Lawrence S.

Chin
William F. Regine
Editors

Principles and
Practice of
Stereotactic
Radiosurgery
Second Edition

13
Principles and Practice of Stereotactic
Radiosurgery
Lawrence S. Chin • William F. Regine
Editors

Principles and Practice

of Stereotactic Radiosurgery
Second Edition
Editors
Lawrence S. Chin William F. Regine
Robert B. and Molly G. King Professor and Chair Isadore and Fannie Schneider Foxman Chair
Department of Neurosurgery and Professor of Radiation Oncology
SUNY Upstate Medical University Department of Radiation Oncology
Syracuse, NY, USA University of Maryland School of Medicine
Baltimore, MD, USA

ISBN 978-1-4614-8362-5 ISBN 978-1-4614-8363-2 (eBook)

DOI 10.1007/978-1-4614-8363-2
Springer New York Heidelberg Dordrecht London

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Contents

Part I Introduction

1 The History of Stereotactic Radiosurgery ............................................................. 3

Marina Kushnirsky, Vaibhav Patil, and Michael Schulder
2 Imaging Techniques in Stereotactic Radiosurgery ............................................... 11
Jessica Zhou, Yue Cao, James Balter, Neeraj Chaudhary, Aditya S. Pandey,
Greg Thompson, and Christina I. Tsien
3 Techniques of Stereotactic Localization ................................................................. 25
Victor C.K. Tse, M. Yashar S. Kalani, and John R. Adler

Part II Radiation Biology and Physics

4 The Physics of Stereotactic Radiosurgery ............................................................. 35

Siyong Kim and Jatinder Palta
5 Radiobiological Principles Underlying Stereotactic Radiation Therapy ............ 57
David J. Brenner and David J. Carlson
6 Treatment Planning for Stereotactic Radiosurgery .............................................. 73
David M. Shepard, Cedric Yu, Martin J. Murphy, Marc Bussière,
and Frank J. Bova
7 Designing, Building, and Installing a Stereotactic Radiosurgery Unit ............... 95
Lijun Ma, Andrew Hwang, and Arjun Sahgal

Part III Stereotactic Radiosurgery Techniques

8 Gamma Knife Radiosurgery ................................................................................... 111

Ajay Niranjan, Greg Bowden, John C. Flickinger, and L. Dade Lunsford
9 LINAC: Past, Present, and Future of Radiosurgery ............................................. 121
Maryam Rahman, Gregory J.A. Murad, Frank J. Bova,
and William A. Friedman
10 Charged Particles in Stereotactic Radiosurgery ................................................... 135
Shervin M. Shirvani and Joe Y. Chang
11 CyberKnife ............................................................................................................... 147
Carolina E. Fasola, Lei Wang, John R. Adler, Scott G. Soltys, Iris C. Gibbs,
Albert C. Koong, and Daniel T. Chang
12 GammaPod ............................................................................................................... 163
Yildirim D. Mutaf, Cedric Yu, Steven J. Feigenberg, and William F. Regine

v
vi Contents

13 Stereotactic Body Radiation Therapy .................................................................... 177

Steven J. Feigenberg, Randi Cohen, Navesh K. Sharma, Zain Husain,
Shifeng Chen, and Laura A. Dawson

