly
related to the extent of the primary tumor in both RT
(Perez et al. 1993; Zagars et al. 1993; Zelefsky et al.
2008a) and expectant management (Albertsen et al.
2005; Chodak et al. 1994; Klotz et al. 2010) series.
The probability of local tumor control (Zagars et al.
1997) and the risk of clinical, (Zagars et al. 1993;
Kuban et al. 1995) metastatic, (Zagars et al. 1997;
Leibel et al. 1994) and biochemical relapse (Zelefsky
et al. 2008a; Kuban et al. 2003a; Fukunaga-Johnson
et al. 1997; Pisansky et al. 1997) are influenced in a
similar manner. The extent of extraprostatic extension
is associated with the risk of clinical failure. Epstein
reported significantly worse rates of progression fol-
lowing radical prostatectomy with established extra-
capsular extension compared to pathology specimens
that had just a few malignant glands outside the
capsule (Epstein et al. 1993).
Long-term case series of EBRT, (Zagars et al.
1993; Kuban et al. 2003a; Swanson et al. 1994),
brachytherapy, (Potters et al. 2005; Blasko et al. 2000;
Zelefsky et al. 2007a) RP, (Han et al. 2001a; Kupelian
et al. 1997a; Roehl et al. 2004; Zincke et al. 1994) and
expectant management (Albertsen et al. 2005; Chodak
et al. 1994) uniformly identify tumor grade as a strong
predictor of disease relapse and mortality in clinically
localized prostate cancer. Studies consistently dem-
onstrate that patients with a poorly differentiated
tumor (i.e., grade 4–5 or Gleason score [7) have an
increased risk of metastatic disease progression, and
reduced OS and disease-specific survival (DSS)
(Albertsen et al. 2005; Zagars et al. 1997; Kupelian
et al. 1997b). For the patient with clinical T1 or T2
disease, tumor grade has greater predictive value than
the distinction between T1 and T2 categories (Chodak
et al. 1994; Zagars et al. 1997; Kuban et al. 2003a;
Potters et al. 2005; Zelefsky et al. 2007a; Zincke et al.
1994) does. The association of tumor grade with
metastatic relapse (Zagars et al. 1997; Kuban et al.
1995, 2003a) and OS (Zagars et al. 1997) is
preserved when pretherapy serum PSA level is
considered.
The pretreatment serum PSA level is an indepen-
dent and highly significant predictor of outcome
(Zagars et al. 1997; Kuban et al. 1998, 2003a; Han
et al. 2001a; Roehl et al. 2004; Zietman et al. 1994;
Martinez et al. 2000a). The pretreatment PSA level
J. M. Michalski and T. Wiegel
generally reflects tumor volume, although some PSA
is contributed from the normal prostate tissue and
some tumors, especially the poorly differentiated
ones, may not produce PSA commensurate with the
tumor burden. The effect of pretreatment PSA on
outcome increases in a continuous fashion (Zagars
et al. 1997; Pisansky et al. 1997). Zagars and col-
leagues described a relationship between pretherapy
PSA and clinical and/or biochemical relapse after RT
(Zagars et al. 1997). They described a significant
difference in the risk of relapse for pretherapy PSA
categories of 4.0 or less, 4.1–10.0, 10.1–20.0, and
more than 20 ng/ml, which was 16, 34, 51, and 89%
at 6-year follow-up, respectively.
Bastacky et al. (1993) noted that perineural
invasion on prostate biopsies is correlated with a
higher probability of capsular penetration, and Bo-
nin et al. (1997) reported a lower 5-year biochem-
ical failure-free survival rate in the presence of
perineural invasion (39 vs. 65%; p = 0.0009) in
patients with PSA \20 ng/ml treated with three-
dimensional conformal radiation therapy (3D CRT).
In a series of 1256 patients undergoing radical
prostatectomy, Epstein reported that perineural
invasion was significantly associated with extra-
prostatic extension and seminal vesicle invasion but
it was not a significant independent predictor of
biochemical progression on multivariate analysis
(Loeb et al. 2010).
D’Amico described a three-tiered prognostic risk-
group categorization that utilizes pretreatment PSA,
biopsy Gleason score, and clinical stage (D’Amico
et al. 1998). Low-risk patients are those with a PSA
B10 ng/ml and a Gleason Score of 2–6 and stages T1–
T2c. Intermediate-risk patients have PSA of 10 ng/ml
to B20 ng/ml and/or Gleason score 7, and no high-risk
features. High-risk patients have PSA [20 ng/ml and/
or Gleason score 8–10 and/or stage CT3. A slightly
modified risk group category has been adopted by the
National Cancer Center Network and is used for
reporting outcomes and to assist in treatment decision
making (Table 4) (NCCN 2011). Most institutional and
other large series now report outcomes by risk stratifi-
cation group. These risk categories were significantly
associated with an increasing rate of biochemical fail-
ure using the ASTRO failure definition (Consensus
statement: guidelines for PSA following radiation
therapy 1997). In a pooled data set of 4839 patients,
Kuban et al. (2003a) reported that pretreatment PSA,
Prostate
Table 4 National Comprehensive Center NetworkÒ (NCCNÒ) prostate cancer recurrence risk [from NCCN Clinical Practice
Guidelines in Oncology (NCCN GuidelinesTM)] (NCCN 2011)
2011 National Comprehensive Center Network (NCCN) prostate cancer recurrence risk
Recurrence risk Stage Grade Diagnostic PSA level
Very low risk T1c GS B 6 PSA \ 10 ng/mL
Low risk T1–2a GS = 2–6 PSA \ 10 ng/mL
Intermediate risk T2b–2c GS = 7 PSA = 10–20 ng/mL
High risk T3a GS = 8–10 PSA [ 20 ng/mL
Very high risk T3b–T4 Any Any
Metastatic Any T Any grade Any PSA
Gleason score, radiation dose, tumor stage, and year of
treatment were all significant prognostic factors in a
multivariate analysis. The risk groups were defined as
follows: low risk (group 1), stages T1b, T1c, or T2a,
Gleason score B6, and PSA B10 ng/ml; intermediate
risk (group 2), stage T1b, T1c, or T2a, Gleason score
B7, and PSA[10 ng/ml but B20 ng/ml or stage T2b or
T2c, Gleason score B7, and PSA B20 ng/ml; and high
risk (group 3), Gleason score 8–10 or PSA[20 ng/ml.
The 5-year clinical DFS rate was 78, 66, and 49% for
low-, intermediate-, and high-risk patients,
respectively.
Kattan et al. (2000) has developed a nomogram
from patients treated at Memorial Sloan-Kettering
Cancer Center to predict outcome after 3D conformal
radiation therapy that employs clinical parameters
including stage, biopsy Gleason score, pretreatment
PSA level, the use of neoadjuvant hormone therapy,
and the radiation dose administered. The nomogram
has been validated using clinical data from the
Cleveland Clinic.
Prognosis is strongly impacted by the presence of
regional lymph node metastases. Patients with posi-
tive pelvic lymph node metastasis have a significantly
greater probability ([ 85% at 10 years) of developing
distant metastasis than those with negative nodes (\
20%; Gervasi et al. 1989). Gervasi et al. (1989)
reported that the risk of metastatic disease at 10 years
was 31% for patients with negative lymph nodes
compared with 83% for those with positive nodes.
The risk of dying of prostate cancer was 17 and 57%,
respectively. Rukstalis et al. (1996) compiled data
from the literature that documented the strong prog-
nostic implications of the number of involved lymph
959
Comments
Fewer than 3 biopsy cores positive, B50% cancer
in each involved core, PSA density \0.15 ng/mL/g
All three factors
Any one of the 3 factors
Any one of the 3 factors
Any T, N1
Any T, any N, M1
nodes. In general, patients with a single metastatic
lymph node have a 5-year survival rate ranging from
60 to 80%, whereas in those with more involved
lymph nodes, the 5-year survival is 20–54%.
Tumor volume is a powerful predictor for patient
outcome. In a series of 151 patients undergoing radical
prostatectomy, investigators found that the number of
positive biopsy sites, tumor bilaterally, and the per-
centage of biopsy sites positive for disease were all
useful predictors of tumor volume in surgical speci-
mens (Poulos et al. 2004). Selek reported that the
percentage positive prostate biopsy (PPPB) was a
predictor of post-external beam radiotherapy PSA
outcome in clinically localized prostate cancer. The 5-
year PSA failure-free survival rate was 79 versus 69%
(p = 0.02) and the clinical disease-free survival rate
was 97 versus 86% (p = 0.0004) for patients
with \ 50% versus C 50% PPPB (Selek et al. 2003).
In a series of 814 patients treated with EBRT,
Spalding et al. reported 5-year PSA-DFS, DSS, and
OS rates of 80, 99, and 91%, respectively, for patients
with PPPB less than 50%, compared with 56, 94, and
87% for patients with PPC 50% or greater (P \
0.0001, \ 0.004, and \ 0.04, respectively) (Spalding
et al. 2007).
4 Radiation Therapy Techniques
4.1 General Treatment Guidelines
The treatment volume guidelines used at Washington
University are outlined in Table 5. Patients are treated
according to their risk category. Some patients may
960 J. M. Michalski and T. Wiegel

Table 5 Washington University radiation 3D and IMRT treatment volume and dose guidelines
NCCN Risk Treatment GTV CTV PTV Dose
Group margin (EBRT;
(mm) Gy)
Low risk EBRT or permanent seed Prostate Prostate 5–10 75.6–
brachytherapy 79.2
Intermediate EBRT ± 4–6 months Prostate Prostate and seminal vesiclesa 5–10 75.6–
risk neoadjuvant hormone therapy or 79.2
EBRT to prostate and SV and
brachytherapy boost
High risk no EBRT with neoadjuvant and 2– Prostate and CTV1 = nodes ? Prostate ? SV 7–10 45
evidence of 3 years adjuvant hormone seminal (A, S,
LN therapy or EBRT to prostate and vesicles I) 5–10
metastases SV and brachytherapy boost (P, R,
with neoadjuvant and 2–3 years L)
adjuvant hormone therapy CTV2 = Prostate ? SV 5–10 75.6–
79.2
High risk EBRT with neoadjuvant and Prostate and CTV1 = nodes ? Prostate ? SV 0.7 (A, 50.4
with permanent adjuvant hormone seminal S, I)
evidence of therapy vesicles and 0.5 (P,
LN involved R, L)
metastases nodes
Involved CTV2 = Involved nodes 0.7 67.2–
nodes 70.4 @
1.6/fx
Prostate and CTV3 = Prostate and seminal 5–10 75.6–
seminal vesicles 79.2
vesicles
Postop EBRT None Prostate and SV bed 0.8 64.8–
adjuvant 68.4
Postop EBRT ± adjuvant hormone None Prostate and SV bed 0.8 64.8–
salvage/ therapy 68.4
rising PSA
High-risk EBRT ± adjuvant hormone If ? imaging CTV1 = Nodes ? Prostate and 7–10 45
postop with therapy or DRE SV Bed ? GTV (if present) (A, S,
rising PSA I) 5–10
(P, R,
L)
CTV2 = Prostate and SV 7–10 66.6 @
Bed ? GTV (if present) (A, S, 1.8/fx
I) 5–10
(P, R,
L)
CTV3 = GTV (if present) 7–10 70.3 @
(A, S, 1.9/fx
I) 5–10
(P, R,
L)
NCCN National cancer center network, PSA Prostate-specific antigen, GTV, CTV, PTV Gross tumor volume, Clinical target
volume, Planning target volume, SV Seminal vesicles, Postop Postoperative, EBRT External beam radiation therapy, A, S, I, P, R,
L Anterior, superior, inferior, Posterior, right, left; External beam doses expressed in Gray with 1.8 Gy/day fraction size unless
indicated
Prostate
Fig. 3 a Diagrams of the pelvis show volumes used to
conventionally irradiate the pelvic lymph nodes, when indi-
cated, and the prostate. Lower margin is at or even 1 cm below
ischial tuberosities. At Washington University, 15 9 15 cm
portals at source-to-skin distance are used for selected stage-
T1b, stage-T2, and all stage-T3 diseases, and for high-risk
postoperative patients, whereas for stage-N1 disease, 18 9 15 cm
portals are used, when necessary, to cover all lymph nodes up
to the bifurcation of the common iliac vessels. Sizes of reduced
fields are larger (up to 14 9 12 cm) when the seminal vesicles
be a candidate for either external-beam radiation
therapy, brachytherapy, or a combination of both.
Unless there are contraindications for one type of
treatment, the choice of primary treatment modality
often depends on patient choice. Elective pelvic
lymph node irradiation is used along with neoadju-
vant hormone therapy when patients have a risk of
lymph node metastases that exceed 15% as deter-
mined by the Roach equation (Roach et al. 2003) or
other nomograms (Kattan et al. 1997; Makarov et al.
2007; Partin et al. 2001).
4.2 External Irradiation
With the advent of megavoltage equipment, an
increase in the use of external irradiation rapidly
emerged for the treatment of patients with carcinoma
of the prostate. Various techniques have been used,
ranging from parallel anteroposterior (AP) portals with
a perineal appositional field to lateral portals (box
technique) or rotational fields to supplement the dose to
the prostate. In recent years, volume-based treatment
planning and conformal delivery techniques such as
3D conformal or intensity modulated radiation therapy
(IMRT) and proton therapy are commonly used.
961
and/or periprostatic tumor is irradiated compared with prostate
boost only (up to 10 9 8 cm) or larger for patients with stage-
T3 tumors. b Lateral portals used in conventional box technique
to irradiate pelvic tissues and prostate. The anterior margin is
1 cm posterior to projected cortex of pubic symphysis.
Presacral lymph nodes are included down to S2; inferiorly
the posterior wall of rectum is spared. c Boost fields, lateral
projection, are used to irradiate the prostate with conventional
radiation therapy
4.3 Conventional Radiation Therapy
Techniques
4.3.1 Volume Treated
When the pelvic lymph nodes are treated, the anterior
and posterior field size is 16.5 9 16.5 cm at isocen-
ter. Patients younger than 71 years of age with clin-
ically localized disease and a risk of lymph node
metastases that exceeds 15%, as well as all patients
with T3 lesions, are treated to the whole pelvis with
four fields (45 Gy) and additional dose to complete
70 Gy or higher to the prostate, with a six-field 3D
conformal or IMRT technique. For node-positive
disease, the pelvic field size is increased to
20.5 9 16.5 cm at isocenter to cover the common
iliac lymph nodes. The inferior margin of the field can
be determined using an urethrogram with 25% radi-
opaque iodinated contrast material. The inferior field
edge is usually 1.5–2 cm distal to the junction of the
prostatic and membranous urethra (usually at or
caudal to the bottom of the ischial tuberosities). The
lateral margins should be about 1–2 cm from the
lateral bony pelvis (Fig. 3a).
With lateral portals, which are used with the box
technique (including the lymph nodes) or to irradiate
the prostate with two-dimensional (2D) stationary
962
Fig. 4 Anteroposterior (a) and lateral (b) virtual simulation
digitally reconstructed radiographs (DRRs) for carcinoma of
the prostate treating the pelvic lymph nodes. Note the
fields or rotational techniques, it is important to
delineate anatomic structures of the pelvis and the
location of the prostate in relation to the bladder,
rectum, and bony structures with computed tomog-
raphy (CT) scan or magnetic resonance imaging
(MRI).
The initial lateral fields encompass a volume
similar to that treated with AP-posteroanterior (PA)
portals. The anterior margins should be 1.5 cm pos-
terior to the projection of the anterior cortex of the
pubic symphysis (Fig. 3b). Some of the small bowel
may be spared anteriorly, keeping in mind the ana-
tomic location of the external iliac lymph nodes.
Posteriorly, the portals include the internal iliac nodes
anterior to the S1–S3 interspace, which allows for
some sparing of the posterior rectal wall distal to this
level.
Figure 4 shows examples of digitally reconstructed
radiograph (DRR) simulation films outlining the AP
and lateral portals used for the box technique with
coverage of the iliac nodes. For the boost with 2D
treatment planning, the upper margin is 3–5 cm above
the pubic bone or acetabulum, depending on extent of
disease and volume to be covered (i.e., prostate with
or without seminal vesicles). The anterior margin is
1.5 cm posterior to the anterior cortex of the pubic
bone. The inferior margin is 1.5 cm inferior to the
J. M. Michalski and T. Wiegel
relationship of the portals to the roof of the acetabulum, the
pubic symphysis anteriorly, and the ischial tuberosities
posteriorly
genitourinary diaphragm as demonstrated by urethr-
ogram. The posterior margin is 2 cm behind the
marker rod in the rectum.
The reduced fields for treatment of the prostatic
volume can be about 10 9 8 cm at isocenter for stages
T1a–T2b to 12 9 10 or 14 9 12 cm for stages T2c–
T3 or T4 (Fig. 3c) or ideally are anatomically shaped
fields, using CT scans or MRI volume reconstructions
of the prostate and seminal vesicles. The seminal
vesicles are located high in the pelvis and posterior to
the bladder, which is particularly critical when
reduced fields are designed in patients with clinical or
surgical stage-T3b tumors. Perez et al. (1993) dem-
onstrated a correlation between size of the reduced
portal and probability of pelvic tumor control.
The boost portal configuration and size should be
individually determined for each patient, depending
on clinical and radiographic assessment of tumor
extent. After the appropriate portals have been
determined, the central axis and some corners of the
reduced portals for both portals are tattooed on the
patient with India ink.
To simulate these portals with the patient in the
supine position, a small radioopaque tube is inserted
in the rectum to localize the anterior rectal wall. A
retrograde urethrogram can assist in defining the
inferior aspect of the prostate. After thorough
Prostate
cleansing of the penis and surrounding areas with e.g.
povidone-iodine, using a sterile technique, 28–40%
iodinated contrast material is injected in the urethra
until the patient complains of mild discomfort. The
contrast is held in place with a penile clamp following
which AP and lateral radiographs are taken after
positioning the small portals under fluoroscopic
examination. The urethrogram documents the junc-
tion of the prostatic and bulbous urethra and accu-
rately localizes (within 1 cm) the apex of the prostate,
which may be difficult to identify on CT scans with-
out contrast. Care should be taken to avoid overdis-
tension of the bulbous urethra with contrast. Malone
et al. (2000) reported that the prostate could be dis-
placed an average of 6.1 mm due to the urethrogram.
Others have described minimal movement due to the
urethrogram, suggesting that it may be related to the
technique of urethrography and not to the contrast
itself (Liu et al. 2004).
A great deal of controversy has developed in refer-
ence to the most accurate anatomic location of the
prostate apex. In a study of 115 patients, none of the
urethrograms showed the urethral sphincter to be cau-
dal to the ischial tuberosities; 10% were located\1 cm
cephalad to a line joining the ischial tuberosities. If
irradiation of 2 cm or more of the urethra is arbitrarily
considered to be excessive, 42.5% of patients would
have received unnecessary irradiation to small volumes
of normal penile tissues if the lower field border was
positioned at the level of the ischial tuberosities
(Sadeghi et al. 1996). Cox et al. (1994) evaluated
urethrograms and CT scans of the pelvis for treatment
planning in prostate cancer. Interobserver identifica-
tion of the prostatic apex varied in 70% of cases. This
variability resulted in an inadequate margin (\1 cm)
beneath the urogenital diaphragm in 5% of patients. In
contrast, placing the inferior border of the portal at the
ischial tuberosities or the base of the penis, as seen on
CT scans, ensured an adequate margin for all patients.
They concluded that urethrography is more accurate
than CT scanning in determining the inferior extent of
the urogenital diaphragm.
Wilson et al. (1994) determined the anatomic
location of the apex of the prostate in 153 patients
undergoing 128-I implants by direct surgical exposure
(133 patients) or transrectal ultrasound (TRUS;
20 patients). There was excellent agreement in the
estimate of location of the prostatic apex between the
two methods. In patients suitable for brachytherapy, it
963
was located 1.5 cm or more above the ischial tuber-
osities in approximately 95% and within 1 cm in 98%
(150 of 153).
Algan et al. (1995) reviewed the location of the
prostatic apex in 17 patients in whom an MRI scan
was obtained in addition to retrograde urethrogram
and CT scan of the pelvis for 3D treatment planning.
The location of the prostatic apex as determined by
the urethrogram alone was, on average, 5.8 mm
caudad to the location on the MRI, whereas the
location of the prostatic apex as determined by CT/
urethrogram was 3.1 mm caudad to that on MRI. If
the prostatic apex is defined as 12 mm instead of
10 mm above the urethrogram tip (junction of mem-
branous and prostatic urethra), the difference between
the urethrogram and MRI locations of the prostatic
apex is no longer present.
Crook et al. (1995a), in 55 patients with localized
carcinoma of the prostate, placed one gold seed under
TRUS at the base of the prostate near the seminal
vesicles, at the posterior aspect, and the apex of the
prostate. At the time of first simulation a urethrogram
was performed, and the rectum was opacified with
10–15 cc of barium. The tip of the urethrogram cone
varied in position from 0 to 2.8 cm above the most
inferior aspect of the ischial tuberosities. At initial
simulation the apex of the prostate was \2 cm above
the ischial tuberosities in 42% of patients, \1.5 cm in
19%, and \1 cm in 8% of patients. Because of vari-
ability in the thickness of the urogenital diaphragm,
only 12 of 22 (55%) of these low-lying prostates
would have been detected by urethrogram.
4.3.2 Beam Energy and Dose Distribution
Ideally, high-energy photon beams (C10 MV) should
be used when applying conventional techniques,
which simplifies beam setup and decreases morbidity.
With photon-beam energies below 18 MV, lateral
portals are always necessary to deliver part of the
dose in addition to the AP–PA portals (box tech-
nique). An advantage of using the box technique is a
decrease in erythema and skin desquamation in the
intergluteal fold, which occurs more frequently with
exclusively AP–PA portals. The additional prostate
dose is administered with anatomically shaped lateral
and oblique or rotational portals.
For the reduced volume, a reasonable dose distri-
bution is obtained with bilateral 120° arc rotation,
skipping the midline anteriorly and posteriorly (60°
964
vectors). However, this technique irradiates signifi-
cantly more volume of bladder and rectum than
contemporary 3D CRT or IMRT.
4.3.3 Standard Tumor Doses
(Non-Conformal Treatment Planning)
A frequently used minimum tumor dose to the pros-
tate is 66–70 Gy for stage T1a, 70–72 Gy for T1b,
c-T2b tumors, and approximately 74 Gy T3. For stage
T4 or node-positive lesions, treatment is usually pal-
liative, and the minimum tumor dose can be held at
60–65 Gy to decrease morbidity. Most institutions
treat with daily fractions of 1.8–2 Gy, five fractions
per week. At least two portals should be treated daily
to improve tolerance to irradiation.
The usual dose for the pelvic lymph nodes (when
the latter are to be irradiated) is 45-50 Gy, with a
boost (24–26 Gy) to the prostate or enlarged lymph
nodes through reduced fields (Perez 1998).
4.4 Conformal Radiation Therapy
Simulation and Treatment Planning
4.4.1 Patient Immobilization
and Positioning
Patient immobilization devices are more frequently
used in 3D CRT or IMRT compared with traditional
treatment planning. Some investigators have reported
improved treatment setup accuracy with these devi-
ces, whereas others have reported no significant
advantage with their use (Nutting et al. 2000;
Rosenthal et al. 1993). In a randomized study,
Kneebone demonstrated that the average simulation-
to-treatment deviation of the isocenter position was
8.5 mm in a control group and 6.2 mm in an immo-
bilized group (p \ 0.001). The use of immobilization
devices reduced isocenter deviations exceeding
10 mm from 30.9 to 10.6% in the immobilized arm
(p \ 0.001). The average deviations in the antero-
posterior, right–left, and superior–inferior directions
were reduced to 2.9, 2.1, and 3.9 mm for the immo-
bilized group, respectively (Kneebone et al. 2003). It
is recommended that each radiation therapy center
study and review the treatment setup variations and
choose the immobilization device that gives the best
reproducibility.
There is significant debate regarding the appro-
priate positioning for patients treated with localized
J. M. Michalski and T. Wiegel
carcinoma prostate. Some groups advocate a prone
position which they claim minimizes prostate posi-
tional uncertainty. Furthermore, in the prone position
the seminal vesicles fall forward and increase the
separation from the rectum, decreasing the volume of
rectum irradiated with conformal radiation therapy
when the seminal vesicles are irradiated (Zelefsky
et al. 1997a). More recent data suggest that a prone
position is associated with greater prostate motion
accompanying normal ventilation. The increased
intra-abdominal pressure associated with breathing in
a prone position results in significant movement of the
prostate and seminal vesicles. Dawson et al. (2000)
evaluated the impact of breathing on the position of
the prostate gland in 4 patients in whom radiopaque
markers were implanted in the periphery of the
prostate using transrectal ultrasound guidance. Fluo-
roscopy was performed in four different positions:
prone in foam cast cradle; prone in thermoplastic
mold; supine on a flat table; and supine with a false
table under the buttocks. During normal breathing
maximum movement of prostate markers seen in the
prone position (cranial–caudal) ranged from 0.9 to
5.1 mm and anterior–posterior ranged up to 3.5 mm.
In the supine position prostate movements during
normal breathing was \1 mm in all directions.
Moreover, deep breathing resulted in movements of
3.8–10.5 mm in the cranial–caudal direction in the
prone position (with and without thermoplastic mold).
This range was reduced to 2.7 mm in the supine
position and to 0.5–2.1 mm with the use of the false
tabletop. Deep breathing resulted in anterior–posterior
skeletal movements of 2.7–13.1 mm in the prone
position, whereas in the supine position these varia-
tions were negligible.
Malone et al. (2000) also characterized inaccura-
cies in prostatic gland location due to respiration
observed fluoroscopically in 28 patients in whom
three gold fiducial markers were implanted under
ultrasound guidance at the apex, posterior wall, and
base of prostate. Patients were immobilized on a
customized thermoplastic shell placed on a rigid
pelvic board. A second group of 20 patients was
evaluated both prone (with or without thermoplastic
shell) and supine (without immobilization shell).
When the patients were immobilized prone in the
thermoplastic shell, the prostate moved synchro-
nously with respiration a mean distance of
3.3 ± 1.8 mm (range 1–10 mm). In 9 out of 40
Prostate
observations (23%) the displacements were 4 mm or
greater. The respiratory-associated prostate move-
ment decreased significantly when the thermoplastic
shells were removed. A study using real-time prostate
tracking with radiofrequency transponders found
prostate displacement [2 mm during 38% of treat-
ment delivery time (Bittner et al. 2010). In a another
study using cine-MRI imaging in 7 prostate cancer
patients, Vargas (2010) reported the variation/stan-
dard deviation of the prostate position during 4 min of
observation : supine: 1.2 mm, and prone: 2.15 mm
(P \ 0.001) (Vargas et al. 2010). Other investigators
have confirmed this finding of prostate movement
with respiration being significantly less in patients
placed in a supine position (Malone et al. 2000;
Dawson et al. 2000; Kitamura et al. 2002; Litzenberg
et al. 2002; McLaughlin et al. 1999; Weber et al.
2000). Bayley et al. (2004) conducted a randomized
trial of the supine versus prone position in patients
undergoing conformal radiation therapy. Twenty-
eight patients were randomized to commence radia-
tion therapy in the prone or supine position and then
change to the alternate position midway through their
treatment course. After placement of fiducial markers
in the prostate for daily prostate localization, the
patients underwent CT simulation and treatment
planning in both positions. Observed prostate motion
was significantly less in the supine position than the
prone position. Pretreatment positioning corrections
were required more often for patients in the prone
position. A DVH (dose-volume histogram) analysis
revealed more bladder wall, rectal wall, and small
bowel in the high-dose volumes when patients were in
the prone position than in the supine position. Finally,
patients were more comfortable in the supine position
than the prone position. Seven patients that started in
the supine position refused to be treated in the prone
position due to discomfort.
4.4.2 Clinical Target Volume Definition
Because prostate cancer is often found to be multi-
focal at the time of radical prostatectomy, the entire
gland is commonly considered the gross tumor vol-
ume for radiation treatment-planning purposes. The
clinical target volume (CTV) may expand around the
gross tumor volume to account for direct extension or
the CTV can be extended to encompass adjacent
organs or regions of spread. In prostate cancer, the
965
CTV may encompass the seminal vesicles and pos-
sibly the regional pelvic lymph nodes.
Additional CTV margin for possible extraprostatic
extension (EPE) has been recommended by several
authors. In a study of radical prostatectomy speci-
mens, Davis et al. (1999) demonstrated that EPE was
present in 28% of 376 patients. The average radial
EPE distance from the prostate capsule was 0.8 mm
with a range of 0.04–4.4 mm. Sohayda et al. (2000)
reported EPE in 35% of 265 cases. When EPE was
present, it extended posterolateral in 53%, lateral in
24%, and posterior in 13%. The 90th percentile of EPE
distance was 3.3 mm for patients with clinical T1–T2,
pretreatment PSA of B10 ng/ml, and biopsy Gleason
score of 6 or less. For patients with more unfavorable
tumors, the 90th percentile of EPE extended to
3.9 mm. Both these series did not correct for possible
specimen shrinkage related to formalin fixation. In
another series of 712 prostatectomy specimens, Teh
et al. (2003) reported that the mean radial distance
from the capsule was 2.93 mm (accounting for for-
malin fixation). In a series of 371 prostatectomies,
Chao et al. (2006) described 121 cases that had EPE.
EPE occurred predominantly posterolaterally along
the neurovascular bundle. In patients with EPE, the
mean distance was 2.4 mm from the capsule and the
90th percentile distance was 5.0 mm. EPE distance
was related to both PSA and Gleason score. In patients
with high-risk factors such as PSA more than 10 or
Gleason score more than 6, posterolateral extension of
the CTV outside the prostate capsule is required to
ensure coverage of microscopic disease. The decision
to add additional CTV margin may be a function of
both the total dose prescription and the degree of
conformality expected to be achieved. With 3D CRT
and escalated radiation doses, the tissues immediately
adjacent to the prostate receive a dose of radiation that
would be expected to control microscopic disease. On
the other hand, with highly conformal radiation plans
with IMRT, proton therapy, or brachytherapy and
small uncertainty margins for the PTV, marginal
misses may be anticipated unless an adequate CTV
margin is added to account for microscopic EPE.
In patients with significant risk factors it is nec-
essary to include the seminal vesicles in the CTV,
which in most patients are well demonstrated on the
cross-section CT or MR scans of the pelvis, superior,
lateral, and posterior to the base of the prostate. The
966
nomograms developed by Partin et al. (1993),
Pisansky et al. (1996b), Kattan et al. (Bjerggaard
Jensen et al. 2009) and Roach et al. (1997) may be
used to determine the probability of seminal vesicle or
pelvic lymph node involvement using clinical stage,
pretreatment PSA, and Gleason score. Kestin et al.
(2002) published an analysis of 344 radical prosta-
tectomy specimens in which they measured the length
of seminal vesicles, length of involvement by carci-
noma, and percentage of seminal vesicle involved.
They found an excellent correlation between the
various prognostic parameters and the probability of
seminal vesicle involvement. Also, in 81 patients
with seminal vesicle involvement, the median length
of tumor presence was 1 cm. In the entire series, only
7% of patients had seminal vesicle involvement
beyond 1 cm. They concluded that in selected
patients seminal vesicles need to be treated and only
up to 2.5 cm (approximately 60% of the seminal
vesicle) should be included within the CTV, unless
there is radiographic evidence of involvement.
When there is clinical evidence of extraprostatic
extension on physical examination or imaging
modalities, such as MRI (clinical stage T3), the
seminal vesicles should be included for the total
radiation dose prescription. In cases where the disease
is clinically confined to the gland (clinical stages
T1–T2) and the risk of seminal vesicle invasion
exceeds 15%, we define two clinical target volumes;
the first encompasses the prostate and the seminal
vesicles, and with the second, the boost target volume
is the prostate alone. In these cases a radiation dose
that controls subclinical disease is prescribed to the
first target volume and a higher dose is intended for
the prostate itself. Alternatively, the proximal 1 cm of
seminal vesicle tissue may be included for patients
with clinical stages T1–T2 disease with a risk of
seminal vesicle invasion as this strategy will encom-
pass more than 90% of disease in most patients. As
the number or severity of risk factors increases, more
seminal vesicle tissue may be included in the CTV.
This single CTV strategy is useful for IMRT as it
eliminates a requirement for two separate plans for
different dose levels or the need for two fractionation
schedules to subclincal and clinical disease.
As described in the section on conventional radi-
ation therapy treatment planning, identification of the
prostatic apex can be facilitated with a retrograde
urethrogram, which can be performed using 25%
J. M. Michalski and T. Wiegel
iodinated contrast material. The prostatic apex is
3–13 mm above the most proximal aspect of the
urogenital diaphragm as defined by the urethrogram
(Rasch et al. 1999; Wilder et al. 1997). Care should be
taken not to overinflate the urethra with iodinated
contrast, as this may distend or move the prostate
from its relaxed position.
Some authors feel that MRI may be more accurate
in delineating the prostate and seminal vesicles
(Perrotti et al. 1996). Several publications have shown
some discrepancy (0.5–1 cm) in defining the location
of the apex of the prostate using CT scanning or MRI
(Kagawa et al. 1997; Roach et al. 1996; Milosevic
et al. 1998; Parker et al. 2003) studied co-registration
of CT and MR images in the radiation treatment
planning of 6 patients with localized prostate cancer
to assist with GTV delineation and identification of
prostate position during radiation therapy. The overall
magnitude of contoured GTV was similar for MR and
CT; however, there were spatial discrepancies in
contouring between the two modalities. The greatest
systematic discrepancy was at the posterior apical
prostate border, which was 3.6 mm more posterior on
MR- than CT-defined contouring. In a series of
294 patients that underwent both MR and CT imaging
for radiation treatment planning, Hentschel et al.
(2011) reported that CT scans overestimate the pros-
tate volume by nearly 35% and the regions of most
frequent disagreement were at the superior and infe-
rior portions of the prostate gland. The MRI also
allowed more precise identification of seminal vesicle
invasion.
The regional lymphatics may be considered a CTV
in high-risk situations. Several observational case
series suggested that elective nodal irradiation (ENI)
contributed a therapeutic benefit for certain patient
subsets (McGowan 1981; Perez et al. 1996; Ploy-
songsang et al. 1986). The RTOG conducted a pro-
spective, randomized trial that evaluated ENI in the
pre-PSA era and no improvement in outcome was
observed (Asbell et al. 1988). Results of a more
contemporary trial, RTOG 94-13, show a higher
biochemical disease-free survival rate in patients with
a risk of lymph node involvement greater than 15%,
provided that hormonal therapy was given neoadju-
vantly (Roach et al. 2003; Lawton et al. 2007). There
was no improvement in clinical disease-free survival
or overall survival in that trial. At present, some feel it
is appropriate to use nomograms that estimate the risk
Prostate
of pelvic nodal involvement (Kattan et al. 1997;
Partin et al. 2001; Roach et al. 1994a) and consider
ENI when the risk of LNI reaches or exceeds 15%
(Roach et al. 2003). The majority of clinical trials that
have demonstrated the value of the use of combined
hormone therapy and definitive radiation therapy used
fields that encompassed the pelvic lymph nodes in
many of the participating patients (Pilepich et al. 2005;
Bolla et al. 2002; Roach et al. 2008; Horwitz et al.
2008; Bolla et al. 2009). Whether or not to irradiate
pelvic lymph nodes remains a controversial issue.
The goal of ENI of the pelvis is to include the
obturator, internal and external iliac lymph nodes.
Defining appropriate lymph node CTVs for conformal
ENI varies considerably amongst radiation oncolo-
gists (Lawton et al. 2009a). The RTOG developed a
consensus atlas for the CTV for pelvic lymph nodes
(Lawton et al. 2009b). The nodal groups to be
included extend from the L5-S1 interspace (i.e., low
common iliac lymph nodes) to the top of the pubic
symphysis (obturator lymph node region). Presacral
lymph nodes (subaortic only, S1–S3) are also inclu-
ded. These volumes correlate well with the nodal
volumes typically treated with the 4-field ‘‘box’’
technique used in all the randomized trials previously
mentioned (Lawton et al. 2009b). A dose of 45–50 Gy
is recommended and is often administered in
1.8–2.0 Gy once-daily fractions (NCCN 2010).
At Washington University we treat the entire
prostate as our CTV for patients with low-risk dis-
ease. For patients with intermediate-risk disease we
treat the prostate and seminal vesicles to 55.8 Gy,
followed by a boost to the prostate alone (with
appropriate PTV margin, vide infra). When using
IMRT we utilize a single CTV for intermediate-risk
patients to avoid the need for two IMRT plans. In this
case we treat the prostate and the first 1–2 cm of
seminal vesicle tissue in our CTV (Fig. 5). For
patients with stage-T3 disease, we treat the prostate
along with the entire seminal vesicles to the total
prescription dose. Patients with high-risk disease or a
predicted risk of lymph node metastases that exceeds
15% receive ENI prior to boosting the high risk CTV.
4.4.3 Planning Target Volume Definition
The magnitude of the PTV margin is dependent upon
several treatment-related factors. A technologist’s
ability to precisely reproduce a patient’s position on a
daily basis is one contributing factor. Some patients
967
may move while on the treatment table because of
fatigue or discomfort. Internal organs, including the
prostate gland, can shift because of variable filling of
the bladder and rectum. The shifts can be anisotropic
with most movement occurring in the anterior and
posterior directions (Langen and Jones 2001). Studies
investigated both internal organ motions and setup
errors to determine an appropriate margin for the
planning target volume. In order to assure that an
adequate radiation dose is encompassing all areas at
risk of harboring disease, the radiation oncologist
needs to include an appropriate PTV margin.
Increasing the size of the PTV margin increases the
probability of encompassing the CTV by the pre-
scribed isodose for a complete course of radiation
therapy. There is, however, a tradeoff between
assuring nearly 100% coverage during each treatment
and the volume of adjacent organs irradiated
unnecessarily.
In a study of 11 patients with repeated CT scans
during a course of radiation therapy for prostate
cancer, van Herk et al. (1995) showed that the largest
deviation in prostate position was 2.7 mm in the
anterior–posterior direction with a rotation about the
left–right axis of 4 degrees. They found that the apex
of the prostate does not move, and the majority of any
motion is rotation around the apex.
Zelefsky et al. (1999) evaluated prostate and
seminal vesicle motion in 50 patients treated in the
prone position using CT scans for initial treatment
planning and three scans obtained throughout the
course of radiation therapy. Before the initial CT
scans, patients had an enema and were given 250 ml
of bowel contrast by mouth. Patients had an empty
bladder and 10 cc of air was inserted into the rectum
via a rectal catheter. Prior to all CT scans, patients
voided, and no additional procedures were performed.
Relative to the initial planning CT, mean displace-
ments of the prostate were -1.2 ± 2.9 mm in the AP,
-0.5 ± 3.3 mm in the superior/inferior, and
–0.6 ± 0.8 mm in the lateral direction. The seminal
vesicle displacements were -1.4 ± 4.9 mm, 1.3 ±
5.5 mm, and -0.8 ± 3.1 mm in the AP, superior–
inferior (SI), and lateral directions, respectively.
(Negative values indicated displacements to the pos-
terior, inferior, and left directions.) A combination of
rectal volume [60 cc or a bladder volume [40 cc
was found to be predictive for systematic deviations
of the prostate and seminal vesicles of more than
968
Fig. 5 Target volumes and organs at risk are defined on serial
images of a treatment-planning CT scan. For illustration
purposes only every fourth CT image is displayed. The bladder
(yellow) and rectum (orange) are contoured as solid organs.
The prostate (red) is contoured from its base superiorly to the
3 mm. Based on the data and the prescription of
irradiation dose to achieve at least 93% coverage of
the CTV, Zelefsky et al. (1999) calculated the mar-
gins to be added to the CTV for defining the PTV.
Based on these reports, it is apparent that beyond the
CTV, additional margins of 5–8 mm are necessary to
provide adequate coverage of the prostate and
J. M. Michalski and T. Wiegel
apex at the genitourinary diaphragm. In this patient the first
1 cm of seminal vesicle tissue (violet) is included with the CTV
and no attempt is made to treat them above this level. The PTV
(cyan) margin is 7 mm from the prostate border. In this
example the fiducial markers are seen inside the prostate gland
6–11 mm for adequate coverage of the seminal vesi-
cles when there is no organ distension that would
result in a systematic error. It should be noted that the
required margins vary based on setup procedures and
experience and should therefore, ideally, be calcu-
lated individually by each radiation therapy depart-
ment for each technique that is used.
Prostate 969

Fig. 6 A pair of (a) left and

(b) right anterior oblique
digitally reconstructed
radiographs (DRR) with
corresponding electronic
portal images demonstrating
positions of intraprostatic
fiducial markers for daily
setup localization. White
arrows indicate the seed
positions which have been
previously defined on the
treatment-planning CT,
making their positions visible
on the DRR. If necessary,
offsets of the isocenter are
calculated and the patient
table position is shifted to
bring the epicenter of the
markers in alignment with the
beam isocenter