Part IV Treatment of Disease Types

14 Metastatic Brain Tumors......................................................................................... 211

Edward W. Jung, John H. Suh, Samuel T. Chao, Michael A. Vogelbaum,
and Gene H. Barnett
15 Metastatic Brain Tumors: Viewpoint—Surgery .................................................. 233
Raymond Sawaya, David M. Wildrick, and Fassil B. Mesfin
16 Metastatic Brain Tumors: Viewpoint: Whole Brain Radiation Therapy ........... 241
William F. Regine, Sarah F. Grabowski, and Roy A. Patchell
17 Stereotactic Radiosurgery and Radiotherapy in the Management
of High-Grade Gliomas ........................................................................................... 249
David Roberge and Luis Souhami
18 Management of Glial Tumors: Viewpoint—Surgery
and Intra-cavitary Radiopharmaceutical Therapy .............................................. 269
Kaisorn L. Chaichana, Linda Chen, Salvador Manrique-Guzman,
Lawrence Kleinberg, and Alfredo Quinones-Hinojosa
19 Malignant Glioma: Viewpoint—Chemotherapy ................................................... 279
Roger Stupp, Krisztian Homicsko, and J. Gregory Cairncross
20 Meningioma .............................................................................................................. 295
Alessandra Gorgulho, Carlos A. Mattozo, and Antonio A.F. De Salles
21 Meningioma: Viewpoint—Surgery......................................................................... 315
Lawrence S. Chin, David J. Padalino, Pulak Ray, and John M. Caridi
22 Meningioma—Viewpoint: Fractionated Radiotherapy ........................................ 323
Igor J. Barani, Arie Perry, and C. Leland Rogers
23 Radiosurgery of Acoustic Schwannomas ............................................................... 339
John C. Flickinger, Hideyuki Kano, and L. Dade Lunsford
24 Acoustic Neuroma: Viewpoint—Surgery .............................................................. 347
Gabriel Zada and Steven L. Giannotta
25 Acoustic Tumors: Viewpoint—Stereotactic Radiotherapy .................................. 355
Christopher J. Farrell and David W. Andrews
26 Stereotactic Radiosurgery for Pituitary Adenomas .............................................. 369
Jason P. Sheehan and Brian Williams
27 Pituitary Tumors: Viewpoint—Surgery................................................................. 379
Khaled M. Krisht, William T. Couldwell, and Martin H. Weiss
28 Pituitary and Pituitary Region Tumors: Viewpoint—Fractionated
Radiation Therapy ................................................................................................... 391
Jonathan P.S. Knisely and Paul W. Sperduto
29 Pituitary Tumors: Viewpoint— Medical Therapy ................................................ 403
Rachel L. Hopkins
30 Pediatric Radiosurgery ............................................................................................ 409
Arthur K. Liu
Contents vii

31 Pediatric Disorders: Viewpoint—Surgery ............................................................. 415

Stephanie L. Da Silva and Mark D. Krieger
32 Pediatric Disorders: Viewpoint—Fractionated Radiotherapy ............................ 427
Thomas E. Merchant and Erin S. Murphy
33 Pediatric Brain Tumors: Viewpoint—Chemotherapy .......................................... 439
Nathan J. Robison
34 Pineal Region Tumors .............................................................................................. 445
Gregory P. Lekovic and Andrew G. Shetter
35 Pineal Region Tumors: Viewpoint—Surgery ........................................................ 459
Adam M. Sonabend, Alfred Ogden, and Jeffrey N. Bruce
36 Pineal Tumors: Viewpoint—Fractionated Radiation Therapy ........................... 469
William G. Rule and Steven E. Schild
37 Pineal Region Tumors: Viewpoint—Chemotherapy ............................................ 477
Christopher Dardis and Roy A. Patchell
38 Skull Base Tumors ................................................................................................... 483
Reinhart A.J. Sweeney and Matthias Guckenberger
39 Skull Base Tumors: Viewpoint—Surgery .............................................................. 499
Richard F. Schmidt, Smruti K. Patel, Robert W. Jyung, Jean Anderson Eloy,
and James K. Liu
40 Skull Base Tumors: Viewpoint—Fractionated Radiotherapy
or Stereotactic Radiotherapy .................................................................................. 517
René-O. Mirimanoff and Laura Negretti
41 Head and Neck Tumors ........................................................................................... 529
Daniel T.T. Chua
42 Head and Neck Tumors: Viewpoint—Surgery...................................................... 543
Scharukh Jalisi
43 Head and Neck Tumors: Viewpoint—Fractionated Radiation Therapy
and Chemotherapy................................................................................................... 549
Michael Rutenberg and Mohan Suntharalingam
44 Spinal Tumors and Radiosurgery ........................................................................... 563
Evangelia Katsoulakis, Ilya Laufer, and Yoshiya Yamada
45 Spinal Tumors: Viewpoint—Surgery ..................................................................... 571
Faiz U. Ahmad, Gabriel Zada, and Michael Y. Wang
46 Spinal Metastases: Viewpoint—Fractionated Radiation Therapy ...................... 583
Quynh-nhu Nguyen, Almon S. Shiu, and Eric L. Chang
47 Arteriovenous Malformation Radiosurgery .......................................................... 589
Bruce E. Pollock
48 Arteriovenous Malformations: Viewpoint—Surgery ........................................... 605
Eric M. Deshaies and Surasak Komonchan
49 Cerebral Arteriovenous Malformations Viewpoint: Endovascular
Therapy Perspective ....................................................................................................... 617
M. Yashar S. Kalani, Richard W. Williamson, Felipe C. Albuquerque,
and Cameron G. McDougal
viii Contents