Strategies to reduce the uncertainty in daily treat-
ment delivery, and therefore to reduce the magnitude
of the PTV margin, have been successfully intro-
duced. Each of these methods employs daily imaging
of the prostate with the patient in the treatment
position on the linear accelerator treatment table.
Some institutions have employed radiopaque
implanted fiducial markers that are subsequently
imaged with electronic portal imaging devices. Crook
et al. (1995a) evaluated prostate motion in 55 patients
in whom gold seeds were implanted at the base of the
gland. Initial simulation was obtained in a supine
position with a full bladder and was repeated after
patients received 40 Gy. Prostate motion was
observed in the posterior direction (5.6 ± 4.1 mm)
and in the inferior direction (5.9 ± 4.5 mm). In 30%
of patients the base of the prostate was displaced
posteriorly and in 11% in the inferior direction by
[10 mm. Vigneault et al. (1997) investigated inter-
and intra-fraction daily motion of the prostatic apex
relative to pelvic bony structures in 11 patients using
radiopaque markers implanted under ultrasound
guidance near the prostatic apex. After the completion
of treatment, a transrectal ultrasound—performed in 8
of 11 patients—verified that the position of the radi-
opaque markers had not shifted. Marker displace-
ments up to 1.6 cm were measured between two
consecutive days of treatment on portal images. The
marker displacement relative to the center of the
irradiation field was sensitive to both setup variations
and internal prostate motion. The authors created
treatment films (six consecutive electronic portal
970
images during the same treatment fraction) and
observed no visible intratreatment displacement of the
markers. The position of the fiducial markers visual-
ized on daily port films or electronic portal images
can be used to align the isocenter on a daily basis to
assure precise and accurate treatment of the PTV.
Paired images need to be acquired in order to calcu-
late the 3D position of the center of three fiducial
markers. We have begun to employ anterior oblique
portal images for daily target localization because the
density of the hips makes viewing the markers on
lateral radiographs difficult (Fig. 6).
Transabdominal ultrasound has been used to
localize the prostate for treatment planning and during
daily radiation therapy delivery with an accuracy
parallel to that of CT scanning of the pelvis. Lattanzi
et al. (2000, 1999) studied 23 patients with CT sim-
ulations in whom prostate-only fields based on CT
scans were created with no PTV margin. Ten of the
patients also had prostate localization with a trans-
abdominal ultrasound system. The absolute mean
magnitude difference between CT and ultrasound was
AP 3.0 ± 1.8 mm, lateral 2.4 ± 1.8 mm, superior/
inferior 4.6 ± 2.8 mm. The authors felt that transab-
dominal ultrasound was simple and expeditious, and
improved the ability to localize the position of the
prostate with the patient at the treatment machine for
daily irradiation.
Several groups have compared ultrasound to other
methods of prostate localization such as cone beam
CT (CBCT), megavoltage CT, and fiducial markers
with port films (Chandra et al. 2003; Scarbrough et al.
2006). While transabdominal ultrasound systems offer
the appeal of being noninvasive, fiducial-based sys-
tems appear to offer an advantage over ultrasound
with respect to the ease of use and the magnitude of
residual error (Scarbrough et al. 2006). Like con-
ventional CT scans, both megavoltage tomographic
CT (e.g. Tomotherapy) and CBCT offer cross-
sectional views of internal anatomy and registration
of daily targets to the original simulation CT. Image
quality for both these volumetric imaging systems is
inferior to simulation CT scans due to the physics of
radiation interactions in the MV range, a limited field
of view and/or organ motion during image acquisition
(Sykes et al. 2005; Smitsmans et al. 2005). Despite
these deficiencies the images are of sufficient quality
to allow daily anatomy-based target localization
(Moseley et al. 2007). The concurrent use of
J. M. Michalski and T. Wiegel
implanted fiducial markers along with MV CT pro-
vides a more objective and reproducible determina-
tion of target localization (Langen et al. 2005).
Recently, electromagnetic radiofrequency transpond-
ers have been introduced that allow real-time tracking
of target position. Compared to other imaging tech-
niques, the implanted transponders have a high tem-
poral resolution, which can be used to monitor
prostate position continuously during treatment
delivery. A study conducted at five centers positioned
41 patients over a full course of therapy (Alcantara
et al. 2007). The study found that the patterns of
motion of the prostate were unpredictable and varied
from persistent drift to transient rapid movements.
Displacements[3 and 5 mm for cumulative durations
of at least 30 sec were observed during 41 and 15% of
treatment sessions. Figure 7 demonstrates the indi-
vidual variation seen with real-time prostate locali-
zation recorded with implanted transponders. With
real-time monitoring and intrafraction position cor-
rection, these displacements can be corrected during
treatment. Li et al. (2009) reported that the population
of patients that may benefit from real-time tracking is
small if an action threshold for positional corrections
was 5 mm or greater. On the other hand, if a cor-
rection threshold of 3 mm was used, 29% of treatment
fractions would have necessitated repositioning. Very
recently, localization and real-time tracking of the
prostate using a radioactive marker was reported. A
gantry-mounted tracking system (RealEye, Navotek
Medical Ltd., Israel) tracks in real-time the location
of an implantable low-activity iridium-192 source
(Tracer, Navotek Medical Ltd) for the purpose of
patient positioning guidance as well as target-position
monitoring during treatment. In Tilburg and Leuven,
a total of 20 patients with prostate cancer were all
successfully implanted with the Tracer alongside
standard gold seeds. During delivery of radiation
therapy, positioning verification was done with the
standard online verification procedure based on the
implanted gold seeds, using MV and/or kV images.
At 5 of the 35 treatment sessions, a cone beam CT
was made before and after delivery of radiotherapy,
and measurements made by the RealEye system were
recorded before and after each CBCT. The absolute
location of the Tracer as measured from the cone
beam CT images and by the RealEye system were
compared pairwise. The mean change in intermarker
distances involving the gold seeds alone was 1.4 mm
Prostate
Fig. 7 Examples of behaviors observed in the continuous
tracking data: a continuous target drift; b transient excursion;
c stable target at baseline; d persistent excursion; e high-
and between the Tracer and the gold seeds 1.2 mm.
The mean 3D vector length difference between cone
beam CT and RealEye localization was 1.3 mm. The
mean 3D vector length between the RealEye mea-
surement before and after cone beam CT, which is a
measure of prostate movement during the measure-
ments, was 1.1 mm. This first clinical study con-
firmed that implantation of the Tracer in the prostate
is feasible and that the stability of the tracer is at least
as good as the stability of the gold markers. The
RealEye tracking system was also shown to be able to
continuously and in real-time localize the implanted
radioactive fiducial marker with sufficient accuracy
for use in patient positioning and target position
monitoring during external beam radiation therapy of
the prostate.
971
frequency excursions; f erratic behavior. Red vertical, green
longitudinal, blue lateral, black vector length (from Kupelian
et al. 2007)
Yan et al. (2000) have developed a strategy of
adaptive radiation therapy. Patients undergo daily CT
imaging during the first week of radiation therapy.
A patient-specific PTV is then calculated and the
patients are reassessed. A patient-specific margin
allows reduction of the PTV, which is otherwise
calculated based on population averages. (Vargas
et al. 2005a) This strategy means that some patients
will be treated to larger PTVs if their CTV error is
larger than average. Those patients may require other
strategies to account for organ motion if dose esca-
lation is necessary.
De Crevoisier et al. (2005) reported that a large
rectal volume (average cross-sectional area more than
11.2 cm2) defined at the time of treatment planning
was associated with a decrease in biochemical tumor
972
control. It has been suggested that a distended rectum
at the simulation results in a systematic anterior dis-
placement of the posterior prostate. Subsequent days
of treatment with a less-distended or empty rectum
results in a geographical miss, unless the PTV is
enlarged posteriorly to accommodate the expected
prostate location. Two other studies have shown an
increase rate of biochemical failures in men simulated
with a distended rectum (Engels et al. 2009;
Heemsbergen et al. 2007). In an analysis of patients
enrolled on a Dutch randomized dose escalation trial,
Heemsbergen et al. (2007) reported a higher rate of
biochemical failure in men that had both a rectum
volume exceeding 90 cm3 and frequent diarrhea. This
implied that a patient’s rectum pushed the prostate
forward at the time of simulation but during treatment
the rectum was frequently empty allowing the gland
to shift posteriorly and partially outside the radiation
volume. In a retrospective analysis of 238 patients at
the University Hospital in Brussels, Engels (Engels
et al. 2009) reported that an average cross sectional
area of the rectum exceeding 16 cm2 was associated
with a higher biochemical failure rate. An enema
prior to the simulation, along with a rubber catheter or
hollow tube to deflate flatus in the rectum at the
treatment-planning CT, helps avoid the introduction
of systematic errors in organ and target definition due
to rectal distension (Tinger et al. 1998). The resulting
movement of the prostate to its most posterior
position also allows the use of a tighter uncertainty
margin posteriorly, as it eliminates the random error
associated with a variably filled rectum.
Several authors have reported the use of an endo-
rectal balloon during each daily treatment to stabilize
the position of the gland. The balloon also moves the
prostate anteriorly, allowing more complete shielding
of the posterior rectal wall. Unlike a rectum distended
by stool and flatus, the endorectal balloon is a con-
trolled intervention that can be reproduced during the
course of radiation therapy. Air in the balloon
decreases the rectal surface dose by decreasing the
electronic build-up and equilibrium at the air–soft
tissue interface. Teh et al. (2002) and associates
reported results of 100 consecutive patients treated
with IMRT and an endorectal rectal balloon. Ten of
those patients also participated in a prostate motion
study following gold-seed implantation. Each of these
ten patients underwent 10 CT scans during the course
of their radiation therapy. The mean and standard
J. M. Michalski and T. Wiegel
deviation of superior–inferior (SI) target displace-
ments were 0.92 and 1.78 mm, respectively. Of the
100 patients treated with a rectal balloon, 80% had no
rectal complaints and 11 and 6% had grade-1 or
grade-2 acute toxicity, respectively. They measured
the radiation dose at a balloon–tissue interface using a
phantom. The dose at the air–tissue interface is
approximately 15% lower than the dose at the same
point without an air cavity. The dose builds up rapidly
so that at 1 and 2 mm away from the interface, the
dose is only approximately 8 and 5% lower, respec-
tively. Wachter et al. (2002) demonstrated in
10 patients that the dose to the posterior wall of the
rectum could be significantly reduced with the use of
an endorectal balloon when the prostate only was
boosted. Similarly, Smeenk et al. (2009) compared
plans with and without an endorectal balloon. The use
of a balloon was associated with a significant sparing
of the anal wall with either 3DCRT or IMRT. The
advantage of the balloon was lost when the seminal
vesicles were treated. Patel et al. (2003) demonstrated
significant dosimetric sparing of the rectum with 3D
CRT or IMRT when a rectal balloon was used during
an entire course of radiation therapy in five patients.
Patients tolerated daily insertion of the balloon
exceptionally well. Whether a long-term clinical
benefit accompanies the use of an endorectal balloon
deserves further investigation (Smeenk et al. 2010).
4.4.4 Organs-at-Risk Definition
Organs at risk need to be defined for the treatment-
planning process. In the treatment of prostate cancer,
the organs at risk include the bladder, rectum, femoral
heads, penile bulb, and occasionally the small bowel.
There can be considerable variation in the definition
of these organs from physician to physician. When
comparing dosimetric constraints and clinical out-
comes from various series, a consistent definition of
these structures is important. The Radiation Therapy
Oncology Group (RTOG) has described their method
for normal organ definition (Michalski et al. 2000).
The femoral heads are contoured from the level of the
ischial tuberosities to their proximal joint at the pel-
vis. The rectum and bladder are both defined as solid
organs. Inferiorly, the rectum is defined from the level
of the ischial tuberosities. It extends superiorly until
the colon moves anteriorly toward the sigmoid. The
bladder is contoured inferiorly from the prostate base
to the dome.
Prostate
The rectum can be considered a ‘‘hollow’’ organ
and has variable daily filling throughout a course of
radiation therapy. Radiation dose to the contents of
this hollow structure plays no role whatsoever in the
risk of injury to the rectum. However, while it makes
intuitive sense to exclude the contents from treatment
planning, the execution of this in treatment planning
is difficult. Some treatment planning systems are
unable to subtract the contents of the organ from a
dose volume histogram (DVH). Furthermore, it may
be very difficult to define both the inner and outer
walls of the rectum. Earlier clinical trials define the
rectum as a solid organ (Michalski et al. 2000; Storey
et al. 2000), but this assumption is unrealistic, also as
thickness of the bowel wall likely varies as a function
of its distention (Meijer et al. 1999). Some have
proposed dose surface histograms as an alternative to
a dose volume histogram (Fenwick et al. 2001; Li
et al. 1997; MacKay et al. 1997).
In reality the shape of the rectal wall DVH or a
dose surface histogram often tracks the shape of the
DVH of solid organs. This should not be surprising
given that the wall and solid bowel contours are
integrally linked to each other. Tucker et al. reported
that the rectal wall DVH provides a better fit to NTCP
models than DVH data derived from solid organs
(Tucker et al. 2004). Koper et al. also reported rectal
bleeding to be more strongly associated with rectal
wall DVHs than DVHs of solid organs (Koper et al.
2004). Vargas also reported that rectal wall dosimetry
was more closely correlated with chronic rectal tox-
icity (Vargas et al. 2005b). However, in a multi-
variable analysis both dose to the rectal wall and dose
to the rectum as a solid organ were predictive of
chronic toxicity. Dale et al. reported a better corre-
lation of chronic rectal toxicity to a solid organ DVH.
Unlike the other reports, their toxicity criteria inclu-
ded other rectal symptoms such as diarrhea, cramps,
mucus discharge, and pain (Dale et al. 1999).
The length of rectum defined has varied among
multi-center clinical trials and single institutional
series. Even within series of patients the length of the
rectum can vary by several centimeters between
patients. In the M. D. Anderson randomized clinical
trial, Storey reported that the rectum was defined as
the rectal volume within the 11 cm superior to the
lower border of the initial anteroposterior field,7
which was typically placed at the inferior aspect of
the ischial tuberosities (Storey et al. 2000). The
973
RTOG 9406 dose escalation trial has used a definition
of rectum to include the anus at the inferior border of
the ischial tuberosities to 15 cm superiorly or until the
rectosigmoid flexure was met (Michalski et al. 2000).
In the Dutch randomized clinical trial the anorectum
was defined from the level of the ischial tuberosities to
the inferior border of the sacroiliac joints, or when the
rectum was no longer adjacent to the sacrum (Peeters
et al. 2006a). Vargas defined the length of the rectum
inferiorly at the level of the anal verge or ischial tub-
erosities (whichever was higher) to the sacroiliac joint
or rectosigmoid junction (whichever was lower)
(Vargas et al. 2005b). In the series where the rectum
was defined according to anatomical landmarks (anus,
ischial tuberosities, rectosigmoid flexure, or sacroiliac
joints) there is good correlation between the relative
rectal or rectal wall DVH parameters and chronic
toxicity. Kupelian et al. defined the rectum relative to
the length of the planning target volume. The rectum
was contoured from 1 cm above to 1 cm below the
target. In their analyses, while they were able to show a
correlation of absolute volume of rectum irradiated to
the incidence of chronic toxicity, there was no corre-
lation for the relative volume of rectum irradiated
(Kupelian et al. 2002).
More so than the rectum, the bladder is a highly
distensible organ. The volume of the bladder changes
continuously and even post-void residual volumes can
be variable. Internal organ motion from respiration or
changes in bowel filling may shift the bladder position.
As a consequence of the distensibility and inherent
mobility, studies with bladder DVH results based on a
single static CT image cannot report truly representa-
tive values of bladder dose during a course of frac-
tionated radiation. Some reports delineate the outer
versus the inner bladder wall, though given the high
degree of variation in bladder filling in a short time
interval, this distinction is likely not clinically relevant.
In a study of prostate cancer, 11 patients treated
with conformal radiotherapy received 4 CT scans
each over the course of treatment (planning, week 2,
week 4, week 6). All were instructed to fill their
bladders prior to scanning. No time trends were seen
in bladder wall volume but the bladder volume
including the contents, decreased over time (*4%/
wk). They concluded that the initial scan DVHs can
only be representative for the whole treatment if the
bladder filling can be kept reasonably constant during
treatment (Lebesque et al. 1995).
974
Fig. 8 Beam’s eye view displays on left anterior oblique and
right posterior oblique (lower panels) digitally reconstructed
radiographs. Graphic representations of multileaf collimator
leaves demonstrate beam shaping relative to the contour of the
PTV (solid light blue) and shielding of the rectum (brown wire
Unfortunately, the calculation of bladder or rectal
wall volumes is not a trivial task and requires the
added work of contouring both the inner and outer
walls or additional software that is not available on
some computer planning systems. As a result, most
institutions and cooperative groups report dosimetry
data to the whole organ volume. In the Quantec
project, contouring of the bladder and rectum as solid
organs was recommended as it is one of the more
common methods used in the published literature
(Michalski et al. 2010; Viswanathan et al. 2010).
Radiation to the penile bulb tissue of the corpora
spongiosa inferior to the prostatic apex and urogenital
diaphragm appears to play a role in the development of
J. M. Michalski and T. Wiegel
cage) and bladder (yellow wire cage). The upper left panel
displays a six-field 3D conformal beam arrangement viewed
along the superior–inferior axis. The upper right panel shows
the 7380-cGy isodose line covering the PTV and prostate in the
isocenter axial plane
radiation induced erectile dysfunction (Fisch et al. 2001;
Roach et al. 2004; Wernicke et al. 2004). Magnetic
resonance imaging allows more accurate definition of
the prostate apex, urogenital diaphragm, and penile bulb
(Steenbakkers et al. 2003). Others have not found a
correlation between penile bulb dose and erectile dys-
function (Selek et al. 2004; van der Wielen et al. 2008).
The femoral heads should be contoured as an organ
at risk from the ball of the femur inferiorly to the level
of the ischial tuberosity. Typical multiple field
arrangements and beam weighting with either 3DCRT
or IMRT are unlikely to approach femoral tolerance
but with dose escalation the dose to these structures
should be monitored.
Prostate 975

4.4.5 Beam Selection and Shaping

A variety of treatment techniques have been described
for 3D conformal radiation therapy for prostate can-
cer. One of the first methods simply applies tradi-
tional orthogonal four-field-beam orientation but
employs BEV shaping (Fiorino et al. 1997; Soffen
et al. 1991). A four-field 3D CRT technique confers a
significant advantage over a conventional four-field
‘‘box’’ or bilateral 120° arc technique (Magrini et al.
1999; Ten Haken et al. 1989). A four-field 3D CRT
technique shields significant portions of the bladder
and rectum from the primary beam in the lateral
projections. This leads to significant sparing of these
organs from a high-radiation dose.
A six-field technique has been favored by many
institutions (Fig. 8). This technique employs parallel
opposed anterior and posterior oblique fields in
addition to the traditional lateral fields. Typically the
oblique fields are angled 45° from the lateral fields,
although they can be at shallower angles to minimize
treatment to the organs at risk. Compared with a
four-field conformal technique employing prescrip-
tion doses of 70–74 Gy, the six-field technique does
not appear to confer a clear dosimetric advantage;
however, institutions that have delivered radiation
doses in excess of 74 Gy have preferred a six-field
technique, as it may reduce dose to the bladder,
rectum, and the bilateral femoral heads (Magrini
Fig. 9 Radiation dose distribution is represented by a color-
et al. 1999; Ten Haken et al. 1989; Perez et al. wash display on axial, sagittal, and coronal CT reconstructions
1997). Unequally weighted beams may be used in for (a) 2D ‘‘arc’’ plan and (b) 3D six-field conformal plan. The
the six-field technique with 40% of the dose contri- upper right panel is a dose-volume histogram of the bladder,
bution coming from the lateral fields and the other rectum, and PTV (from Sandler and Michalski 2005)
60% of the dose divided evenly between the anterior
and posterior oblique fields. The lateral beams are histograms showed a two-thirds reduction with 3D-
weighted more heavily in a six-field technique CRT in normal bladder or rectum receiving C70 Gy
because this direction allows maximum shielding of with 3D-CRT.
the bladder and rectum. Beam’s eye view treatment A noncoplanar technique was described and used
planning with a six-field technique significantly at the University of Michigan since 1992. This tech-
improves PTV coverage and provides better bladder nique employs two lateral fields paired with nonco-
and rectum sparing compared with traditional bilat- planar anterior inferior oblique fields. The direction of
eral arcs (Figs. 8 and 9). the anterior inferior oblique fields is selected on a
Perez compared 312 patients planned with 3D patient-by-patient basis using angles that optimally
conformal radiation therapy to 135 planned with exclude bladder and rectum. This technique was
standard 2D bilateral arc radiation therapy and demonstrated to effectively reduce the volume of the
demonstrated that when field sizes were adjusted to bladder and rectal walls that receive significant radi-
adequately encompass the planning target volumes ation dose (Marsh et al. 1992). A technique employ-
there was a significant reduction in the volumes of ing blocked arc fields was used at the University of
bladder and rectum irradiated with the conformal California San Francisco. This technique was used in
technique (Perez et al. 2002). Dose-volume patients with prostate treatment without the seminal
976
vesicles. Bilateral 120° arc fields are blocked in the
corners with a 2-cm margin on the PTV. This tech-
nique results in a lower dose to the rectum and a
tighter dosimetric margin around the prostate com-
pared with either a six-field or four-field fixed-beam
3D CRT technique (Akazawa et al. 1996; Roach et al.
1994b).
The choice of technique for any given institution
may depend as much on the availability of technical
resources as on any dosimetric advantage that the
various techniques may or may not have. For example,
the non-coplanar method may not be possible on all
linear accelerators due to the presence of a beam stop or
due to limited clearance of the gantry and collimator to
the patient. In some busy clinics, the longer treatment
times with six fields, as compared with four, may not be
justified if doses\74 Gy are used.
4.5 Intensity-Modulated Radiation
Therapy
Intensity-modulated radiation therapy planning begins
in nearly an identical manner to that of forward-
planned 3D CRT; however, patient positioning and
reproducibility is even more important due to the
sharper dose gradients that are seen with this modal-
ity. Daily target localization methods are critical in
patients receiving IMRT for prostate cancer. Suitable
methods include transabdominal ultrasound, intra-
prostatic fiducial markers with daily megavoltage
portal or X-ray imaging, endorectal balloon immobi-
lization, daily in-room CT imaging, or implanted
radiofrequency transponders. Figure 10 demonstrates
the close proximity of the prescribed isodose to the
edge of the PTV and emphasizes the importance of
precise daily localization.
The definition of organs at risk should include all
radiosensitive structures in the pelvis including the
rectum, bladder, femoral heads, small bowel near the
PTV and the penile bulb.
The IMRT treatment planning requires defining
dose constraints for the target volumes and each
critical structure. The IMRT plan may create more
heterogeneity of dose than 3D CRT, and the planning
prescription needs to define a minimum dose to cover
a predetermined volume of the PTV as well as a
maximum dose to a small volume inside the PTV.
Evaluation of an IMRT plan should include a careful
J. M. Michalski and T. Wiegel
review of isodose distributions and dose volume his-
tograms of both target and organs at risk. Figure 11
illustrates dose volume histograms with favorable
sparing of the adjacent rectum and bladder compared
to 3D CRT. Dose limits to organs at risk need to take
into account both upper dose limits as well as the
volume of those organs that are allowed to exceed
predefined limits. The dose guidelines for normal
organs at risk generally keep the risk of common
toxicity criteria (CTC) grade 2 complications to less
than 15% and grade 3 complications to less than 5%.
The Quantitative Analyses of Normal Tissue Effects
in the Clinic (QUANTEC) group (Marks et al. 2010)
summarized the expected risks of complications
associated with volume-based radiation therapy
planning in many clinical scenarios. As an example,
careful attention should be given to avoid excessive
dose to the femoral heads by overemphasizing lateral
beam directions with 3D CRT or IMRT. Of note, the
risks of complications summarized by the QUANTEC
group are largely based on volumetric planning using
3D CRT techniques. These constraints may be more
conservative with IMRT where both high dose and
low dose volumes may be minimized.
Treatment techniques depend highly on the treatment
planning system and on the treatment delivery equip-
ment. (See ‘‘Linac-Based Image Guided Intensity
Modulated Radiation Therapy’’, ‘‘Tomotherapy Image
Guided Radiation Therapy’’, and ‘‘Robotic Image
Guided Radiation Therapy’’ for details about the vari-
ous methods used for delivering IMRT including slice-
based tomotherapy, dynamic MLC, step-and-shoot
static MLC, and compensator-based systems.)
4.6 Dose Prescription for 3D CRT or IMRT
There is growing evidence supporting the existence of
a radiation dose response for local control of prostate
cancer. Several institutions have reported a radiation
dose response based on retrospective data analyses.
Whether all patients in all risk groups benefit from
dose escalation is a matter of debate.
In some series there has not been a benefit for
doses in excess of 70 Gy for low-risk prostate cancer
(Hurwitz et al. 2002; Pollack et al. 2004; Symon et al.
2003). Pollack et al. (2004) reported no benefit to
doses above 77 Gy compared with 67–77 Gy for low-
risk patients. The Fox Chase Cancer Center
Prostate
Fig. 10 An intensity-modulated radiation therapy dose distri-
bution demonstrates the 75.60-Gy isodose in a color-wash
display in the axial (upper left), coronal (lower left), and sagittal
(lower right) planes. The dose distribution is tighter against the
experience also did not suggest a dose response for
doses higher than 72 Gy. Hurwitz et al. (2002) did not
see a difference in biochemical disease-free survival
for patients receiving more than 68 Gy compared
with those patients treated to lower doses. This lack of
benefit to higher doses may be due to the small local
tumor burden that is readily controlled with conven-
tional doses. Early reports from Memorial Sloan
Kettering did suggest a benefit to low-risk patients but
with further follow-up the advantage was no longer
statistically significant (Zelefsky et al. 2001, 2008b).
On the other hand, investigators from the Cleveland
Clinic have shown a biochemical disease-free sur-
vival benefit for patients with low-risk disease who
receive escalated doses with 3D CRT or IMRT
(Khuntia et al. 2004) from the Cleveland Clinic
reported a 5-year biochemical disease-free survival of
52, 82, and 93% for low-risk patients receiving B68,
68–72, and [72 Gy, respectively.
977
PTV than the similar six-field 3D CRT plan demonstrated in
Figs. 9 and 11. More heterogeneity is also demonstrated with
‘‘hot spots’’ in this target exceeding 80 Gy for the prescribed
dose of 75.60 Gy
Intermediate-risk disease has been shown to ben-
efit from escalated radiation doses in most retro-
spective analyses (Hurwitz et al. 2002; Pollack et al.
2004; Zelefsky et al. 2008b; Khuntia et al. 2004).
Pollack et al. (2004) reported a 5-year biochemical
disease-free survival of 24, 65, and 79% for patients
receiving isocenter doses of \72, 72–75.9, and
C76 Gy, respectively. Khuntia et al. (2004) reported
5-year biochemical disease-free survival rates of 27,
51, and 83% for radiation doses of B68, 68–72, and
[72 Gy, respectively. In the Cleveland Clinic series
the low-dose patients were treated with either stan-
dard techniques or 3D CRT with doses prescribed to
the isocenter. The intermediate- and high-dose
patients were treated with either 3D CRT or IMRT.
Radiation dose was prescribed to an isodose line that
covered the PTV when IMRT was utilized at the
Cleveland Clinic. Zelefsky et al. (2002) reported a
5-year biochemical disease-free survival in
978 J. M. Michalski and T. Wiegel

PTV DVH Patients with high-risk disease do not uniformly

100
demonstrate a benefit to escalated radiation doses
80
(Symon et al. 2003; Pollack et al. 1994). This may be
due to the greater burden of subclinical metastases in
Volume %

60 patients with high pretreatment PSA or high Gleason

scores. Khuntia et al. (2004) reported improved
40 5-year biochemical disease-free survival rates for
high-risk patients of 21, 29, and 71% for radiation
20 doses of B68, 68–72, and [72 Gy, respectively. Ze-
lefsky reported 5-year biochemical relapse-free sur-
0
0 1000 2000 3000 4000 5000 6000 7000 8000 vival rates of 40, 61, 66, and 71% for patients
receiving 70.2 or less, 75.6, 81, and 86.4 Gy,
Bladder DVH respectively (Zelefsky et al. 2008b). They suggested
100
that dose remains a significant factor for high-risk
patients even above 75.6 Gy. Patients treated to
80
86.4 Gy had a significant improvement in biochemi-
Volume %

60
cal outcome compared to those men treated to
75.6 Gy (p = 0.05). In a systematic review of 38
40 published studies from 1990 to 2003, an OS benefit to
dose escalation in the range of 70–80 Gy was dem-
20 onstrated (van Tol-Geerdink et al. 2006). In a pooled
analysis of four RTOG trials from 1975 to 1992,
0 Valicenti demonstrated that higher radiation dose was
0 1000 2000 3000 4000 5000 6000 7000 8000
a significant predictor for improved DFS and OS for
Rectal DVH patients with Gleason scores 8–10 (p \ 0.05) (Vali-
100
centi et al. 2000). After adjusting for other known
clinical prognostic factors, a higher radiation dose
80
was associated with a 29% lower relative risk of death
Volume %

60
40
20
0 niques employed, and whether or not hormones were
0 1000 2000 3000 4000 5000 6000 7000 8000
Dose (cGy)
Fig. 11 Cumulative dose-volume histograms (DVH) demon-
strate coverage of the PTV and a reduction in dose to the
bladder and rectum using 3D CRT (solid curve) compared with
a 2D plan with bilateral 120° arcs (dashed curve) (from Sandler
and Michalski 2005)
intermediate-risk patients of 50 and 70% in patients
receiving 64–70.2 or 75.6–86.4 Gy, respectively. In
an update of that experience, the effect of dose was
most apparent in those receiving more than 75.6 Gy
compared to those receiving less than 70.2 Gy
(Zelefsky et al. 2008b).
from prostate cancer and a 27% reduced mortality rate
(p \ 0.05).
Several randomized trials have been completed to
determine whether there is a benefit to high-dose
radiation in localized prostate cancer. Table 6 sum-
marizes the trial target volumes, doses studied, tech-
allowed. In each of the trials (Al-Mamgani et al.
2008; Dearnaley et al. 2007; Kuban et al. 2008;
Zietman et al. 2010), dose escalation has unequivo-
cally improved biochemical DFS for the populations
of patients enrolled in the trials. Table 7 summarizes
subgroup analyses that suggest some populations
benefit more than others. The first completed and
published study from M.D. Anderson demonstrated a
significant advantage in biochemical disease-free
survival in patients randomized to receive 78 Gy
compared with 70 Gy (Kuban et al. 2008). In this trial
all patients began with radiation to a limited pelvic
field with a standard four-field arrangement. Patients
were then randomized to receive a conventional field
Prostate 979

Table 6 Phase III dose escalation trials for localized prostate cancer: Treatment details and prescribed doses
Group Prescription CTV PTV Technique Eligibility
(Gy)
MDA (Kuban et al. 68 versus 78 P ? SV ‘‘Block Edge’’ 4F 2D to 46 Gy T1b-T3
2008) Isocenter Ant-Inf 12– (All) iPSA = any
15 mm 4F 2D to 68 Gy No ADT
Pos-Su 7– (Low)
10 mm 6F 3DCRT 78 Gy
(High)
2 Gy/fraction
PROG (Zietman et al. 70.2 versus Phase I (Proton) 7–10 mm Proton boost T1b–T2b
2010) 79.2 P ? 5 mm, 19.8 or 4F 3DCRT iPSA \ 15
Min PTV 28.8 Gy 1.8 Gy No ADT
Phase II (XRT)
P = SV ? 1 cm,
50.4 Gy
MRC (Dearnaley et al. 64 versus 74 Low: P ? ProxSV 10 mm to 3–4F 3DCRT T1b–T3a
2007) Isocenter High: P ? SV 64 Gy PTV1 iPSA \ 50
0 mm last 4–6F 3DCRT ADT 3–6 m
10 Gy PTV2
2 Gy/day
Dutch (Al-Mamgani 68 versus I:P only 10 mm to 3DCRT per All T-stages
et al. 2008) 78 Gy II:Prostate +SV 68 Gy institution iPSA \ 60
Isocenter (50 Gy) 0–5 mm final 2 Gy/day ADT allowed
III:Prostate +SV 10 Gy *10% short
(68 Gy) *10% long
IV:Prostate +SV
(full Rx)
GETUG (Beckendorf 70 versus 80 CTV1 = P+SV 5–10 mm 4–6F 3DCRT T2–T3a
et al. 2008) ICRU ref (46 Gy) 2 Gy/day T1 if GS C 7 or
point CTV2 = P (full iPSA [ 10
Rx) iPSA \ 50
No ADT
RTOG (Michalski 2011 70.2 versus 3D: P ? SV 510 mm 3DCRT or IMRT T1b–T2b
RTOG url) 79.2 55.8 Gy 1.8 Gy iPSA = 10–20
Min PTV 3D: P to full Rx (GS \ 7)
IMRT: P ? prox iPSA \ 15 (GS7)
SV No ADT

boost to a total isocenter dose of 70 Gy or a 3D CRT
boost to a total isocenter dose of 78 Gy. The largest
gain from this 8 Gy dose increase was seen in the
patients with pretreatment PSA [10 ng/ml. With a
median follow-up of 8.7 years in M.D. Anderson trial,
Kuban reported a significant reduction in the clinical
failure rate from 15 to 7% (p = 0.014) with 70 Gy as
compared to 78 Gy (Kuban et al. 2008). While distant
metastases were infrequent, dose escalation improved
the distant metastasis free survival rate from 95 to
99% (p = 0.059). In the NCCN high-risk patients, the
reduction in distant metastatic rate from 96 to 83%
was significant (p = 0.035). In the MRC trial, all
NCCN subgroups benefited from dose escalation
(Dearnaley et al. 2007). The MRC trial showed an
improvement in clinical DFS, 90 versus 87%
(p = 0.064) (Dearnaley et al. 2007). In the Dutch
trial, only intermediate and high-risk patients had
improved outcome with higher doses (Al-Mamgani
et al. 2008). The Proton Radiation Oncology Group
trial showed a significant benefit to both low- and
intermediate-risk groups (Zietman et al. 2010). There
was an insufficient number of high-risk patients
(\5%) to determine the value of dose escalation in
that trial. Results from the completed RTOG rando-
mized trial of 70.2 versus 79.2 Gy in intermediate-
risk patients with pretreatment PSA of 10–20 and
Gleason score 6 or pretreatment PSA of 0–15 with
980
Table 7 Treatment results of phase III dose escalation trials for localized prostate cancer
Author N Hormones Biochemical disease-free
survival benefit
Kuban et al. 301 No p = 0.004
(2008)
Zietman et al. 393 No p \ 0.001
(2010)
Al-Mamgani 664 Some p = 0.02
et al. (2008)
Dearnaley et al. 843 All p = 0.0007
(2007)
Gleason score 7 are awaited. In that U.S. cooperative
group trial, the radiation doses were prescribed as a
minimum to the PTV with either 3D CRT or IMRT.
The study has been powered to detect an overall
survival difference between the two arms. Quality-of-
life end points will also be evaluated.
4.7 Normal Tissue Constraints
Normal tissue dose limits play an important role in 3D
CRT and are critical in IMRT treatment planning.
Reports of morbidity following 3D CRT provide
radiation oncologists with dose guidelines for
acceptable conformal radiation treatment plans that
minimize the risk of complications. In the RTOG
prospective dose escalation trial, Michalski et al.
(2000, 2005, 2004) and Ryu et al. (2001) reported the
administration of minimum PTV doses from 64.8 to
79.2 Gy in 1.8 Gy/day fractions and 74–78 Gy in
2 Gy/day fractions with lower than expected inci-
dence of grade-3 or worse intestinal or urinary tox-
icity based on comparisons with historical controls.
Boersma et al. found a significantly higher actu-
arial incidence of severe rectal bleeding in patients
where more than 40 and 50% of the rectal wall vol-
ume received at least 65 Gy (p \ 0.02) than in
patients in whom these volumes were smaller. Other
significant cutoff levels were a rectal wall volume of
30% receiving at least 70 Gy (p \ 0.008), and a rectal
wall volume of 5% receiving at least 75 Gy
(p \ 0.02) (Boersma et al. 1998). Based on their
review of rectal toxicity in patients who received 3D
CRT in the Memorial Sloan-Kettering dose escalation
study, Jackson et al. (2001) recommended keeping
J. M. Michalski and T. Wiegel
Clinical disease free Overall Subgroup
survival benefit survival benefit
benefit
p = 0.014 None PSA [ 10
Not reported None Low, Int
p = ns None Int, High
p = 0.064 None All
B60% of the rectal wall to receive C40 Gy and
B30% of the rectal wall to receive C75.6 Gy to
minimize the risk of grade-2 or greater rectal toxicity.
In a recent update on their IMRT experience,
Zelefsky et al. (2002) reported that the rate of late
grade-2 rectal bleeding was 1.5%, and only 0.5%
experienced grade-3 toxicity requiring one or more
transfusions or laser cauterization procedures. Late
grade-2 urethritis occurred in 10% of patients and
another 0.5% experienced grade-3 urethral stricture.
Dose constraints for this study were 100% of the
prescription to the PTV (excluding overlap with
normal organs) and limits of 40 and 58% of the pre-
scription dose to the rectal wall and bladder wall,
respectively. In the overlap region between the PTV
and these critical organs, the constraint was set at
88% of the prescription dose for the rectum and 98%
for the bladder. The prescription doses to the PTV
ranged from 81.0 to 86.4 Gy in 1.8 Gy fractions
(Zelefsky et al. 2002).
Data from M D. Anderson indicate that volumes
receiving relative high radiation dose are of major
importance. The incidence of grade-II/III toxicity at
3 years decreased from 28 to 12%, if \25% of the
rectal volume received 70 Gy or more (Storey et al.
2000; Pollack et al. 2002). Huang et al. (2002) rec-
ommended additional volume cutoff points at other
dose levels: 41% not to exceed 60 Gy, 16% not to
exceed 75.6 Gy, and 5% not to exceed 78 Gy.
According to an update, 26% of patients treated to
78 Gy developed complications as compared to 12%
treated to 70 Gy (Kuban et al. 2003b). However, it
was also shown that this complication rate could be
minimized by decreasing the amount of rectum trea-
ted above 70 Gy. If \ 26% of the rectal volume was
Prostate
treated to [70 Gy, Grade 2 and 3 complications
occurred in 13% of patients as compared to 51% of
patients if more than 26% of the rectal volume was
treated to this dose level. In an analysis of patients
treated on the Dutch dose escalation trial, Peeters
reported an association of fecal incontinence with
dose delivered to the distal 3 cm of the anal canal
wall, whereas rectal bleeding and high stool fre-
quency were associated with dose to the anorectal
wall (Peeters et al. 2006b). A high rate of acute rectal
toxicity is now recognized as associated with late RT
proctopathy (Heemsbergen et al. 2006; Denham et al.
1999; O’Brien et al. 2002). In the Dutch randomized
dose trial for localized prostate cancer, acute toxicity
was an independent significant predictor for late GI
toxicity. Zelefsky reported a similar association of
acute toxicity to late toxicity in the Memorial Sloan
Kettering dose escalation experience (Zelefsky et al.
2008c). Clinical factors associated with complication
risk include: diabetes mellitus, hemorrhoids, inflam-
matory bowel disease, advanced age, androgen
deprivation therapy, rectum size, prior abdominal
surgery, and severe acute rectal toxicity (Michalski
et al. 2010).
In a dose escalation trial employing an adaptive
radiotherapy process, Brabbins et al. (2005) escalated
dose to the PTV as long as normal organ dose con-
straints could be met. Minimum dose prescriptions to
the PTV ranged between 70.2 and 79.2 Gy based
upon the following rectal and bladder constraints:
\5% of the rectal wall has a dose [82 Gy, \30% of
the rectal wall has a dose [75.6 Gy, \50% of the
bladder volume has a dose [75.6 Gy, and the maxi-
mum bladder dose is 85 Gy. Employing these dose
constraints and a patient specific ‘‘confidence-
limited’’ PTV margin determined by daily CT scans
acquired during the first week of radiation, they were
able to administer a dose of 70.2–72 Gy in 49 of
277 patients (18%), [72–75.6 Gy in 131 patients
(47%), and [75.6–79.2 Gy in 100 patients (36%).
Chronic toxicity of patients receiving [75.6 Gy was
not significantly worse than it was in patients in the
lower dose groups.
Kupelian et al. (2002) reported a dose–volume
relationship between rectal bleeding and rectal
dosimetry in 128 patients treated with either 3D CRT
or hypofractionated IMRT. The actuarial rate of rectal
bleeding at 24 months was only 8% with a prescribed
dose of 78 Gy in 2 Gy fractions with 3D CRT or
981
70 Gy in 2.5 Gy fractions with IMRT. Patients
receiving hypofractionated IMRT were localized daily
using a transabdominal ultrasound. The IMRT PTV
margins were 4 mm posterior, 8 mm laterally, and
5 mm in all other directions. The absolute volume of
rectum receiving the prescription dose was signifi-
cantly associated with the risk of rectal bleeding. The
relative volume of rectum exceeding the prescription
dose was not associated with toxicity, but the length of
rectum was variably contoured and dependent on the
height of the PTV. The rectum was only contoured
1 cm above and below the PTV and not for a uniform
length or anatomic definition. Kupelian et al. (2002)
recommends keeping the absolute volume of rectum
receiving the prescription dose to below 15 cm3.
It is becoming common to report dose constraints
by a volume threshold exceeding a specified dose.
The VN refers to the volume of an organ that exceeds
that dose. For example, a V25 of 70 Gy means only
25% of the organ receives more than 70 Gy. Fiorino
et al. (2003) reported acceptable rectal toxicity rates
in 245 patients treated with 3D CRT and doses
ranging from 70 to 78 Gy to the ICRU reference
point. With a median follow-up of 2 years they had
23 patients with late grade-2 or worse rectal bleeding.
To keep the rate of severe bleeding below 5–10% they
recommend keeping the rectal V50 to 60–65%, the
V60 to 45–50%, and the V70 to 25–30%. In an update
with 1,132 patients they reported that V40 and V70
were highly predictive of rectal bleeding and the V70
along with prior abdominal surgery were the main
predictors for grade 3 bleeding (p = 0.02) (Fiorino
et al. 2008).
A recent review led by the Quantitative Analyses
of Normal Tissue Effects in the Clinic (QUANTEC)
group addressed the time, dose and volume relation-
ships associated with radiation related toxicity in the
management of a broad spectrum of malignancies
(Michalski et al. 2010; Viswanathan et al. 2010). The
normal tissue dose constraints recommended by this
group are summarized in Table 8. Of note, most
normal tissue constraints are derived from common
fractionation and 3D conformal techniques. While the
highest dose-volumes were consistently predictive of
late rectal toxicity, the low and moderate dose-
volume constraints were inconsistently predictive
from series to series suggesting that in single insti-
tutional reports there may be a correlation between
lower dose distributions and techniques employed
982 J. M. Michalski and T. Wiegel