50 Radiosurgery for Cavernous Malformations and Other Vascular Diseases ....... 623
Ajay Niranjan, Greg Bowden, John C. Flickinger, and L. Dade Lunsford
51 Cerebral Cavernous Malformations: Viewpoint—Surgery ................................. 637
Robert L. Dodd and Gary K. Steinberg
52 Trigeminal Neuralgia ............................................................................................... 649
Lawrence S. Chin, Seung S. Hahn, Shilpen Patel, Thomas Mattingly,
and Young Kwok
53 Trigeminal Neuralgia: Viewpoint—Surgery ......................................................... 659
Craig Rabb and Ahmed Cheema
54 Trigeminal Neuralgia: Viewpoint—Medical Management .................................. 665
Neil C. Porter
55 Stereotactic Radiosurgery for Movement Disorders ............................................ 671
Yoshinori Higuchi
56 Perspective on Radiosurgery Versus Conventional Surgery for
Movement Disorders ................................................................................................ 681
Zion Zibly, Andrew B. Shaw, John Y.K. Lee, and Ali R. Rezai
57 Movement Disorders: Viewpoint—Medical Therapy........................................... 695
Abraham N. Lieberman and Sara S. Dhanani
58 Radiosurgery for Drug-Resistant Epilepsies: State of the Art, Results,
and Perspectives ....................................................................................................... 699
Jean Régis, Romain Carron, Fabrice Bartolomei, and Patrick Chauvel
59 Epilepsy: Viewpoint—Surgery ............................................................................... 711
David Carter and Zulma Tovar-Spinoza
60 Epilepsy: Viewpoint—Medical ............................................................................... 723
Gregory K. Bergey
61 Stereotactic Radiosurgery for Psychiatric and Pain Disorders ........................... 731
Chun-Po Yen and Jason P. Sheehan
62 Ocular and Orbital Lesions..................................................................................... 743
Yan Michael Li, Gabriela Šimonová, Roman Lisčák, Josef Novotný Jr.,
Amit Singla, and Lawrence S. Chin
63 Ocular and Orbital: Viewpoint—Surgery ............................................................. 765
Bryant P. Carruth, Robert H. Hill, and Thomas A. Bersani
64 Ocular and Orbital Tumors: Viewpoint-Fractionated Radiation ....................... 773
Nicolas Girard, Françoise Mornex, and Alain Vighetto

Part V Patient Care and Socio-Economic Issues

65 Complications and Management in Radiosurgery ............................................... 785

Igor J. Barani and Minesh P. Mehta
66 Building a Radiosurgery Practice........................................................................... 807
Ali Farooqui and N. Scott Litofsky
67 Patient Care in Stereotactic Radiosurgery ............................................................ 817
Terri F. Biggins

Index .................................................................................................................................. 829

Contributors

John R. Adler, M.D. Department of Neurosurgery, Stanford University, Stanford, CA, USA
Varian Medical Systems, Stanford, CA, USA
Faiz U. Ahmad, M.D., M.Ch. Department of Neurosurgery, Emory University, Atlanta,
GA, USA
Felipe C. Albuquerque, M.D. Division of Neurological Surgery, Barrow Neurological
Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA
David W. Andrews, M.D. Department of Neurological Surgery, Thomas Jefferson University,
Philadelphia, PA, USA
James Balter, Ph.D. Department of Radiation Oncology, University of Michigan Hospital
and Health Systems, Ann Arbor, MI, USA
Igor J. Barani, M.D. Department of Radiation Oncology, University of California, San
Francisco, San Francisco, CA, USA
Gene H. Barnett, M.D., M.B.A. Department of Neurosurgery, Cleveland Clinic Foundation,
Cleveland, OH, USA
Fabrice Bartolomei, M.D., Ph.D. Department of Neurophysiology, Aix-Marseille
University—Timone University Hospital, Marseille, France
Gregory K. Bergey, M.D. Department of Neurology, Johns Hopkins University School of
Medicine, Baltimore, MD, USA
Thomas A. Bersani, M.D. Department of Ophthalmology and Otolaryngology, SUNY
Upstate Medical University, Syracuse, NY, USA
Terri F. Biggins, R.N., B.S.N., C.N.R.N. Department of Nursing, University of Maryland
Medical Systems, Baltimore, MD, USA
Frank J. Bova, Ph.D. Department of Neurosurgery, University of Florida, Gainesville,
FL, USA
Greg Bowden, M.D., M.Sc. Department of Neurological Surgery, University of Pittsburgh,
Pittsburgh, PA, USA
David J. Brenner, Ph.D., D.Sc. Center for Radiological Research, Columbia University
Medical Center, New York, NY, USA
Jeffrey N. Bruce, M.D. Department of Neurological Surgery, Brain Tumor Center, Columbia
University Medical Center, New York Presbyterian Hospital, New York, NY, USA
Marc Bussière, M.Sc. Department of Radiation Oncology, Massachusetts General Hospital,
Boston, MA, USA

ix
x Contributors

J. Gregory Cairncross, M.D. Southern Alberta Cancer Research Institute, University of

Calgary, Calgary, AB, Canada
Yue Cao, M.D. Department of Radiation Oncology, Radiology, and Biomedical Engineering,
University of Michigan Hospital and Health Systems, Ann Arbor, MI, USA
John M. Caridi, M.D. Department of Neurosurgery, Ichan School of Medicine at Mount
Sinai, New York, NY, USA
David J. Carlson, Ph.D., D.A.B.R. Department of Therapeutic Radiology, Yale University
School of Medicine, New Haven, CT, USA
Romain Carron, M.D., Ph.D. Department of Functional Neurosurgery, Aix-Marseille
University—Timone University Hospital, Marseille, France
Bryant P. Carruth, M.D. Department of Ophthalmology, SUNY Upstate Medical University,
Syracuse, NY, USA
David Carter, M.D., Ph.D. Department of Neurosurgery, SUNY Upstate Medical University,
Syracuse, NY, USA
Kaisorn L. Chaichana, M.D. Department of Neurosurgery, Johns Hopkins University School
of Medicine, Baltimore, MD, USA
Daniel T. Chang, M.D. Department of Radiation Oncology, Stanford University, Stanford,
CA, USA
Eric L. Chang, M.D. Department of Radiation Oncology, Keck School of Medicine of USC,
USC Norris Cancer Hospital, Los Angeles, CA, USA
Joe Y. Chang, M.D., Ph.D., M.S. Department of Radiation Oncology, The University of
Texas M.D. Anderson Cancer Center, Houston, TX, USA
Samuel T. Chao, M.D. Department of Radiation Oncology, Cleveland Clinic, Cleveland,
OH, USA
Neeraj Chaudhary, M.D., M.R.C.S., F.R.C.R. Department of Neuro-radiology, University
of Michigan Hospital and Health Systems, Ann Arbor, MI, USA
Patrick Chauvel, M.D. Department of Neurophysiology, Aix-Marseille University—Timone
University Hospital, Marseille, France
Ahmed Cheema, M.D. Department of Neurosurgery, University of Oklahoma-Oklahoma
City, Oklahoma City, OK, USA
Linda Chen, M.D. Department of Radiation Oncology, Johns Hopkins University School of
Medicine, Baltimore, MD, USA
Shifeng Chen, Ph.D. Department of Radiation Oncology, University of Maryland School of
Medicine, Baltimore, MD, USA
Lawrence S. Chin, M.D., F.A.C.S., F.A.A.N.S. Department of Neurosurgery, SUNY Upstate
Medical University, Syracuse, NY, USA
Daniel T.T. Chua, M.D., F.R.C.R., F.H.K.C.R. Department of Radiotherapy, Hong Kong
Sanatorium & Hospital, Happy Valley, Hong Kong
Randi Cohen, M.D., M.S. Department of Radiation Oncology, University of Maryland,
Baltimore, MD, USA
William T. Couldwell, M.D., Ph.D. Department of Neurosurgery, Clinical Neurosciences
Center, University of Utah, Salt Lake City, UT, USA
Contributors xi