Table 8 QUANTEC recommended normal tissue dose contraints

Organ Endpoint Dose (Gy) or dose/volume Rate Notes on dose/volume parameters
parameters (%)
Rectum Grade C 2 late rectal V50 \ 50% \15 Solid organ
toxicity,
Grade C 3 late rectal \10
toxicity
Grade C 2 late rectal V60 \ 35% \15
toxicity,
Grade C 3 late rectal \10
toxicity
Grade C 2 late rectal V65 \ 25% \15
toxicity,
Grade C 3 late rectal \10
toxicity
Grade C 2 late rectal V70 \ 20% \15
toxicity,
Grade C 3 late rectal \10
toxicity
Grade C 2 late rectal V75 \ 15% \15
toxicity,
Grade C 3 late rectal \10
toxicity
Bladder Grade C 3 late V65 B 50% Solid organ, based upon
bladder toxicity V70 B 35% RTOG 0415 dose guidelines

V75 B 25%
V80 B 15%
Penile Severe erectile Mean dose to 95% of penile \35
bulb dysfunction bulb \ 50 Gy
D90 \ 50 Gy \35
D60–70 \ 70 Gy \55
Small Grade C 3 acute V15 \ 120 cc \10 Volume based on segmentation of the
bowel toxicity individual loops of bowel
Grade C 3 acute V45 \ 195 cc \10 Volume based on the entire
toxicity potential space within the peritoneum

(Michalski et al. 2010). The use of hypofractionation
and techniques that are more conformal than 3D CRT
such as IMRT, SBRT, or proton therapy may require
modification of these constraints. Bladder tolerance
and dose constraints are far less consistent from series
to series. First of all, bladder toxicity tends to occur
later than rectal toxicity (Gardner et al. 2002).
Secondly, the variable shape and size of the bladder
on a day-to-day basis may make prediction of toxicity
based upon a single planning CT far more challenging
(Viswanathan et al. 2010). With 3D-CRT, Pollack
et al. did not see a difference in complication rates
when increasing dose from the 70 Gy to the 78 Gy
level (Pollack et al. 2002). In the RTOG dose esca-
lation study, Michalski et al. saw a correlation
between late bladder complications and the percent of
bladder receiving radiation doses [ the defined ref-
erence doses of 60 Gy and 65 Gy (Michalski et al.
2003). In general, the greater the percentage of
bladder receiving higher doses, the higher the com-
plication rate. However, there was no dose-volume
cutoff above which a complication was more expected
as has been seen in rectal DVH analyses. Finally, the
urethra courses through the prostate and symptoms of
Prostate 983

Table 9 Randomized trials of hypofractionated radiation therapy for localized prostate cancer
Author n Median FU Regimen Total/Fx Biochemical failure Efficacy Toxicity
(year) size/Fx # rate (ASTRO)
Lukka et al. (2005) 936 5.7 66/2/33 53% \0.05 NS
52.5/2.6/20 60% Favors conventional
fractionation
Yeoh et al. (2010) 217 7.5 64/2/32 NS NS
55/2.75/20
Arcangeli et al. 168 2.9 80/2/44 21% \0.05 F NS
(2010) 62/3.1/20 13% Favors
hypofractionation
Pollack et al. (2009, 303 3.3 76/2/38 19% NS NS
Abstract) 70.2/2.7/26 14%
Kuban et al. (2010, 204 4.7 75.6/1.8/42 8% NS NS
Abstract) 72/2.430 4%

urethritis are similar to those of radiation cystitis and
it is difficult to relate dose to bladder and symptoms
related to that organ.
Potency typically begins to diminish one to two
years after radiation and actuarial analysis appears
similar to the natural aging process. Additionally,
some patients have compromised potency due to
concurrent illnesses such as diabetes, vascular dis-
ease, or as a result of medications taken for other
medical conditions. According to single institution
reports and a meta-analysis, it appears that 50–60% of
potent patients remain so after EBRT (Robinson et al.
2002). The specific target tissue for loss of erectile
function is unclear but it has been suggested that
either the periprostatic neurovascular bundles or the
penile components just inferior to the prostate may be
responsible. As part of the QUANTEC project, Roach
summarized the risk of erectile dysfunction and the
association with mean doses to the penile bulb in
excess of 50 Gy (Roach et al. 2010).
4.8 Hypofractionation and Stereotactic
Radiation Therapy
There is growing attention that the outcomes of
prostate cancer may be improved with hypofraction-
ation (higher dose per fraction with a shortened
overall course of therapy). Unlike other epithelial
cancers, it has been suggested that the alpha–beta
ratio of prostate cancer is lower than that of the
adjacent bladder and rectum. A low alpha–beta ratio
implies that a fraction size greater than the common
1.8–2.0 Gy could offer a therapeutic advantage. An
early proposal that the alpha–beta ratio for prostate
cancer is approximately 1.5 comes from an analysis
of patient outcomes in men treated with permanent
seed prostate brachytherapy to a dose of 145 Gy
compared to a group of men treated with external
beam radiation therapy with conventional fraction-
ation to doses of 70–74 Gy (Brenner and Hall 1999;
Duchesne and Peters 1999). Later, Fowler calculated
a similarly low estimate of an alpha–beta ratio of
2 Gy with external beam radiation therapy and
brachytherapy with either Iodine-125 or Palladium-
103 (Fowler et al. 2001). Brenner completed another
alpha–beta estimation with a group of men treated on
a dose escalation trial using high-dose-rate (HDR)
brachytherapy with doses ranging from 5.5 to 10.5 Gy
per fraction (Brenner et al. 2002). Patients treated
with dose escalated hypofractionated HDR brachy-
therapy had better biochemical control with a calcu-
lated alpha–beta ratio of 1.2 Gy (95% confidence
interval, 0.03–4.1 Gy). In a series of 3,756 patients
treated with EBRT with or without an HDR brachy-
therapy boost, Williams et al. estimated the alpha–
beta ratio to be 2.6 Gy albeit with a wide confidence
interval of 0.9–4.8 Gy. (Williams et al. 2007) Criti-
cisms of those studies include the uncertainties asso-
ciated with retrospective studies in general, the use of
data pooled from multiple institutions, and the failure
to account for dose heterogeneities related to brach-
ytherapy (D’Souza and Thames 2001).
Three published phase III trials have compared
standard fractionation to hypofractionation but whe-
ther or not there is an advantage to the shorter course
984
of therapy remains a matter of debate (Arcangeli et al.
2010a; Lukka et al. 2005; Yeoh et al. 2006). The
biological equivalent doses chosen for the Canadian
and Australian studies were relatively low, even with
hypofractionation and therefore would not have been
expected to yield improved outcomes (Lukka et al.
2005; Yeoh et al. 2006). An Italian study was
designed to show equivalent cancer control with a
lower rate of toxicity with the hypofractionated
schedule (Arcangeli et al. 2010a). Surprisingly, the
trial showed similar rates of toxicity yet higher rates
of biochemical disease-free survival in the short
course arm. Several multi-institutional phase III trials
with biologically corrected dose escalated hypofrac-
tionation schedules have completed accrual in North
America (RTOG, NCIC) and Europe (MRC) and are
expected to yield important information about the role
of the fraction size in prostate cancer. Table 9 sum-
marizes the reported hypofractionation series and
their treatment schedules.
The growing availability of stereotactic body
radiation therapy (SBRT) has encouraged some
investigators to explore increasingly aggressive frac-
tionation schedules consisting of five treatments. With
stereotactic localization, daily and real-time image
guidance, and strict normal tissue dose constraints, it
has been established that delivering SBRT is feasible
in the management of early stage prostate cancer.
These studies have employed fraction sizes of more
than 6 Gy and total doses ranging from 33.5 to
36.25 Gy. The estimated equivalent dose in 2 Gy
fractions (EQD2) reported in these series ranges from
78 to 90.6 Gy for tumor and 64.9 to 74.3 Gy for
normal tissue late effects with estimated a/b ratios of
1.5 and 3 Gy, respectively (Ritter et al. 2009). With
limited follow-up, the early and late toxicity with
these regimens appears to be acceptable. With a
median follow-up of 41 months, Madsen reported a
7.5 and 20% rate of grade 2 or greater GI and GU
toxicities, respectively (Madsen et al. 2007). The
5-year biochemical DFS was 70 or 90% using the
ASTRO or Phoenix definitions of biochemical failure,
respectively (Madsen et al. 2007). With 17 months of
follow-up, Katz reported a series of 254 patients
treated to 36.25 Gy in 7.25 Gy fractions experiencing
rates of grade 2 or greater GI and GU toxicity of 2.9
and 6.3%, respectively (Katz et al. 2010a). In a pro-
spective phase II trial of 67 patients at Stanford
University acceptable toxicity was reported in
J. M. Michalski and T. Wiegel
patients treated to 36.25 Gy in 5 fractions with a
Cyberknife unit (King et al. 2009, 2011). King
reported grades 2 and 3 late GU toxicity in 5 and 3%
of patients and grades 2 and 3 late GI toxicity in 2 and
0% of patients, respectively (King et al. 2011).
Importantly, there was significantly less GI or GU
toxicity with a regimen that delivered treatment every
other day rather than daily.
The published series of stereotactic radiation
therapy have utilized a variety of treatment delivery
systems including conventional linear accelerators
with custom-shaped noncoplanar beams (Madsen
et al. 2007) to the Cyberknife system utilizing more
than 100 beamlets with variable collimation (King
et al. 2003). Each of these methods requires daily
imaging using implanted fiducial markers. The Cy-
berknife delivery can take as much as 60–90 min
(Hossain et al. 2010; Katz 2010) and imaging of the
fiducials should take place every 40–60 s to minimize
the impact of patient or internal organ motion. Plan-
ning comparisons of IMRT plans to Cyberknife plans
suggest that the conformality indices are better for
Cyberknife but at the cost of an increase in dose
heterogeneity within the target. King reported con-
siderable sparing of the rectum and bladder with
Cyberknife based SBRT with localization margins of
3–5 mm compared to an IMRT plan with PTV mar-
gins of 10 mm (Arcangeli et al. 2010b). Hossain
evaluated plans in 8 Cyberknife treated cases and
reported an improvement in the conformality index
from 1.44 ± 0.11 to 1.18 ± 0.12 with IMRT and
Cyberknife SBRT, respectively (Hossain et al. 2010).
This improvement in normal tissue dose outside the
target was associated with worsening of the homo-
geneity index from 1.28 ± 0.06 to 1.45 ± 0.12 for
IMRT and Cyberknife plans, respectively. The dose
prescription method for SBRT will often normalize to
lower isodose lines than either conventional or IMRT
treatment planning. In the Stanford experience, King
reported dose normalized to the 90 ± 2% isodose line
to cover 95% of the PTV (Epstein et al. 2005). Rectal
dose constraints in that series were V50 \ 50%,
V80 \ 20%, V90 \ 10%, and V100 \ 5%. The
bladder DVH goals were V50 \ 40% and
V100 \ 10%. The femoral head DVH goal was
V40 \ 5%. In the series reported by Katz, the isodose
volume that covered the PTV ranged from 83 to 87%
of the maximum dose. Most SBRT series require
strict bowel management with daily enemas or
Prostate 985

Table 10 Overview of all three randomized trials for adjuvant radiation therapy after radical prostatectomy
Reference N Inclusion Randomization Definition of Median Biochemical Overall
criteria biochemical follow up progression survival
recurrence PSA (ng/ free survival
ml) (bNED)
Bolla et al. 1005 pT3 ± involved 60 Gy [0.2 60 months 5 years: 91.5
(2005) SM cN0 versus 79 versus 56% versus
EORTC pT2 involved ‘‘wait and see’’ 90.8
22911 (2) SM n. s.
Thompson 431 pT3 c N0 60–64 Gy [0.4 152 months 10 years: 10 years:
et al. (2009) versuss 53 versus 30% 74 versus
(1) ‘‘wait and see’’ (p \ 0.05) 66%
SWOG 8794 Median
time:
15.2
versus
13.3 years
p = 0.023
Wiegel et al. 388 pT3 (±involved [undetectable 54 months 5 years: Not given
(2009a ,b) SM) pN0 range ? confirmation 72 versus 54%
(3) ARO PSA post OP
96–02 undetectable
n.s. not significant, PSA Prostate Specific Antigen, SM surgical margins

suppositories to assure a reproducible rectal volume
(Katz et al. 2010).
While hypofractionation schedules are appealing
on the grounds of patient convenience and potential
cost savings, these regimens require longer term fol-
low-up before they can be considered to be superior
or even equivalent to standard fractionation regimens.
The more extreme SBRT fractionation regimens
should be approached cautiously as the data available
to support their use are limited (Buyyounouski et al.
2010).
4.9 Proton Beam Radiation Therapy
Proton beam radiation therapy had been confined to
relatively few specialized centers but the past decade
has witnessed a growing availability and interest in
this previously unique radiation modality. Indeed, one
of the dose escalation trials that has contributed to our
knowledge on the dose response of prostate cancer
employed proton beam radiation therapy as a boost
for achieving the high total doses examined in that
study (Zietman et al. 2010). While that study was not
intended to demonstrate the value of proton therapy in
prostate cancer, it did show that high doses could be
safely given with that modality and that it leads to
improved biochemical control.
There are unique considerations in planning proton
therapy that are covered in greater detail in ‘‘Proton
Therapy’’ , which is dedicated to this modality. While
the definition of the clinical target volume is identical
to that of conventional external beam radiation ther-
apy or IMRT, differences in other aspects of treatment
planning exist. More attention needs to be given to the
planning scan acquisition, patient positioning and
immobilization. The fixed distance of the Bragg peak
dose deposition depth makes small changes in skin to
target depth having a significant impact on the dose
delivered anteriorly and posteriorly of the target.
Furthermore, subtle rotations in the hip can perturb
the beam attenuation resulting in a shift of the Bragg
peak in an unpredictable manner. Finally, localization
methods such as implanted fiducials can attenuate the
proton beam and create dose shadowing inside the
prostate. Because uncertainties in dose delivered are
specific to the beam, a PTV needs to take into account
not just organ motion and setup uncertainties, but also
physical uncertainties associated with protons. Some
have recommended beam specific PTV parameters
while others have incorporated beam smearing into
the treatment planning dose computation algorithms.
986
4.10 Considerations for Postoperative
Radiation
Postoperative radiation therapy plays an important
role in maintaining tumor control in patients who
have high-risk disease on pathological examination of
the surgical specimen (for example pT3R1) and
patients who have biochemical failure following
radical prostatectomy.
Three randomized phase III trials demonstrated a
nearly 20% absolute benefit for biochemical progres-
sion-free survival (bNED) after adjuvant radiation
therapy (60–64 Gy) compared with a ‘‘wait and see’’
policy, mostly for pT3 cN0 or pN0 tumors (Table 10).
The greatest benefit (30% bNED after 5 years) has
been demonstrated in patients with positive margins
and pT3 tumors. Moreover, in the prospective study of
the South Western Oncology Group (SWOG), overall
survival was improved from 13.5 years without to
15.2 years with adjuvant radiation therapy (Thompson
et al. 2006; Bolla et al. 2005; Wiegel et al. 2009a;
Thompson et al. 2009). Notably, central pathological
review on the outcome at 5 years in the EORTC-trial
showed that only surgical margin status caused a sta-
tistically significant interaction with the treatment
effect, to such an extent that the treatment benefit in
patients with negative margins did not remain signifi-
cant. The hazard ratio for the treatment benefit in the
group with negative surgical margins was 0.87
(P = .601), compared to 0.38 (P \ .0001) in the group
with positive surgical margins according to the review
pathology. Excluding the patients with a PSA of
[0.2 ng/mL after prostatectomy, the hazard ratio for
postoperative irradiation was 1.11 (P = .740) and 0.29
(P \ .0001) for the patients with negative and positive
margins, respectively (Van der Kwast et al. 2007). This
benefit was also seen in the real adjuvant situation,
when the PSA was undetectable before the start of
radiation therapy (Wiegel et al. 2009a). In the trial of
the German cancer society 159 patients were ran-
domized into the observation and 193 into the adjuvant
irradiation arm (60 Gy in 30 fractions over 6 weeks).
After a median follow-up of nearly 5 years there was a
significant benefit from adjuvant radiation therapy for
bNED: 72 versus 54% (p \ 0.03). In the subgroup of
pT3 R1-tumors this benefit increased from 18 to 28%
(Wiegel et al. 2009a).
It is well known that the location, the extent, and the
number of positive surgical margins after radical
J. M. Michalski and T. Wiegel
prostatectomy are the most significant predictors of
biochemical progression after radical prostatectomy.
The investigators of the Cleveland Clinic/Ohio found
in their retrospective series of 7160 patients treated
with radical prostatectomy 1,540 patients with positive
margins. The 7-year progression-free probability was
60% in those patients, resulting in an hazard ratio for
biochemical recurrence of 2.3 in the case of positive
surgical margins compared with negative margins.
There was also an increased risk of biochemical
recurrence in patients with multiple versus solitary
positive surgical margins (HR 1.4) and extensive ver-
sus focal positive surgical margins (adjusted HR 1.3)
(Stephenson et al. 2009). From the data of the ran-
domized trials mentioned above, these patients with
positive margins and pT3-tumors do stand to profit
mostly from postoperative radiation therapy.
The three mentioned trials included only patients
with cN0 or pN0-disease. However, there are inter-
esting retrospective data raising the question of whe-
ther men with nodal involvement confirmed during
prostatectomy could benefit from adjuvant radiation.
In a huge retrospective series reported by Briganti, an
overall survival advantage of 19% in favor of adjuvant
radiation therapy ? hormonal treatment compared
with hormonal treatment alone for pN ? patients after
radical prostatectomy was reported (Briganti et al.
2011). In this series from Milan and Jacksonville a total
of 703 patients were treated, with a median follow-up
of 95 months. Because of the retrospective nature of
this series with no standardized definition of target
volumes, radiation dose and duration of hormonal
treatment, these results should be interpreted with
caution. However, it provides support for this treat-
ment in selected cases, whereas it should be validated
in prospective clinical trials.
There was a remarkably low rate of late severe side
effects grade 3: \5% in the EORTC trial and \2% in
the German trial (Bolla et al. 2005; Wiegel et al.
2009a). For these reasons, in the European guideline
published by the EAU (Heidenreich et al. 2011) and
in the German S3 guideline (Wenz et al. 2010) rec-
ommendations were made for immediate external
beam irradiation after radical prostatectomy.
As an alternative, salvage radiation therapy should
be considered for men who have a persistent PSA
after prostatectomy or show an increase of the PSA
levels after initially postoperative undetectable values
(Stephenson et al. 2007; Wiegel et al. 2009b; Neuhof
Prostate
et al. 2007; Trock et al. 2008). The level of PSA at the
time of salvage radiation therapy is one of the most
important predictors for response. Stevenson et al.
reported the results of 1,540 patients from 16 con-
tributors. These patients received salvage radiation
therapy with a median dose of 66 Gy and had a
median follow-up of 53 months. A 6-year biochemi-
cal progression-free survival rate of 48% could be
achieved when the PSA was \0.5 ng/ml compared
with only 18%, when the preradiation therapy PSA
was [1.5 ng/ml. In the whole series, the 6-year pro-
gression-free survival rate was 32% (Stephenson et al.
2007). The authors identified several prognostic fac-
tors that were associated with a poor response to
radiation therapy including Gleason score of 8–10,
preradiation PSA [2 ng/ml, negative surgical mar-
gins, postoperative PSA doubling time \10 months,
and seminal vesicle invasion. Patients without these
adverse features had a 6-year progression-free sur-
vival of 69%. Also, some subsets of patients with
Gleason score 8–10 would benefit from salvage
radiation therapy if the pretreatment PSA was
\2.0 ng/ml, surgical margins were positive, and PSA
doubling time was [10 months. In this situation, the
6-year bNED was 33% (Stephenson et al. 2007).
It is important to point out that achieving an
undetectable PSA after salvage radiation therapy
offers a second chance of cure. Wiegel et al. reported
the results of a homogeneously treated group of
162 patients, all pN0 treated with a median dose of
66 Gy in fractions of 1.8 Gy. In the multivariate
analysis, the most important predictor for biochemical
progression-free survival was the achieving of an
undetectable PSA after salvage radiation therapy
(Wiegel et al. 2009b). These results were confirmed
by others (Neuhof et al. 2007). There remains, how-
ever, a controversy about the best irradiation dose for
those patients. In the guidelines, total doses of ‘‘at
least 66 Gy’’ are recommended (Heidenreich et al.
2011; Wenz et al. 2010). However, some recently
published series demonstrated a better outcome with
higher total doses (Bernard et al. 2010; Siegmann
et al. 2011; King et al. 2008). Bernard et al. from the
Mayo Clinic, Jacksonville investigated 364 men with
salvage radiation therapy after radical prostatectomy
after a median follow-up of 6.0 years. They inves-
tigated three dose groups (low: \64.8 Gy, moderate:
64.8–66.6 Gy, high: [66.6 Gy). In multivariate
analysis they found that, compared with the high
987
dose level, there was a decreased bNED for patients
treated to the low-dose level (HR 0.60) (Bernard
et al. 2010). This was similar to the results published
by Siegmann et al. from the group in Berlin and
Ulm. In their retrospective series including
301 patients, 234 received 66.6 Gy while 67 patients
with a PSA decrease during salvage radiation ther-
apy were selected and irradiated up to 70.2 Gy. In
the multivariate analysis the total dose was a sig-
nificant predictor of reduced risk of biochemical
progression (p = 0.017) (Siegmann et al. 2011).
These results were also seen by others for suspected
nodal disease (cNx), treated with whole pelvic
radiation therapy. Therefore, it can be anticipated
that in the near future higher total doses will be
recommended (King et al. 2008). Up to the publi-
cation of more data, the need for a higher irradiation
dose remains uncertain, especially in patients with a
histologically confirmed local recurrence after radi-
cal prostatectomy. Some data suggest a better out-
come with a total dose of more than 66 Gy in these
patients (Roscigno et al. 2007).
An important, but unsolved question is the value of an
additional whole pelvic irradiation compared with
prostate bed irradiation alone. Spioto from the Stanford
University reported on 160 patients who underwent
adjuvant or salvage radiation therapy, out of which 87
had short course total androgen suppression. A total of
114 of these were considered at high risk of lymph node
involvement although cN0 (Gleason Score [8, preop-
erative PSA level [20 ng/ml, seminal vesicle involve-
ment). 72 underwent whole pelvic radiation therapy and
42 underwent prostate bed radiation therapy. The med-
ian follow-up was [5 years. Limited to high-risk
patients, there was a superior bNED of whole pelvic
radiation therapy compared with prostate bed radiation
therapy (5-year rate 47 vs. 21%, p \ 0.05). Whereas
these data have to be confirmed in a prospective trial,
whole pelvic radiation therapy combined with modern
delivery techniques like IMRT can be offered as an
attractive option for high-risk patients (Heidenreich et al.
2011; Wenz et al. 2010; Spiotto et al. 2007).
Interesting retrospective data has been reported
from the Mayo Clinic and from the University of
Michigan (Choo et al. 2009; Soto et al. 2011). They
raise the question of the efficacy of an additional
androgen deprivation during and after salvage radia-
tion therapy. Choo and coworkers reported on
75 patients treated with salvage radiation
988 J. M. Michalski and T. Wiegel

Table 11 Ulm University 3D CRT and IMRT Treatment Volume and Dose Guidelines for postoperative irradiation (in com-
bination with IGRT)
Risk group Treatment GTV CTV PTV Dose
margin (EBRT;
(mm) Gy)
Postop adjuvant EBRT None CTV = prostate bed (pT2) or prostate and SV 7 64–66
(pN0) bed (pT3)
Postop adjuvant EBRT None CTV1 = pelvic LN ? prostate bed (pT2) 7 45–50.4
(pN+) or ? prostate and SV bed (pT3)
CTV2 = Prostate bed (pT2) or Prostate and SV 7 64–66
bed (pT3)
Postop salvage/ EBRT ± adjuvant None CTV = prostate bed (pT2) or prostate and SV 7 66.6–72
rising PSA hormonal therapy bed (pT3)
High-risk postop EBRT ± adjuvant None CTV1 = pelvic LN ? prostate bed (pT2) 7 45–50.4
with rising PSA hormonal therapy or ? prostate and SV bed (pT3)
CTV2 = prostate bed (pT2) or prostate and SV 7 66.6–72
bed (pT3)
Local recurrence EBRT ± adjuvant If visible High risk: CTV1 = pelvic LN ? prostate bed 7 45–50.4
(histological hormonal therapy on (pT2) or prostate and SV bed (pT3) including
proven) imaging GTV (if visible)
CTV2 = prostate bed (pT2) or prostate and SV 75.6
bed (pT3) including GTV (if visible)
PSA Prostate Specific Antigen GTV, CTV, PTV, Gross tumor volume, Clinical target volume, Planning target volume, SV Seminal
Vesicles, LN Lymph Nodes, Postop Postoperative, EBRT External Beam Radiation therapy
External beam doses expressed in Gray with 1.8 Gy/day fraction size unless indicated otherwise

therapy ? 2-year androgen deprivation treated in a
pilot prospective study. With a median follow-up
from salvage radiation therapy of 6.5 years, all
patients achieved an initially complete PSA response
(\0.2 ng/ml). Relapse-free survival rate at 7 years
was 78% of the whole population (Choo et al. 2009).
A group of the University of Michigan treated a total
of 630 men for salvage indications after radical pro-
statectomy. Of this group, 66% had high-risk factors
and the mean radiation therapy dose was 68 Gy and
24% of all patients received concurrent androgen
deprivation. With a median follow-up of 3 years the
concurrent androgen deprivation was shown to be a
significant independent predictor of progression-free
survival in the high-risk group (p \ 0.05) (Soto et al.
2011). Therefore, it seems attractive to treat selected
patients with salvage radiation therapy and an addi-
tional androgen deprivation. The optimal duration of
this androgen deprivation therapy remains uncertain.
Multiple prospective and retrospective studies dealt
with the clinical question of whether adjuvant radiation
therapy or salvage radiation therapy is preferable in
terms of local control and freedom from biochemical
failure (FFBF) (Thompson et al. 2006; Bolla et al.
2005; Wiegel et al. 2009a, b; Stephenson et al. 2007;
Neuhof et al. 2007; Trock et al. 2008; Loeb et al. 2008;
Bernard et al. 2010; Siegmann et al. 2011; King et al.
2008). A consistently higher improvement in local
control and FFBF has been observed in adjuvant
radiation therapy compared with salvage radiation
therapy patients. The 5-year FFBF rates are approxi-
mately 69–89% after adjuvant radiation therapy. Local
control is 96–100% after adjuvant radiation therapy
and 79–93% after salvage radiation therapy. Recently,
Trabulsi and colleagues studied a group of patients
undergoing adjuvant radiation therapy with a matched
control group undergoing salvage radiation therapy
after biochemical failure. Using a multi-institutional
database of 2,299 patients, 449 patients with pT3–4
N0 disease were eligible, including 211 patients
receiving adjuvant radiation therapy and 238 patients
receiving salvage radiation therapy. Adjuvant
radiation therapy significantly reduced the risk of long-
term biochemical progression after radical prostatec-
tomy compared with salvage radiation therapy (5-year
FFBF was 73% after adjuvant radiation therapy com-
pared with 50% after salvage radiation therapy;
p = 0.007). Gleason score 8 was a significant predictor
Prostate 989

of FFBF (Trabulsi et al. 2008). These results were

confirmed by others (Budiharto et al. 2010), but Ost
et al. reported a better outcome after salvage radiation
therapy compared with after adjuvant radiation therapy
(Ost et al. 2011a). For all of these reasons the best
choice for treatment (adjuvant radiation therapy vs.
salvage radiation therapy) has to be discussed indi-
vidually with each patient, taking into account the
possible risk for overtreatment with immediate post-
operative irradiation.
In 2007, a prospective randomized study was ini-
tiated to address this question as well as the potential
role of concomitant androgen deprivation (Parker
et al. 2007). The Radiotherapy and Androgen
Deprivation in Combination after Local Surgery
(RADICALS) trial is an effort to evaluate adjuvant
versus salvage radiation therapy. Patients are ran-
domized after surgery to early or delayed radiation.
Delayed radiation will be given when there are either
two consecutive PSA rises and a final PSA[0.1 ng/ml
or three consecutive PSA rises. The planned accrual is
2,600 patients with cause-specific survival being the
primary outcome. There is a second randomization
regarding androgen deprivation therapy.
Table 11 shows the 2011 guidelines for postoper-
ative irradiation used at the Ulm University.

4.11 Postoperative Radiation Therapy

Techniques

Traditionally, a 4-field technique has been used

(Fig. 12). The conventional treatment volumes were
typically very generous, being approximately
10 9 10 cm in the anterior-posterior fields with the
inferior border at the ischial tuberosities. The lateral
fields extended from the anterior aspect of the pubic
symphysis and split the rectum posteriorly.
After the introduction of modern 3D CRT techniques,
a major controversy about the target volumes of post-
operative radiation therapy started. Critical evaluation of
target volume delineation by different authors and par-
ticipation of experienced radiation oncologists showed
that variations up to 65% may be present even in cases of
adjuvant or salvage radiation to the prostatic fossa
(Michalski et al. 2009b). These differences have been
presented despite the presence of guidelines published
on behalf of the EORTC Radiation Oncology Group 2
years earlier (Poortmans et al. 2007).
Fig. 12 Digitally reconstructed radiographs (AP and right
lateral) demonstrate boost fields for patients receiving postop-
erative radiation therapy utilizing a four-field box technique.
The CTV (red) is encompassed by a PTV margin (blue). In the
lateral field the contours of the bladder and rectum are shielded
by the block edges
In 3D CRT, the target volume should include the
bladder neck (pulled into the prostate bed), the peri-
prostatic tissue and surgical clips, and the seminal
vesicle bed (including any seminal vesicle remnants if
present) if initially involved or as a confirmed site of
recurrence. There are some anatomic landmarks that
are useful in maximizing coverage of the surgical bed.
Inferiorly, the vesical-urethral anastomosis should be
990 J. M. Michalski and T. Wiegel

Fig. 13 Postoperative target

volumes and critical
structures displayed on axial
CT (a–f) and sagittal
reconstruction (g) for
volumetric treatment
planning. For illustration
purposes, only every fourth
CT image is displayed. The
postoperative CTV (white)
encompasses the region of the
resected seminal vesicles
superiorly and the bladder
neck inferiorly. The PTV (not
shown) encircles the CTV.
The rectum is posterior

included. This anastomosis is the most frequent area
of positive prostate bed biopsies. By placing the
inferior field edge at the top of the bulb of the penis
(best seen on magnetic resonance imaging) and add-
ing a margin for uncertainties, there should be ade-
quate coverage. Laterally, the field should extend to
about the medial aspect of each obturator internus
muscle. Although the rectum is a landmark posteri-
orly, the relative position of the rectum appears to
shift after the prostate is removed as well as during
radiation therapy (Naya et al. 2005; Fiorino et al.
2005). For this reason, a generous margin from CTV
to pTV posteriorly is recommended, such as setting an
8 mm margin with image guidance (Paskalev et al.
2005). The superior margin is more subjective. The
former prostate can extend above the pubic symphy-
sis, but it is recommended that the anterior part of the
bladder be avoided at this level because this is the
least likely area for extracapsular extension and
involved margins. Treatment of the seminal vesicle
bed, lying behind the bladder, is advised for pT3b
tumors. If vascular clips were used at prostatectomy,
Prostate
Fig. 14 Anterior (a) and lateral view (b) of the PTV for postoperative irradiation for a pT2-tumor. Red PTV, yellow bladder, blue
hips, orange rectal wall
Fig. 15 a–b Same patient case as in Fig. 14. 5-field-IMRT treatment plan compared with rotational IMRT
they are likely to be seen in this region. The level of
the posterior-superior clinical target volume is
somewhat subjective and should be guided by the
extent of disease at the prostate base and whether the
seminal vesicles were involved.
For all these reasons the recommendations of the
RTOG (Michalski et al. 2009) and of the EORTC
(Poortmans et al. 2007b) should be considered as
being very helpful in delineation of the target volume
for irradiation of the prostatic fossa. A typical target
volume as designed by the RTOG is shown in Fig. 13
and an example of Ulm University is displayed in
Fig. 14.
Given the potential for late toxicity after postop-
erative radiation therapy, the use of IMRT is appeal-
ing, as displayed in Fig. 15 for two different
techniques (Bastasch et al. 2002). As with 3D CRT, a
generous definition of the prostate bed target volume
and adequate margins to account for target motion
991
(especially due to the variation in rectal and bladder
filling) and setup uncertainties are critical. The theo-
retical advantages of IMRT are that dose falloff is
more geometrically rapid than for 3D CRT, and the
better conformation of the dose to irregularly shaped
targets (e.g., the superior-posterior aspect of the
postoperative field). A greater sparing of the superior-
anterior part of the bladder, the posterior part of the
rectum, and the penile bulb can be achieved using
IMRT, despite using the same target volume definition
(Pinkawa et al. 2007). For optimization of the margins
needed for delivery of IMRT, IGRT remains a helpful
tool. Ost and coworkers from Gent University dem-
onstrated a significant reduction of acute toxicity using
patient positioning with cone beam CT (Ost et al.
2011b). Sandhu et al. from the University of California
used IGRT in patients undergoing post-prostatectomy
irradiation. Prostate bed localization was done using
image guidance based on surgical clips, relative to the
992
Fig. 16 PTV for postoperative irradiation for the pelvic
lymphatics and the prostate bed including the base of the
seminal vesicles. Red PTV pelvic lymphatics, orange PTV
prostate bed, blue hips
reference isocenter on the digitally reconstructed
radiographs made during radiation therapy planning.
They assumed that surgical clips are a useful surrogate
for the prostate bed and measured daily shifts of the
position of the surgical clips in 3D. With an average
(standard deviation) prostate bed motion in anterior-
posterior, superior-inferior and left–right directions of
2.7 mm (2.1), 2.4 mm (2.1) and 1.0 mm (1.7), the
majority of the patients experienced only grade 1 side
effects. They recommended daily IGRT for accurate
target localization (Sandhu et al. 2008). However the
most efficient approach for IGRT during the 68 weeks
of irradiation remains controversial (Kupelian et al.
2006; Schiffner et al. 2007).
When indicated, as in patients at a high risk for
lymph node involvement or confirmed pelvic lymph
node involvement, the pelvic lymphatics should be
irradiated (Heidenreich et al. 2011; Wenz et al. 2010).
For this case, the recommendations from the RTOG,
published by Lawton et al. following a consensus
reached by a group of specialized uro-oncologic
radiation oncologists, can be used (Lawton et al.
2009a). Figure 16 demonstrates a PTV on a treatment-
planning CT based upon the RTOG guidelines. The
comparison of a 5-field IMRT and a rotational IMRT
(for example ‘‘Rapid Arc’’) technique is displayed in
Fig. 17. The typical dose recommended for pelvic
irradiation is 1.8 Gy per fraction up to a total dose of
45–50.4 Gy. The value of IMRT for irradiation of the
J. M. Michalski and T. Wiegel
pelvic lymphatics has been proven by reducing acute
and late gastrointestinal and genitourinary toxicity
(Lawton et al. 2009a; Alongi et al. 2009).
5 Prostate Brachytherapy
5.1 Introduction
Prostate brachytherapy permits dose escalation far
exceeding other radiation modalities with oncologic
treatment margins substantially larger than those
obtainable with radical prostatectomy (RP). The
resurgence of interest in brachytherapy followed the
availability of transrectal ultrasonography, the devel-
opment of a closed transperineal approach and
sophisticated treatment-planning software. These
imaging and planning advances dramatically
improved the accuracy of seed placement. In addition,
computed tomography (CT)-based postoperative
dosimetry provided the ability to evaluate implant
quality and proactively influence outcome, especially
for future patients (Merrick et al. 2003a).
5.1.1 Patient Selection Criteria
Although not all patients are acceptable candidates for
brachytherapy, a reliable set of pretreatment criteria
for predicting outcome has not been formulated
(D’Amico et al. 1998; Merrick et al. 2003a, b; Blasko
et al. 2002; Crook et al. 2001, 2011; Hakenberg et al.
2003; Nag et al. 1999). The continued elucidation and
adoption of evidence-supported planning philoso-
phies, intraoperative techniques, and medical man-
agement should further improve cancer control and
quality-of-life (QOL) outcomes. The success of any
prostate brachytherapy program is highly dependent
on careful patient selection.
5.1.2 Prostate Size
Large prostate size remains a relative contraindication
to brachytherapy due to technical limitations and the
association of large prostate size to acute and pro-
longed urinary morbidity (Ash et al. 2000; Pedley
2002). Whereas in a study using a validated patient-
administered instrument Expanded Prostate Cancer
Index Composite (EPIC), long-term urinary function
did not correlate with prostate size (Merrick et al.
2003c). A European series of 72 patients did deter-
mine that the prostate volume was an independent
Prostate
Fig. 17 a-b Same patient case as in Fig. 2. 5-field-IMRT treatment plan compared with rotational IMRT at the level of the lower
part of the pelvic lymphatics and at the level of the iliac lymph nodes, respectively
factor that predicted for a worse urinary morbidity
(Steggerda et al. 2008). Similarly, a Canadian series
of 219 men treated with permanent 125I were more
likely to require postoperative urinary catheterization
if they had larger prostates (Neill et al. 2007). One
group reported that a prostate base to apical length of
more than 39 mm had 3-month postimplant IPSS
score more than 3 points higher than patients with
shorter prostates (Pal et al. 2011). Not all series
support a risk for increased urinary morbidity and
some investigators have successfully implanted large
prostate glands with acceptable morbidity (Merrick
et al. 2003c, 2000a; Sherertz et al. 2001; Stone and
Stock 2000). On the other hand, favorable dosimetry
with minimal urinary morbidity has been reported for
patients with small glands (\20 cm3) (Merrick et al.
2003c).
5.1.3 Prostate Lobar Anatomy
The size of the transition zone (TZ) has consistently
correlated with brachytherapy-related urinary mor-
bidity (Fig. 18) (Hinerman-Mulroy et al. 2004;
Merrick et al. 2001a; Thomas et al. 2000). Harvard
University investigators reported TZ volume to be the
993
most important predictor of acute urinary retention
following brachytherapy (Thomas et al. 2000). In
patients receiving neoadjuvant androgen deprivation
therapy (ADT) for cytoreduction, International Pros-
tate Symptom Score (IPSS) normalization, prolonged
catheter dependency, and the need for a postbrachy-
therapy transurethral resection (TURP) were best
predicted by the percentage of decrease in TZ volume
(Hinerman-Mulroy et al. 2004). In particular, pro-
longed urinary morbidity was extremely unlikely in
patients with a [30% decrease in TZ volume fol-
lowing ADT (Hinerman-Mulroy et al. 2004).
Median lobe hyperplasia (MLH; the protrusion of
hypertrophied prostate tissue into the bladder) is a
relative contraindication to brachytherapy because of
an increased risk of postimplant urinary morbidity
and/or technical difficulties associated with the
implantation of intravesical tissue (Pedley 2002). In a
small series of patients with MLH, complete dosi-
metric coverage of the median lobe was reported;
however, 38% of the patients developed prolonged
postimplant urinary retention, whereas others experi-
enced persistent IPSS elevation (Wallner et al. 2000).
In a case control study of 50 patients with acute
994
Fig. 18 Sagittal (a) and transverse (b) ultrasound images of
the prostate for a permanent brachytherapy preplan. The
prostate is outlined in light red. The images also illustrate the
urinary retention (AUR), Roeloffzen reported that
AUR was significantly more common in patients that
had preoperative prostate protrusion into the bladder
exceeding 3.5 mm (Roeloffzen et al. 2011). Although
MLH should not be considered an absolute contrain-
dication to brachytherapy, such patients should be
approached with caution. It is conceivable that pre-
implant resection of the intravesical component may
reduce the incidence of brachytherapy-related urinary
morbidity. This should not be done as part of the
implant procedure itself as it is associated with
unacceptable complications. Cosset reported an
unacceptable AUR rate of 23% in men that had a one-
step TURP and prostate implant (Cosset et al. 2011).
5.1.4 Urinary Obstructive Symptoms
The role of a high International Prostate Symptom
Score (IPSS) in predicting urinary morbidity (includ-
ing urinary retention) has been studied extensively
with conflicting conclusions (Hakenberg et al. 2003;
Ash et al. 2000; Pedley 2002; Merrick et al. 2000a;
Bucci et al. 2002; Gelblum et al. 1999; Landis et al.
2002; Terk et al. 1998). Although almost all brachy-
therapy patients develop urinary irritative/obstructive
symptoms with up to 34% developing acute urinary
retention (Merrick et al. 2000a; Thomas et al. 2000;
Gelblum et al. 1999; Landis et al. 2002; Terk et al.
1998; Han et al. 2001b), \5% require a urinary
catheter for[1 week (Merrick et al. 2000a, 2002a). In
J. M. Michalski and T. Wiegel
planning target volume in cyan. The 100% (yellow), 150%
(orange) and 200% (dark red) isodose lines (145 Gy for an
125-Iodine implant) for the preplan are displayed
a series of 127 patients, the group in Utrecht reported
that the pretreatment IPSS and the use of neoadjuvant
hormonal therapy were significant predictors for acute
urinary retention and patients that had retention were
more likely to have a negative impact on their quality
of life (Roeloffzen et al. 2010). Preimplant IPSS pre-
dicted the duration of postimplant obstructive symp-
tomatology (Merrick et al. 2000a; Bucci et al. 2002;
Terk et al. 1998) but does not consistently correlate
with long-term urinary QOL (Merrick et al. 2003c).
Published patient-selection guidelines (Frank et al.
2011; Hakenberg et al. 2003; Nag et al. 1999; Ash
et al. 2000; Pedley 2002) discourage the use of
brachytherapy in patients with IPSS scores exceeding
15 or 20. On the other hand, a few prospective studies
have demonstrated little correlation between preim-
plant IPSS, urodynamic studies, postvoid residual
urine or preimplant cystourethroscopy, and acute or
long-term urinary function (Landis et al. 2002; Gray
et al. 2000).
5.1.5 Pubic Arch Anatomy
Pubic arch interference (the obstruction of anterior
needle placement insertion by a narrow pubic arch) is
a relative contraindication to brachytherapy. Surpris-
ingly, prostate volume has proved to be a poor pre-
dictor of pubic arch interference (Bellon et al. 1999).
With the use of the extended lithotomy position and/
or veering needles around the arch, most patients can
Prostate
be successfully implanted with favorable postimplant
dosimetry regardless of the degree of pubic arch
interference (Bellon et al. 1999).
5.1.6 Transurethral Resection
of the Prostate
In contemporary brachytherapy series with the use of
peripheral source loading and limitation of the radia-
tion dose to the TURP defect to approximately 110%
of the prescription dose, the risk of incontinence in
patients with a preimplant TURP has been reported to
be B6% (Stone et al. 2000; Wallner et al. 1997). Using
EPIC, patients with a preimplant TURP have been
found to have urinary QOL approaching that of non-
TURP brachytherapy patients (Merrick et al. 2004a).
Following brachytherapy, approximately 2% of
patients develop prolonged urinary retention with the
vast majority eventually spontaneously urinating
(Merrick et al. 2004a). If a postimplant TURP or
transurethral incision of the prostate (TUIP) is nec-
essary, it should be delayed for as long as possible
(ideally a minimum of 12 months). Significant uri-
nary morbidity has been demonstrated in approxi-
mately half of patients undergoing an early
postimplant TURP. Patients requiring a pre- and
postimplant TURP have an especially high risk of
urinary incontinence (Merrick et al. 2004a).
To minimize postbrachytherapy TURP-related
incontinence, the preservation of the bladder neck at
the 5 and 7 o’clock positions with minimal use of
cautery is essential to maintain sufficient prostatic–
urethral blood supply (Stone and Stock 2002).
5.1.7 Patient Age and Comorbidity
Although there remains a surgical bias to recommend
RP for younger patients, patient age alone should not
influence treatment decisions. In fact, patient age may
be a stronger predictor of prostate cancer curability
than differences in preimplant PSA (Carter et al.
1999). Older patients have been reported to be at
increased risk for extracapsular extension, higher
Gleason scores, and a greater propensity for distant
metastases when compared with younger patients
(Carter et al. 1999; Herold et al. 1998; Smith et al.
2000). Following brachytherapy, outstanding out-
comes of 95% 8-year biochemical disease free
(median PSA \0.4 ng/ml) have been reported for 108
hormone-na patients B54 years of age (Merrick et al.
2006). The group from Mt. Sinai reported 5- and 8-
995
year biochemical disease-free survivals of 95 and
92% for men less than 60 years compared to 93 and
87% in 378 men older than 60 years (Burri et al.
2010). The Princess Margaret Hospital group reported
a 7-year biochemical disease-free survival rate of
98.9% for 96 men treated at age 55 years or younger
(Gomez-Iturriaga Pina et al. 2010). Furthermore,
older patients tolerate brachytherapy as well as
younger men (Merrick et al. 2003c, 2000a; Burri et al.
2010). In a series of 145 patients aged 75 and older,
Merrick reported a 9-year cause specific and bio-
chemical disease-free survival of 99.3 and 97.1%,
respectively (Merrick et al. 2008). These data suggest
that prostate brachytherapy is an option in selected
men of every age.
Obesity presents substantial procedural difficulties
for RP and external-beam radiation therapy (XRT),
but only relatively minor problems for brachytherapy
(Merrick et al. 2005a). Favorable biochemical and
QOL outcomes have been demonstrated for brachy-
therapy patients regardless of body mass index (BMI)
(Efstathiou et al. 2008; Merrick et al. 2007a; van
Roermund et al. 2010).
Inflammatory bowel disease, ulcerative colitis, and
regional enteritis (Crohn’s disease) have been con-
sidered relative contraindications to radiation therapy;
however, in a small brachytherapy series, no increased
risk of gastrointestinal morbidity was reported (Grann
and Wallner 1998). In a series of 24 patients with a
history of inflammatory bowel disease, Peters reported
that 19% experienced grade 2 and no grades 3 or 4 late
rectal toxicity was observed with follow-up ranging
from 2 to 126 months (median 48.5 months) (Peters
et al. 2006).
5.1.8 Adverse Pathological Features
High Gleason score, perineural invasion, and per-
centage of positive biopsies correlate with a greater
likelihood of extracapsular extension leading some to
conclude that patients with high-risk features may not
be adequately treated with brachytherapy (D’Amico
et al. 1998; Crook et al. 2001; Hakenberg et al. 2003).
In contrast, multiple brachytherapy studies have
demonstrated favorable biochemical outcomes for
hormone-na patients at high risk of extraprostatic
extension (Blasko et al. 2000; Dattoli et al. 2003;
Fang et al. 2010c; Merrick et al. 2001b, 2003d;
2004b). Pathological evaluation of RP specimens
demonstrate that extraprostatic extension is almost
996
90
120 60
(bladder) 150 30
Base 180 0 Apex
(seminal
vesicles)
240 330
310 300
Pd-103 270
Posterior
Fig. 19 Mean postimplant dosimetric margins [6 mm at the
100% isodose line
always limited to within 5 mm of the prostate capsule
(Davis et al. 1999). As such, high-quality brachy-
therapy with or without supplemental XRT should
sterilize extraprostatic extension (Fig. 19) (Merrick
et al. 2003e). The relative effectiveness of brachy-
therapy against adverse pathological features is likely
a result of intraprostatic dose escalation with thera-
peutic radiation dose delivery to the periprostatic
region (Fang et al. 2010c; Merrick et al. 2004b,
2003e, 2001c).
5.2 Brachytherapy Planning
Favorable biochemical results have been obtained
with a variety of planning and intraoperative tech-
niques, of which no method has been proven superior
(Butler et al. 2000; Merrick and Butler 2000). In
general, four seed loading philosophies (uniform
loading, peripheral loading, modified uniform load-
ing, and modified peripheral loading) have been uti-
lized with peripherally based planning philosophies
most commonly used (Prete et al. 1998). Although
quality is easy to conceptualize, it is more difficult to
quantitate. It is universally accepted that an adequate
implant should encompass the target volume, but no
consensus exists as to what represents the target. In
addition, urethral and rectal tolerances have not been
well defined, and the significance and degree of dose
homogeneity throughout the implant region remains
unclear. A multi-institutional analysis revealed that
J. M. Michalski and T. Wiegel
although prostate brachytherapy prescription doses
are uniform, substantial variability exists regarding
target volume, seed strength, dose homogeneity,
treatment margins, and extracapsular seed placement
(Merrick et al. 2005b).
Brachytherapy planning entails either preplanning
(in which a transrectal ultrasound volumetric study of
the prostate gland is obtained before implantation) or
intraoperative planning using nomograms or real-time
techniques (Merrick and Butler 2000; Stock et al.
1998). In patients with intermediate or high-risk fac-
tors, a clinical target volume margin of 2-5 mm to
account for extraprostatic extension of tumor can be
added. In the preplanned approach, the planning target
volume (the prostate gland with a periprostatic mar-
gin) is determined by a 3–8 mm enlargement of each
ultrasound slice with a resultant planning target vol-
ume approximately 1.75 times the ultrasound-deter-
mined volume (Merrick and Butler 2000). The
rationale for the planning target volume margin is that
seed placement uncertainty is approximately 5 and
3 mm in the longitudinal and transverse directions,
respectively (Roberson et al. 1997). In addition, the
utilization of treatment margins significantly decrea-
ses the effect of edema on postoperative dosimetry
(Butler et al. 2000; Waterman et al. 1998). At the
periphery of the implant target volume, the radiation
dose decreases by as much as 20 Gy/mm (Dawson
et al. 1994). In practice, many clinicians will include
the clinical risk into the planning target volume rather
than define two separate target structures. Table 12
outlines criteria by which all plans are evaluated based
on a DVH of the planning target volume and urethra.
Most permanent prostate brachytherapy incorpo-
rates real-time ultrasonography to visualize the pros-
tate. The probe is placed on a fixed stepping device
that allows independent movement relative to the
transperineal template. With, or without the addition
of fluoroscopy, the use of a bi-plane ultrasound probe
allows prostate visualization in sagital and axial mode
for accurate prostate imaging. Others are using real-
time magnetic resonance imaging techniques in order
to perform permanent prostate brachytherapy
(D’Amico et al. 2000). The ‘Seattle’ technique
employs the use of a pre-plan based on serial axial
transrectal ultrasonography performed in lithotomy
position in advance of the implant (Blasko et al.
1991). Hollow brachytherapy needles are loaded with
I-125, Pd-103 or Cs-131, and spacers, in the operating
Prostate 997