Christopher Dardis, M.D. Barrow Neurological Clinics, Phoenix, AZ, USA

Laura A. Dawson, M.D., F.R.C.P.C. Department of Radiation Oncology, Princess Margaret
Cancer Centre, University of Toronto, Toronto, ON, Canada
Eric M. Deshaies Department of Neurosurgery, SUNY Upstate Medical University, Syracuse,
NY, USA
Sara S. Dhanani, M.D. Department of Neurology, Banner Sunreach Research Institute, Sun
City, AZ, USA
Robert L. Dodd, M.D., Ph.D. Department of Neurosurgery, Stanford University School of
Medicine, Stanford, CA, USA
Jean Anderson Eloy, M.D. Endoscopic Skull Base Surgery Program, Department of
Otolaryngology—Head and Neck Surgery, Rutgers New Jersey Medical School, Newark,
NJ, USA
Ali Farooqui, M.D. Division of Neurological Surgery, Department of Surgery, University of
Missouri School of Medicine, Columbia, MO, USA
Christopher J. Farrell, M.D. Department of Neurological Surgery, Thomas Jefferson
University, Philadelphia, PA, USA
Carolina E. Fasola, M.D. Department of Radiation Oncology, Stanford University, Stanford,
CA, USA
Steven J. Feigenberg, M.D. Department of Radiation Oncology, The University of Maryland
School of Medicine, Baltimore, MD, USA
John C. Flickinger, M.D. Department of Radiation Oncology, University of Pittsburgh,
Pittsburgh, PA, USA
William A. Friedman, M.D. Department of Neurosurgery, University of Florida, Gainesville,
FL, USA
Steven L. Giannotta, M.D. Department of Neurological Surgery, Keck School of Medicine
of USC, Los Angeles, CA, USA
Iris C. Gibbs, M.D. Department of Radiation Oncology, Stanford University, Stanford,
CA, USA
Nicolas Girard, M.D., Ph.D. Department of Respiratory Medicine, Oncology, Hospices
Civils de Lyon, Lyon, France
Alessandra Gorgulho, M.D., M.Sc. Department of Neurosurgery, Hospital de Coração-
Associação do Sanatório Sírio, São Paulo, Brazil
Department of Neurosurgery, University of California at Los Angeles, Los Angeles, CA, USA
Sarah F. Grabowski, M.D. Department of Radiation Oncology, University of Maryland
Medical Center, Baltimore, MD, USA
Matthias Guckenberger, M.D. Department of Radiation Oncology, University Würzburg,
Würzburg, Germany
Seung S. Hahn, M.D. Department of Radiation Oncology, SUNY Upstate Medical University,
Syracuse, NY, USA
Yoshinori Higuchi, M.D., Ph.D. Department of Neurological Surgery, Chiba University
Graduate School of Medicine, Chiba, Japan
Robert H. Hill, M.D. Department of Ophthalmology, SUNY Upstate Medical University,
Syracuse, NY, USA
xii Contributors

Krisztian Homicsko, M.D., Ph.D. Department of Oncology, Centre Hospitalier Universitaire

Vaudois, Lausanne, Switzerland
Rachel L. Hopkins, M.D. Division of Endocrinolgy & Metabolism, SUNY Upstate Medical
University, Syracuse, NY, USA
Zain Husain, M.D. Department of Therapeutic Radiology, Yale University, New Haven, CT, USA
Andrew Hwang, Ph.D. Department of Radiation Oncology, Alta Bates Summit Medical
Center, Oakland, CA, USA
Scharukh Jalisi, M.D., M.A. Division of Head and Neck Surgical Oncology and Skullbase
Surgery, Department of Otolaryngology and Neurological Sciences, Boston University,
Boston, MA, USA
Edward W. Jung, M.D. Department of Radiation Oncology, Cleveland Clinic Foundation,
Cleveland, OH, USA
Robert W. Jyung Department of Otolaryngology-Head and Neck Surgery, Rutgers New
Jersey Medical School, Newark, NJ, USA
M. Yashar S. Kalani, M.D., Ph.D. Division of Neurological Surgery, Barrow Neurological
Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA
Hideyuki Kano, M.D., Ph.D. Department of Neurological Surgery, University of Pittsburgh
School of Medicine, Pittsburgh, PA, USA
Evangelia Katsoulakis, M.D. Department of Radiation Oncology, Memorial Sloan Kettering
Cancer Center, New York, NY, USA
Siyong Kim, Ph.D. Department of Radiation Oncology, Virginia Commonwealth University,
Richmond, VA, USA
Lawrence Kleinberg, M.D. Department of Radiation Oncology, Johns Hopkins University
School of Medicine, Baltimore, MD, USA
Jonathan P.S. Knisely, M.D. Department of Radiation Medicine, North Shore LIJ Health
System, Hofstra North Shore LIJ School of Medicine, Manhasset, NY, USA
Surasak Komonchan, M.D. Department of Neurology, Prasat Neurological Institute,
Rajthevee, Thailand
Albert C. Koong, M.D., Ph.D. Department of Radiation Oncology, Stanford University
School of Medicine, Stanford, CA, USA
Mark D. Krieger, M.D. Division of Neurosurgery, Children’s Hospital Los Angeles, Los
Angeles, CA, USA
Khaled M. Krisht, M.D. Department of Neurosurgery, Clinical Neurosciences Center,
University of Utah, Salt Lake City, UT, USA
Marina Kushnirsky, B.A. Department of Neurosurgery, Hofstra North Shore LIJ School of
Medicine, Manhasset, NY, USA
Young Kwok, M.D. Department of Radiation Oncology, University of Maryland Medical
Center, Baltimore, MD, USA
Ilya Laufer, M.D. Department of Neurosurgery, Memorial Sloan Kettering Cancer Center,
New York, NY, USA
John Y.K. Lee, M.D. Department of Neurosurgery, University of Pennsylvania, Philadelphia,
PA, USA
Contributors xiii