Table 12 Preimplant Evaluated quantity Parametera Value

dosimetric evaluation criteria
I-125 Pd-103
b
Patient-specific needs Tx volume, TURP , Primary importance
etc.
Coverage of the planning V100 [99.8% volume 125–140% mPD
volume D90
Dose homogeneity V150 40–55% 55–70%
volume volume
High dose volume V200 \15% volume 15–25%
volume
Urethra volume coverage UV125 80–100% 50–100%
volume volume
UV150 \15% volume \25% volume
Urethra dose UD50 130–145% 120–140%
mPD mPD
UD10 140–150% 130–160%
mPD mPD
a
V100, V150, and V200 are the percentages of the planning target volume (PTV) covered by 100,
150, and 200% of the prescribed dose (mPD), respectively. D90 is the minimum dose covering
90% of the PTV. UV125 and UV150 are percentage of volume of the urethra at the defined mPD.
UD50 and UD10 are the minimum doses covering 50 and 10%, respectively, of the urethra volume
b
TURP Transurethral resection of prostate

room, to correspond with the plan. Needle placement
follows the plan with deposition of each successive
needle’s seeds. Use of fluoroscopy may assist to
assure that the needles are positioned to the base or
‘zero’ plane as a reference position. An advantage of
a preplan approach is that it allows for dose optimi-
zation in advance of the case and needle placement in
the operating room is generally easy and can be per-
formed efficiently. The disadvantage of this process is
that it remains difficult to duplicate the exact position
of the prostate relative to the preplan, and that there is
no ability to compensate for discrepancies during the
case, except to add additional sources at the discretion
of the physician. An alternative technique, originally
developed at Mount Sinai, uses an applicator to place
each seed individually (Stone et al. 2003). The seed
applicator can be utilized with a preplan, but is more
commonly utilized in combination with a real-time
implant, where needle positions can be adjusted as
needed. There are no studies that have directly com-
pared these techniques but it is generally understood
that implant quality is similar between the real-time
and preplanned techniques (Merrick et al. 2003a)
With advances in software treatment planning sys-
tems, Potters described an intraoperative technique
that achieves dose conformality based on set param-
eters for minimum and maximum prostate dose with
inverse planning (Potters et al. 2003). Using intraop-
erative treatment planning software, seed location can
be determined on actual needle placement, and then
followed by real-time assessment of the dosimetry
during the implant procedure. Final intraoperative
dosimetry appears to correlate to the CT-based
dosimetry, with the advantage of using 8% less iso-
tope activity per case. Others are using techniques
including the integration of intraoperative computer-
ization and seed planning to allow greater flexibility
during the procedure to achieve a high implant quality
with fewer seeds (Stone et al. 2003; Todor et al. 2003;
Woolsey et al. 2004).
5.2.1 Isotope
Currently, three isotopes are available for permanent
seed prostate brachytherapy: I-125, Pd-103 and
Cs-131. Table 13 summarizes the important physical
characteristics and prescription parameters for each of
them. While I-125 has the longest history and expe-
rience, no definitive data support the potential cura-
tive superiority of one isotope over another for any
clinical stage, Gleason score, or pretreatment PSA
998 J. M. Michalski and T. Wiegel

Table 13 Physical Isotope Half-life Average Indication Nominal Nominal seed

characteristics and (days) energy prescribed dose activity
prescription guidelines for
permanent seed mCi U
brachytherapy 125
Iodine 60 28.5 keV Monotherapy 145 Gy 0.33– 0.42–
0.42 0.53
Combined 108–110 Gy 0.28– 0.36–
therapy 0.35 0.44
103
Palladium 17 20.8 keV Monotherapy 125 Gy 1.7– 2.2–
2.1 2.7
Combined 100 Gy 1.2– 1.6–
therapy 1.5 1.9
131
Cesium 9.7 30.4 keV Monotherapy 115 Gy 2.5– 1.6–
3.5 2.2
Combined 85 Gy 1.9– 1.2–
therapy 2.5 1.6
I-125: 1.27 U/mCi, Pd103: 1.29 U/mCi, Cs 137: 0.637 U/mCi

(Cha et al. 1999; Wallner et al. 2002a, 2003). The
higher energy and short overall treatment duration of
Cs-131 requires that during treatment planning the
seeds be placed further away from the rectum and
urethra than either I-125 or Pd-103 to achieve the
acceptable tolerance for these organs (Bice et al.
2008).
5.3 Post-Implant Evaluation
Postoperative CT-based dosimetric analysis provides
detailed information regarding the coverage and uni-
formity of an implant, affords the ability to compare
various intraoperative techniques, and provides a
sound basis for future improvement. Accurate delin-
eation of prostate contours on postimplant CT may be
difficult because of postoperative edema, degradation
of the image due to implanted metallic seeds, and a
possible tendency to overestimate prostate volume
from CT compared with transrectal ultrasound; how-
ever, a close correlation has been demonstrated for
CT and ultrasound-determined prostate volumes,
provided that the levator ani muscles and the anterior
venous complex are excluded from the CT-defined
prostate volume (Badiozamani et al. 1999; Merrick
et al. 1999a). When provided with instructions for
prostate volume determination, postbrachytherapy
prostate volumes were comparable among multiple
brachytherapists (Han et al. 2003). The use of post-
operative MRI fused with either X-rays or CT is
being explored to enhance the interpretation of post-
operative dosimetry (Acher et al. 2008).
The timing of CT after implantation remains con-
troversial. Some groups recommend that CT evalua-
tion be obtained 3–7 weeks following implantation to
allow for resolution of edema, whereas others propose
day-0 dosimetry to provide information about edema
when it is close to its maximum extent and for prompt
closure of the learning curve (Merrick et al. 2001c;
Prestidge et al. 1998; Waterman and Dicker 2002).
Day-0 CT based dosimetry may underestimate the
coverage by 10% (Moreland 1998; Yue et al. 1999).
Due to the slow resolution of perioperative edema and
the relatively low dose rate from the implanted iso-
topes, a postimplant CT scan at 3 ± 1 and
7 ± 2 weeks best represents the dose delivered to the
prostate over the life of the implant for Pd-103 and
I-125, respectively (Yue et al. 1999). Because of the
very short half-life of Cs-131, it has been recom-
mended that postimplant imaging for dose assessment
be performed on day-0 (Bice et al. 2008). In a series
of 50 consecutive patients implanted with I-125 that
had both day-0 and repeat scans 46 ± 23 days later,
Waterman and Dicker found that the V100 and D90
coverage improved by 5% ± 6% and 15% ± 17%
during the interval between scans (Waterman and
Dicker 2002). On the other hand, urethral dosimetry
may actually worsen in that time interval (Waterman
and Dicker 2000). The data would suggest that while
later CT scans may more accurately reflect dose
delivery, earlier scans are acceptable. If postimplant
Prostate
dosimetry from a day-0 CT scan is suboptimal, a
repeat CT scan and dose assessment 3–7 weeks later
may demonstrate improvement in the dose distribu-
tion from resolution of prostate edema.
The American Brachytherapy Society (ABS) rec-
ommends three steps in postimplant dosimetric eval-
uation: (1) examination of the isodose distribution on
the postimplant CT, (2) generation of DVH for
prostate, urethra, and rectum, and (3) determination of
dose uniformity and conformity indices. (Nag et al.
2000) The ABS recommends the following dose
report metrics: (1) D100, D90, and D80 of the pros-
tate, (2) V200, V150, V100, V90, and V80 of the
prostate, (3) the total volume of the prostate on the
postimplant CT, (4) relative timing of implantation to
the date of the postimplant CT, and (5) urethral and
rectal doses. The Groupe Européen de Curiethérapie
and the European Society for Therapeutic Radiology
and Oncology (GEC-ESTRO) recommended criteria
for postimplant dosimetry include the target volume
D90, V100, and V150 for both the prostate (CTV)
and the prostate with a 3 mm margin (CTV-PM) and
V200, D100, natural dose rate, homogeneity, and
conformality indices (Salembier et al. 2007).
Biochemical progression-free survival is related to
implant quality (Potters et al. 2005; Zelefsky et al.
2007a; Stock et al. 1998; Merrick et al. 2001d; Stone
et al. 2009). Stock et al. (1998) first reported a dose–
response curve for patients undergoing monothera-
peutic I-125 with superior biochemical results with a
day-30 D90 C 140 Gy. Of note, in the experience
reported by Stock, a minimum prescribed dose of
160 Gy (TG-43) was used in that series. In an eleven
institution series, Zelefsky reported the results of
2,693 patients treated with brachytherapy alone (no
external beam radiation or pretreatment hormone
therapy) (Zelefsky et al. 2007a). Among the patients
treated with I-125, a D90 C 130 Gy was associated
with an 8-year PSA relapse-free survival of 93%
compared to only 76% with lower D90 values
(p \ 0.001).
Because of the use of various isotopes with dif-
ferent dose rates, prescription values, and use of
supplemental external beam radiation therapy, Stock
described a method of calculating a Biologically
Equivalent Dose (BED) for these dissimilar pre-
scribing and treatment methods (Stock et al. 2006a).
Utilizing the linear quadratic model commonly used
in external beam therapy
999
BED ¼ nd ½1 þ ðd=a=bÞ
Where n = number of fractions; d = dose per
fraction; and a/b = a tissue and effect specific
parameter associated with the model. Stock applied
this to permanent seed implants
BED ¼ ðR0 =kÞf1 þ ½R0 =ðl þ kÞða=bÞg
where R0 = initial dose rate of implant =
(D90)(k); k = radioactive decay constant = 0.693/
T1/2; T1/2 = radioactive half-life of isotope;
l = repair rate constant = 0.693/t1/2; and t1/2 = tis-
sue repair half-time. The proposed values used for
these constants for prostate carcinoma were
a/b = 2 Gy, t1/2 = 1 h, and the known values
T1/2 = 60 days for I-125 and 17 days for Pd-103. In a
12 year update of their experience with
2,111 patients, Stone reported that higher post-
implant BED was associated with better biochemical
disease and local control. In a subset of 586 men that
underwent a 2-year postimplant biopsy to assess local
control, the persistent cancer rate was 21.5, 5.6 and
1.6% for BEDs B 150 Gy, 150–200 Gy, and
[200 Gy, respectively (Stone et al. 2011). In a multi-
institutional study, it was suggested that customized
dose prescriptions could be used based upon NCCN
risk groups (Stone et al. 2007). Patients with low-risk
disease had excellent biochemical disease control
with BED doses ranging from 140 to 200 Gy whereas
patients with intermediate or high-risk disease benefit
from a BED dose in excess of 200 Gy.
Detailed day-0 dosimetry demonstrated that pre-
scribed radiation doses are routinely obtainable with
day-0 evaluation using brachytherapy target volumes
that include generous periprostatic margins and ure-
thral sparing techniques (Figs. 20 and 21) (Merrick
et al. 2003e, 2001c). Extracapsular treatment margins
of 6.5 and 9.6 mm at the 100 and 75% isodose lines,
respectively, have been reported (Fig. 19) (Merrick
et al. 2003e). Except for the bladder neck and pos-
terior prostate border, the 100% isodose margin was
5 mm or greater. Approximately 35% of the seeds are
placed in extracapsular locations with a seed fixity rate
[98% (Merrick et al. 2000b). Generous periprostatic
treatment margins are useful in patients with an ele-
vated risk of extracapsular extension and a low risk of
pelvic lymph node involvement/distant metastases.
Postimplant dosimetry has also been associated
with toxicity and patient quality of life. Wallner
1000 J. M. Michalski and T. Wiegel

recommended keeping the central urethral dose to less

Fig. 20 Transverse postimplant isodose coverage of the
prostate, urethra, and rectal wall for a 145 Gy 125-Iodine
monotherapy implant of a prostate which had a preimplant
ultrasound volume of 36.5 g and a day-0 CT volume of 43.9 g.
The isodoses displayed are 100% (yellow) and 150% (orange)
of the prescribed dose. The urethra (purple) is contoured in the
prostate center and the rectum (blue) posteriorly
100
% Structure volume
than 400 Gy and the rectal surface dose to less than
100 Gy (Wallner et al. 1995). Snyder reported an
18% incidence of grade 2 proctitis if more than 1.3 cc
of rectal tissue received the prescription dose com-
pared to only 5% if less volume received that dose
(Snyder et al. 2001). Based upon a series of 98
patients, Waterman suggested that keeping the max-
imum rectal doses to \200, 250, and 300 Gy would
keep the incidence of late rectal toxicity to 1, 3, or
5%, respectively (Waterman and Dicker 2003). In a
series of 160 patients, Han reported that the RV100
(rectal volume receiving at least 100% of the pre-
scription dose) was 0.6 cc for patients without tox-
icity compared to 2.5 cc for patients experiencing late
rectal bleeding (Han and Wallner 2001). Similarly, in
a series of 562 patients implanted with real time
intraoperative dosimetry, Zelefsky reported an asso-
ciation of an RV100 C 2.5 cm3 and grade 2 rectal
bleeding (Zelefsky et al. 2007b). Urinary toxicity has
not been consistently associated with postimplant
dosimetric parameters. Crook was unable to demon-
strate an association between urethral dosimetry and a
risk of retention or other urinary toxicity (Crook et al.
2008, 2002). Merrick reported that urethral strictures
were most prevalent when the membranous urethra
distal to the prostate apex received a considerable
dose (Merrick et al. 2002b). It should be noted that the
association of toxicity with postimplant dosimetry has
been substantiated for I125 and Pd103 only. The new
isotope, Cs131 may have dose metrics for rectal and

80 urinary toxicity that differ from the others.

Prostate
60
Rectal
wall 5.4 Supplemental Therapies
40
Urethra
Both XRT and adjuvant ADT are commonly used as
20
supplements to brachytherapy in patients with adverse
pathological and/or biochemical features. Contempo-
0
0 50 100 150 200 250 300 rary series, however, suggest that with high-quality
% Prescription dose brachytherapy dose distributions and generous peri-
prostatic treatment margins (Blasko et al. 2000;
Fig. 21 Cumulative dose volume histograms of the prostate,
urethra, and the volume encompassed by the rectal wall.
Merrick et al. 2003e), in many patients adverse risk
Prostate dosimetric summary parameters of interest are factors can be managed with the implant alone.
V100 = 98.3% of the 38.7 cm3 day-0 CT volume. The
prostate: V150 = 68.8% and V200 = 34.0% of the volume, 5.4.1 External-Beam Radiation Therapy
and D90 = 116.7% of the 125-Gy monotherapy Pd-103 dose
prescribed; the urethra: V100 = 100%, V120 = 1.0%, and
The rationale for supplemental XRT combined with
V150 = 0%. The volume of the rectal wall receiving 100% of brachytherapy is to enhance the coverage of peri-
the prescribed dose was 0.18 cm3 prostatic tissue, escalate the dose to the intraprostatic
Prostate
tumor, supplement inadequate radiation dose distri-
butions, and/or treat locoregional disease. The ABS
has recommended monotherapy for patients with
clinical stage T1–T2a, PSA B 10 ng/ml, and Gleason
score B6 with the addition of supplemental XRT for
all other patients (Nag et al. 1999). When the com-
bination is used, external beam is administered to a
target volume that encompasses the prostate, seminal
vesicles, and 5–10 mm of periprostatic tissue. Most
centers administer the external beam followed by the
seed implant 2–4 weeks later. Some centers will
administer external beam therapy after the seed
implant if adequate time (2 months) has passed to
prevent simultaneous irradiation from the implant and
external therapy (Stone et al. 2011).
The utility of supplemental XRT has been ques-
tioned by favorable biochemical outcomes following
monotherapeutic brachytherapy in patients with
higher pretreatment PSAs and/or Gleason scores
(Blasko et al. 2000). The RTOG is conducting a
randomized trial comparing brachytherapy mono-
therapy to combined modality therapy for patients
with intermediate-risk disease (RTOG 2011). Most
brachytherapy centers continue to use combined
modality therapy for NCCN high-risk prostate cancer
(Potters et al. 2005; Stone et al. 2011; Dattoli et al.
2007; Merrick et al. 2007b; Stock et al. 2006b;
Sylvester et al. 2007).
Supplemental XRT may exacerbate brachyther-
apy-related morbidity. (Merrick et al. 2003c, f;
Kalakota et al. 2010). In a series of 110 patients
treated with either brachytherapy alone or in combi-
nation with external beam radiation therapy, Kalakota
reported that only men receiving EBRT along with a
brachytherapy RV100 C 0.05 cc had a 26% risk of
grade 2 toxicity compared to 0% if they did not
receive EBRT or with a RV100 \ 0.05 cc (Kalakota
et al. 2010). Zelefsky found that rates of Grade 2 GI
toxicity with combined modality therapy was 9 versus
1% with an implant alone (p \ 0.0001) (Zelefsky
et al. 2008b).
5.5 PSA Bounce
Following radiation treatment many patients may
experience a transient increase in their PSA followed
by a subsequent decline. While first described in
conjunction with brachytherapy (Critz et al. 2000), it
1001
has been reported in patients undergoing external
beam radiation therapy as well (Horwitz et al. 2006).
Depending on the magnitude of the rise used in the
definition of PSA bounce as many as half of patients
may experience an increase of 0.1 or 0.2 ng/ml
(Crook et al. 2007; Merrick et al. 2003g; Toledano
et al. 2006). While PSA bounce has been associated
with an increase in failure following external beam
radiation therapy (Horwitz et al. 2006), it has not
been associated with failure following brachytherapy
(Crook et al. 2007). It has been proposed that
bounces are a result of compromised membrane
integrity in PSA-producing epithelium (Merrick et al.
2003g). In a series of 24 patients undergoing 3D
magnetic resonance spectroscopy, Kirilova described
diffuse metabolic activity unrelated to residual
malignancy supporting the benign nature of the PSA
bounce and suggesting an inflammatory etiology
(Kirilova et al. 2011). The PSA spikes have been
correlated with younger patient age, clinical stage,
benign prostatic hyperplasia, baseline postimplant
PSA, and postoperative dosimetric parameters
(Merrick et al. 2003g).
Posttreatment prostate biopsies to differentiate
viable cancer from a PSA bounce can be misleading
(Crook et al. 1995b). Previous studies of prostate
biopsies following XRT alone have demonstrated a
slow resolution of the histological evidence of pros-
tate cancer presence which may require up to 3 years
of follow-up for accurate pathological assessment.
Despite an increasing PSA and a biopsy positive for
recurrent cancer, prostate brachytherapy patients have
been reported to normalize serum PSA without
additional therapeutic intervention (Reed et al. 2003).
Patients that experience a PSA bounce should be
reassured with consideration of doing a repeat biopsy
if PSA elevation persists beyond 30 months or eval-
uation for systemic disease if the PSA exceeds 10 ng/
ml (Crook et al. 2007).
5.6 Approaches to Minimize Morbidity
5.6.1 Urinary
An enlarging body of data demonstrates that brachy-
therapy-related urinary morbidity can be lessened
with refinements in patient selection, medical inter-
vention, and intraoperative techniques.
1002
Urinary morbidity in the immediate postimplant
setting has been well documented with preimplant IPSS
correlating with the duration of postimplant obstructive
symptoms (Merrick et al. 2000a; Terk et al. 1998; Desai
et al. 1998). Alpha blockers are widely used to amelio-
rate brachytherapy-related urinary morbidity, and the
timing of their initiation may substantially influence
their effect (Merrick et al. 2000a, 2002a). Following a
policy of prophylactic and prolonged medication use,
IPSS values returned to baseline values 3 months fol-
lowing brachytherapy (Merrick et al. 2000a, 2002a). In
contrast, without the use of prophylactic alpha blockers,
a timeline of approximately 12 months was reported for
IPSS resolution (Desai et al. 1998); however, the use of
alpha blockers did not correlate with the incidence of
prolonged urinary catheter dependency or the need for
postimplant surgical intervention (Merrick et al. 2002a).
The initiation of alpha blockers 2–3 weeks before
implantation, with continuation until IPSS normaliza-
tion, maximizes their beneficial effect. In terms of iso-
tope, a prospective randomized trial comparing Pd-103
with I-125 reported a statistically faster rate of IPSS
resolution in the Pd-103 arm (Wallner et al. 2002a).
Although dysuria is a relatively common event
during the first few years following brachytherapy,
only rarely is it severe in frequency or intensity
(Merrick et al. 2003h). To date, no significant factors
for the prediction of dysuria have been reported. In
addition, the use of alpha blockers has not signifi-
cantly diminished the duration of dysuria; however,
anti-inflammatory agents (low-dose prednisone,
5–10 mg daily) and the avoidance of bladder irritants
(i.e., caffeine, alcohol) may alleviate the intensity and
frequency of treatment-related dysuria.
Wallner et al. (1995) reported an association
between urinary morbidity and urethral doses [250%
of the minimum peripheral dose (mPD). In contem-
porary series, urethral doses have not been correlated
with urinary morbidity because of sophisticated
treatment planning with urethral sparing (100–140%
mPD) (Allen et al. 2005). While urethral doses
[150% mPD should be minimized, underdosage
(\100% mPD) should be avoided as well. Leibovich
et al. (2000) reported that the mean distance from the
urethra to the nearest foci of cancer was 3 mm with
17% of all prostate cancers abutting the urethra. In a
series of 458 men with favorable risk prostate cancer,
Crook reported that 27% of men had significant uri-
nary sequellae after the first year but no clinical or
J. M. Michalski and T. Wiegel
technical parameters were correlated with a poor
outcome (Crook et al. 2008).
It is conceivable that certain segments of the ure-
thra may be more sensitive to radiation-induced
morbidity; however, detailed urethral dosimetry did
not substantially improve the ability to predict urinary
morbidity (Allen et al. 2005). Radiation doses of 100–
140% mPD were well tolerated by all segments of the
prostatic urethra with resultant tumoricidal doses to
foci of periurethral cancer (Allen et al. 2005).
Urethral strictures occur in 5–12% of patients and
are directly related to overimplantation of the periapi-
cal region (Merrick et al. 2002b). Strictures typically
involve the bulbomembranous urethra and are easily
managed with dilatation. Day-0 CT-based dosimetry
demonstrated that radiation doses to the bulbomem-
branous urethra were significantly greater in patients
with strictures than in those without (Merrick et al.
2002b). With careful attention to implant technique,
including extensive use of the sagittal plane for depo-
sition of the seeds, it is possible to implant the apex with
a 5 mm margin without ‘‘dragging’’ seeds into the
region of the bulbomembranous urethra. An ADT of
longer than 6-month duration also increased the like-
lihood of urethral strictures (Merrick et al. 2002b).
5.6.2 Rectal Morbidity
Rectal complications primarily consist of mild self-
limiting proctitis with an incidence of 4–12% and
usually resolve spontaneously (Snyder et al. 2001;
Merrick et al. 2003f, i; Gelblum and Potters 2000).
Snyder et al. (2001) reported grade-II proctitis to be
volume dependent for a given dose with no case
developing proctitis more than 36 months following
implantation. With day-30 dosimetry, an 8% rate of
grade-II proctitis was reported when \1.8 cm3 of
rectum was exposed to C160 Gy following I-125
monotherapy, whereas the risk increased to 25% when
[1.8 cm3 of rectum was exposed to this dose. In a
prospective randomized trial, the minimum dose
received by 5% of the rectum best correlated with
brachytherapy-related rectal dysfunction (Merrick
et al. 2003i). A limited number of errant perirectal
sources did not increase the risk of rectal bleeding,
provided that the overall rectal wall doses were within
acceptable values (Mueller et al. 2004). In a series of
458 men treated with combined XRT and brachy-
therapy, Shiraishi reported a 4.2% rate of grade 2
rectal bleeding with both the RV100 B 0.5 ml and
Prostate
Fig. 22 Transverse magnetic
resonance image of the
proximal penis
the V30 B 35% compared to 22.4% with an
RV100 C 0.5 ml and V30 C 35% (Shiraishi 2011c).
To compare rectal doses between series, the timing of
postimplant CT must be documented. Waterman and
Dicker (1999) reported that the minimum dose that
encompassed 10% of the surface area of the rectum
increased on average by 68% from day 0 to day 30.
Rectal ulceration and fistula formation have occa-
sionally been reported by Howard et al. (2001).
Although dose is associated with rectal bleeding, no
correlation between rectal dose and the development of
a fistula was identified with the subsequent conclusion
that severe complications may occur in an unpredict-
able manner typically unrelated to known clinical,
treatment, or dosimetric parameters (Howard et al.
2001). Although no studies have correlated constipa-
tion with rectal toxicity, constipation significantly
increases the radiation dose to the rectum (Merrick
et al. 2000c). Postimplant attention to bowel habits for
two half-lives of the implanted isotope will minimize
rectal distention and decrease the dose to the anterior
rectal wall. Bowel function assessment by patient-
administered questionnaires has documented that long-
term bowel dysfunction following brachytherapy is
relatively uncommon (Merrick et al. 2003f, i; Talcott
et al. 2001).
Intraoperatively, careful attention to implant tech-
nique and ultrasound anatomy will reduce the dose to
the anterior rectal wall and minimize bowel dys-
function. Extensive use of both transverse and sagittal
images to confirm appropriate needle placement and
the use of multiple ultrasound frequencies helps
ensure proper seed placement. Higher transducer
frequencies results in clearer definition of anatomy
closer to the probe. Posterior-row needle placements
1003
performed with the 7.5-MHz setting help ensure that
needles are placed just within the posterior prostate
capsule and not in the rectal wall.
5.6.3 Erectile Dysfunction
The specific anatomic structure(s) and physiological
mechanisms of post-irradiation erectile dysfunction
are unclear (van der Wielen et al. 2007). The penile
erectile bodies (the paired corpora cavernosa and
midline corpora spongiosum) represent potential tar-
gets for structure-specific radiation-associated erectile
dysfunction (ED; Fig. 22). Detailed reports illustrat-
ing the image-based anatomy of the proximal penis
have been published (van der Wielen et al. 2007;
Wallner et al. 2002b). The penile bulb is best visu-
alized on T2-weighted MR images and appears as an
oval-shaped, hyperdense midline structure located on
average 10–15 mm inferior to the apex of the prostate
gland. As the penile bulb has relatively little role in
achieving and maintaining an erection, its relationship
to erectile dysfunction may be its proximity to
structures such as the neurovascular bundles, the crura
of the corpora cavernosa or the internal pudendal
arteries (van der Wielen et al. 2007).
In XRT studies, the dose to the proximal penis has
been related to posttreatment ED with the conclusion
that XRT either directly or indirectly damages the
vascular supply of the erectile tissue as well as the
nerves that supply the cavernosa smooth muscles
(Fisch et al. 2001; Roach et al. 2004; Carrier et al.
1995). Subsequent histological examination of proxi-
mal penile shaft specimens demonstrated that the
number of nitric oxide synthase-containing nerve fibers
per corpora cavernosa were significantly decreased in
an irradiated group of men (Carrier et al. 1995).
1004
Following brachytherapy, Merrick et al. (2003e,
2001e) reported that treatment-induced ED was highly
dependent on the radiation dose to the proximal penis.
With day-0 dosimetry, maximum potency preservation
was dependent on limiting the penile bulb D50 to
B30% of prescription dose and the proximal crura D50
to B50% of prescription dose (Merrick et al. 2005c).
With adherence to these cutpoints, [70% of patients
maintained potency versus only 30% in patients who
received higher doses to these structures. In a study of
226 previously potent patients, Taira found that pre-
implant potency (as measured by the International
Index of Erectile Function), hypertension, diabetes,
prostate size, and brachytherapy dose to the proximal
penis strongly predicted for potency preservation (Ta-
ira et al. 2009). Not all studies support dose to the
corpora cavernosa as relevant to the development of ED
(Selek et al. 2004; van der Wielen et al. 2007). In an
analysis of patients enrolled on a randomized dose
escalation trial with EBRT, van der Wielen found no
correlation between ED and dose to the crura or penile
bulb (van der Wielen et al. 2007).
Following RP, ED has been correlated with sur-
gical trauma to the neurovascular bundles (NVB). It is
conceivable that excessive NVB radiation could also
represent a potential mechanism of brachytherapy-
induced ED (DiBiase et al. 2000); however, in both
prospective and retrospective studies, no relationship
between NVB radiation doses and the development of
brachytherapy-induced ED was discerned (Merrick
et al. 2000d, 2001f). Although initial reports have
been negative, it is possible that with additional fol-
low-up, radiation dose to the NVB may contribute to
brachytherapy-related erectile dysfunction.
From a clinical perspective, potency preservation
after brachytherapy is most closely related to preimplant
erectile function (Merrick et al. 2005c, 2002c; Stock
et al. 2001). The role of neoadjuvant ADT has been
mixed (Merrick et al. 2005c, 2002c; Stock et al. 2001;
Potters et al. 2001), whereas the choice of isotope
appears unrelated (Merrick et al. 2005c, 2002c; Stock
et al. 2001). A prospective randomized trial reported that
only preimplant erectile function and dose to the proxi-
mal penis were statistically significant predictors of
brachytherapy-related ED (Merrick et al. 2005c). For-
tunately, brachytherapy-related ED responds favorably
to sildenafil citrate (Merrick et al. 2002c, 1999b).
A lack of erectile activity may be deleterious to
long-term erectile function, and as such, patients
J. M. Michalski and T. Wiegel
should be encouraged to develop regular erections
with or without sexual relations (Mulhall 2001). In the
absence of routine penile erections, the corporal
smooth muscle experiences chronic hypoxia with a
resultant loss of elasticity and distensibility which
may lead to a venous leak (Moreland 1998). The early
institution of phosphodiesterase (PDE)-5 inhibitors in
patients with compromised or absent erections may
help restore erectile function (Mulhall 2001; Pahlajani
et al. 2010; Schiff et al. 2006). Several studies support
the possibility for recovery of sexual dysfunction after
initial deterioration following brachytherapy (Taira
et al. 2009; Ash et al. 2007).
Although brachytherapy-induced ED is likely
multifactorial, the available data strongly support the
proximal penis as an important site-specific structure.
Suboptimal seed placement (either due to poor plan-
ning or poor implementation) of periapical radiation
sources results in excessive radiation doses to the
proximal penis. Refinements in implant technique to
avoid overaggressive periapical implantation, along
with the extensive use of sagittal ultrasonography
during implantation, will decrease the radiation dose
to the proximal penis and may ultimately improve
potency preservation.
Although the majority of the brachytherapy litera-
ture has demonstrated biochemical results and mor-
bidity profiles that compare favorably with competing
local modalities, it has become increasingly apparent
that efficacy and morbidity are highly dependent on
implant quality. Sophisticated dosimetric analyses
have demonstrated that cure rates, urinary and rectal
complications, and potency preservation are related to
specific source placement patterns and the subsequent
dose gradients produced. Our upcoming challenges
include the development of intraoperative planning and
dosimetry to improve implant quality, improved
intraoperative technique to include manual dexterity
and imaging, and the development of evidence-based
algorithms.
6 High-Dose-Rate Brachytherapy
6.1 Introduction
Just as in permanent LDR brachytherapy, the devel-
opment of sophisticated technologies has contributed
to the resurgence of high-dose-rate brachytherapy
Prostate
Fig. 23 Representative dose distribution of an HDR plan, a PPI pre-plan, and a PPI postplan (from Wang et al. 2006)
(HDR-BT) as a viable option for the treatment of
localized prostate cancer. With HDR-BT the delivery
of highly conformal radiotherapy can be achieved to
the target combined with comparatively low radiation
exposure to the adjacent normal tissues (e.g., rectum
and bladder). The apparent advantages with hypo-
fractionation in prostate cancer and the total doses
achievable with HDR-BT are discussed below.
6.2 Technological Aspects
The HDR-BT techniques using temporary iridium-
192 implantation were introduced in the early 1980s
(Charyulu 1980; Martinez et al. 1985; Syed et al.
1983), and encouraging long-term outcome data have
been reported (Borghede et al. 1997; Demanes et al.
2011d, 2005; Galalae et al. 2004; Hoskin et al. 2007;
Hsu et al. 2005; Kovács et al. 1999; Martinez et al.
2003, 2005; Yamada et al. 2006; Yoshioka et al.
2006). The introduction of transrectal ultrasound
(TRUS)-guided implantation technologies and 3D
dose-planning systems have further revolutionized
this treatment modality. A large variety of dose-
planning systems are currently being used, both
commercially available systems and systems devel-
oped at different treating centers. There are also dif-
ferent optimization programs available, such as dose-
point optimization, geometrical optimization, and
inverse optimization programs (Fig. 23) (Edmundson
1994; Hsu et al. 2004; Kolkman-Deurloo et al. 1994;
Lessard and Pouliot 2001; Yoshioka et al. 2005).
Many centers use intraoperative optimization dose-
planning systems, whereas others perform pre-therapy
1005
dose planning. Most dose-planning techniques are
TRUS-based, but CT- and MRI-based dose-planning
systems are being advocated at other centers. Briefly,
when using the TRUS-based techniques, the patient is
placed in an extended lithotomy position and a Foley
catheter is inserted into the bladder to visualize the
urethra. An ultrasound transducer is introduced to the
rectum to evaluate the prostate, urethra, urinary
bladder, and seminal vesicles. A matrix indicating
possible positions for the needles (according to the
template to be used for the transperineal insertion of
needles) is overlaid in the TRUS image. During
TRUS, axial cross-sections are acquired in 5-mm
steps using a stepping device and transferred to the
treatment-planning software. The dose-planning sys-
tem is used to optimize the dose in such a way that, in
each 5-mm step, it enables coverage of the target
without exceeding tolerance of rectum, urethra, and
bladder. The planning target volume (PTV) is defined
as the entire prostate without the central area around
the urethra. One of the obvious advantages with
HDR-BT is, in comparison with permanent seed
implantation, the greater ability to optimize dose
distribution by varying source dwell times along the
needles/catheters.
Most patients have spinal anesthesia for pain
management, and the treatment is performed with the
patient placed in the extended lithotomy position with
a Foley catheter inserted into the bladder. The treat-
ment is usually delivered with the use of 17-G needles
which are inserted transperineally into the prostate
through the template mounted on the probe stand.
Some centers prefer the use of flexible catheters
instead of needles for application of the iridium-192
1006 J. M. Michalski and T. Wiegel