Gregory P. Lekovic, M.D., Ph.D. Good Samaritan Gama Knife Radiosurgery Center,
Los Angeles, CA, USA
Yan Michael Li, M.D., Ph.D. Department of Neurosurgery, UT MD Anderson Cancer Center,
Houston, TX, USA
Abrahim N. Lieberman, M.D. Department of Neurology, Barrow Neurological Clinics,
Phoenix, AZ, USA
Roman Lisčák, M.D. Third Faculty of Medicine, Clinical Department of Neurosurgery,
Charles University, Prague, Czech Republic
Department of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech
Republic
N. Scott Litofsky, M.D., F.A.A.N.S., F.A.C.S. Division of Neurological Surgery, Department
of Surgery, University of Missouri School of Medicine, Columbia, MO, USA
Arthur K. Liu, M.D., Ph.D. Department of Radiation Oncology, University of Colorado
Cancer Center, Aurora, CO, USA
James K. Liu, M.D., F.A.A.N.S. Center for Skull Base and Pituitary Surgery, Rutgers New
Jersey Medical School Neurological Institute of New Jersey, Newark, NJ, USA
Departments of Neurological Surgery and Otolaryngology—Head and Neck Surgery, Rutgers
New Jersey Medical School Neurological Institute of New Jersey, Newark, NJ, USA
L. Dade Lunsford, M.D. Department of Radiation Oncology, University of Pittsburgh,
Pittsburgh, PA, USA
Lijun Ma, Ph.D. Department of Radiation Oncology, University of California San Francisco,
San Francisco, CA, USA
Salvador Manrique-Guzman, M.D. Department of Neurosurgery, Johns Hopkins Hospital,
Baltimore, MD, USA
Thomas Mattingly, M.D. Department of Neurosurgery, University of Maryland, Baltimore,
MD, USA
Carlos A. Mattozo, M.D. Department of Surgery, Division of Neurosurgery, David Geffen
School of Medicine at UCLA, Los Angeles, CA, USA
Assistant Professor of Neurosurgery, Department of Neurosurgery,Pontificia Universidade
Catolica de Curitiba, Brazil
Cameron G. McDougall, M.D. Division of Neurological Surgery, Barrow Neurological
Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA
Minesh P. Mehta, M.B.Ch.B., F.A.S.T.R.O. Department of Radiation Oncology, University
of Maryland, Baltimore, MD, USA
Thomas E. Merchant, D.O., Ph.D. Department of Radiological Sciences, St. Jude Children’s
Research Hospital, Memphis, TN, USA
Fassil B. Mesfin, M.D., Ph.D. Department of Neurosurgery, SUNY Upstate Medical
University, Syracuse, NY, USA
René-O. Mirimanoff, M.D. Radiation Oncology Department, CHUV, University Hospital
Lausanne, Lausanne, Switzerland
Clinique de La Source, Switzerland
Françoise Mornex, M.D., Ph.D. Department of Radiation Oncology, Centre Hospitalier
Lyon Sud, Hospices Civils de Lyon, Lyon, France
xiv Contributors

Gregory J.A. Murad, M.D. Department of Neurosurgery, University of Florida, Gainesville,