Table 14 HDR prescription and dose constraints employed at California EndocurieTherapy and William Beaumont Hospital
prescription tumor doses (Gy) and maximum normal doses (as percent of prescription)
Protocol Tumor Bladder Rectum Urethra D90 V100 BED EBRT equivalent
CET 7 Gy 9 6 80% 80% 110% [100% [97% 205 103 Gy
42 Gy
WBH 9.5 Gy 9 4 80% 75% 120% [100% [96% 239 119 Gy
38 Gy
CET and WBH doses are nearly identical because CET dose is calculated 5 mm beyond the prostate capsule and WBH calculated
at the capsule
BED biologic equivalent dose with alpha/beta ratio of 1.8, EBRT equivalent external beam dose equivalent using 1.8 Gy fraction
daily, CET California Endo curietherapy, WBH William Beaumont Hospital
Demanes et al. IJROBP (2011) epub ahead of print

sources. The positioning (x–y axis) of each needle
according to the template–matrix coordinates and the
insertion length (z axis) are verified with the TRUS.
The positioning of each needle should be within
0–2 mm from the position recommended by the dose
plan. Typically, 9–20 needles are used depending on
the size and anatomy of the prostate and adjacent
organs at risk.
The treatment is performed using a computer-
based remote afterloading technique in which the
iridium-192 source is inserted into each of the needles
or catheters utilizing stop positions and dwell times
according to the dose plan. There is no consensus on
dose constraints to normal tissues; however, the
Radiation Therapy Oncology Group (RTOG) phase-II
HDR study (p0321) has limited to 1 cc the volume of
urethra receiving 125% of the prescription dose and to
1 cc of rectum and bladder receiving 75% of pre-
scription dose. Usually it is possible to achieve these
dose constraints while obtaining at least 90–95% of
the prescribed dose to the clinical target volume.
Demanes and Martinez recently summarized the
prescription and organ at risk dose guidelines used at
William Beaumont Hospital and the California En-
docurietherapy center (Table 14) (Demanes et al.
2011d).
6.3 Radiobiological and Dose
Fractionation Aspects
There is ample clinical data supporting the assump-
tion that prostate tumors have (for malignant disease)
exceptionally low a/b values, i.e., reflecting a stronger
enhancement of tumor effect than late complications
for larger and fewer radiation dose fractions (Brenner
and Hall 1999; Fowler et al. 2001, 2003; Brenner
et al. 2002; Fowler 2005). The careful dose escalation
studies by Martinez et al. (2001), and the remarkably
good outcome data, have resulted in the first direct
clinical evidence that a/b is as low as 1.2–1.5 Gy
(Brenner et al. 2002). In most studies, HDR-BT has
been used as a radiation boost technique in combi-
nation therapy with external-beam radiation therapy
(EBRT). A wide range of HDR fractionation sched-
ules have been reported in these studies. A review of
the literature shows that the median brachytherapy
dose used in the larger trials is 20 Gy and the median
EBRT dose 45 Gy in 5 weeks (Morton 2005). Two
different approaches to HDR fractionation have
evolved: separate catheter insertions for each brach-
ytherapy treatment or, alternatively, one single
insertion followed by two to four fractions delivered
over 2 days. The approach can be performed on an
outpatient basis, whereas the latter, which is more
commonly used in the U.S., requires hospital admis-
sion. The treatment regimens, technological aspects,
and calculated biologically equivalent doses from the
largest treatment series are summarized in Table 15.
6.4 Clinical Outcome Data From HDR-BT
Plus EBRT
The technique of HDR prostate brachytherapy has
been in clinical practice since the 1980s (Kestin et al.
2000; Martinez et al. 1995, 2000b). Kovacs et al.
reported one of the earliest experiences using HDR
brachytherapy boost at University of Kiel (Kovács
et al. 1999). Patients selected were mostly those with
Table 15 Outcomes with combined External Beam Radiation therapy (EBRT) and High-Dose Rate Brachytherapy (HDR)
Author Year N EBRT HDR dose BED3 Biochemical Endpoint % Intermediate B-DFS CSS OS
Prostate

dose (Gy) endpoint interval (y) and High risk

Mate et al. 1998 104 50.4 Gy 3–4Gy 9 4 105– ASTRO 5 ns 84% if iPSA \ 20 NS NS
(1998) 118
Galalae et al. 2002 144 40– 9–15 Gy 9 1 139 ASTRO 8 68% 69% 90% 70%
(2002) 50 Gy
Pellizzon 2003 108 45 Gy 4–5Gy 9 4 109– ASTRO 4 49% 75% NS NS
et al. (2003) 153
Hiratsuka 2004 71 41.8– 5.5Gy 9 3–4 119– ASTRO 5 93% NS 95%
et al. (2004) 45Gy 135
Martin et al. 2004 102 39.6 Gy– 5–7Gy 9 4 125– ASTRO 3 85% 82% 98% 90%
(2004) 45 Gy 146
Demanes 2005 209 36 Gy 5.5–6Gy 9 4 126– ASTRO 10 66% 81% 97% 79%
et al. (2005) 144 Phoenix 80%
Astrom et al. 2005 214 50 Gy 10Gy 9 2 170 ASTRO 5 63% 82% 97% 89%
(2005)
Deger et al. 2005 411 40– 9–10Gy 9 2 144– ASTRO 5 79% 65% 94% 87%
(2005) 50.4 Gy 153
Hsu et al. 2005 64 45 Gy 6Gy 9 3 126 ASTRO 4 91% 92% 92% 98%
(2005)
Chin et al. 2006 67 37.5 Gy 8.5Gy 9 2 134 ASTRO 3 92% 91% NS NS
(2006)
Izard et al. 2006 165 50.4 6 Gy 9 3 135 ASTRO 3 83% 88% 98% 93%
(2006)
Vargas et al. 2006 197 46Gy 5.5–6.5 Gy 9 3 or 123– ASTRO 5 100% 83% 98% 93%
(2006) 8.25–11.5 Gy 9 2 188
Yamada et al. 2006 105 45Gy 5.5–6.5Gy 9 3 119– ASTRO 5 85% 96% NS NS
(2006) 151
Hoskin et al. 2007 109 37.5Gy 8.5Gy 9 2 134 ASTRO 5 80% NS NS
(2007)
Rades et al. 2007 41 50.4 Gy 9Gy 9 2 153 ASTRO 3 100% 57% w/o SVdose
(2007) 79% w SVdose
(continued)
1007
1008 J. M. Michalski and T. Wiegel

ASTRO American Society of Radiation Oncology definition of biochemical failure, Phoenix current nadir ? 2 ng/ml definition of biochemical failure, SVdose dose delivered to
high grade T2b-T3 lesions who were treated with a

91%

84%
OS

NS
combination of split course EBRT and two 15 Gy
98% HDR treatments. The positive biopsy rate was 18% at

94%

96%
CSS

18 months post treatment. The results were updated at

10 years and 78% of 171 patients remained free of
disease at a median follow-up of 55 months. Mate
et al. at Swedish Medical Center reported their
experience with HDR brachytherapy (Mate et al.
1998). This group used a more moderate hypofrac-
B-DFS

tionated schema with four HDR treatments of 3–4 Gy

86%

84%

86%

each combined with 45–50 Gy EBRT. Pretreatment

patient characteristics were stage T1b to T3c, mean
initial PSA of 12.9 and Gleason grade range of III to
% Intermediate
and High risk

IX. The 5-year biochemical DFS was 84%. In a

pooled analysis of 611 patients from the University of
[63%

Kiel, the Seattle Prostate Institute and the William

78%

54%

Beaumont Hospital, Galalae reported 5- and 10-year

biochemical DFS rates of 77 and 73%, respectively
interval (y)

(Galalae et al. 2004). Of note, more than half the

Endpoint

patients in this multicenter analysis had two or more

high-risk features.
5

A prospective randomized clinical trial comparing

PSA \ 2 ng/

EBRT plus an Iridium brachytherapy boost and

Biochemical

EBRT was performed by Sathya et al. (2005) at

endpoint

Phoenix
ASTRO

Hamilton Regional Cancer Center, Ontario. Patients

ml

with localized T2 and T3 disease were randomly

assigned to EBRT of 66 Gy in 33 fractions during
BED3

126–

6.5 weeks (n = 53) or to iridium brachytherapy of

(Gy)

144
170

127

35 Gy delivered to the prostate over 48 h plus EBRT

of 40 Gy in 20 fractions during 4 weeks (n = 51).
While iridium was the isotope utilized in this study,
the dose rate is slower than typical HDR-BT and
5–6Gy 9 3-4

without fractionation. The primary outcome consisted

5.5Gy 9 3
HDR dose

10Gy 9 2

of biochemical or clinical failure (BCF), defined by

biochemical failure, clinical failure, or death as a
result of prostate cancer. Secondary outcomes inclu-
ded 2-year postradiation biopsy positivity, toxicity,
50.4 Gy

50.4 Gy

and survival. The median follow-up was 8.2 years. In

EBRT

50 Gy
dose

the brachytherapy plus EBRT arm, 17 patients (29%)

36–

experienced BCF compared with 33 patients (61%) in

seminal vesicles, NS not stated

the EBRT arm (hazard ratio 0.42; p = 0.0024).

309

154

85
N

Eighty-seven patients (84%) underwent a postradia-

tion biopsy; 10 (24%) of 42 in the brachytherapy plus
2007

2007

2007
Year
Table 15 (continued)

EBRT arm had biopsy positivity compared with 23

(51%) of 45 in the EBRT arm (odds ratio 0.30;
Kalkner et al.

p = 0.015). It was concluded that the combination of

Chen et al.
Phan et al.

brachytherapy plus EBRT was superior to EBRT

Author

(2007)

(2007)

(2007)

alone for BCF and postradiation biopsy. The trial

provides evidence that higher doses of radiation
Prostate
delivered in a shorter duration of time results in
improved local as well as biochemical control in
locally advanced prostate cancer (Sathya et al. 2005).
A second phase III trial compared EBRT alone with
EBRT combined with a temporary HDR-BT implant
(Hoskin et al. 2007). A total of 220 patients were
randomized to receive 55 Gy in 20 fraction or
35.75 Gy in 13 fractions followed by an HDR-BT
boost of 17 Gy in two fractions over 24 h. With a
median follow-up of 30 months, a significant
improvement in the biochemical relapse-free survival
was seen with the combined modality regimen. There
was also an improvement in rectal toxicity and quality
of life in men treated with the combined EBRT and
HDR-BT regimen. It should be noted that the bio-
logical equivalence of the EBRT dose of 55 Gy in 20
fractions is relatively low by modern dose escalation
standards. Assuming an a/b = 1.5 or 3, the compa-
rable dose in 2 Gy fractions is only 66.8 or 63.2 Gy,
respectively. These studies demonstrate the value of
dose escalation and not necessarily that and HDR-BT
boost is better to achieve disease control over other
conformal methods.
Vargas et al. at the William Beaumont Hospital
reported results of a prospective dose escalation trial
using increasingly larger fractions of HDR from
5.5–6.5 Gy 9 3 to 8.25–11.5 Gy 9 2 combined with
46 Gy of EBRT in patients intermediate and high-
risk disease.(Vargas et al. 2006). Assuming an a/b
ratio of 1.2, the calculated biologically equivalent
doses ranged from 80.2 to 94.2 Gy for the low dose,
three fraction group and 99.9–136.3 Gy for the high
dose, two fraction group. While the rate of mild
grade 1–2 dysuria was significantly higher with the
high-dose group, there were no other significant
differences in toxicity for the two groups. The
11.5 Gy 9 2 regimen was considered a tolerable
regimen. Despite a high frequency of poor prog-
nostic factors, the 5-year actuarial biochemical
control rate was 67 and 86% for the low-dose and
high-dose groups, respectively. The 5-year clinical
DFS was 75.5 and 91.7% for the low- and high-dose
arms, respectively (Vargas et al. 2006).
Early results of HDR implant monotherapy in the
management of low-risk prostate cancer have been
reported (Yoshioka et al. 2006; Grills et al. 2004).
The rates of acute urinary and rectal toxicities were
reported to be less frequent than with permanent seed
implantation using 103Palladium and the rates of
1009
chronic urinary frequency and urgency were also less
common (Grills et al. 2004). Biochemical DFS
appeared good but the follow-up was too short to
claim equivalence to other RT methods (Yoshioka
et al. 2006; Grills et al. 2004).
6.5 The Role of Neoadjuvant
and Concomitant Endocrine Therapy
Several prospective randomized trials have demon-
strated that hormonal manipulation, in conjunction
with conventional doses (65–70 Gy) of EBRT, results
in improvements in disease-free survival and overall
survival in patients with locally advanced prostate
cancer. The role for hormone therapy in conjunction
with combined HDR-BT with or without EBRT is
less clear. Martinez and co-workers have presented
outcome data on this topic from a large series of
consecutive patients (n = 1,260) treated between
1986 and 2000 at William Beaumont Hospital, Kiel
University Hospital, and California Endocurietherapy
Cancer Center, respectively. The biologically equiv-
alent EBRT dose used in this study ranged between
90 and 123 Gy (median 102 Gy) using an a/b of 1.2.
Patient eligibility criteria included iPSA C10, Glea-
son score C7, or clinical stage C T2b. A total of 934
of 1,260 patients met the inclusion criteria and were
included in the study. These patients were divided up
for analysis between the 406 who received up to
6 months of androgen deprivation therapy and the
528 patients who did not. Median follow-up time was
4.4 years for androgen-deprivation therapy patients
and 4.9 for radiation alone. There was no difference at
5 and 8 years in overall survival, cause-specific sur-
vival, or biochemical control. The corresponding
8-year rates, with and without androgen deprivation
therapy, were as follows: biochemical control 85 and
81%; overall survival 83 and 78%; cause-specific
survival 89 and 94%; and metastatic rates of 16.6 and
7.3%. The authors concluded that at 8 years, the
addition of a course of 6 months or more of neoad-
juvant/concurrent androgen-deprivation therapy to a
very high radiation dose did not confer a therapeutic
advantage (Martinez et al. 2005). The question that
remains to be answered is whether the favorable
interaction between hormone therapy and external
beam radiation therapy seen with respect to disease-
free and overall survival in the large prospective trials
1010
may be a result of the inability of conventional doses
of EBRT as a monotherapeutic approach to sterilize
large prostate cancers, and as such it may not be
applicable to dose escalated local therapy such as
HDR-BT. Carefully designed prospective studies
stratifying between low-, intermediate-, and high-risk
groups could give a conclusive answer as to whether
or not short-term neo-adjuvant hormone therapy
increases the cure rate also after combination therapy
HDR-BT and EBRT.
6.6 Discussion/Future Aspects
The large gap in the rate of prostate cancer death
compared to the very high incidence of new prostate
cancer diagnoses underlines the significant heteroge-
neity in the biology of this disease. Understanding
which individuals harbor clinically significant disease
remains an important challenge for clinical investi-
gation. The value of PSA screening has been ques-
tioned due to its low sensitivity and specificity. Once
the diagnosis of prostate cancer is established, genetic
screens for cancer aggressiveness will help identify
patients for whom aggressive local or systemic ther-
apy is warranted. Treatment decisions in the future
will be driven less by conventional anatomic-based
stage grouping but rather by clinical and biological
markers.
Radiation oncologists will select treatment vol-
umes, radiation doses, and adjuvant therapies that
target individual cancer specific sensitivity or host
factors to maximize tumor control and minimize side
effects. Adaptive radiation therapy strategies are cur-
rently focusing on tailoring technical aspects of treat-
ment delivery to escalate radiation dose in patients that
are best able to tolerate the therapy. Eventually, assays
of normal tissue radiation sensitivity could allow
biology-based dose and fractionation prescriptions.
The choice between conventionally fractionated as
opposed to short course, hypofractionated RT will be
made based upon patient and tumor biology.
The choice between radiation and other treatment
modalities may be driven largely by the impact a
therapy has on a patient’s future quality of life and not
on the expected cancer control outcome. This deci-
sion applies not only to surgery or radiation, but also
on the choice between conformal X-rays, IMRT,
proton therapy, stereotactic radiation therapy, and
J. M. Michalski and T. Wiegel
brachytherapy. Radiation oncologists will need to
support clinical trials to allow us to draw meaningful
conclusions about the relative benefits of the variable
treatment options available to our patients.
Continued investigation on systemic therapies and
the interplay between the androgen receptor and
hormone sensitivity will allow discovery of more
effective androgen deprivation and chemotherapeutic
regimens. The complementary role of local therapies
such as RT or surgery, along with new systemic
agents in locally advanced and high-risk disease is
currently undergoing evaluation in clinical trials.
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 Testicular Cancer
Gerard C. Morton and Maria Pearse

Contents 6.2 Acute Side Effects..................................................... 1037

6.3 Late Side Effects ....................................................... 1038

1 Introduction and General Management ............... 1028 7 Summary................................................................... 1038

1.1 Anatomy..................................................................... 1029
1.2 Natural History .......................................................... 1030
2 Management by Stage ............................................. 1030
2.1 Stage I Seminoma ..................................................... 1030
2.2 Stage II Seminoma .................................................... 1031
3 Radiation Therapy Techniques..............................
3.1 Target Volume and Field Borders ............................
3.2 Simulation and Treatment Planning .........................
3.3 Dose and Fractionation .............................................
3.4 Treatment Delivery....................................................
4 Intratubular Germ Cell Neoplasia ........................ 1035
5 Special Considerations ............................................
5.1 Scrotal Invasion/Scrotal Interference........................
5.2 Contralateral Germ Cell Tumors ..............................
5.3 Residual Mass Post-Chemotherapy...........................
6 Treatment Results.................................................... 1037
6.1 Disease-Free Survival................................................ 1037
G. C. Morton (&)
M. Pearse
Radiation Oncologist,
Sunnybrook Odette Cancer Centre,
University of Toronto, 2075 Bayview Avenue,
Toronto, ON M4N 3M5, Canada
e-mail: gerard.morton@sunnybrook.ca
M. Pearse
Department of Radiation Oncology,
University of Auckland Medical School,
Auckland, New Zealand
References.......................................................................... 1038
Abstract
Testicular cancer is a common malignancy of young
1031 men, and almost always of germ cell origin.
1031 Radiotherapy has an important role in the manage-
1032
ment of seminoma, whereas non-seminoma is
1035
1035 typically managed by surgery and chemotherapy.
Stage I seminoma may be managed by surveillance,
adjuvant radiotherapy or chemotherapy. The clini-
1036 cal target volume includes the para-aortic nodes and
1036
usually the ipsilateral common and proximal exter-
1036
1037 nal iliac nodes. Renal hilar nodes are included for
left-sided tumors. No follow-up pelvic imaging is
required if the upper pelvic lymph nodes are
included in the treatment volume, whereas ongoing
CT surveillance of the pelvis is required if treatment
is limited to the para-aortic region alone. Radiation
dose ranges from 20 Gy in 10 fractions to 25 Gy in
20 fractions. Relapse-free survival is 95-97%, and
cause-specific survival close to 100%. Stage II
seminoma with nodal disease \ 5 cm, is also
managed by para-aortic and ipsilateral pelvic nodal
irradiation. A further 8-10 Gy boost is commonly
given to gross disease [ 4 cm, resulting in disease-
free survival of 85-92%. Patients with stage I
disease who relapse on surveillance are managed in
the same fashion. Bulkier stage II or stage III
disease is best managed with cisplatin-based
combination chemotherapy, again resulting in a
long-term disease-specific survival of [ 90%.

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 1027
DOI: 10.1007/174_2011_329, Ó Springer-Verlag Berlin Heidelberg 2012
1028 G. C. Morton and M. Pearse

Table 1 Diagnostic work-up for testicular cancer

1 Introduction and General Testicular ultrasound
Management Serum tumor markers: alpha-fetoprotein (AFP), human
chorionic gonadotropin (HCG) and lactate dehydrogenase
The majority of testicular tumors occurs in young (LDH). If elevated, markers should be repeated following
orchidectomy
men with a peak incidence at 30 years of age. Most
patients present with a painless enlarging mass in the Radical (inguinal) orchidectomy to confirm pathologic
diagnosis and for local staging
testicle. Less commonly, patients present with
CT scan of abdomen and pelvis
symptoms from metastatic disease e.g. back pain,
respiratory or neurological symptoms. Standard Chest X-Ray
diagnostic work-up is indicated in Table 1. Over 95% CT scan of chest for non-seminomatous histology and stage II
of testicular malignancies are germ cell tumors or higher seminoma
(Table 2), with just over half being seminoma. CT scan of head (or MRI) for choriocarcinoma
If the clinical and radiological features are con-
sistent with a testicular tumor, a radical orchidectomy Table 2 Pathological classification of testicular tumors
is performed. The testicle and spermatic cord are Germ cell tumors ([95%)
removed en bloc, via an inguinal incision, with high Intratubular germ cell neoplasia (IGCN)
ligation of the spermatic cord at the deep inguinal Seminoma
ring. An inguinal approach is used to minimize the Spermatocytic seminoma
risk of aberrant lymphatic spread and local contami-
Embryonal carcinoma
nation. A transscrotal approach risks development of
Yolk sac tumor
alternative lymphatic drainage to the inguinal and
pelvic lymph nodes. In addition, the spermatic cord is Choriocarcinoma
left in place from the external to the internal ring. Teratoma
Laboratory investigations include a complete Mixed tumors
blood count, renal and liver function tests and serum Sex cord/stromal tumors (\5%)
tumor markers including alpha-fetoprotein (AFP), Leydig cell tumor: benign and malignant
human chorionic gonadotropin (HCG) and lactate Sertoli cell tumor: benign and malignant
dehydrogenase (LDH). To assess the extent of meta-
Granulosa cell tumor
static disease, a chest X-ray and computed tomogra-
Thecoma/Fibroma
phy (CT) scan or MRI of the abdomen and pelvis are
Others
obtained. PET scanning is not routinely required, but
may help in identifying disease within enlarged
lymph nodes. Table 3 Prognostic factors influencing management
Radical orchidectomy provides pathologic diag- In patients with stage I disease
nosis and helps guide further management. Prognostic Seminoma
factors are indicated in Table 3. For patients with
Tumor size
clinical stage I disease, a number of factors have been
Rete testis invasion
identified which predicts risk of subclinical micro-
scopic spread. Many series have identified tumor size, Age
rete testis invasion and older age as increasing risk of Non-seminoma
relapse in stage I seminoma, while local extent and Lymphovascular invasion
presence of lymphovascular invasion and embryonal Pathology (proportion of embryonal component)
component have prognostic value in non-seminomas. In patients with metastatic disease
For patients with metastatic disease, very high-serum Pathologic subtype
marker elevation and presence of non-pulmonary
Level of tumor markers
visceral metastases are key prognostic factors.
Non-pulmonary visceral metastases
Patients are staged according to the American Joint
Committee on Cancer (AJCC) criteria as indicated Primary site (testis/retroperitoneal vs. mediastinal)
Testicular Cancer 1029

Table 4 American joint committee on cancer (AJCC) (2010) marker (S). The nodal staging is based on the
staging for testicular neoplasms greatest dimension of the largest involved lymph
Primary tumor (T) (pathologic classification) node and does not take into account the total bulk
Tx Primary tumor cannot be assessed of lymphadenopathy, a well-recognized prognostic
T0 No evidence of primary tumor (scar, etc.) factor.
T is intratubular, noninvasive Patients with non-seminomatous germ cell tumors
pT1 Tumor limited to testis and epididymis, no vascular/
are generally managed by surgery and cisplatin-based
lymphatic invasion combination chemotherapy, and further discussion is
pT2 Tumor limited to testis and epididymis, with beyond the scope of the present chapter. For semi-
vascular/lymphatic invasion or involvement of the noma, radiotherapy plays an important role in the
tunica vaginalis management of stage I and II disease, and also has a
pT3 Tumor invades spermatic cord role in the management of Intratubular Germ Cell
pT4 Tumor invades scrotum Neoplasia (IGCN) and in selected patients with
Lymph node (N) residual disease following chemotherapy.
N0 No regional node metastasis
N1 Metastasis in single or multiple nodes 2 cm or less in
greatest dimension 1.1 Anatomy
N2 Metastasis in single or multiple nodes 2–5 cm
greatest dimension In the developing embryo, the testes originate from
N3 Metastasis in lymph nodes [5 cm in maximum the genital ridge located near the second lumbar
diameter vertebra. Accompanied by their blood supply and
Distant metastasis (M) lymphatics, they descend into the scrotum via the
M0 No distant metastasis
inguinal canal. As a result, the primary lymphatic
drainage is from the testis to the retroperitoneal lymph
M1a Non-regional lymph node or pulmonary metastasis
nodes. The lymphatic vessels first drain into the
M1b Non-pulmonary visceral metastasis
collecting trunks at the hilum of the testicle. These
Serum tumor markers (S) lymphatic trunks accompany the testicular artery,
Sx Serum tumor markers not performed vein and spermatic cord through the internal inguinal
S0 Serum tumor markers within normal limits ring, and then continue proximally to the retroperi-
S1 LDH \1.5 9 N and HCG \5,000 and AFP \ 1,000 toneal lymph nodes. The retroperitoneal lymph nodes
S2 LDH 1.5–10 9 N or HCG 5,000–50,000 or AFP are situated anterior to the T11 to L4 vertebral bodies,
1,000–10,000 although they are concentrated at the L1-L3 level.
S3 LDH [10 9 N or HCG [50,000 or AFP [10,000 On the left, the lymphatics drain primarily into the
Staging groupings pre-aortic and para-aortic lymph nodes around the left
IA T1, N0, M0, S0
renal hilum and thence to the inter-aortocaval nodes.
On the right, the first echelons of nodes is in the inter-
IB T2–4, N0, M0, S0
aortocaval region, followed by the pre-aortic and
IS Any T, N0, M0, S1–3
para-aortic lymph nodes. Early lymphographic studies
IIA Any T, N1, M0, S0/1 demonstrated rapid crossover from right to left as well
IIB Any T, N2, M0, S0/1 as from left to right. Clinically, however, contralateral
IIC Any T, N3, M0, S0/1 spread is mainly seen with right-sided tumors and
IIIA Any T, Any N, M1a, S0/1 rarely with left-sided.
IIIB Any T, Any N, M1a, S2 From the retroperitoneal nodes, the lymph
IIIC Any T, Any N, M1b or S3 drains into the cisterna chyli, thoracic duct, posterior
mediastinum and the left supraclavicular fossa. The
thoracic duct drains into the left subclavian vein in
in Table 4 (Edge et al. 2010). This staging system the left supraclavicular region. In 5–10% of patients,
incorporates the features of the primary tumor (T), drainage into the right supraclavicular area can
nodes (N), metastases (M) and level of serum tumor occur.
1030
Aberrant lymphatic drainage may occur in the
event of previous scrotal or inguinal surgery. Hernia
repair alters the drainage of the testicle. The testicular
lymphatic vessels anastomose with the regional
lymph vessels resulting in drainage into the ipsilateral
inguinal and iliac lymph nodes (Morton and Thomas
2008). In addition, the testicular trunks may abandon
the spermatic vessels at the internal inguinal ring and
pass posteriorly and superiorly into the external iliac
lymph nodes. The scrotum drains directly into the
inguinal and external iliac lymph nodes.
1.2 Natural History
In the majority of patients, pathological examination
of the radical orchidectomy specimen reveals the
tumor confined to the testis. Occasionally, invasion of
the rete testis, epididymis or spermatic cord can
occur. Rarely, the tumor extends through the tunica
albuginea to involve the scrotum.
Seminoma has an orderly and predictable pattern
of spread. Loco-regional lymphatics are the first site
of metastatic disease. From the retroperitoneal lymph
nodes, seminoma spreads proximally to involve the
next echelon, the mediastinal lymph nodes, and then
the supraclavicular lymph nodes. Very occasionally,
metastases from retroperitoneal lymph nodes can
drain directly via the thoracic duct to the supracla-
vicular fossa, resulting in supraclavicular metastases
in the absence of mediastinal disease.
Hematogenous metastases are rare in pure semi-
noma, being much more common with NSGCT. Lung
is the most common site of distant disease, although
bone, liver and brain may also be involved.
2 Management by Stage
2.1 Stage I Seminoma
Following orchidectomy alone, relapse occurs in
about 20% of patients with stage I seminoma. The
majority of these relapses occur in the para-aortic
lymph nodes. The management approaches include
surveillance, adjuvant radiotherapy and adjuvant
chemotherapy which provide similar overall cure
rates (Mead et al. 2011). For those who will adhere to
frequent follow-up visits and investigations, active
G. C. Morton and M. Pearse
surveillance is the preferred option. This has the
advantage avoiding treatment-related complications
without compromising overall survival rates.
Historically, the standard post-operative manage-
ment of patients with stage I seminoma has been
adjuvant radiotherapy to the para-aortic and ipsilateral
pelvic lymph nodes (the ‘‘dog-leg’’ or ‘‘hockey stick’’
radiation field). In view of the exquisite radiosensi-
tivity of seminoma, this treatment results in a recur-
rence-free survival of 97% and a disease-specific
survival greater than 99% (Morton and Thomas
2008). Similar disease-free and overall survival rates
are reported with para-aortic radiotherapy alone. The
Medical Research Council performed a randomized
controlled trial comparing classic dog-leg and para-
aortic irradiation in stage I seminoma (Fossa et al.
1999). Those with previous ipsilateral inguinal or
scrotal surgery were excluded. Radiotherapy was
better tolerated in the para-aortic alone arm with a
reduction in the severity and frequency of acute
gastrointestinal and hematological toxicity. The post-
treatment peptic ulcer rate was similar in both arms.
Sperm counts within the first 18 months were
significantly higher in the para-aortic alone arm,
although, there was no difference at 3 years. At a
median follow-up of 4.5 years, there was no differ-
ence in the 3 year relapse-free survival or overall
survival. For those in the para-aortic radiotherapy arm
the pelvis was the most frequent site of recurrence,
whereas, the pelvis was a rare site of recurrence in
those in the para-aortic and ipsilateral pelvis radio-
therapy arm (Fossa et al. 1999; Jones et al. 2005).
A retrospective review showed the median size of
pelvic nodal recurrence as 7.3 cm (range 2.8–13 cm)
if CT scans were not included in the follow-up
schedule of patients treated with para-aortic radio-
therapy (Livsey et al. 2001). Regular pelvic CT scans
are therefore advised in those treated with para-aortic
radiotherapy.
Given that nearly all recurrences following para-
aortic radiotherapy are in the lower common iliac or
upper external iliac nodes, a common approach is to
use a modified dog-leg wherein the inferior border is
placed at the mid-pelvic level (Skliarenko et al.
2009). This encompasses the nodal areas at risk while
further reducing volume of irradiated normal tissue.
Prior to radiotherapy, sperm analysis and sperm
banking may be carried out in patients who wish to
preserve fertility.
Testicular Cancer
Single agent carboplatin chemotherapy has
emerged as another option for patients with stage I
seminoma. The U.K. Medical Research Council/
European Organisation for Research and Treatment of
Cancer clinical trial randomized 1,447 patients with
stage I seminoma to either adjuvant radiotherapy or a
single infusion of carboplatin (Oliver et al. 2011).
Relapse-free rates were similar in both arms (96 and
94.7%, respectively) at 5 years, but with a significant
reduction in risk of contralateral testicular cancer in
the chemotherapy arm.
2.2 Stage II Seminoma
Only 10–20% of patients are diagnosed with stage II
disease, mostly of small volume.
Patients with stage IIA and IIB disease treated with
radiotherapy (para-aortic and ipsilateral pelvic nodes)
have an excellent disease-free survival (88–93%) and
overall survival (95–100%), which is superior to that
with single agent carboplatin (Krege et al. 2006).
However, following radiotherapy alone, the relapse
rate ranges between 20 and 50% in patients with bulkier
stage II disease, primarily because of risk of relapse
beyond the retroperitoneum. Primary chemotherapy
with cisplatin-based chemotherapy is usually the
treatment of choice for patients with nodal disease
[5 cm. In addition, radiotherapy in bulky stage II
disease may be technically difficult, particularly if
nodal disease covers a significant portion of the kidney.
3 Radiation Therapy Techniques
3.1 Target Volume and Field Borders
For stage I disease, the Clinical Target Volume
(CTV) consists of the inter-aortocaval, pre-aortic and
para-aortic nodes. The left renal hilar nodes are
included for left-sided tumors. The ipsilateral external
iliac and common iliac nodes may also be included,
particularly if there is concern about aberrant drain-
age. Inclusion of the inguinal scar, inguinal lymph
nodes or hemiscrotum is not warranted in the routine
treatment of stage I disease. For stage II disease, a
gross tumor volume is identified from diagnostic
imaging, and the CTV also usually includes the
ipsilateral pelvic nodes.
1031
The planning target volume (PTV) includes the
CTV plus a margin to account for positional and
set-up uncertainties. To cover the known location of
the retroperitoneal and iliac lymph nodes with an
appropriate margin, standard anatomical field bor-
ders have been used. This is commonly referred to
as the ‘‘dog-leg’’ or ‘‘hockey stick’’ field (Fig. 1).
Classically, the superior border is placed between
the T9 and T10 vertebral bodies, with the inferior
border at the top of the obturator foramen. The field
is approximately 9 cm wide in the para-aortic
region, and usually covers the transverse processes.
On the left, the lateral border is extended to include
the left renal hilum and customized shielding is
positioned to reduce the amount of kidney irradi-
ated. Field width here is typically 11–12 cm. At the
mid L4 level the field is extended laterally to cover
the ipsilateral external iliac nodes. Shielding is
placed forming the ‘‘dog-leg’’ configuration. Multi-
leaf collimators now largely replace lead blocks to
define the field shape.
If retroperitoneal nodes alone are to be treated, the
superior and lateral borders are as described above
and the inferior border is placed at the L5/S1 disk
space, (Fig. 2). Some use a lower superior border,
T10/11 and a higher inferior border, the bottom of L4
(Bruns et al. 2005).
A modified ‘‘dog-leg’’ approach is now commonly
used wherein the superior border is placed between
T11 and T10, and the inferior border is placed at the
superior aspect of the acetabulum (Fig. 3). These
fields cover the nodal areas of still at risk in patients
treated with para-aortic fields only.
Once these borders are placed, the planning CT
can be used to ensure adequate coverage of the target.
Distance from the PTV to the field border is 8–15 mm
depending on field size, energy, separation and
shielding. It should be noted that there is often a
distance of several centimeters between the cranial
and caudal field edges and the 95% isodose (Fig. 4),
related to the large field size and variability in body
thickness.
In stage II disease, the PTV includes the same
CTV as for stage I disease with an appropriate
margin. Care must be taken to include the gross nodal
disease in the CTV (Fig. 5). An isodose distribution is
checked to ensure that the nodal disease is adequately
encompassed by the relevant isodose. Organs at risk,
including the kidney and liver, can be identified.
1032
Fig. 1 ‘‘Dog-Leg’’ fields for treatment of stage I seminoma.
The superior border is placed at the T9/T10 interspace, lateral
borders at the edge of the transverse processes and inferior
border above the obturator foramen. For left-sided tumors, the
Shielding is customized to allow adequate coverage
of disease, while reducing the dose to normal tissues.
If the retroperitoneal lymphadenopathy is greater than
4 cm in size, a boost to gross disease is commonly
used. This may be delivered either concurrently or
sequentially. The advantage of a sequential approach
is that it allows for reduction in disease volume and
less irradiation of normal tissues. This is particularly
appropriate where the initial disease is large and
overlies kidney.
In the past, irradiation of both contralateral and
ipsilateral pelvic nodes was recommended using an
‘‘inverted Y’’ field. The evidence does not support this
approach. In a prospective multicenter trial evaluating
reduced treatment portals for stage IIA and IIB
seminoma the superior field border was at the cranial
rim of the 11th thoracic vertebrae and the inferior
field border at the cranial rim of the acetabulum. The
actuarial relapse-free survival at 6 years was 97.3%.
Only one patient relapsed at the lateral para-aortic
field edge with no relapses in the pelvic or inguinal
lymph nodes (Classen et al. 2003).
G. C. Morton and M. Pearse
field is expanded around the left renal hilum (a). Renal vessels
are outlined. This expansion is not necessary for right-sided
tumors (b). Kidneys, aorta, common iliac and external iliac
arteries are contoured
3.2 Simulation and Treatment Planning
The patient is simulated in the supine position with
arms at his sides. This simple position is comfortable.
Foot stocks and knee or ankle restraints may be used.
Testicular shielding (often in the form of a clam-shell
device) is used. A volumetric planning CT scan is
acquired with the patient in this position. Contiguous
5 mm CT slices are taken from the seventh thoracic
vertebra to 2 cm below the ischial tuberosities.
Utilization of a CT based planning technique enables
visualization of the location of the lymph-node
regions, adjacent tissues and critical normal structures
including the kidneys and liver. In addition, the beams
eye view (BEV) allows evaluation of the coverage of
the PTV, and shielding can be appropriately placed.
Tattoos are placed at the center, superior and
inferior borders of the field. A lateral tattoo is also
placed at mid-plane.
Treatment is delivered with a linear accelerator
using an anterior and posterior parallel opposed pair.
The beams are equally weighted. Both fields are treated
Testicular Cancer 1033

Fig. 2 Smaller para-aortic fields may be used as an alternative to classic ‘‘dog-leg’’ fields for left-sided (a) and right-sided
(b) tumors. Superior border is often placed at the superior border of T12 and the inferior border at the bottom of L5

Fig. 3 A modified ‘‘dog-leg’’ for left-sided (a) and right-sided placed at the top of T11, and the inferior border at the top of the
(b) tumors also includes the common iliac and upper external acetabulum
iliac nodes, targeting nodal areas at risk. The superior border is
1034 G. C. Morton and M. Pearse

Fig. 4 Sagittal isodose distribution of a standard ‘‘dog-leg’’

beam arrangement. Note the distance between the field edge
superiorly and the 95% isodose

daily, 5 days per week. Depending on the separation,

6–18 MV photons are utilized. If the separation is
greater than 20 cm, a higher energy is preferred. The
patient is treated with either an isocentric, source axis
distance (SAD) technique or, alternatively, a standard
source skin distance (SSD) technique. In most patients,
standard SSD is adequate, although if the field is longer
than 40 cm, the patient is treated with extended SSD. Fig. 5 Standard borders are modified for stage II disease to
encompass the nodal mass. A further boost is given for nodal
With extended SSD, the patient may need to change
disease [4 cm in size (a). Isodose distributions are required to
position between fields. If extended SSD is employed, confirm adequate coverage of disease (b)
the width of the penumbra is increased, and this must be
taken into account when selecting the field borders.
Rarely dose inhomogeneity due to contour obliq- relative to the mass, a CT planned technique with
uity occurs and a compensator is placed in the beam. oblique fields may result in a reduced dose to normal
For a 10 MV beam at 100 cm SSD, a difference in structures.
separation of 7 cm results in a variation in dose of Coverage of the target may be improved with CT
approximately 10%. This may be corrected with use planning based on vascular structures. The dosimetry
of segments or tissue compensator. of a traditional para-aortic field defined by bony
For stage II disease, a parallel opposed anterior and landmarks on a digitally reconstructed radiograph was
posterior pair is used. However, depending on the compared with a CT plan based on vascular anatomy.
location of the mass and the position of organs at risk The CT-based field had a greater median field width
Testicular Cancer
and equivalent square field size when compared with
the traditional field. The CT based dosimetry was
consistently superior to the traditional dosimetry, with
the suggestion that CT-based plans may avoid under
dosage and geographical miss that can sometimes
occur with traditional plans (Martin et al. 2005). More
elegant treatment techniques using intensity modu-
lated radiotherapy (IMRT) to cover the target volume
with greater sparing of organs at risk are described
(Zilli et al. 2011). While enabling reduction of dose to
organs at risk (stomach, bowel, bone marrow) it is not
clear how this is reflected in reduction of early or late
side effects of treatment.
3.3 Dose and Fractionation
3.3.1 Stage I Seminoma
Radiation doses between 25 and 40 Gy at 1.25–2.0 Gy
per fraction have been most commonly used in the past.
A dose of 25 Gy in 20 fractions has been the standard
dose at many North American institutions, which pro-
vides close to 100% control of retroperitoneal disease.
More recently, several authors have reported
similar excellent results with lower doses. The U.K.
Medical Research Council (MRC TE18) completed a
randomized controlled trial of 30 Gy in 15 fractions
over 3 weeks or 20 Gy in 10 fractions over 2 weeks.
Relapse-free survival was similar in both groups.
Acutely, there was significantly more moderate or
severe lethargy and inability to carry out normal work
in the group that received 30 Gy. However, by
12 weeks, there were no differences between the two
groups (Jones et al. 2005).
Radiation dose is generally prescribed to a point in
the midline, and ideally a homogeneous dose distri-
bution is obtained with a variation in the coverage of
the PTV of -5 and +7% (Fig. 5).
3.3.2 Stage II Seminoma
The optimal radiation dose in stage II seminoma is yet
to be determined and a number of regimens are used.
25 Gy in 20 fractions is frequently used with a boost
(10 Gy in five to eight fractions) to the residual mass
for lymphadenopathy [4 cm. Alternatively, 30 Gy in
15 fractions for stage IIA and 36 Gy in 18 fractions
for stage IIB seminoma provides excellent local
control (Schmoll et al. 2010; Albers et al. 2011;
Classen et al. 2003).
1035
3.4 Treatment Delivery
3.4.1 Testicular Shielding
During a fractionated course of radiotherapy to the
retroperitoneal and ipsilateral iliac lymph nodes, the
dose to the remaining testis ranges between 0.3
and 1.5 Gy. Dose received is strongly dependent on
distance from the testicle to field edge (Mazonakis
et al. 2006). A variety of factors contribute to this
dose. A component is from leakage from the head.
External scatter is generated from the collimator,
field-shaping blocks and air. A significant proportion
of the scattered dose is produced internally within the
patient. A number of effective shielding devices have
been described (Bieri et al. 1999; Fraass et al. 1985)
to reduce dose received by the testicle to \1% of the
midplane dose. Most departments use simple forms of
gonadal shielding such as the clam-shell device,
which consists of a 1 cm thick cup. This shields the
testicle from low-energy scattered photons, and
effectively reduces the testicular dose by a factor
of four.
3.4.2 Treatment Verification
An electronic portal image or port film is obtained
on day one and optionally at weekly intervals to
verify the field placement. This is compared with the
simulation film or digitally reconstructed radiograph,
which is important to verify the geometric set-up.
The patient is reviewed weekly to assess toxicity.
4 Intratubular Germ Cell Neoplasia
IGCN is considered to be a precursor of invasive
germ cell tumors. Untreated, 50% of patients with
IGCN will progress to invasive disease at 5 years and
70% at 7 years. Diagnosis is generally made by
biopsy of areas of microlithiasis identified on ultra-
sound (Tan et al. 2010). Options for management
include observation or radiotherapy (Lee and
Holzbeierlein 2009). IGCN is a radiosensitive tumor.
The aim of treatment is to eradicate the IGCN while
preserving hormone function. The CTV is the whole
testis.
At simulation, the patient is supine, with the thighs
abducted and soles together (this is commonly
referred to as the ‘‘frog-leg’’ position). A lead shield
is placed posteriorly to shield the perineum and
1036
immobilize the testis. The penis is taped out of the
field, usually over the symphysis pubis.
The optimal radiotherapy technique to treat the
testis is not defined. A number of different methods
have been employed. A direct anterior technique is
preferred. Although parallel opposed beams provide a
more homogeneous dose distribution, in this setting,
the addition of a posterior beam would irradiate a
large area of perineum resulting in extra toxicity.
Historically, a direct orthovoltage beam was
commonly used to treat the testis. Although this
provided a simple technique, there were several
disadvantages. For a standard orthovoltage beam, the
maximum dose is at or very close to the skin. The
90% depth dose for 270 kV is at approximately 2 cm.
In view of this, a single direct field does not ade-
quately treat to the depth required, and the posterior
testis is underdosed. In addition, the high-skin dose
results in an increase in the skin reaction.
A direct electron beam has the advantage of a rapid
fall off in dose with depth, reducing the dose to the
perineum. A testicular ultrasound is acquired with the
patient in the treatment position. This ultrasound
provides a measurement of the thickness of the testis
in the anterior–posterior plane. This measurement is
used to determine the depth required for treatment.
The electron energy is then selected. Commonly, the
energy ranges between 9 and 15 MeV. A customized
lead cut out is made to ensure that the testis with a
1 cm margin is treated and any adjacent tissue is
shielded. Bolus is used to provide a homogeneous
dose distribution, avoiding hot spots, and a rapid fall
off in dose at the field edge. The bolus covers the
entire testis, which also provides backscatter, thereby
improving the dosimetry.
A direct cobalt beam has also been used as a
treatment modality in this setting. As with orthovol-
tage, the depth dose characteristics of a cobalt beam
results in under dosing of the posterior part of the
target volume. For a 10 9 10 cm field, the Dmax is at
approximately 5 mm and 93% at approximately
2 cm. A further disadvantage is the relatively wide
penumbra when compared with that of a linear
accelerator. This must be taken into account when
defining the lateral field borders.
In summary, the optimal treatment modality and
technique for irradiation of the testis is unclear.
However, electrons appear to have the advantage of
delivering an adequate dose at depth. The curved
G. C. Morton and M. Pearse
contour of the testis can be adjusted for using bolus
resulting in a homogeneous dose distribution.
A dose of 18–20 Gy in nine to ten fractions over
2 weeks is a widely accepted fractionation schedule
for IGCN, and has been found to provide excellent
control of disease, with minimal impairment of tes-
tosterone production (Morton and Thomas 2008).
5 Special Considerations
5.1 Scrotal Invasion/Scrotal Interference
Although most patients present with T1 disease, tes-
ticular GCT can invade locally to involve the rete
testis, epididymis and spermatic cord. As the tunica
albuginea acts as a natural barrier, direct invasion of
the scrotum is rare and occurs late. Historically, the
hemiscrotum and inguinal lymph nodes were included
in the treatment portal in patients with tunica
albuginea invasion or scrotal interference. This prac-
tice has now been abandoned, as the risk of relapse is
low and treatment would result in high dose to the
remaining testis. However, if scrotal invasion occurs,
adjuvant radiotherapy to the hemiscrotum and
ipsilateral inguinal lymph nodes is recommended. The
scrotal field is matched to the tattoo at the inferior
border of the dog-leg field. Electrons are commonly
used and a lead cut out is custom made to limit the
dose to the remaining testis.
5.2 Contralateral Germ Cell Tumors
The prevalence of bilateral testicular cancer ranges
between 1.5 and 5% (Fossa et al. 2005). Although
synchronous tumors occur, the majority is metachro-
nous occurring at a median time interval of 5–8 years.
A similar incidence of a second testicular tumor is
observed in patients on surveillance.
Standard treatment has been radical orchidectomy.
Following this procedure, the patient is sterile and
requires life-long hormone replacement. Organ-spar-
ing techniques have been proposed as an alternative to
radical orchidectomy with the advantage of avoiding
long-term hormone replacement and less psycholog-
ical morbidity (Chung et al. 2006; Flaquer et al. 2008;
Lawrentschuk et al. 2011). Partial orchidectomy may
be considered in selected men with smaller tumors
Testicular Cancer
where an adequate amount of normal testicle can be
left in place. Radiation is typically given to a dose of
18–20 Gy at 2 Gy per fraction. Radiation technique is
the same as that described for management of IGCN.
5.3 Residual Mass Post-Chemotherapy
For patients with stage II or III disease treated with
primary chemotherapy, residual masses are present at
one month in up to 80% of patients. Most of these
then gradually regress over a period of several
months. Management strategies involve the use of
consolidative radiotherapy, surgical resection or
observation. The MRC UK study of consolidative
radiotherapy following chemotherapy in 302 patients
with advanced seminoma concluded that it increased
disease-free survival by only 2%, and is therefore not
warranted (Duchesne et al. 1997). The most important
prognostic factors for progression were the presence
of pre-chemotherapy visceral metastases or raised
LDH, or persistent visceral metastases post-chemo-
therapy. The incidence of positive biopsy following
chemotherapy is 15–30%, depending on timing of
biopsy, size and radiological appearance.
Observation alone is adequate for a residual mass less
than 3 cm in size. Two patterns of response to chemo-
therapy are evident in CT—the residual mass may be
well-defined with discrete, well defined borders, or the
mass may have indistinct borders merging into sur-
rounding structures and resembling a fibrous plaque.
The former are more amenable to surgical resection.
Furthermore, if the tumor is well defined on CT, and
measures more than 3 cm in greatest dimension, positive
histology can be found in 50%. It is reasonable to resect
these masses (Herr et al. 1997). If the mass is poorly
defined, even if larger than 3 cm, the chance of finding
positive histology is less than 10%. Resecting such a
mass is hazardous, with risk of great vessel, ureteric and
small bowel injury. These should be observed.
PET scanning is more sensitive than CT and
should be considered in the evaluation and monitoring
of post-chemotherapy residual masses. FDG-PET has
a high sensitivity for residual seminoma, but a low
specificity with false–positive results quite common
(Becherer et al. 2005; Hinz et al. 2008). Therefore a
residual mass that does not take up FDG is very
unlikely to contain active seminoma.
1037
6 Treatment Results
6.1 Disease-Free Survival
For stage I seminoma, routine irradiation of the ret-
roperitoneal nodes, with or without inclusion of the
ipsilateral pelvic nodes results in 10 year relapse-free
survival rates of 95–97%, and disease-specific
survival rates of close to 100% (Jones et al. 2005;
Niewald et al. 2006; Classen et al. 2004; Oliver et al.
2011; Bruns et al. 2005; Santoni et al. 2003; Logue
et al. 2003). If relapse is going to occur, it usually
happens within the first 3 years, and most commonly
occurs in the mediastinum or supraclavicular nodes.
Pelvic nodal recurrence occurs in 2% of patients
treated with Para-Aortic fields alone. Relapse beyond
3 years occurred in only 0.2% of patients in the MRC
randomized clinical trials.
Patients with stage II seminoma have a disease-
specific survival of 90–95% at 10 years. Relapse rates
following radiotherapy for stage II seminoma are
related to nodal size (Detti et al. 2009; Chung et al.
2004; Schmidberger et al. 1997; Classen et al. 2003;
Zagars and Pollack 2001). Relapse rates are approx-
imately 8% for stage IIA and 14% for stage IIB. Even
when relapse occurs, cisplatin-based chemotherapy is
a highly effective salvage treatment. For nodes greater
than 5 cm, approximately one-third of patients will
relapse, usually in the mediastinum or supraclavicular
nodes, and so are generally managed with initial
chemotherapy.
6.2 Acute Side Effects
Low-dose infradiaphragmatic radiotherapy is well
tolerated acutely. From the available literature, some
nausea is reported in most patients, with vomiting and
diarrhea in up to 80%. These side effects are generally
mild in most patients, with the incidence of grade-3
and grade-4 acute toxicity ranging between 1.5 and
2.5%. Most of the data reporting toxicity was
collected in an era when higher total dose higher dose
per fraction and larger treatment volumes were used.
With lower dose and more effective anti-emetic
medications, very few patients have significant acute
toxicity.
1038
6.3 Late Side Effects
Late effects are uncommon. The risk of major bowel
complications is less than 1% with radiation dose
\35 Gy. Peptic ulcer disease was reported in the past
as a significant late effect of infradiaphragmatic
radiotherapy, but is rare with currently used dose and
technique.
However, men are at increased risk of death from
cardiovascular disease and radiation-induced second
malignancy over time (Zagars et al. 2004). The
increased risk of cardiovascular disease is seen even
without mediastinal radiotherapy. Following treat-
ment, the relative risk of developing a second solid
tumor is approximately double that of the general
population (Travis et al. 2005). The risk is increased
whether patients are treated with radiotherapy or
chemotherapy, with the greatest relative risk seen for
gastric, pancreatic and bladder cancers. Patients
remain at increased risk of second malignancy for at
least 35 years following treatment. In absolute terms,
the cumulative risk of being diagnosed with a second
cancer is 13% higher than that of the general
population 40 years after treatment for seminoma.
Para-Aortic irradiation may reduce the risk of second
malignancy compared to dog-leg fields (Zwahlen
et al. 2008).
Following radiotherapy or chemotherapy for
testicular germ cell tumors, impairment of spermato-
genesis can occur. At diagnosis, approximately 50%
of patients will have low-sperm counts.
Radiotherapy leads to further reduction in sperm
count. The spermatogonia are more radiosensitive
than the differentiated stages and, at low doses
of radiation, aspermia occurs at approximately
10–12 weeks.
Factors which delay recovery of sperm count
include radiation dose, older age and lower baseline
sperm count. For example, recovery of sperm count
occurs within 12 months with radiation dose
\0.8 Gy, but may be delayed for over 2 years with
higher dose. The use of chemotherapy further delays
or impairs recovery. Nevertheless, with appropriate
gonadal shielding, up to 80% of men are able to father
children following radiotherapy for testicular cancer.
In fact, there is some evidence that fertility is no
different in men managed by surveillance and adju-
vant radiotherapy (Matos et al. 2010).
G. C. Morton and M. Pearse
Table 5 Summary recommendations for management of
seminoma
Stage 1
Surveillance with treatment at time of relapse or
Adjuvant radiotherapy to the para-aortic and upper ipsilateral
pelvic nodes (modified dog-leg) to 25 Gy in 25 fractions or
20 Gy in ten fractions or
Single course of carboplatin
Stage IIa and IIb
Radiotherapy to the para-aortic and ipsilateral pelvic nodes to
25 Gy in 25 fractions or 20 Gy in ten fractions
Boost to gross disease [4 cm to further 10 Gy in five
fractions
Stage IIc and III
Cisplatin-based combination chemotherapy
7 Summary
Testicular cancer is a common malignancy among
young men. For men with early stage disease, the
cancer is highly curable and the challenge is to maintain
high-cure rates while minimizing late morbidity of
treatment. For stage I seminoma, the 10-year disease-
specific survival approaches 100%, whether an initial
approach of surveillance, radiotherapy or chemother-
apy is taken. Patients with stage II disease and nodal size
\5 cm also have an excellent outcome following
radiotherapy. Because of the risk of distant relapse in
patients with bulkier disease, initial treatment with
cisplatin-based combination chemotherapy is pre-
ferred. Recommendations are summarized in Table 5.
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 Extremity Soft Tissue Sarcoma in Adults
Karl E. Haglund, Thomas F. DeLaney, David C. Harmon,
Andrew E. Rosenberg, and Francis J. Hornicek

Contents 5 Management of the Primary Tumor..................... 1050

5.1 Overview.................................................................... 1051
5.2 Surgical Considerations............................................. 1051
1 Introduction.............................................................. 1042 5.3 Selection of Patients for Treatment with Surgery
Alone.......................................................................... 1052
2 Clinical Evaluation .................................................. 1042
5.4 Combining Surgery with RT..................................... 1053
2.1 Clinical History ......................................................... 1042
5.5 Pre-operative (Neoadjuvant) Versus Post-operative
2.2 Anatomical Site, Sex, and Age................................. 1044
(Adjuvant) Radiotherapy ........................................... 1053
2.3 Physical Examination ................................................ 1044
5.6 Brachytherapy ............................................................ 1054
2.4 Laboratory Investigations .......................................... 1044
5.7 EBRT Planning.......................................................... 1055
2.5 Radiographic Evaluation ........................................... 1044
5.8 Radiation Treatment Volumes and Dose.................. 1056
2.6 Biopsy ........................................................................ 1046
5.9 Intensity-Modulated Photon RT................................ 1060
3 Pathology .................................................................. 1047 5.10 Proton Beam Radiotherapy ....................................... 1061
3.1 Histological Classification......................................... 1047 5.11 Neoadjuvant Doxorubicin-Based .............................. 1062
3.2 Grading ...................................................................... 1048 5.12 STSs of the Hand and Foot ...................................... 1063
5.13 Wound Healing After Surgery and Radiation.......... 1063
4 Staging....................................................................... 1049 5.14 Pre-operative Radiation and Wound
Complications ............................................................ 1064
5.15 BRT and Wound Complications............................... 1064
5.16 Strategies to Reduce Wound Morbidity ................... 1064
5.17 Adjuvant Chemotherapy............................................ 1064
K. E. Haglund (&) 5.18 Functional Outcome .................................................. 1067
Radiation Oncology Branch, National Cancer Institute, 5.19 Treatment of Local Recurrence ................................ 1067
10 Center Drive, Building 10/CRC, Bethesda, 5.20 Treatment of Locally Advanced Soft Tissue
MD 20892, USA Sarcoma...................................................................... 1068
e-mail: haglundke@mail.nih.gov
6 Treatment of Metastatic Disease ........................... 1068
T. F. DeLaney 6.1 Overview.................................................................... 1068
Francis H. Burr Proton Therapy Center, 6.2 Resection of Pulmonary Metastases ......................... 1069
Massachusetts General Hospital, Harvard Medical School, 6.3 Chemotherapy for Metastatic Disease ...................... 1069
30 Fruit Street, Boston, MA 02114, USA
7 Summary................................................................... 1070
D. C. Harmon
Hematology Oncology, Department of Medicine, References.......................................................................... 1070
Massachusetts General Hospital, Harvard Medical School,
Yawkey 7944, 30 Fruit Street, Boston, MA 02114, USA
A. E. Rosenberg Abstract
Surgical Pathology, Department of Pathology, When treating soft tissue sarcomas (STSs) of the
Massachusetts General Hospital, Harvard Medical School, extremities, the major therapeutic goals are sur-
Warren 2, 30 Fruit Street, Boston, MA 02114, USA
vival, local tumor control, optimal function, and
F. J. Hornicek minimal morbidity. Surgical resection of the
Orthopedic Oncology, Department of Orthopedic Surgery,
Massachusetts General Hospital, Harvard Medical School, primary tumor is the essential component of
Yawkey 3B, 30 Fruit Street, Boston, MA 02114, USA treatment for virtually all patients. A wide surgical

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 1041
DOI: 10.1007/174_2011_166,  Springer-Verlag Berlin Heidelberg 2012
1042
margin is necessary for local tumor control when
surgery is used without radiation, i.e., the cut should
traverse normal tissue outside the reactive tumor
zone. This is because sarcomas tend to infiltrate
normal tissue adjacent to the evident lesion. Thus,
removal of the gross lesion by a simple excision
alone (only a narrow margin) is followed by
relatively high rates of local recurrence. Radical
resections are associated with a reduction in the
local recurrence rate, but they may compromise
limb function. The combination of function-sparing
surgery and radiation achieves better rates of local
control than either treatment alone, for nearly all
patients with STSs, although combined treatment
can be associated with acute wound complications
in some patients and late normal tissue complica-
tions in others. Because both surgical and radiation
techniques are both critically important for opti-
mizing local control of tumor and functional
outcome, it is important to manage these patients
in dedicated multispecialty clinics comprised of
physicians with expertise in sarcomas, including
orthopedic and general oncology surgeons, radia-
tion oncologists, medical oncologists, sarcoma
pathologists, and bone and soft tissue diagnostic
radiologists. Radiation therapy can be given by
external beam radiation (EBRT) or brachytherapy
or combination thereof. EBRT can be given either
pre-operatively or post-operatively.
1 Introduction
Sarcomas are malignant tumors that arise from skel-
etal and extraskeletal connective tissues, including the
peripheral nervous system. The term sarcomas of soft
tissues embraces all the malignant tumors that arise
from the mesenchymal tissues with the exception of
bone, i.e., malignant fibrous histiocytoma, liposar-
coma, leiomyosarcoma, synovial sarcoma, rhabdo-
myosarcoma, epithelioid sarcoma, angiosarcoma,
fibrosarcoma, etc. In addition, malignant tumors of
peripheral nerve sheaths are included despite being
ectodermal in origin, as their clinical behavior is not
measurably different from the other sarcomas.
STSs are rare, with an estimated incidence in the
United States of approximately 10,520 diagnosed
annually, representing \1% of all newly diagnosed
malignant tumors (Jemal et al. 2010). Approximately
K. E. Haglund et al.
37% of these patients are expected to die of this
disease. Review of the statistics of recent years sug-
gests an increase in the incidence of STSs, although it
is not clear whether this represents a true increase or
merely reflects more accurate diagnosis and increas-
ing interest in these tumors (Weiss and Goldblum
2008). Although the malignant tumors of soft tissue
are rare, benign tumors are common. It is estimated
that the frequency of benign tumors is 100 times that
of the malignant lesions (Jemal et al. 2010; Weiss and
Goldblum 2008).
Sites of appearance of STSs, in order of frequency,
are the lower extremity (46%), torso (19%), upper
extremity (14%), retroperitoneum (13%), and head/
neck (8%) (Abbas et al. 1981; Potter et al. 1985;
Lawrence et al. 1987; Torosian et al. 1988). The small
number of cases seen and the great diversity in ana-
tomic site, histopathology, and biology complicate
understanding of the natural history of these tumors
and their response to diverse therapies. This discus-
sion will be focused on STSs arising in the extremities
and treatment strategies designed to maximize cure
rates while optimizing post-treatment function.
2 Clinical Evaluation
The recommended components of the clinical evalu-
ation and diagnostic workup of extremity soft tissue
sarcomas is presented in Table 1.
2.1 Clinical History
The most frequent initial complaint is that of a
painless lump with a duration of a few weeks to
several months. Occasionally, pain or tenderness
precedes the detection of a lump. With progressive
growth of tumor, symptoms that are secondary to
infiltration of or pressure on adjacent structures
(e.g., tendons, muscles, nerves) or organs appear.
Occasionally, symptoms secondary to the metabolic
effects of the tumor products are seen, e.g., fever,
anemia, lethargy, weight loss, and histamine-like
reactions. These are not rare in patients with malig-
nant fibrous histiocytoma (Weiss and Goldblum
2008). To accrue clinical genetic data in sarcoma
patients, the history should include details of the
Extremity Soft Tissue Sarcoma in Adults 1043

Table 1 Clinical evaluation and diagnostic workup for extremity soft tissue sarcomas
History
Presenting complaint
Onset of mass and temporal change in size or character
Onset of other symptoms
Constitutional symptoms (fever, weight loss, etc.)
Local weakness or paresthesias
Family history of malignancy or genetic cancer predisposition
Prior therapeutic radiation or environmental radiation exposure
Exposure to sarcomagenic compounds (e.g., Dioxin)
Physical Examination
Complete physical examination
Primary site evaluation
Site and size of mass(es)
Superficial versus deep
Unifocal versus multifocal
Fixation to underlying tissue or involvement of skin
Limb neurovascular function
Distal edema
Regional lymphadenopathy
Postoperative evaluation
Incision healing
Limb function and range of motion
Ecchymosis or hematoma
Laboratory Evaluation
Complete blood count
Blood urea nitrogen, creatinine
Liver function tests
Imaging
CT of the chest
MRI of primary site with gadolinium contrast enhancement
Plain radiographs or CT of the primary site, if bone involvement suspected
F-18 fluorodeoxyglucose PET scanning may be considered for histologies with predilection for lymph node metastases or for
monitoring response in patients receiving neoadjuvant therapy.
Biopsy
Core needle biopsy, in office or under image directed guidancea
Incisional biopsy using a longitudinal incision with meticulous hemostasis
Excisional biopsy (generally limited to small, superficial lesions)
Note The initial evaluation is ideally conducted in a multidisciplinary setting involving surgical oncologists, medical oncologists,
and radiation oncologists with expertise in treating soft tissue sarcoma.
a
Core needle biopsy should only be considered if it can be performed safely without damaging nearby vascular or neural
structures, as assessed on adequate imaging.
CT computed tomography; MRI magnetic resonance imaging; PET positron emission tomography
1044
cause of death and history of malignant disease in
siblings, parents, grandparents, and progeny.
2.2 Anatomical Site, Sex, and Age
As previously mentioned, the sites of appearance of
STSs, in order of frequency, are the lower extremity
(46%), torso (19%), upper extremity (14%), retro-
peritoneum (13%), and head/neck (8%) (Abbas et al.
1981; Potter et al. 1985; Lawrence et al. 1987;
Torosian et al. 1988). There is a very slight prepon-
derance of STSs in males. They are more common in
older people, with 40% in persons 55 years of age or
older and 15% in patients 15 years of age or younger
(Weiss and Goldblum 2008). Rhabdomyosarcomas
almost always arise in children, synovial sarcomas
develop in late adolescence and early adulthood, and
liposarcoma and malignant fibrous histiocytoma usu-
ally occur during mid and late adulthood.
2.3 Physical Examination
A complete physical examination is essential, with
particular attention paid to the region of the primary
lesion. Of particular importance are definition of size,
site of origin (superficial or deep, attached to or fixed
to deep structures), solitary or multinodular presen-
tation, involvement or discoloration of overlying skin,
functional status of vessels and nerves, presence of
distal edema, muscular strength, range of motion of
the affected part, etc. If the patient has had prior
excision, the operated site should be examined for
presence of ecchymosis, status of wound healing,
palpable evidence of residual tumor, and location of
drain site(s). The regional and distant lymph-node
groups need to be examined with care in all patients,
especially in those with large ([5 cm) grade-2 and -3
sarcomas. In an analysis of the experience at Massa-
chusetts General Hospital, no patient with grade-1
sarcoma developed regional node involvement. The
incidence in patients with grade-2 and -3 sarcomas
were 2% and 12%, respectively. Of the patients with
grade-3 sarcoma, the incidences for lesions 5 cm or
less and those more than 5 cm were 3 and 15%,
respectively (Mazeron and Suit 1987). Fong et al.
(1993) found a slightly lower frequency of metastasis
to regional nodes in the Memorial Hospital series.
K. E. Haglund et al.
Involvement of regional nodes is most frequent in
patients with rhabdomyosarcoma and epithelioid
sarcoma, but is also seen in patients with angiosar-
comas, clear cell sarcomas, and synovial sarcomas.
However, regional nodal involvement is uncommon
in patients with fibrosarcoma and malignant fibrous
histiocytoma. Myxoid liposarcoma may also metas-
tasize to soft tissue or bone.
2.4 Laboratory Investigations
Laboratory studies need not go beyond a complete
blood count and blood urea nitrogen/creatinine (if IV
contrast is to be administered for the chest computed
tomography [CT] scan or for radiation-planning CT
scan) unless the patient is to receive chemotherapy, in
which case liver-function tests should be performed
as well.
2.5 Radiographic Evaluation
For the primary site, the radiographic evaluation
should include plain films and magnetic resonance
imaging (MRI) scanning. The most useful radiologi-
cal study to evaluate the primary site is the MRI
(Bland et al. 1987); CT can be useful to evaluate the
relatively uncommon situation where there is sus-
pected bony involvement. Plain radiographs are
helpful in evaluation of soft tissue tumors by dem-
onstrating bone involvement and soft tissue masses
arising from bone tumors. However, unlike bone
tumors, imaging studies cannot be used to assess the
biological behavior of soft tissue tumors (Kransdorf
et al. 1993). Indeed, specific diagnosis remains
impossible for many soft tissue lesions, regardless of
the choice of imaging (O’Keefe et al. 1990). Imaging
studies alone cannot definitively distinguish malig-
nant from benign soft tissue lesions. MRI (Fig. 1)
may prove to be of clinical value in planning the
biopsy site, either using needle or incisional tech-
niques. Furthermore, the demonstration of necrotic
regions appears to be of diagnostic importance in dis-
crimination between benign and malignant tumors
(Gustafson et al. 1992). Positron emission tomography
(PET) scanning (Fig. 2) has been shown to be useful in
discriminating between benign and high-grade lesions,
although it is unsuitable for distinguishing between
Extremity Soft Tissue Sarcoma in Adults 1045

between lesion and muscle and are helpful in outlin-

ing the extent of tumor associated edema, which has
been shown to contain tumor cells in some patients
(White et al. 2005). Contrast-enhanced, T1-weighted
images (especially with fat suppression techniques)
are helpful at delineating extent of the gross tumor.
Fat suppression sequences may help further charac-
terize liposarcomas. MRI often provides a clearer
demonstration of the anatomical location of the lesion
and the pattern of local extensions. The findings from
these scans should be correlated with those of the
physical examination to assess the details of the
anatomical site of the tumor. It should be determined
whether the lesion is in the subcutaneous tissue,
transgressing the fascia, intermuscular or intramus-
cular, displacing or enveloping major vessels or
nerves, abutting or invading bone, etc. Depending on
the pattern of presentation and the nature of any
planned surgery, an arteriogram or CT angiogram
may be of value. For rhabdomyosarcoma, epithelioid
Fig. 1 T1-weighted, fat-suppressed magnetic resonance image sarcoma, high-grade synovial sarcomas, angiosarco-
of a high-grade, biphasic synovial sarcoma in the right popliteal mas, clear cell sarcomas and unclassified sarcomas,
fossa of a 27-year-old man following gadolinium
PET or PET/CT evaluation of the regional nodes may
administration
be of value. Bone scans need not be performed unless
specifically indicated. We do not consider a positive
Fig. 2 FDG (F18- bone scan of bone near or adjacent to a STS to be
fluorodeoxyglucose)–positron
emission tomography (PET)
proof of invasion of periosteum or bone. For a diag-
scan demonstrating markedly nosis of invasion of bone, there must be clear radio-
increased FDG avidity at the graphic evidence of destruction of cortical bone. The
site of the high-grade, single most important examination for distant
biphasic synovial sarcoma,
also seen on magnetic
metastasis is whole-lung CT; this should be obtained
resonance imaging (MRI) in all patients with intermediate or high-grade tumors.
scan in Fig. 1 This has been extensively confirmed by the study of
Peuchot and Libshitz (1987), who reported that, of the
nodules detected using CT but not by chest X-ray and
those biopsied, 94% were metastatic tumors.
Volumetric imaging of the response to treatment
has been generally disappointing up to the present.
Decrease in tumor size may occur (Sanchez et al.
1990) but does not correlate well with successful
radiation or chemotherapy. Furthermore, although
tumor volume can be approximated from two-
dimensional (2D) images (CT or plain films), reliable
benign and low- to intermediate-grade lesions (Nieweg algorithms to objectively distinguish tumor from
et al. 1996). PET is of substantial value in defining surrounding tissues are not available, and, thus, three-
response to pre-operative therapy (Prosnitz et al. 1999; dimensional (3D) imaging techniques have not, as
Schuetze et al. 2005). yet, found a role. Changes in MRI signal character-
MRI studies should always include T2-weighted istics have been unreliable. Absence of high signal
sequences, as these provide the optimum contrast intensity on T2 images has been shown to indicate
1046
freedom from tumor. However, residual high signal
may be due to tumor, edema, or fibrosis (Vanel et al.
1987). MRI spectroscopy has been used to detect
high-energy phosphate metabolism in the lesions.
This has helped in the distinction between malignant
and benign tumors (Negendank et al. 1989). Several
studies with phosphorus-31 magnetic resonance
spectroscopy have shown changes in high-energy
phosphate metabolism after effective chemotherapy
(Dewhirst et al. 1990; Koutcher et al. 1990; Redmond
et al. 1992), but the range of variation in sarcoma is
large, and, because of limitations in spatial resolution,
the procedure cannot be done reliably unless a large
soft tissue mass is present. Schuetze and colleagues
used PET scans to evaluate 46 patients with
high-grade sarcoma who received neoadjuvant che-
motherapy and reported that reductions in SUVmax
correlated with the degree of necrosis in the resection
specimen (Schuetze et al. 2005). They also noted that
tumors with a baseline SUVmax of six or more had a
higher risk of developing subsequent metastatic dis-
ease with disease recurrence. Patients with a 40% or
greater decrease in tumor SUVmax had a significantly
lower risk of disease recurrence and of metastasis. All
four patients with local disease recurrence as the
initial event had \40% reduction in tumor SUVmax
after chemotherapy. A reduction in the pre-surgery
sarcoma SUVmax of greater than or equal to 40%
relative to the baseline SUVmax correlated with
overall survival (OS). A metabolic response deter-
mined using F-18 fluorodeoxyglucose–PET scans
correlated with a pathological response to pre-opera-
tive doxorubicin-based chemotherapy, but it was a
stronger determinant of distant recurrence of disease
than the pathological response. Changes in SUV as
early as after the first cycle of neoadjuvant chemo-
therapy might ultimately prove useful in identifying
poor responders to chemotherapy so that the treatment
regime can be adjusted accordingly (Benz et al.
2009).
2.6 Biopsy
An adequate biopsy must be obtained so that the best
feasible histopathological diagnosis as to tumor type
and grade can be made. The optimal treatment strat-
egy is based on the correct diagnosis. Under optimal
conditions, the biopsy procedure should be performed
K. E. Haglund et al.
by an experienced surgeon who will be responsible
for the definitive surgery or by a diagnostic radiolo-
gist who is part of the multidisciplinary sarcoma
team. Prior to the biopsy, the imaging studies should
be carefully studied to ascertain the most logical
approach to the lesion, with explicit consideration of
the regions to be traversed in subsequent surgical
procedures (including marginal or wide resection or
amputation), so that the biopsy track will not interfere
with either surgery or radiation field.
The most commonly employed biopsy technique is
currently the core needle biopsy. For palpable lesions
with a superficial component that is away from the
neurovascular bundle, a Tru-Cut needle biopsy can
often be obtained in the clinic. For non-palpable,
deeper lesions and those near the neurovascular
bundle, core biopsies can be obtained under CT or
ultrasound guidance. There is experience in some
centers with cytological diagnosis by ‘skinny’ needle
aspiration. The amount of tissue obtained using these
procedures is limited, and this should be considered
before deciding which procedure to perform. Inci-
sional biopsy may be required in some cases to his-
tologically classify a tumor or obtain sufficient tissue
for immunohistochemical, electron microscopic, and/
or gene arrays. Needle biopsy is particularly useful to
confirm metastatic or recurrent tumor. Biopsy by the
needle technique may also be used in those anatom-
ical situations where incisional biopsy would require
a major procedure.
When incisional biopsies are performed, the inci-
sion for the biopsy of lesions on an extremity should
be longitudinal (there is almost never a reason for a
transverse incision on an extremity). The incision
should be as short as possible, yet long enough to
avoid excessive retraction of tissue or to make dis-
section and hemostasis difficult. The biopsy track
should go through a muscle belly rather than along
fascial planes (the former tends to keep the tumor
‘spill’ within an anatomical compartment while the
latter allows transgression of two or more compart-
ments) and careful attention should be paid to achieve
hemostasis in order to avoid ecchymosis or a hema-
toma. The wound should be closed in layers with a
narrow skin closure. As a rule, drains should not be
utilized (the tract of the drain is considered to be
contaminated with tumor and may greatly extend the
planes of subsequent surgery or the radiation treat-
ment volume).
Extremity Soft Tissue Sarcoma in Adults
For the occasional small lesion in a readily
accessible site (e.g., wrist or ankle), an excisional
biopsy may be the approach of choice. The surgeon
should adhere to the same principles as for the
definitive surgery (see below) if complications are to
be avoided.
The biopsy specimen needs to be of sufficient
volume to be certain that it is representative. A
pathological assessment of a frozen section is useful
in assuring that the tissue obtained is from the lesion
and is adequate for the diagnostic evaluation. Cultures
should always be obtained. Specimens are processed
for hematoxylin and eosin staining and various
immunohistochemical stains considered necessary to
aid in the diagnosis. A small portion of the tissue is
set aside for electron microscopy, cytogenetics, and in
some cases gene arrays.
3 Pathology
3.1 Histological Classification
The rationale for developing a well-defined, com-
prehensive, and flexible classification system of soft
tissue tumors is to provide morphological guidelines
that expand our understanding of neoplasia, predict
biological behavior, and facilitate the development of
more effective treatment. Originally, classification
schemes were descriptive in nature and based on
tumor cell configuration. Subsequently, they have
evolved through the concept of histogenesis or ‘cell of
origin’ to the current belief that a primitive or stem-
like mesenchymal cell undergoes neoplastic trans-
formation and, depending on the genetic code trans-
lated, differentiates along one or multiple cell lines.
Light microscopy in most instances is the modality
of choice for determining whether a soft tissue tumor
is benign or malignant, and for determining the sub-
type, grade, margins, and presence or absence of
vascular invasion. However, electron microscopy,
immunohistochemistry, DNA flow cytometry, cyto-
genetics, and molecular analysis can provide valuable
information that substantiates the histological inter-
pretation. Cytogenetic analysis is now being per-
formed more frequently on sarcomas. It is a
diagnostically useful technique, because some sarco-
mas have specific cytogenetic alterations that appear
to be pathognomonic. Characteristic translocations
1047
are found in a number of soft tissue sarcomas,
including Ewing’s sarcoma/primitive neuroectoder-
mal tumors (Delattre et al. 1994), alveolar rhabdo-
myosarcomas (DeChiara et al. 1993; Parham et al.
1994), myxoid liposarcomas (Aman et al. 1992), clear
cell sarcomas (Zucman et al. 1993), extraskeletal
myxoid chondrosarcomas (Stenman et al. 1995),
synovial sarcomas (Clark et al. 1994), myxoid-round
cell liposarcomas (Crozat et al. 1993), and alveolar
soft part sarcomas (Ladanyi et al. 2001). Molecular
biology will play a more important role in evaluating
STSs in the near future, as the technology becomes
more widely available. The identification of specific
DNA and RNA gene sequences and oncogenes will
help to diagnose and predict the biological behavior
of sarcomas. For example, the expression of the gene
product MYO D1 has already proven to be helpful in
recognizing tumors showing skeletal muscle differ-
entiation (Angervall and Kindblom 1993; Dias et al.
1994).
Currently, the most widely used classification
system is the Enzinger and Weiss modification of the
World Health Organization formulation (Weiss and
Goldblum 2008). In this system, soft tissue tumors,
including non-neoplastic tumor-like lesions, are cat-
egorized into three broad groups: (1) tumors that
differentiate along cell or tissue lines and have normal
counterparts, i.e., fibrous tissue, fat, vessels, smooth
muscle, skeletal muscle, nerve, ganglia, synovium,
bone, and cartilage; (2) tumors whose lines of dif-
ferentiation have no normal counterpart but are con-
sistent and recognized by a distinctive morphology,
i.e., myxoma, epithelioid sarcoma, and alveolar soft
part sarcoma; and (3) tumors that are so poorly dif-
ferentiated and morphologically unique that they defy
classification. The vast majority of tumors fall into the
first two groups. Overall, there are approximately 200
different entities, of which 80 are malignant.
As intensive study of these tumors is rapidly
expanding and new diagnostic procedures are
increasingly employed, there is inevitably some flux
in the diagnostic criteria for the diverse groups of soft
tissue tumors. Examples include (1) the reclassifica-
tion of most adult malignant fibrous histiocytomas by
some pathologists to undifferentiated pleomorphic
sarcomas, pleomorphic fibrosarcomas, or pleomor-
phic myofibroblastic sarcomas (Segal et al. 2003); (2)
the recognition that a granular cell tumor is a Schw-
ann cell neoplasm; (3) clear cell sarcoma shares many
1048 K. E. Haglund et al.

Table 2 Frequency of histopathological types of soft tissue sarcoma in a large series of patients with extremity and trunk soft
tissue sarcomas. MPNST malignant peripheral nerve sheath tumor, NR not reported, MGH Massachusetts General Hospital,
MSKCC Memorial Sloan–Kettering Cancer Center. MFH malignant fibrous histiocytoma (DeLaney et al. 2003a); Milan (Gronchi
et al. 2005); Lund (Engellau 2004); MSKCC (Pisters et al. 1996b)
MGH 1994 Milan 2005 Lund 2004 MSKCC 1996
Number of patients 738 911 298 1041
MFH (%) 22 8 13 25
Liposarcoma (%) 16 31 14 29
Fibrosarcoma (%) 11 NR 13 10
Leiomyosarcoma (%) 10 14 33 8
Sarcoma, not otherwise specified (%) 9 NR 9 NR
Synovial sarcoma (%) 8 15 6 12
MPNST (%) 10 10 7 5
Rhabdomyosarcoma (%) 3 NR NR NR
Vascular sarcomas (%) NR 5 1 NR
Other (%) 11 16 4 12

features characteristic of malignant melanoma but
arising in the soft tissues; and (4) extraskeletal
Ewing’s sarcoma is a primitive neuroectodermal
tumor.
The distribution of histological types of sarcoma of
soft tissue, from several large series is presented in
Table 2.
3.2 Grading
The histological typing of soft tissue tumors does not
provide sufficient information per se on which to base
therapeutic decisions. Tumor grading is based on the
concept that morphology reflects biological behavior.
The World Health Organization employs a four-
tiered grading system: G1 well differentiated, G2
moderately differentiated, G3 poorly differentiated,
and G4 undifferentiated; with the G1 and G2 lesions
considered low grade and the G3 and G4 considered
high grade. Some institutions and the AJCC now
employ a three-step grading, i.e., low-, intermediate-,
and high-grade neoplasms, with the intermediate- and
high-grade designations considered to be high grade
for most staging purposes. The designation of grade is
based on a consideration and integration of each of
these morphological features: degree of cellular dif-
ferentiation, extent of necrosis, number of mitoses,
cellularity, pleomorphism or anaplasia, quantity of
matrix, vascularity, hemorrhage, vascular invasion,
and encapsulation (Suit et al. 1975; Myhre-Jensen
et al. 1975; Rydholm et al. 1984; Costa et al. 1984;
Trojani 1984; Lack et al. 1989; Kulander et al. 1989).
Among these variables, necrosis, mitoses, and degree
of differentiation appear to be the best predictors of
outcome.
Until the recent past, both the International Union
Against Cancer (UICC) and the American Joint
Committee on Cancer (AJCC) staging systems for
soft tissue tumors have used a two-tiered grading
system, dividing tumors into low- and high-grades.
With each system’s most recent 2010 update, both the
UICC and the AJCC staging systems for soft tissue
sarcoma have adopted a three-tiered grading system.
The change in the AJCC grading system was imple-
mented in order to conform to recommendations of
the College of American Pathologists, which favors
the French (FNCLCC) system of grading. The
FNCLCC grade is determined by summing separate
scores for differentiation (1–3), mitotic activity (1–3),
and necrosis (0–2). The tumor is labelled as grade 1, if
the sum of the above scores is two to three; grade 2, if
the sum is four to five; and grade 3, if the sum is six to
eight (Rubin et al. 2006).
Grading, more than any clinical and pathological
parameter available, is the most important prognos-
ticator, despite some lack of agreement on the number
of grades employed and the significance of individual
morphological parameters (there is inevitably a sub-
jective component in assigning grade, and only a part
Extremity Soft Tissue Sarcoma in Adults
of the tumor is examined)(Russell et al. 1977). High-
power views of STS of grades 1, 2, and 3 of 3 are
shown in Fig. 3a–c. The problems with current
grading systems are that their criteria are not precisely
defined, application and interpretation is subjective,
and implementation is also complex. Consistent
grading requires adequate tissue and experienced
Fig. 3 Photomicrographs showing low-, intermediate-, and
high-grade soft tissue liposarcoma
1049
pathologists. The use of a gene expression signature
to predict clinical outcome in soft tissue sarcomas has
recently been published, and may allow further
refinement and reproducibility of grading (Chibon
et al. 2010).
4 Staging
The Task Force on Soft Tissue Sarcomas of the
AJCC Staging and End-Result Reporting has estab-
lished a staging system for STSs, which is an
extension of the tumor node metastasis (TNM) sys-
tem to include G for histological grade. Grade, size,
depth, and presence of nodal or distant metastases
are the determinants of stage. This staging system is
applied to all sarcomas of soft tissue except rhab-
domyosarcoma (for which there is a special staging
system), Kaposi’s sarcoma, dermatofibrosarcoma,
desmoid, and sarcoma arising from the dura mater,
brain, parenchymatous organs, or hollow viscera.
The staging system was revised in 1998 with the
addition of subgroupings of the T stage to designate
superficial and deep lesions. Superficial lesions do
not involve superficial investing fascia in extremity
lesions. In the current system, updated in the 7th
edition in 2010, regional nodal involvement was
reassigned from stage IV to stage III. This change is
validated by at least one recent study showing that,
when appropriately treated, individuals with node-
positive disease without distant metastases fare bet-
ter than those with distant metastases (Al-Refaie
et al. 2008). Therefore, Stage IV in the current
system is only assigned to those with distant
metastases. The 7th edition of the AJCC staging
system for soft tissue sarcoma is outlined in Table 3.
Grade of sarcoma is determined on the basis of the
histological features of the individual tumor. No
tumor is assigned a grade because of the histological
type alone. The grading system cited in the AJCC
staging manual is outlined in Table 3. As of the 7th
edition, the grading system recommended for use
with AJCC staging groupings has changed from a
four-tiered system to a three-tiered system. T stage is
determined on the basis of size and depth. As evi-
dence for the importance of size as a determinant of
frequency of distant metastasis, we present, in
Table 4, an analysis of distant metastasis versus
tumor size among patients who have achieved local
1050 K. E. Haglund et al.

Table 3 American Joint Committee on the Staging of Cancer Table 3 (continued)

staging system for soft tissue sarcomas (2010) IV: any distant metastasis:
Primary tumor (T) Any G or T or N, M1
TX: primary tumor cannot be assessed a
Superficial tumor is located exclusively above the superficial
T0: no evidence of primary tumor fascia without invasion of the fascia; deep tumor is located
either exclusively beneath the superficial fascia, superficial to
T1: tumor 5 cm or less in greatest dimension
the fascia with invasion of or through the fascia or both
T1a: superficial tumora superficial and beneath the fascia
b
T1b: deep tumora This staging system is not to be used for Kaposi’s sarcoma,
dermatofibrosarcoma (protuberans), fibrosarcoma grade I
T2: tumor more than 5 cm in greatest dimension (desmoid tumor) and sarcoma arising from the dura mater,
T2a: superficiala brain, parenchymatous organs, or hollow viscera
T2b: deepa
Regional lymph nodes (N)
NX: regional lymph nodes cannot be assessed
Table 4 The 5-year actuarial distant metastasis (DM) proba-
N0: no regional lymph node metastasis bility in 501 consecutive local control patients as a function of
N1: regional lymph node metastasis tumor size for grades 2 and 3 in series from Massachusetts
General Hospital (treatment by radiation and surgery) (DeLa-
Distant metastases (M)
ney et al. 2003a)
M0: no distant metastasis
Size (mm) No. of patients DM (%)
M1: distant metastasis
\25 58 3
Histological grade (G)
26–50 128 22
GX: grade cannot be assessed
51–100 177 34
G1: low grade
101–150 68 43
G2: intermediate grade
151–200 49 58
G3: high grade
200 21 57
Stage groupingb
Total 501 35
I: low grade, small or large, superficial or deep:
G1, T1a–2b, N0, M0
IA: low grade, small, superficial or deep:
control. For patients with grade-1 sarcomas, distant
G1, T1a–b, N0, M0
metastases are quite uncommon. The pooled data for
IB: low grade, large, superficial or deep: G2 and G3 lesions show regular increases in distant
G1, T2a–b, N0, M0 metastases with tumor size. From these data, there is
II: intermediate-high grade, small or large, superficial or deep: clearly importance in stratification of patients
G2-3, T1a–b, T2a N0, M0 according to grade and size, in attempts to compare
IIA: intermediate-high grade, small, superficial or deep: efficacy of different modes of treatment, defining the
G2-3, T1a–b, N0, M0
natural history of various histological types or
assessing the role of site, patient age, sex, etc.
IIB: intermediate grade, large, superficial or deep:
G2, T2a–b, N0, M0
III: high grade, large, superficial or deep: 5 Management of the Primary Tumor
G3, T2a–b, N0, M0
–or – The intent of treatment is to eradicate tumor while
Any grade, any T (small or large, superficial or deep), optimizing limb function. The National Comprehen-
regional node metastasis: sive Cancer Network (NCCN) maintains a detailed
G any, T any, N1, M0 treatment algorithm for soft tissue sarcomas that may
(continued) prove a useful reference in treatment decision-making
(NCCN 2010).
Extremity Soft Tissue Sarcoma in Adults
5.1 Overview
Because sarcomas tend to infiltrate normal tissue
adjacent to the evident lesion, simple excision alone is
followed by local recurrence (LR) in 60–90% of
patients (Markhede et al. 1981). Radical resection of a
wider margin of apparently normal tissue around the
tumor reduces the local failure rate to approximately
25–30% (Simon and Enneking 1976). More recently,
with the advent of compartmental resections, the local
failure rate has fallen to 10–20% with surgery alone
(Simon and Enneking 1976). One study that reported
a zero local failure rate derives from the amputation
arm of the National Cancer Institute trial comparing
amputation with limb salvage treatment (Rosenberg
et al. 1982). Careful selection of patients and attention
to technique in some recent series, however, has also
allowed high rates of local control in patients with
generally smaller, lower grade lesions with conser-
vative surgery alone (Baldini et al. 1999; Rydholm
et al. 1991).
The combination of surgery and radiation gener-
ally achieves better outcomes than either treatment
alone for nearly all STS (Suit et al. 1975; Lindberg
et al. 1981). The rationale for combining radiation
with surgery is to avoid the functional and cosmetic
deformity associated with radical resection and to
avoid the late consequences of high radiation doses to
large volumes of normal tissue in patients treated with
primary radiation alone. Radiation at moderate dose
levels (50–65 Gy) is as effective as radical resection
in eradicating the microscopic extensions beyond the
gross lesion, resulting in similar high rates of local
control. This has allowed maximization of functional
and cancer-related outcome without the significant
morbidity of radical surgery. Most centers report local
control rates of approximately 90% for high-grade
extremity STS and 90–100% for low-grade STS
depending on the size (Rosenberg et al. 1982; Potter
et al. 1985; Karakousis et al. 1986; Brant et al. 1990;
Harrison et al. 1993; DeLaney et al. 2003a; Eilber
et al. 2003; Abbatucci et al. 1986; Wilson et al. 1994).
In addition to its benefit in improving local tumor
control rates, adjunctive radiation therapy (RT) has
also had a significant impact on limb salvage for
extremity sarcomas. As an example, in the 1970s,
50% of patients with extremity sarcoma underwent
amputation; those patients treated by wide excision
alone with limb preservation experienced a 30% rate
1051
of LR. With the subsequent application of RT and
advanced reconstructive techniques, the rate of
amputation at major centers has been reduced to
\10%, and the incidence of LR with limb preserva-
tion has been reduced to 10–15% without any mea-
surable fall in OS (Rosenberg et al. 1982; Williard
et al. 1992; LeVay et al. 1993; Karakousis and Dris-
coll 1999). A single, prospective randomized trial
showed similar rates of disease-free survival and OS
for patients treated with amputation or the combina-
tion of limb-sparing surgery and radiotherapy for
extremity STS (Rosenberg et al. 1982).
The current indications for amputation include:
massive disease such that a functional limb is not
achievable, as well as severely compromised normal
tissues due to age, peripheral vascular disease, or
other comorbidities. The functional and cosmetic
results of conservative procedures are dependent on
the size and anatomic location of the tumor, the
magnitude of the surgical procedure, the extent to
which muscles, tendons or nerves must be sacrificed,
the volume of tissues irradiated, and the radiation
dose administered.
5.2 Surgical Considerations
The most important surgical variable that influences
local control is the presence or absence of tumor cells
at the surgical margins (Rosenberg et al. 1982; Wil-
liard et al. 1992; LeVay et al. 1993; Sadoski et al.
1993; Tanabe et al. 1994; Pisters et al. 1996b; Trovik
et al. 2000; Zagars et al. 2003b; Jebsen et al. 2008).
In a series that report resection with clear margins,
such as the Scandinavian Sarcoma Group, the local
failure rates are quite low (8%) (Alvegard et al. 1989).
In contrast, in a second study of 559 patients who
were treated with surgery alone from the same group,
an inadequate surgical margin led to a 2.9-fold greater
risk of LR than did clear surgical margins (Trovik
et al. 2000). Distant metastases are extremely
uncommon for low-grade lesions but occur with high-
grade lesions with a frequency that is influenced by
the size of the lesion (Potter et al. 1985) and whether
local control is achieved. In the Scandinavian Sar-
coma Group experience, local recurrence was identi-
fied as a risk factor for distant metastasis (4.4-fold
higher) (Alvegard et al. 1989). Analysis of outcomes
in 997 consecutive patients treated in Milan
1052
documented significant associations between margin
status (R1 vs. R0 resection) and local recurrence-free
survival, and disease-specific survival, but not distant
metastasis-free survival. Estimated 5-year cause-spe-
cific mortality for those who had R0 resections and
those who had R1 resections were 16 and 29%,
respectively (Gronchi et al. 2010).
The status of the surgical margins also influences
the local recurrence rate in patients treated with
combined surgery and radiation (LeVay et al. 1993;
Sadoski et al. 1993; Zagars et al. 2003b). In one
review of 132 consecutive patients with STS of the
extremities who were treated with pre-operative RT
followed by resection, the 5-year actuarial local
control rates were 97 and 81%, respectively, for
patients with negative and positive margins (Sadoski
et al. 1993). Local control was not a function of sar-
coma size in patients with negative surgical margins.
In a second series of 225 patients, all of whom
received combined surgery and radiotherapy (either
pre-operative, post-operative, or both), local control
rates at 5 years were 88, 76, and 64% for patients with
negative, uncertain, and positive margins, respec-
tively (Zagars et al. 2003b).The exact size of the
negative margin that is optimal for local control is not
known. In one study, the local control rate did not
differ in patients with a margin of 1 or less or more
than 1 mm (local control 96 vs. 97%) (Sadoski et al.
1993). Most clinicians recommend that if surgery is
used as the sole modality of treatment, the margin
should be at least 1 cm in all directions (Eilber and
Eckardt 1997) or, if less, include a supervening fascial
barrier. If surgery is combined with RT, the surgical
margin can probably be safely reduced to 0.5 cm
without compromising the rate of local control (Sa-
doski et al. 1993). In a recent series including 56
patients undergoing pre-operative radiotherapy by
Kim et al. (2010), all five local recurrences occurred
in patients with surgical margins that were positive
(three patients) or \1 mm (two patients).
The guiding principle of surgery is total en bloc
excision of the primary tumor without cutting into
tumor tissue. Tissue cuts should be made outside of the
tumor pseudocapsule, if one exists, through normal
uninvolved tissue. Violation of the tumor results in a
higher local failure rate. In one report, for example, the
local control rate in 95 patients with extremity STS
was 47% if tumor violation occurred compared
with 87% without violation (Tanabe et al. 1994).
K. E. Haglund et al.
The majority of STSs do not involve bone; as a result,
it is seldom necessary to resect adjacent bone. It is also
rarely necessary to resect a major nerve unless the
tumor is a neurogenic sarcoma. Likewise, it is usually
unnecessary to resect major blood vessels unless the
tumor arises in the blood vessel wall (for example, a
leiomyosarcoma). Nonamputative surgery is now
accomplished in more than 90% of patients.
In planning primary therapy for a patient who has
had a suboptimal or ‘‘unplanned’’ resection (i.e., by a
surgeon unaware that he or she was removing a
malignant tumor) and insufficient imaging with pre-
operative CT or MRI, it is important to consider re-
resection. Approximately 37–68% of such patients
will have residual tumor in a re-resection specimen
(Noria et al. 1996; Karakousis and Driscoll 1999;
Zagars et al. 2003a). A partial excision of the tumor
before referral to a tertiary center does not appear to
compromise limb preservation, local control, or sur-
vival rates in such patients (Karakousis and Driscoll
1999), although the re-resection may entail a larger
procedure than a de novo procedure and impact on the
functional result. In one series of 295 patients who
underwent re-resection at a single institution (final
resection margins negative in 87%), local control
rates at 5, 10, and 15 years were 85, 85, and 82%; the
corresponding values for those who did not undergo
re-resection were 78, 73, and 73%, respectively
(Zagars et al. 2003a). A similar degree of benefit for
re-resection was apparent for metastasis-free and
disease-specific survival.
5.3 Selection of Patients for Treatment
with Surgery Alone
Because of potential acute and late morbidity from
RT, it is important to select patients who may be
effectively treated with surgery alone. Several pub-
lished series have evaluated wide-excision, limb-
sparing surgery alone. In one report, 119 selected
patients with extremity STS were grouped according
to anatomic location as subcutaneous (n = 40),
intramuscular (n = 30), or extramuscular (n = 49)
(Rydholm et al. 1991). The 70 patients with subcu-
taneous and intramuscular tumors were all treated by
local surgery, and a wide margin (requiring a cuff of
fat tissue around the tumor and inclusion of the deep
fascia beneath the tumor) was obtained in 56.
Extremity Soft Tissue Sarcoma in Adults
These patients were followed without post-operative
radiation. During a median follow-up of 5 years
(range, 3.5–10 years), only 4 had a local recurrence,
despite the fact that 84% had high-grade tumors. The
authors concluded that post-operative radiation may
not be necessary in this subgroup. A similar study at
M. D. Anderson Cancer Center evaluated local con-
trol for T1 tumors after excision alone with negative
margins. Wide local excision was performed with
the intent of including a 1–2 cm margin of normal
tissue around the mass. Negative surgical margins
were achieved in 84% of the 88 enrolled patients; the
remaining 16% with microscopically positive margins
received post-operative radiation. In those with exci-
sion alone, the 5-year local recurrence rate was 7.9%,
and the 5-year sarcoma-specific death rate was 3.2%
(Pisters et al. 2007). In another study, 74 patients with
localized STS of the extremity or trunk underwent
function-sparing surgery without radiation (Baldini
et al. 1999). The overall 10-year actuarial local con-
trol rate was 93% and was dependent on the adequacy
of surgical margins (87 vs. 100% for patients with
margins of \1 cm and 1 cm or more, respectively).
The 10-year survival rate was 73%. This approach
may be appropriate for carefully selected patients
with small (\5 cm), superficial tumors or small, deep
tumors that can be resected with all margins 1 cm or
more.
5.4 Combining Surgery with RT
The recommended treatment for most patients who
are medically and technically operable is the combi-
nation of function-preserving surgery and radiation,
with the exception of that minority of patients with
small, generally superficial lesions that can be widely
excised with secure margins and good functional
results. Radiation is an effective treatment for STS, as
the radiation sensitivity of cell lines derived from
sarcomas is not less than that of epithelial cell lines
(Ruka et al. 1996). For small sarcomas, good local
control rates can be achieved by radiation alone.
However, local tumor control probabilities of more
than 90% for tumors of estimated volumes of
15–65 ml (approximately a sphere of 3–5 cm in
diameter) require high radiation doses ([75 Gy)
(Tepper and Suit 1985). For unresected sarcomas,
there appears to be an advantage for doses above
1053
63 Gy (Kepka et al. 2005). As most treatment vol-
umes are relatively large, the late normal tissue
changes resulting from these dose levels are clinically
important in nearly all patients. In animal models, a
significantly lower radiation dose is required to
achieve local control when radiation is combined with
simple excision than with radiation alone (Todoroki
and Suit 1985).
The impact of combined modality treatment that
includes EBRT on both local control and survival has
been evaluated in only one prospective randomized
trial. In this study, 91 patients with high-grade lesions
were randomly assigned to surgery plus post-opera-
tive chemotherapy, with or without post-operative
adjuvant EBRT, and 50 with low-grade lesions were
randomized to surgery plus adjuvant EBRT or surgery
alone (Yang et al. 1998). In patients with high-grade
lesions, there were no LRs in the patients randomized
to EBRT, while the patients receiving only adjuvant
chemotherapy had a 22% actuarial local failure rate at
10 years. In patients with low-grade sarcoma, the LR
rates were 4 versus 33% in the post-operative EBRT
and surgery alone groups, respectively. There was no
influence of post-operative radiation on OS for either
high- or low-grade tumors.
5.5 Pre-operative (Neoadjuvant) Versus
Post-operative (Adjuvant)
Radiotherapy
There are potential advantages to both pre-operative
and post-operative administration of radiation. Pre-
operative RT might be expected to reduce tumor
burden prior to resection, theoretically allowing more
conservative surgical therapy. Radiation fields can be
limited to the tumor and adjacent tissues at risk for
microscopic infiltration, a volume that is considerably
smaller than that which must be treated following
surgery, where the entire surgical bed is included in
the initial target volume irradiated to 50 Gy. Radia-
tion doses are lower (50 Gy pre-operative vs.
60–66 Gy post-operative). Post-operative radiother-
apy allows histological examination of the tumor
specimen, especially the margins, aiding in further
treatment planning; it is also associated with fewer
acute wound complications.
There is one randomized, controlled study com-
paring pre-operative versus post-operative radiation
1054
therapy, designed to evaluate the incidence of acute
wound healing complications in patients with poten-
tially curable extremity STS (O’Sullivan et al. 1999).
In this Canadian trial, 190 patients were randomly
assigned to either pre-operative radiation (50 Gy pre-
operative for all 94 patients randomized to this arm
with 16–20 Gy post-operative boost reserved for the
14 patients in this arm with a positive margin) or post-
operative radiation (50 Gy initial field ? 16–20 Gy
boost field for all patients). Complications were
defined as secondary wound surgery, hospital admis-
sion for wound care, or the need for deep packing or
prolonged wound dressings within 120 days of tumor
resection.
With a median follow-up period of 3.3 years, a
significantly higher percentage of preoperatively
treated patients had acute wound complications (35
vs. 17%). Other factors associated with wound com-
plications were the volume of resected tissue and
lower limb location of the tumor. Late morbidity was
initially not reported. Because the RT fields for the
post-operative RT were larger, and the dose delivered
for most patients was higher, the authors indicated
that more follow-up would be needed to assess whe-
ther these larger radiation volumes and higher radia-
tion doses would lead to more late treatment effects in
these patients.
In a later publication, the local recurrence rate,
regional or distant failure rate, progression-free sur-
vival, and functional outcome did not differ between
the groups (Davis et al. 2002). This data has now been
updated with a median follow-up period of 6.9 years.
There remain no differences in local tumor control
between the two arms of the study with over 90% local
control. The regional and distant failure rates as well
as the progression-free and OS rates are also no dif-
ferent between the two arms of the study (O’Sullivan
et al. 2004). The post-operative patients, however,
have greater 5-year actuarial rates of grade-2 to -4 late
toxicity (86%) when compared with the pre-operative
patients (68%), P = 0.0002. Notably, subcutaneous
toxicity rated as grade 3 (severe induration and loss of
subcutaneous tissue or field contracture greater than
10% linear measurement) or grade 4 (necrosis) was
significantly more common in the post-operative
group, 36 versus 23%, P = 0.02.
There is, thus, a higher rate of generally reversible
acute wound healing complications in patients
receiving pre-operative treatment, which was offset
K. E. Haglund et al.
by a higher rate of generally irreversible late com-
plications, including grade 3–4 fibrosis, in patients
receiving post-operative RT. Because very few acute
wound-healing complications occurred in either
group when the tumor was in the upper extremity, it
would seem prudent to treat these patients with pre-
operative RT. We have also favored pre-operative
radiation for the majority of lower extremity patients,
because acute wound complications can usually be
managed and will go on to heal, whereas the late
treatment effects are generally irreversible. For
patients with lower extremity lesions, this study,
however, makes it clear that new strategies are needed
to (1) reduce the risk of acute wound healing prob-
lems when patients receive pre-operative RT and (2)
reduce the risk of late-treatment-induced effects when
higher dose, larger field post-operative radiation is
given.
5.6 Brachytherapy
Compared with EBRT, BRT minimizes the radiation
dose to surrounding normal tissues, maximizes the
radiation dose delivered to the tumor, and shortens
treatment times. In the usual dosage schedule, treat-
ment is completed within 5 days and requires only
one hospitalization. At the time of surgery, after-
loading catheters are placed in a target area of the
tumor operative bed, defined by the surgeon, and
spaced at 1 cm intervals to cover the entire area of
risk (Fig. 4). BRT can also be used for delivery of a
boost to the tumor bed in conjunction with EBRT
(Schray et al. 1990).
A phase-III trial of post-operative BRT versus no
BRT was conducted in 126 patients who had com-
plete resection of either extremity or superficial trunk
STS (Harrison et al. 1993). The BRT dose was 45 Gy
using low dose rate Iridium-192. The 5-year local
control rates were 82 and 67% for the BRT and sur-
gery alone groups, respectively. The advantage of
BRT was seen only in the high-grade sarcomas
(Harrison et al. 1993; Pisters et al. 1996a) and was
limited to local tumor control, since there was no
difference between the groups in distant metastasis or
disease-specific survival (Harrison et al. 1993).
Although it is unclear whether BRT is associated
with a higher risk of wound complications (see
‘‘Wound healing after surgery and radiation’’ below),
Extremity Soft Tissue Sarcoma in Adults
Fig. 4 a–c This boy with a recurrent epithelioid sarcoma on
the hypothenar eminence of his left hand following an
excisional biopsy 1 year earlier (lesion mistakenly called a
benign fibrous histiocytoma at that time by an inexperienced
pathologist) was treated at age 11 years with a combination of
excision (a), 45 Gy of low dose rate iridium-192 brachytherapy
(b), and 20 Gy delivered following the implant with 6-MeV
electrons (c). At 10 years, he is free of any evidence of disease
with normal hand function and only slight dryness of skin at the
site of radiation
1055
the rate of wound reoperation may be higher (Alektiar
et al. 2000). BRT has been combined with free flap
construction as a means of enhancing primary healing
in difficult anatomic situations without an increase in
the incidence of wound breakdown (Panagopoulos
et al. 1996). There have been no randomized com-
parisons of the relative efficacy or morbidity of EBRT
compared with BRT.
BRT for sarcomas has traditionally been given by
low dose rate. There are emerging data on the use of
fractionated high dose rate schedules (Nag et al. 2001;
Kretzler et al. 2004; Petera et al. 2004). High dose
rate BRT has been used in conjunction with EBRT for
the tumor bed boost in doses of 15–24 Gy, often
hyperfractionated at 2.3–4 Gy b.i.d. (Nag et al. 2001).
Early retrospective evidence suggests that comparable
rates of local control can be achieved when combin-
ing either LDR or HDR BT with EBRT (Beltrami
et al. 2008). However, one report using high dose rate
BRT alone in doses of 40 Gy at 2.3–3 Gy b.i.d
unfortunately reported poor local control of only 20%,
in contrast with 100% when BRT was combined with
EBRT (Petera et al. 2004).
5.7 EBRT Planning
The radiation treatment technique should be carefully
planned so that the tissues being irradiated are only
those judged to be at risk. To utilize smaller target
volumes, the part to be irradiated must be securely
and reproducibly immobilized. We have special
immobilization devices prepared for the individual
patient. This may require casting, especially for hand,
foot, or elbow sites (Fig. 5). For some sites, the part is
placed in standard plastic supports and the extremity
fastened tightly in place using a Velcro fastener.
Others describe their experience with casts and
polyurethane foam systems (Niewald et al. 1990) or
an adaptable baseplate and thermoplastic shell system
(Dickie et al. 2009).
The principal tasks involved in the development of
a treatment plan are:
• Design an immobilization device and a means to
ensure that the target is on the beam (Fig. 6).
• CT scan the immobilized, affected extremity for
radiotherapy planning. This is facilitated by the
availability of a large bore scanner that allows
maximum flexibility in arranging the limb such that
1056
Fig. 5 Customized immobilization device for a 34-year-old
physician with a G3/3T1bN0MO (stage II) monophasic syno-
vial sarcoma of the thenar eminence of his right hand
undergoing 50 Gy of external beam photon radiation therapy
prior to tumor bed excision
Fig. 6 Customized immobilization device for a 23-year-old
female undergoing 60 Gy of post-operative radiation therapy
for treatment of grade-1–2/3 myxoid liposarcoma of the medial,
left thigh, low-to-intermediate grade, pT2BN0 M0 (stage III)
with negative but close (0.2 cm) medial and deep resection
margins. Involved lower extremity was rigidly immobilized for
computed tomography (CT) simulation, while contralateral
extremity was placed in a neutral position to allow it to get
through a conventional-width CT simulator bore. For treatment,
the involved extremity remains in same rigid immobilization,
while additional immobilizer was added to frog-leg the
contralateral extremity out of the treatment beam
the contralateral extremity and the trunk will be out
of the beam.
• Define the target volume(s) (on each section of the
CT/MRI of the affected region).
K. E. Haglund et al.
• Define non-target critical structures in the treatment
volume and specify dose constraints for each such
structure.
• Estimate the distribution and number of tumor
clonogens/unit volume of tissue throughout the
target volume.
• Define one or more target volumes to realize the
appropriate dose distribution using ‘‘shrinking
treatment volume methods’’.
• Design treatment techniques that achieve the clos-
est feasible conformation of treatment to target
volume(s). This may require complex field
arrangements, treatment angles, gapped fields,
wedge filters, tissue compensators, and/or bolus.
• Avoid inclusion of an entire joint space.
• Avoid full dose irradiation of adjacent bone to
reduce the risk of pathological fracture.
• Utilize wedges and tissue compensators as needed
to account for tissue heterogeneities and minimize
dose inhomogeneity.
• Incorporate an appropriate planning target volume
(PTV) expansion to account for treatment setup
variability and any target motion.
• Review the treatment plan at multiple levels along
the extremity to assess dose homogeneity to the
target and normal tissues (Fig. 7).
5.8 Radiation Treatment Volumes
and Dose
The extent of normal tissue to be irradiated adjacent
to the tumor bed in the case of pre-operative RT and
adjacent to the surgical bed in the case of post-oper-
ative RT is not definitively known. Few patterns of
failure studies that relate the extent of the RT field to
the site of local tumor recurrence have been reported.
Because sarcomas are judged to infiltrate along rather
than through tissue planes, longitudinal margins
proximally and distally have traditionally been con-
siderably more generous than radial margins. Histor-
ically, fields that extended from the muscle origin to
insertion (Tepper et al. 1982) or provided generous
proximal/distal margins on the tumor were employed
(Suit et al. 1988). In some centers from the 1970s
through the mid 1990s, 5- to 10-cm proximal and
distal block margins were used for large grade-1 and
small grade-2 lesions and more generous fields with
10- to 15-cm margins were encompassed for large
Extremity Soft Tissue Sarcoma in Adults
Fig. 7 a–c A 3D conformal radiation therapy plan for a patient
with a grade-3/3 T2bN0M0 (stage III) malignant fibrous
histiocytoma along the anteromedial aspect of the left knee
just above the patella and superficial to the quadriceps tendon
undergoing pre-operative radiation therapy of 50 Gy in 25
fractions
grade-2 to -3 lesions (Suit et al. 1988). The advent of
improved MRI delineation of tumor extent and sub-
sequent surgical experience with high rates of local
1057
control, when surgical margins of 1 cm or more could
be obtained, prompted radiation oncologists to
employ proximal/distal margins of 5 cm or less for
small grade-1 lesions and 5- to 7-cm proximal/distal
margins for larger, higher grade lesions. Newer (3D)
treatment planning systems appear to allow smaller
and more accurate treatment volumes in patients with
extremity STS.
There are very few studies in the literature looking
at the appropriate target volume used when planning
RT for extremity soft tissue sarcomas. This tends to
be poorly reported. One group found a remarkable
difference in 5-year local control where the margin
was less than 5 cm (30%) or at least 5 cm (93%)
(Mundt et al. 1995). This conflicts with the BRT data,
where acceptable results are achieved using 4 cm
margins longitudinally and 2 cm laterally. A study
from the Royal Marsden Hospital has suggested that,
as in other tumor sites, the great majority of local
recurrences occur within the high dose volume
(Cleator et al. 2001). The use of 5-cm proximal and
distal block margins and 2-cm radial block margins
(on the tumor for pre-operative RT or on the surgical
bed for post-operative RT) for the first 50 Gy pro-
vided very high rates of local control in the random-
ized National Cancer Institute Canada trial discussed
above (O’Sullivan et al. 2004).
A recent retrospective study lends valuable insight
into optimal field size in pre-operative radiation. Pat-
terns of local failure were evaluated in 56 patients who
underwent pre-operative radiation to a median dose of
50 Gy. The field size used for all patients was a clinical
target volume (CTV) that included the T1 post-gado-
linium tumor with a 1- to 1.5-cm radial and 3.5 cm
longitudinal margin, with an additional expansion of
5–7 mm to define the planning target volume. Boost
doses of 10–20 Gy were administered to the 12
patients with close or positive margins. The 5-year
actuarial local control rate of 88.5% is comparable to
other series. Tumor size and surgical margin status
were the primary predictors of local failure. All five
local failures occurred in patients with either positive
resection margins or resection margins of\1 mm. No
local failures occurred in those with margins of 1 mm
or greater. Interestingly, although good local tumor
control rates were achieved, all local failures occurred
within the pre-operative CTV (Kim et al. 2010).
This raises the question as to whether the large-
volume phase 1 is necessary or whether the boost is
1058
necessary where an adequate surgical margin has
been achieved. This question is particularly relevant
now because of the advent of techniques such as
intensity-modulated radiotherapy (IMRT) and protons
that allow us to selectively spare normal tissues. It
will be important to determine the volumes that can
safely be spared before these techniques can be
optimally implemented. Such studies are currently
being considered by cooperative groups in the US and
Europe. A phase II study by the Radiation Therapy
Oncology Group (RTOG) which completed accrual in
September 2010 is evaluating the role of image-gui-
ded RT (conebeam CT, tomotherapy, etc.) in deliv-
ering pre-operative RT to soft tissue sarcoma patients
using more limited CTV margins (RTOG 0630).
CTVs in this study encompass the T1 post-gadolinium
enhancing region plus a 3-cm longitudinal margin and
1.5-cm radial margin for intermediate- or high-grade
tumors that are 8 cm or greater. For all other tumors, a
2-cm longitudinal margin and a 1-cm radial margin
are used. The primary outcome of interest is toxicity
2 years after treatment, and secondary outcomes will
evaluate local control and other survival measures.
Another study, performed by investigators in
Toronto, which will need to be very carefully con-
sidered in the discussion of RT volumes, correlated
MRI and surgical findings in patients undergoing
surgery without any neoadjuvant therapy. It provided
a histological assessment of peritumoral edema as
demonstrated by increased T2-weighted signal
intensity on MRI scans performed preoperatively on
15 patients with high grade extremity or truncal sar-
comas ranging from 3.1 to 30.1 cm (mean, 13.8 cm)
(White et al. 2005). The extent of peritumoral T2-
weighted signal intensity changes beyond the tumor
ranged from 0 to 7.1 cm (mean, 2.5 cm); contrast
enhancement ranged from 0 to 5.3 cm (mean 1.1 cm).
Tumor cells were identified histologically in the tis-
sues beyond the gross tumor in 10 of 15 cases. In 6
cases, the tumor cells were located within 1 cm of the
tumor margin, and in 4 cases, malignant cells were
found at a distance [1 cm and up to 4 cm. The
location of the tumor cells did not correlate with
tumor size or extent of peritumoral changes on the
MRI scans. In 9 of 10 cases, however, the tumor cells
were identified histologically in areas with corre-
sponding high T2-weighted signal changes on MRI.
With ever-increasing ability of the available radiation
oncology technology to conform the radiation dose to
K. E. Haglund et al.
the target, this study has very significant implications
for radiotherapy target design and must be considered
in future studies of radiotherapy volumes in this
disease.
The radial CTV margins should be viewed with
respect to the direction of most likely spread and are
rationally derived from surgical series with high rates
of local control without adjuvant radiotherapy with
surgical margins [1 cm. Because the gross tumor
delineation with radiation planning imaging will be
less precise than that achievable in the operating
room, radial CTV margins of 1.5–2.0 cm with
approximately 0.5 cm for PTV expansion are added
to account for daily set-up variation. Where there is
intervening bone, interosseous membrane, or major
fascial planes, and these planes are intact in the
imaging studies, the radial CTV margins can be
constricted to the surface of these structures. When a
fascial plane has been violated, wider margins are
appropriate to cover areas of potential contamination
by tumor.
For patients receiving pre-operative radiation,
50 Gy is administered over 5 weeks, followed
3–5 weeks later by a conservative resection. For
patients with negative surgical margins and no other
unfavorable prognostic features such as tumor cut-
through or satellite lesions after prior surgical inter-
ventions, 50 Gy of pre-operative RT appears sufficient
to provide local control in a very high proportion of
patients. Sadoski et al. (1993) analyzed 132 consecu-
tive patients with STS of the extremities treated with
pre-operative radiotherapy and resectional surgery and
found that: (1) the 5-year actuarial local control rates
were 97% and 81% for patients with negative margins
and positive margins, respectively (this difference is
highly significant); (2) there was no difference in local
control between the various sub-categories of negative
margins (negative at \1 mm, 96%; negative at [
1 mm, 97%; not measured, 94%; and no tumor in the
specimen, 100%); (3) there was no difference in local
control for treatment of primary and locally recurrent
lesions (after previous surgery alone) when the tumors
were stratified for margin status; and (4) for the
patients with negative margin, local control was not a
function of sarcoma size.
For patients with positive margins following pre-
operative RT, it is recommended to use a ‘‘shrinking
treatment volume technique’’ with delivery of either
BRT or a post-operative EBRT boost dose of
Extremity Soft Tissue Sarcoma in Adults
16–18 Gy to the tumor bed once the surgical wound
has healed. A boost dose to 66 Gy is given post-
operatively or intraoperatively for microscopically
positive margins and to 75 Gy if there is gross
residual disease. In patients with frozen section evi-
dence of close or positive margins, a boost dose can
be administered intraoperatively using BRT or elec-
tron beam. For BRT, it is appropriate to deliver
approximately 16 Gy by low dose rate techniques or
14–16 Gy by HDR given as 3.5–4 Gy b.i.d. for
microscopically positive margins. Gross residual
disease will need a dose of approximately 20–25 Gy.
Although delivery of a post-operative radiation boost
after resection with positive margins remains the
standard of care, its efficacy in achieving local control
has been called into question by the results of at least
one retrospective study using EBRT (Al Yami et al.
2010).
For patients undergoing post-operative RT, irradi-
ation usually begins 14–20 days following surgery,
once the wound is healed. Following resection of
large tumors, it may be necessary to wait 3–4 weeks
to allow resorption of the seroma. The initial volume
must include all tissues handled during the surgical
procedure, including the drain site, often encom-
passing the surgical bed with 5-cm proximal/distal
block margins and 2-cm radial block margins, which
means CTVs of approximately 3.5 cm proximally and
distally and 1.5 cm radially. The dose to the initial
CTV is 50 Gy. Progressively shrinking treatment
volumes are then employed to encompass the tumor
bed and, if needed, areas of positive margins or gross
residual disease; the final dose is 60 Gy for volumes
with negative margins, 66–68 Gy for areas of positive
margins or locally recurrent disease (Zagars and Ballo
2003), and 75 Gy for gross residual sarcoma.
The available information on a dose–response
relationship for the local control of sarcomas treated
with surgery and post-operative RT is somewhat
conflicting. Mundt reported that local control was
dose dependent. While post-operative patients
receiving \60 Gy had a worse local control than
those receiving 60 Gy or more, no difference was
seen in local control between patients receiving
60–63.9 Gy (74.4%) and those receiving 64–66 Gy
(87.0%) (P = 0.5). Severe late sequelae were more
frequent in patients treated with doses of 63 Gy or
more, than in patients treated with lower doses (23.1
vs. 0%) (Mundt et al. 1995).
1059
Fein noted that patients receiving\62.5 Gy had a 5-
year local control of 78 versus 95% where the dose was
[62.5 Gy (Fein et al. 1995). In a multivariate analysis
of patients undergoing post-operative radiotherapy,
Zagars and Ballo (2003) identified dose as an inde-
pendent variable for local control. Doses of 64 Gy or
more correlated with improved local control. Recog-
nizing that the effectiveness of a particular dose was
also related to other factors influencing local control,
such as margin status, anatomic site, and locally
recurrent presentation, they recommended post-oper-
ative doses of 60 Gy for patients with negative margins
and otherwise favorable prognostic features, while
suggesting increasing doses for less favorable presen-
tations, up to doses of 68 Gy for positive margins. In
contrast, other investigators have not been able to
demonstrate a clear dose–response relationship in their
reviews of their patients undergoing post-operative RT
(Bell et al. 1989; Pao and Pilepich 1990; LeVay et al.
1993; Robinson et al. 1990). In practice, most centers
give 60 Gy of post-operative radiotherapy for patients
with negative margins and 66–68 Gy for positive
margins, using shrinking fields as described above.
With regard to pre-operative RT, Robinson et al.
failed to demonstrate a variation in local tumor con-
trol according to dose, although the response rate to
pre-operative radiotherapy was clearly dose depen-
dent (Robinson et al. 1992). The accepted dose for
pre-operative radiotherapy is 50 Gy.
For treatment of an extremity lesion, a good func-
tional result demands that a portion of the cross section
of the extremity be spared from high dose radiation
(Stinson et al. 1991). Thus, some tissue should not be
irradiated to a high dose to provide for lymphatic
drainage. For very large tumors that are treated with
wide resection, there may be persistent leg edema,
requiring the use of a pressure-type stocking, even
though the radiation treatment volume is less than
circumferential. This can be a problem for patients
with large ([10 cm) sarcomas of the medial thigh.
When post-operative radiation is combined with
adjuvant chemotherapy, radiation daily dose has been
reduced in some series by 10% from 200 to 180 cGy;
radiation is not given concurrently with doxorubicin.
Instead, 2–3 days are allowed between the doxorubi-
cin and radiation. Some pre-operative protocols have
interdigitated chemotherapy and RT (see below); total
pre-operative radiation has been reduced (i.e., 44 Gy)
in this setting.
1060
Fig. 8 Axial intensity-modulated radiotherapy (IMRT) treat-
ment plan for an 82-year-old gentleman with a history of type-2
insulin-dependent diabetes mellitus treated for a 5.7-cm, grade-
2–3/3 malignant fibrous histiocytoma arising deep in his left
anterior thigh adjacent to the femur, clinical stage T2B N0 M0
(stage III). He underwent pre-operative radiation therapy to a
total dose of 48.6 Gy at 1.8 Gy, with reduction in fraction size
5.9 Intensity-Modulated Photon RT
The purpose of RT is to maximize the dose delivered
to the tumor while minimizing the exposure of dose-
sensitive critical structures to high dose. This has
been achieved traditionally by shaping the spatial
distribution of the high radiation dose to conform to
the target volume (hence, 3D conformal RT), thereby
reducing the dose to the non-target structures.
Although this approach is satisfactory in the treatment
of targets that are roughly convex in shape, it is less
than optimal for targets that contain complex con-
cavities or that wrap around critical structures
(Verhey 1999). Growing experience suggests that
intensity-modulated photon RT (IMRT) plans
K. E. Haglund et al.
and total dose because of his diabetes. An IMRT plan was used
to contour the dose around the femur, to reduce the risk of late
pathological fracture. The IMRT plan was able to accomplish
this, but as would be anticipated, more low-dose radiation was
delivered to the posterolateral thigh normal tissues than would
have been the case for a three-dimensional conformal plan
produce dose distribution to the patient superior to 3D
conformal plans, both in terms of dose conformity in
the tumor and dose reduction to the specified critical
normal structures, albeit at the cost of increased
integral dose to the normal tissues (Fig. 8). Recent
dosimetric studies comparing IMRT and conformal
radiotherapy for STS have been reported. When
evaluating sarcomas arising in the extremities, pelvis,
trunk, and paranasal sinuses, IMRT plans were more
conformal. In the extremities, bone and subcutaneous
doses were reduced by up to 20%. A conformal-
IMRT comparative planning study has been reported
for a large extraskeletal chondrosarcoma of the
extremity (Chan et al. 2001). Not surprisingly, IMRT
produced excellent conformal treatment plans for this
Extremity Soft Tissue Sarcoma in Adults
complex target volume, with a greater reduction of
the maximum dose to the bone than the 3D-photon
plan. Hong et al. (2004) performed treatment-plan-
ning comparisons of IMRT and 3D conformal radio-
therapy for ten patients with STS of the thigh. They
were able to document a reduction in femur dose
without compromising tumor coverage. In addition,
IMRT reduced dose inhomogeneity (i.e., ‘‘hot spots’’)
in the surrounding soft tissues and skin.
In a single-institution retrospective study, Alektiar
et al. (2008) recently reported on a series of 41 adult
patients with STS of the extremity treated with limb-
sparing surgery and IMRT. In their cohort, 51% had
positive or close (\1 mm) margins, and 68% had
tumors greater than 10 cm. At a median follow-up time
of 35 months, an encouragingly low rate of compli-
cations was observed, with 4.8% developing fractures
and 32% developing edema (the majority of whom had
grade-1 edema). The 5-year actuarial local control rate
was 94%. Both the toxicities and local control rates
reported in this study are comparable to those achieved
with 3D conformal radiation techniques.
It is worth noting, however, that IMRT treatment
plans often have localized areas within the high dose
volumes, where dose inhomogeneities can be in the
range of 10–15% above the prescription dose. Because
there can also be dose inhomogeneities in the range of
5% below the target dose, treatment plans may be nor-
malized to the 95% isodose line, meaning that selected
areas of the treatment volume are receiving daily frac-
tions and total doses of 15–20% above the target dose.
Depending on the location of these ‘‘hot spots’’, there
can be unanticipated acute normal tissue toxicity
(Lee et al. 2002). Because of the multiple field angles
employed with IMRT, a greater volume of the extremity
will see some radiation dose, albeit in the low-to-mod-
erate dose range. Although early experience suggests
overall acceptable levels of late toxicity, further study
and longer follow-up is required to determine whether
there are late effects specifically attributable to these
focal areas of high dose or larger volume of normal
tissue exposed to these low-to-moderate doses.
5.10 Proton Beam Radiotherapy
The rationale for the use of protons (or other charged
particles) rather than photons (i.e., X-rays, which have
traditionally been used for RT) is the superior dose
1061
100
SOBP
80
Dose/%
10 MV Photon
60
Pristine Peak
40
20
50 100 150
Depth/mm
Fig. 9 Depth-dose distributions for a spread-out Bragg peak
(SOBP, red), its constituent pristine Bragg peaks (blue), and a
10-MV photon beam (black). The SOBP dose distribution is
created by adding the contributions of individually modulated
pristine Bragg peaks. The penetration depth, or range, measured
as the depth of the distal 90% of plateau dose, of the SOBP
dose distribution is determined by the range of the most distal
pristine peak (labeled ‘‘Pristine Peak’’). The dashed lines
(black) indicate the clinically acceptable variation in the
plateau dose of ±2%. The dot-dashed lines (green) indicate
the 90% dose and spatial range and modulation width intervals.
The SOBP dose distribution of even a single field can provide a
complete target volume coverage in depth and lateral dimen-
sions, in sharp contrast to a single photon dose distribution;
only a composite set of photon fields can deliver a clinical
target dose distribution. Note the absence of dose beyond the
distal fall-off edge of the SOBP. (Reprinted with permission
from Levin et al. (2005)
distribution that can be achieved with protons. Protons
and other charged particles deposit little energy in
tissue until near the end of the proton range, where the
residual energy is lost over a short distance, resulting in
a steep rise in the absorbed dose, known as the Bragg
peak (Fig. 9) (Wilson 1946; Austin-Seymour et al.
1989). The Bragg peak is too narrow for practical
clinical applications, so for the irradiation of most
tumors, the beam energy is modulated by superim-
posing several Bragg peaks of descending energies
(ranges) and weights to create a region of uniform dose
over the depth of the target; these extended regions of
uniform dose are called ‘‘spread-out Bragg peaks’’
(Fig. 9). Although the beam modulation to spread out
the Bragg peaks does increase the entrance dose, the
proton dose distribution is still characterized by a lower
dose region in normal tissue proximal to the tumor, a
uniform high dose region in the tumor, and zero dose
beyond the tumor (Fig. 9).
1062
Fig. 10 Proton dose distribution for a 38-year-old man with
newly diagnosed alveolar sarcoma involving the soft tissues
anterior to the right shoulder. The use of protons allowed
sparing of the shoulder joint, which was not in the CTV (CTV
contoured in fine purple line). The posterior portion of the CTV
was too deep for the use of electrons, and use of intensity-
modulated radiotherapy would have markedly increased the
integral dose received by the patient
Although protons have been extensively employed
for sarcomas of the skull base and spine/paraspinal
tissues, there are clearly opportunities to employ pro-
tons with very significant sparing of normal tissues in
patients with extremity STSs. Large, medial proximal
thigh lesions can be effectively treated with sparing of
the femur, hip joint, genitalia, and anorectal tissue.
Lesions around the shoulder can be treated without
irradiating the lung apex and avoiding the shoulder
(Fig. 10). With the recent or anticipated completion of
proton beam facilities in major sarcoma centers in the
United States (Massachusetts General Hospital, MD
Anderson Cancer Center, University of Florida, and
University of Pennsylvania) and Europe (Paul Scherrer
Institute in Switzerland, Institute Curie in France, as
well as other centers in France, Italy, Sweden, and
Germany), it is anticipated that a larger proportion of
these patients will be treated with protons.
5.11 Neoadjuvant Doxorubicin-Based
5.11.1 Chemotherapy Plus RT
The UCLA group popularized pre-operative regional
chemotherapy and RT followed by limb salvage sur-
gery in patients with high-grade sarcomas (Eilber
et al. 2001). They were able to achieve a high rate of
primary limb salvage, low rate of local recurrence
K. E. Haglund et al.
(approximately 9%), and long-term survival in 65%
of patients. The current regimen consists of doxoru-
bicin (30 mg per day for 3 days) followed by radia-
tion given at 28 Gy in eight fractions.
A number of other groups have utilized this regi-
men, also obtaining low rates of local recurrence with
varying degrees of toxicity. As an example, the
Southeastern Cancer Study Group evaluated this pro-
tocol in 66 patients with nonmetastatic high-grade
extremity sarcoma who received intraarterial doxoru-
bicin infused directly into the vessel feeding the tumor
(30 mg per 24 h for 3 days) (Wanebo et al. 1995).
Concurrent RT was administered (30 Gy in 10
fractions, 35 Gy in 10 fractions, or 46 Gy in 23–25
fractions). Limb-sparing surgery was possible in 60
of 66 patients; an additional two patients required
amputation due to wound healing complications. The
5-year survival and disease-free survival rates were 59
and 44%, respectively. The local failure rate was 1.5%.
It is not clear whether intraarterial administration
provides added benefit to intravenous doxorubicin.
One study compared these two methods of adminis-
tration (Eilber et al. 1995). The intraarterial route was
thought to be associated with a higher incidence of
complications and no improvement in survival or
function. Another report evaluated two separate pro-
tocols utilizing pre-operative treatment with intrave-
nous doxorubicin and ifosfamide with or without
intraarterial cisplatin; the histological response and
local failure rate following surgery were better with
the all-intravenous regimen (Merimsky et al. 1999).
Combination chemotherapy regimens such as
MAID (mesna, doxorubicin, ifosfamide, and dacar-
bazine) may provide better anti-tumor activity than
single-agent doxorubicin. Interesting results have been
noted with neoadjuvant MAID plus RT (Kraybill et al.
2006; DeLaney et al. 2003b). The experience with pre-
operative MAID chemotherapy interdigitated with
44 Gy radiation and followed by surgery, post-oper-
ative MAID, and further radiation (16 Gy) for those
with positive margins was reported in a series of 48
patients with high-grade extremity sarcomas greater
than or equal to 8 cm (DeLaney et al. 2003b). Despite
the low objective response rate to pre-operative ther-
apy (partial response in five, stable disease in 36), all
patients were able to undergo limb-sparing surgery
initially, with 7 having positive margins. Median
tumor necrosis was 95%, suggesting that conventional
imaging in this setting may underestimate the degree
Extremity Soft Tissue Sarcoma in Adults 1063

of response to therapy. Of the patients, 25% required

hospitalization for febrile neutropenia at some time
during treatment. Wound healing complications
occurred in 14 of 48 MAID patients (29%). One
MAID patient developed late fatal myelodysplasia.
The 5-year rates of local control (92 vs. 86%), freedom
from distant metastases (75 vs. 44%), disease-free
survival (70 vs. 42%), and OS (87 vs. 58%) all com-
pared favorably with the outcomes of a cohort of
historical control patients who were matched for
tumor size, grade, patient age and era of treatment.
Similar results were noted when this regimen was
utilized in a multicenter United States Cooperative
Group trial, in which 66 patients (64 of whom were
analyzed) with primary high-grade STS 8 cm or larger
in diameter received a modified MAID regimen plus
granulocyte colony-stimulating factor and radiation,
followed by resection and post-operative chemother-
apy (Kraybill et al. 2006). Although pre-operative
chemotherapy and radiation was successfully com-
pleted by 79 and 89% of patients, respectively, grade-4
hematological and non-hematological toxicity was
experienced by 78 and 19% of patients. Grade-3 or -4
skin toxicity was noted in 34%. The limb preservation
rate was 92%. With a median follow-up of 2.75 years,
the estimated 3-year survival, disease-free survival
and locoregional control rates were 75, 56, and 82%,
respectively. Three patients (5%) experienced fatal
grade-5 toxicities, among whom two developed late
Fig. 11 a–c A 51-year-old right-handed composer and pianist
myelodysplasia and one developed infection. It with low-grade spindle cell neoplasm with features most
remains to be confirmed in randomized studies whe- suggestive of fibrosarcoma involving the flexor tendon sheath
ther these aggressive interdigitated approaches offer of the fourth finger, initially excised with a positive margin,
benefit to the subgroup of patients with large, high- subsequently treated with tumor bed re-excision and low-dose
rate Ir-192 brachytherapy (a) of 45 Gy over 4.5 days. She
grade sarcomas, who are at the highest risk of treat- returned to playing the piano approximately 2 months later.
ment failure. Photos taken 8 months after her brachytherapy document
excellent functional and cosmetic results, as seen in (b) and (c)

5.12 STSs of the Hand and Foot
The 5-year survival rate for sarcoma of the hand and
foot is approximately 80%, better than that usually
given for extremity STSs (Talbert et al. 1990;
Johnstone et al. 1994; Karakousis et al. 1998;
Pradhan et al. 2008). This is likely related to the
smaller size of these lesions at presentation. With
surgical excision and the use of adjunctive radio-
therapy when the minimum surgical margin is nar-
row (\2 mm), limb amputation can be avoided as
primary therapy in most patients, and up to two-
thirds of patients can retain a normal or fairly nor-
mal extremity (Fig. 11).
5.13 Wound Healing After Surgery
and Radiation
In general, the use of adjunctive radiation is associ-
ated with a higher frequency of wound complications.
However, precise quantification of the impact of
radiation on wound healing is difficult because of the
significant complications seen with surgery alone.
1064
In addition, there is much heterogeneity among
patients with STS with respect to anatomic site,
histological type, lesion size, prior surgery, medical
status, and age. The use of adjunctive radiotherapy
can also be associated with joint stiffness, edema, and
decreased range of motion (Bujko et al. 1992; Yang
et al. 1998). In one trial, extremity radiation resulted
in significantly worse limb strength, edema, and range
of motion than with surgery alone for extremity STS,
but the symptoms were transient and did not affect
global quality of life (Yang et al. 1998).
5.14 Pre-operative Radiation and Wound
Complications
Pre-operative radiation is associated with a higher
incidence of acute wound complications (O’Sullivan
et al. 2002). In the randomized study of pre-operative
versus post-operative RT, a significantly higher per-
centage of pre-operatively treated patients had acute
wound complications (35 vs. 17%). In another series
of 202 patients undergoing pre-operative RT, the
overall wound complication rate was 37% (Bujko
et al. 1992). Of the patients, 1 died with necrotizing
fasciitis, and 33 (17%) required secondary surgery,
including 6 (3%) who required amputation. In a
recent retrospective study of 173 patients, major
wound complications were more likely to occur in the
lower extremity than in the upper extremity (Tseng
et al. 2006). In this cohort, 59% of whom also
received pre-operative chemotherapy, the rate of
major wound complications was 32% after pre-oper-
ative radiation. In another report, wound morbidity
was 25% (4 of 16) in patients treated with pre-oper-
ative EBRT plus BRT at the time of surgery but only
5% (2 of 40) in those treated post-operatively with
BRT followed by EBRT (Schray et al. 1990).
5.15 BRT and Wound Complications
The use of perioperative BRT may increase the
incidence of wound complications. In one study of
105 patients with extremity and truncal sarcomas,
major wound complications occurred in 9 of 41 (22%)
cases treated with BRT compared with 2 of 64 (3%)
non-BRT-treated patients (Arbeit et al. 1987).
Patients treated with BRT also had a higher total
K. E. Haglund et al.
number of complications as well as a higher com-
bined frequency of major and moderate wound com-
plications (44 vs. 14%), and a longer time to wound
healing (189 days versus 49 days).
However, the findings were different in a ran-
domized trial of adjuvant BRT versus no BRT in 164
patients with resected extremity or truncal STS (Ar-
beit et al. 1987). The incidence of serious wound
complications was not significantly increased in the
group receiving BRT (24 vs. 14%, P = 0.133), but
the incidence of wound reoperation was increased
(6 vs. 0%) (Alektiar et al. 2000).
5.16 Strategies to Reduce Wound
Morbidity
Based on published experience, the following strate-
gies are suggested to reduce acute wound morbidity in
patients being treated with pre-operative radiation
(Bujko et al. 1992) or perioperative BRT (Alektiar
et al. 2000):
• Gentle handling of tissue during surgery.
• Meticulous attention to achieving hemostasis
before wound closure.
• Avoidance of closure under tension.
• Elimination of all wound dead space, using a
rotated flap to fill the space, if necessary.
• Wound drainage with tubes remaining in place until
drainage is decreasing in a satisfactory manner.
• Use of compression dressings.
• Immobilization of the affected part for approxi-
mately 7 days.
• Delineation of a subgroup of patients where post-
operative boost dose can be omitted, which would
include patients with negative margins and no tumor
cut-through, complete tumor necrosis, absence of
tumor in the resection specimen, and perhaps some
patients with low grade tumors and planned, focally
positive margins (Al Yami et al. 2010).
5.17 Adjuvant Chemotherapy
Adjuvant chemotherapy is a standard treatment for
rhabdomyosarcoma (Crist et al. 2001), osteosarcoma
(Bramwell 1997), and Ewing’s sarcoma (Rosen et al.
1981) but is not definitively established in other adult
STSs (Antman 1997; Scurr and Juson 2005).
Extremity Soft Tissue Sarcoma in Adults
5.17.1 Rhabdomyosarcoma
The vast majority of patients with rhabdomyosarcoma
are children. In this population, the use of post-opera-
tive multiagent chemotherapy (typically vincristine,
dactinomycin, and cyclophosphamide) contributes to
cure rates of 65–75% in children with localized rhab-
domyosarcoma (stages I–III), who are also treated with
surgery and/or irradiation (Crist et al. 2001) is the
standard of care. Ifosfamide has also found a role as part
of the chemotherapy for patients with poorer prognosis
disease, and topotecan is in the early stages of evalua-
tion for patients with metastatic disease (Pappo et al.
2007). In addition, the use of high-dose induction
chemoradiotherapy followed by autologous bone mar-
row transplantation is being evaluated in younger
patients with high-risk disease (Boulad et al. 1998).
5.17.2 Adjuvant Chemotherapy for Other
STSs
Many randomized trials and meta-analyses have
addressed the potential benefit of adjuvant chemo-
therapy in resected extremity STS in adults. The vast
majority of available studies have utilized doxorubicin,
either alone or with dacarbazine. Among 14 previously
published randomized trials, two reported a significant
OS advantage for combination chemotherapy, while
three noted higher survival in the observation arm
(Antman 1997). The remainder showed no significant
difference when patients receiving adjuvant therapy
are compared with controls.
Individual patient data from these studies, which
involved 1,568 adults with localized resectable STS
(only some of which were on the extremities), were
analyzed by the Cochrane Collaborative and published
in 1997 (Sarcoma Meta-Analysis Collaboration 1997).
All evaluated studies randomly assigned patients post-
operatively to receive or not receive adjuvant che-
motherapy containing doxorubicin. The following
benefits were noted in the chemotherapy group:
• Longer local recurrence-free interval—hazard ratio
0.73 [95% confidence interval (CI) 0.56–0.94].
• Longer distant recurrence-free interval—hazard
ratio 0.70 (95% CI 0.57–0.85).
• Higher overall recurrence-free survival—hazard
ratio 0.75 (95% CI 0.64–0.87), corresponding to a
significant absolute benefit of 6–10% at 10 years.
• For OS, the hazard ratio of 0.89 was not significant
but potentially represented an absolute benefit of
4% (95% CI-1–9) at 10 years.
1065
There was no consistent evidence of a difference in
effect according to age, sex, stage, site, grade, his-
tology, extent of resection, tumor size, or exposure to
radiotherapy. However, the strongest evidence of a
beneficial effect on survival was shown in patients
with sarcoma of the extremities. Among these
patients, the hazard ratio was 0.80 (P = 0.029),
equivalent to a 7% absolute benefit at 10 years.
In summary, doxorubicin-based adjuvant chemo-
therapy appears to significantly improve the time to
local and distant recurrence and overall recurrence-
free survival in adults with localized resectable STS
of the extremities. There is some evidence of a trend
toward improved OS.
Since the publication of the meta-analysis, three
additional randomized trials have explored the benefit
of doxorubicin or ifosfamide-based chemotherapy in
extremity STS (Brodowicz et al. 2000; Frustaci et al.
2001; Petrioli et al. 2002), two of which have shown a
survival benefit for adjuvant chemotherapy (Frustaci
et al. 2001; Petrioli et al. 2002):
• In a trial in which two-thirds of the enrolled patients
had either synovial sarcoma or liposarcoma (two
particularly chemosensitive STS histologies), 144
patients with high-grade large (5 cm or larger) or
recurrent spindle cell sarcomas involving the
extremities or girdles were randomly assigned to no
post-operative therapy or to five cycles of a dose-
intensive epirubicin/ifosfamide combination
(epirubicin 60 mg/m2 on day 1 and day 2 plus if-
osfamide 1.8 g/m2 on days 1–5) with mesna and
granulocyte colony-stimulating factor support
(Frustaci et al. 2001). Accrual was prematurely
discontinued at 2 years, when a significant differ-
ence in the cumulative incidence of distant metas-
tasis was found (45 vs. 28%, favoring the
chemotherapy group); the OS difference (85 vs.
72%), also favoring the chemotherapy group, did not
reach the level of statistical significance.
• When the trial was reported, the 4-year OS rates
were significantly higher in favor of chemotherapy
(69 vs. 50%), although the distant relapse rates
were by then similar in both groups (44 and 45%
for the chemotherapy and control groups, respec-
tively). It is difficult to interpret these results, since
the main benefit of adjuvant systemic chemother-
apy is expected to be in reducing the rate of distant
relapse. There was a trend toward improved local
control in the adjuvant chemotherapy group, with a
1066
17% local failure rate at 4 years in the control
group compared with 6% in the adjuvantly treated
group, P = 0.07.
• The second trial, also from Italy, randomly
assigned 88 patients with high-risk STS to surgery
with or without RT (n = 43) or to surgery plus
chemotherapy (n = 45, 26 with epirubicin alone,
and 19 to epirubicin plus ifosfamide) with or
without RT (Petrioli et al. 2002). The 5-year sur-
vival rate of patients treated with chemotherapy
was significantly higher than that of patients who
did not receive chemotherapy (72 vs. 47%). How-
ever, the large number of treatment variables and
the small number of studied patients makes inter-
pretation of this result impossible.
• The importance of long-term follow-up in assessing
benefit from chemotherapy was shown in a report
of the combined experience of two major cancers
(Memorial Sloan Kettering and MD Anderson) that
included 674 consecutive adults undergoing resec-
tion of a stage-III extremity STS between 1984 and
1999 (Cormier et al. 2004). Adjuvant doxorubicin-
based chemotherapy was administered to 336
(50%), while the remainder received local therapy
only. Although not a randomized trial, there were
no significant differences between the chemother-
apy and non-chemotherapy groups with respect to
tumor size, anatomic site, histopathological sub-
type, or resection margin status. With a median
follow-up of 6.1 years, the effect of chemotherapy
appeared to vary over time. During the first year,
the hazard ratio (HR) for disease-specific survival
for chemotherapy versus no chemotherapy was
0.37 (95% CI 0.20–0.69); thereafter, the HR was
1.36 (95% CI 1.02–1.81).
More recent retrospective data from a large data-
base with long follow-up, lends support to the concept
that adjuvant chemotherapy may improve outcomes in
selected patients. A retrospective review of the French
Sarcoma Group database identified 1,513 patients with
soft tissue sarcoma treated from 1980 to 1999 with
median follow-up of 9 years, a proportion of whom
received adjuvant doxorubicin-based chemotherapy
(Italiano et al. 2010). In a subgroup of 262 patients with
FNCLCC grade-3 sarcomas, 62% of whom received
adjuvant chemotherapy, a significant benefit to
adjuvant chemotherapy for OS was identified with a
HR of 0.6 (95% CI 0.5–0.8, P = 0.0002). Five-year
OS rates were 58% with and 45% without adjuvant
K. E. Haglund et al.
chemotherapy. Adjuvant chemotherapy was also
associated with improved metastasis-free survival with
a HR of 0.7 (95% CI 0.6–0.9, P = 0.01). Five-year
metastasis-free survival rates were 58% for the adju-
vant chemotherapy group and 49% for the group that
did not receive chemotherapy. Analysis of outcomes
over time, however, revealed that the benefit of adju-
vant chemotherapy on metastasis-free survival was no
longer evident by three-years after treatment. These
results are similar in magnitude to those reported in
both meta-analyses and randomized trials.
Another recent study from Memorial Sloan Ket-
tering Cancer Center retrospectively analyzed the
relationship between neo-adjuvant chemotherapy
(NAC) and outcome in patients with high-grade, deep,
greater than 5-cm extremity sarcomas. Patients diag-
nosed between 1990 and 2001 were treated with sur-
gery only (n = 282) or NAC containing doxorubicin/
ifosfamide/mesna (AIM) (n = 74). NAC was associ-
ated with improved disease-specific survival for this
cohort of patients (P = 0.02). This overall improve-
ment appears to be driven by the benefit of NAC on
disease-specific survival for patients with tumors
[10 cm. The 3-year disease-specific survival for
tumors of this size was 0.62 (95% CI: 0.53–0.71) for
patients not receiving NAC and 0.83 (95% CI:
0.72–0.95) for patients receiving NAC (Grobmyer
et al. 2004). A study of concurrent, interdigitated
neoadjuvant MAID chemotherapy and RT in patients
with extremity sarcomas 8 cm or larger showed higher
disease-free and OS than that of a historical matched
patient cohort (DeLaney et al. 2003b). These data
emphasize the need for further prospective clinical
studies of neo-adjuvant or adjuvant chemotherapy for
patients with large high-grade extremity sarcomas.
Despite many randomized trials, the role of adju-
vant chemotherapy remains uncertain and cannot be
adopted as the standard of practice for all extremity
sarcomas. The positive Italian trial is the only study
that enrolled predominantly patients with chemosen-
sitive types of STS (i.e., liposarcomas and synovial
sarcomas) (Frustaci et al. 2001). However, the lack of
a difference in the distant metastatic rate at 4 years
(the time point at which the survival benefit was most
pronounced) calls into question the validity of the
conclusion that adjuvant chemotherapy improves
survival in patients with high-grade or recurrent sar-
comas. If there is a survival benefit for adjuvant
chemotherapy, it is probably small (no more than
Extremity Soft Tissue Sarcoma in Adults
4–8% absolute increase in survival at 5–10 years).
Although it has been proposed that patients be
selected for adjuvant chemotherapy based on poor
prognostic tumor characteristics such as histology
(i.e., synovial sarcoma [Ferrari et al. 2004]), grade, or
size, there is no evidence to date that this approach
leads to improved outcome in any subset of patients
(Coindre et al. 1996). The absolute benefit, patient
selection, and optimal regimen remain to be defined.
A study of 351 patients randomized to observation or
five cycles of post-operative adjuvant Adriamycin and
ifosfamide was recently completed by the European
Organization for Research and Treatment of Cancer
(EORTC) Group. Interim study results, reported in
abstract form, showed no relapse-free or OS benefit
for the adjuvant chemotherapy. The relapse-free sur-
vival in the observation group at 5 years was 53%
compared with 51% in the chemotherapy group. Even
this large study, however, had only a statistical power
of 13.1% to show a 4% survival benefit, illustrating a
clinical trials statistical problem when studying
orphan diseases (Woll et al. 2007).
5.18 Functional Outcome
There are increasing data available on the functional
outcome of patients undergoing limb salvage pro-
cedures (Robinson et al. 1991; Stinson et al. 1991;
LeVay et al. 1993; Davis et al. 1999). The majority
of patients have good or excellent functional out-
come. In one series of 88 patients treated with sur-
gery and either pre-operative or post-operative RT,
68 had acceptable functional results, and 61 returned
to work (LeVay et al. 1993). Large tumors, neural
sacrifice, proximal thigh tumors, and post-operative
complications were associated with poor outcome.
Subcutaneous tumors have a more favorable func-
tional outcome (Gerrand et al. 2004). In a single
institution series of 145 patients who underwent
limb-sparing surgery plus RT, long-term treatment
complications included bone fracture in 6%, con-
tracture in 20%, significant edema in 19%, moderate
to severe decrease in muscle strength in 20%,
requirement for a cane or crutch in 7%, and tissue
induration in 57% (Stinson et al. 1991). Of these
patients, 3 (2%) required amputations for treatment-
related complications. The percentage of patients
ambulating without assistive devices and with mild
1067
or no pain was 84%. Higher doses of RT, a long
radiation portal, and irradiation of more than 75% of
the extremity diameter were associated with
increased complications. Another study examined
issues related to quality of life in patients with STS
of the lower limb (Robinson et al. 1991). Although
RT was associated with reduced muscle power and
range of motion compared with the use of surgery
alone, most patients retained good to excellent limb
function and quality of life.
The functional outcome is often not as good in
patients requiring amputation. In a matched case–
control study of patients with lower extremity
sarcoma undergoing amputation (n = 12) or a limb-
sparing approach (n = 24), there was a trend
toward increased disability and handicap for those
in the amputation group (Davis et al. 1999). Of the
12 amputees, seven reported ongoing problems with
the soft tissue overlying the stump. A few studies
have assessed quality of life issues in amputees
who had been treated for STS with amputation and
chemotherapy compared with patients who under-
went limb salvage with radiotherapy and chemo-
therapy (Weddington et al. 1985; Sugarbaker et al.
1982). Contrary to expectations, there were no
significant differences in measures of psychological
outcome. Thus, a psychological advantage of limb-
salvage surgery over amputation has yet to be
demonstrated.
5.19 Treatment of Local Recurrence
Approximately 10–15% of patients with extremity
STS who are treated with complete resection and
adjuvant radiation will develop a local tumor failure,
the majority within the first 2 years (LeVay et al.
1993; Sadoski et al. 1993; Karakousis and Driscoll
1999; Zagars et al. 2003b). The approach to the
patient with an isolated local recurrence is similar to
that for primary disease with some modifications. As
with primary treatment, the goal is to achieve tumor
control, and, if possible, limb salvage with conser-
vative resection. However, approximately 10–25% of
patients with locally recurrent disease will require
amputation (Catton et al. 1996a, b; Karakousis et al.
1996; Ueda et al. 1997). Surgery is an important
component of successful salvage therapy (Catton
et al. 1996b). For patients whose primary treatment
1068
was surgery alone, re-excision combined with adju-
vant radiation is the treatment of choice. If RT was
used in primary treatment, further radiation may not
be possible because the maximal tolerance for
adjacent normal tissues would have to be exceeded,
resulting in a significant risk of problems with
wound healing or radiation fibrosis. A recent study
comparing outcomes in patients treated with wide
local excision alone or combined with EBRT dem-
onstrated that 80% of those treated with excision and
EBRT required additional outpatient or surgical
management in contrast to only 17% of those treated
with excision alone. The predominant delayed
complications in the EBRT group were soft tissue
necrosis and edema (Torres et al. 2007). However,
additional radiation given by BRT (mean dose
47.2 Gy) has been employed in some of these cases,
with a 52% local control and a 33% disease-free
survival rate in one series of 26 patients (Pearlstone
et al. 1999a).
Optimal treatment for a local recurrence may
require both surgery and radiation. This was illus-
trated in one report of salvage therapy using surgery
alone or surgery plus re-irradiation for 25 patients
with locally recurrent extremity STS (Catton et al.
1996b). Of the patients, 18 underwent surgery alone;
11 were treated by a conservative procedure and 7
required amputation. Of these 18 patients, 7 relapsed.
Of the 10 patients treated with surgery plus radiation,
none experienced relapse, with a median follow-up of
24 months. Of these patients, six (60%) experienced
significant wound healing complications, but three
recovered completely.
5.20 Treatment of Locally Advanced Soft
Tissue Sarcoma
In patients with advanced STS in whom the tumor has
progressed to a point that the functional morbidity of
an attempted limb salvage resection is too great for
the patient, non-amputative treatment options depend
on the site of tumor involvement. For patients with
this type of disease limited to the extremity, isolated
limb perfusion protocols have been applied with
striking early success. Selected patients can also have
their tumors controlled with RT with or without
K. E. Haglund et al.
chemotherapy, especially when the tumors are small.
For patients treated with a dose of 6,400 cGy or
greater, Tepper and Suit noted control of unresected
STSs in 87.5% of cases where tumors were \5 cm in
diameter (Tepper and Suit 1985). Treatment was less
effective for larger tumors, with local control falling
to 53% for lesions 5–10 cm diameter (53%) and 30%
for those [10 cm. Kepka and colleagues recently
updated and expanded this experience, reporting on
the efficacy of radiation on 112 patients with unre-
sected STSs. For patients receiving 63 Gy or more,
local control at 5 years was 72.4% in patients with
lesions 5 cm or less, 42.4% for lesions 5–10 cm, and
25.4% for lesions [10 cm (Kepka et al. 2005).
Several centers have reported local control rates of
approximately 50% with fast neutron irradiation of
inoperable STS (Pickering et al. 1987; Schmitt et al.
1990; Steingraber et al. 1996). In addition, several
radiation sensitizers have been used to treat patients
with extensive sarcoma, with promising early pre-
liminary results (Goffman et al. 1991; Rhomberg et al.
1996; Jakob et al. 2009). Trabectidin (ET-743), a
novel anti-tumor agent, has also shown promise in
advanced soft tissue sarcoma, both as a single agent
and in combination with other agents (Garcia-Car-
bonero et al. 2005; Blay et al. 2008).
6 Treatment of Metastatic Disease
6.1 Overview
Metastatic disease rarely occurs in patients with low-
grade sarcomas (Coindre et al. 1996). With interme-
diate or high-grade sarcomas, this risk may exceed
50% when the tumor is larger than 10 cm (Pisters
et al. 1996b; Trovik et al. 2000; Gronchi et al. 2005).
For extremity sarcomas, the lung is the most common
site of metastatic disease (Potter et al. 1985; Gadd
et al. 1993). Some histologies—notably myxoid lip-
osarcoma, which can metastasize to abdominal sites
and bone (Pearlstone et al. 1999b; Spillane et al.
1999), and epithelioid sarcomas, which manifest
regional nodal failure—are exceptions to the more
general pattern. While most patients with metastatic
sarcoma will ultimately die from their tumor, a
modest proportion of patients will be long-term
Extremity Soft Tissue Sarcoma in Adults
survivors after management with surgery and/or
chemotherapy.
6.2 Resection of Pulmonary Metastases
The median survival of patients with pulmonary
metastases is in the range of 15 months. Patients whose
lung metastases can be resected fare better than those
who are unresectable. In one series, patients treated
with resection had a median survival after complete
resection of 33 months (Billingsley et al. 1999). Their
3-year actuarial survival rate was 46%, with a 5-year
actuarial survival rate of 37%. The patients who did not
undergo resection had a median survival of 11 months
and a 3-year actuarial survival rate of 17%.
Those who might be considered for pulmonary
resection are medically fit patients with controlled
primary tumors without pleural effusion or hilar dis-
ease. The procedure generally involves wedge resec-
tions of the nodules. Patients with a limited number of
nodules fare better, but there is no consensus on the
upper limit of nodules that should be considered for
resection. The role for additional adjuvant chemo-
therapy after resection is not settled. A subset of
patients may benefit from repeat thoracotomy for
recurrent disease in the chest (Pogrebniak et al. 1991).
In addition, select patients may be eligible for a less
invasive, video-assisted approach to metastasectomy
(Gossot et al. 2009). There are also reports of resection
of isolated metastatic disease in liver and other extra-
pulmonary sites (Lang et al. 2000; Pawlik et al. 2006).
6.3 Chemotherapy for Metastatic
Disease
For most patients with metastatic disease that is not
resectable, treatment with chemotherapy is likely to
be palliative in outcome. A small number of patients
will be long-term survivors. An analysis of 1888
patients treated on studies organized by the Soft
Tissue and Bone Sarcoma Group of the EORTC
reported 66 5-year survivors, which translates to an
8% 5-year survival rate (Blay et al. 2003). A brief
discussion of chemotherapy for metastatic disease
will be presented here; readers can find more com-
plete discussion in recent reviews on this subject
(Judson 2004; Krikelis and Judson 2010).
1069
Doxorubicin and ifosfamide have been demon-
strated to be the most active chemotherapy agents in
widely disseminated STS (Clark et al. 2005). For
doxorubicin, objective response rates between 20 and
40% for the single agent have been reported; few are
complete responses, and response duration averages
8 months. A steep dose-response curve for objective
responses was described by O’Bryan et al. (1977).
There is also a dose–response for ifosfamide
(Christman et al. 1993; van Oosterom et al. 2002).
Dacarbazine (DTIC) by itself has a modest response
rate of approximately 16% (Gottlieb et al. 1976).
Cyclophosphamide appears less active in adults than
in children and less active than the related compound
ifosfamide (Bramwell et al. 1993). Gemcitabine with
or without a taxane is active in a subset of patients
with sarcomas (Hensley et al. 2002). Taxanes are
active against angiosarcomas (Fata et al. 1999).
Newer agents such as ecteinascidin-743 have at least
some activity against sarcomas (Yovine et al. 2004;
Garcia-Carbonero et al. 2005). Other less active
agents include methotrexate (Subramanian and Wilt-
shaw 1978; Pinedo and Verweij 1986) and cisplatin
(Karakousis et al. 1979; Grabois et al. 1994).
Many combination chemotherapy regimens for
metastatic disease have been studied in phase-II trials.
Responses are higher than with single agents. Most of
these trials include doxorubicin (or epirubicin) and an
alkylating agent. Adding DTIC to doxorubicin
improved the response rate to 41%, as described by
Gottlieb et al. (1972), but the response rate has
decreased over time (Gottlieb et al. 1976). Compari-
sons have shown that the addition of less active drugs
necessitate lower doses of doxorubicin and, accord-
ingly, reduces overall effectiveness (Cruz et al. 1979;
Schoenfeld et al. 1982). Adding ifosfamide, however,
seems to be clearly beneficial as reported by Blum
et al. (1993) and Schutte et al. (1993). Nevertheless,
the improvement in response rate has not clearly
translated into an improvement in OS. A prospective
randomized trial was performed by EORTC, which
compared single-agent doxorubicin with a combina-
tion of doxorubicin and ifosfamide and also the four-
drug CYVADIC (cyclophosphamide/vincristine/
doxorubicin/dacarbazine) combination. There was no
improvement in progression-free or OS associated
with combination therapies, although they were sig-
nificantly more toxic.
1070
Similar findings were reported by Eastern Coop-
erative Group, which conducted a three-arm trial
comparing doxorubicin alone, doxorubicin plus if-
osfamide, and mitomycin plus doxorubicin plus
cisplatin (Santoro et al. 1995). Objective tumor
regression occurred more frequently in the combi-
nation arms than in the single agent arm (20% with
doxorubicin alone, 34% in doxorubicin plus ifosfa-
mide, and 32% in the mitomycin plus doxorubicin
plus cisplatin arm). However, the combination regi-
mens resulted in significantly greater myelosuppres-
sion, e.g., 80% of the doxorubicin/ifosfamide group
had grade-3 or greater myelosuppression. Most
notably, no significant survival differences were
observed among the three treatment regimens (Ed-
monson et al. 1993). A popular regimen adds if-
osfamide to Adriamycin and DTIC (Elias and
Antman 1986). A combination of ifosfamide with
mesna, doxorubicin and dacarbazine (MAID regi-
men) has resulted in response rates in measurable
metastatic sarcomas as high as 47%, with complete
response rates as high as 10% (Elias et al. 1989). In
the absence of any clear benefit for the combination
regimens, many clinicians favor initiation of che-
motherapy with single-agent Adriamycin (Judson
2004).
Attempts to intensify treatment by increasing the
dose of doxorubicin in combination with ifosfamide,
although promising in phase-II studies (Steward et al.
1993), were not confirmed in a subsequent random-
ized trial compared with the standard doses (Le Cesne
et al. 2000). On the other hand, intensification of
treatment by increasing the dose of ifosfamide in
combination with doxorubicin has increased toxicity
without improving survival (Lorigan et al. 2007).
High-dose therapy with growth factor support has
been evaluated in several investigational studies, but
the data to-date demonstrate increased toxicity with-
out clear evidence of therapeutic gain; thus, this is
still considered investigational treatment (Dumontet
et al. 1992; Schwella et al. 1998).
7 Summary
Treatment for STS requires individual tailoring of the
approach because of the wide variety of clinical sit-
uations that can arise from a tumor that involves a
variety of anatomic sites with a range of histologies of
K. E. Haglund et al.
variable grade and size. Nevertheless, the following
suggestions can serve as useful guides. Surgery is
always indicated, but the use of adjuvant therapy can
vary according to the anatomic site, size, and histo-
logical grade.
• In general, patients with superficial, low-grade
tumors that are less than 5 cm in diameter can be
treated with surgical excision alone when negative
margins of C1 cm or an investing fascial barrier or
high quality tissue plane such as periosteum are
resected with the tumor. Such patients can expect
excellent local control and survival rates approxi-
mating 90%.
• In patients with intermediate grade lesions, surgical
excision with negative margins in combination with
radiotherapy has achieved excellent local control,
with OS rates approximating 80%. For larger, deep-
seated tumors, pre-operative RT or post-operative
radiation appear to have similar efficacy in pre-
venting local tumor recurrence, although post-
operative radiotherapy generally treats a larger
target volume and requires higher doses to the
tumor bed. Acute wound healing complications are
higher with pre-operative RT for lower extremity
lesions, but generally irreversible late complica-
tions, including grade 3–4 fibroses, are more com-
mon in those patients receiving post-operative RT.
• In patients with high-grade STS [5 cm, excellent
local control can be achieved with surgery and
radiotherapy, but at least 50% of these patients will
develop metastatic disease. In this setting, the use of
neoadjuvant chemotherapy may benefit some, and
should be considered in the context of a clinical trial,
to be followed by definitive surgery combined with
either pre- or post-operative radiotherapy or BRT.
• BRT can provide excellent local control and func-
tional results in appropriately selected patients.
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 Total Body Irradiation Conditioning
Regimens in Stem Cell Transplantation
Kathryn E. Dusenbery and Bruce J. Gerbi
Contents
1 Conditioning Regimen............................................. 1078
2 Fractionation and Dose Rate.................................. 1079
3 Sequence.................................................................... 1080
4 Technical Aspects .................................................... 1081
5 Right and Left Lateral TBI.................................... 1081
6 Simulation and Patient Measurements ................. 1081
6.1 Compensators for TBI............................................... 1083
7 Compensator Design................................................ 1084
7.1 Patient Treatment....................................................... 1086
7.2 Dose Verification....................................................... 1087
Abstract
Total body irradiation (TBI) is often used in the
preparative regimens of stem cell transplants. The
goal of TBI is to administer a specific dose of
irradiation to the entire body. Technically this is
complicated by limitations in field sizes obtainable
on a linear accelerator and the resultant need to
treat at extended distances. Variations in patient
thickness and decreased attenuation through the
lung are additional technical challenges. This
chapter describes the techniques in use at the
University of Minnesota for accomplishing TBI.
Since the first successful bone ma