FL, USA
Erin S. Murphy, M.D. Department of Radiation Oncology, Taussig Cancer Institute,
Cleveland, OH, USA
Martin J. Murphy, Ph.D. Department of Radiation Oncology, Virginia Commonwealth
University, Richmond, VA, USA
Yildirim D. Mutaf, Ph.D. Department of Radiation Oncology, University of Maryland
School of Medicine, Baltimore, MD, USA
Laura Negretti, M.D. Radiation Oncology Department, CHUV, University Hospital
Lausanne, Clinica Luganese, Ticino, Switzerland
Quynh–nhu Nguyen, M.D. Department of Radiation Oncology, Keck School of Medicine of
USC, USC Norris Cancer Hospital, Los Angeles, CA, USA
Ajay Niranjan, M.D., M.B.A. Department of Neurological Surgery, University of Pittsburgh,
Pittsburgh, PA, USA
Josef Novotný Jr., M.Sc., Ph.D. Department of Radiation Oncology, University of Texas
Southwestern Medical Center, Dallas, TX, USA
Alfred Ogden, M.D. Department of Neurological Surgery, Columbia University Medical
Center, New York Presbyterian Hospital, New York, NY, USA
David J. Padalino, M.D. Department of Neurosurgery, SUNY Upstate Medical University,
Syracuse, NY, USA
Jatinder Palta, Ph.D. Department of Radiation Oncology, Virginia Commonwealth
University, Richmond, VA, USA
Aditya S. Pandey, M.D. Department of Neurosurgery, University of Michigan Hospital and
Health Systems, Ann Arbor, MI, USA
Roy A. Patchell, M.D. National Brain Tumor Center, Capital Institute for Neurosciences,
Capital Health Medical Center-Hopewell, Pennington, NJ, USA
Shilpen Patel, M.D. Department of Radiation Oncology, University of Washington Medical
Center, Seattle, WA, USA
Smruti K. Patel, B.A. Department of Neurological Surgery, University of Medicine and
Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA
Vaibhav Patil, M.D., M.S. Department of Information Technology, Commonwealth Care
Alliance, Boston, MA, USA
Arie Perry, M.D. Department of Pathology and Neurological Surgery, University of California
San Francisco, San Francisco, CA, USA
Bruce E. Pollock, M.D. Department of Neurological Surgery and Radiation Oncology, Mayo
Foundation, Rochester, MN, USA
Neil C. Porter, M.D. Department of Neurology, University of Maryland School of Medicine,
Baltimore, MD, USA
Alfredo Quinones-Hinojosa, M.D. Department of Neurosurgery and Oncology, Johns
Hopkins University School of Medicine, Baltimore, MD, USA
Craig Rabb, M.D. Department of Neurosurgery, University of Oklahoma College of
Medicine, Oklahoma City, OK, USA
Contributors xv

Maryam Rahman, M.D., M.S. Department of Neurosurgery, University of Florida,

Gainesville, FL, USA
Pulak Ray, M.D. Department of Neurosurgery, Delaware Neurosurgical Group, Newark,
DE, USA
William F. Regine, M.D. Department of Radiation Oncology, University of Maryland
Medical Center, Baltimore, MD, USA
Jean Régis, M.D. Department of Functional Neurosurgery, Aix-Marseille University—
Timone University Hospital, Marseille, France
Ali R. Rezai, M.D. Department of Neurological Surgery and Neuroscience, The Ohio State
University, Columbus, OH, USA
David Roberge, M.D. Department of Radiation Oncology, Centre Hospitalier de l’Université
de Montréal—Notre Dame, Montreal, QC, Canada
Nathan J. Robison, M.D. Children’s Center for Cancer and Blood Diseases, Children’s
Hospital Los Angeles, University of Southern California Keck School of Medicine, Los
Angeles, CA, USA
C. Leland Rogers, M.D. GammaWest Cancer Services, Salt Lake City, UT, USA
William G. Rule, M.D. Department of Radiation Oncology, Mayo Clinic College of Medicine,
Mayo Clinic Arizona, Phoenix, AZ, USA
Michael Rutenberg, M.D., Ph.D. Department of Radiation Oncology, University of
Maryland, Baltimore, MD, USA
Arjun Sahgal, M.D. Department of Radiation Oncology, University of Toronto, Toronto,
ON, Canada
Antonio A.F. De Salles, M.D., Ph.D. Clinical and Scientific Division, Hospital do Coração
Neuroscience, Hospital de Coração-Associação do Sanatório Sírio, São Paulo, Brazil
Department of Neurosurgery, University of California at Los Angeles, Los Angeles, CA, USA
Raymond Sawaya, M.D. Department of Neurosurgery, The University of Texas
M.D. Anderson Cancer Center, Houston, TX, USA
Steven E. Schild, M.D. Department of Radiation Oncology, Mayo Clinic College of Medicine,
Mayo Clinic Arizona, Phoenix, AZ, USA
Richard F. Schmidt, B.A. Department of Neurological Surgery, Rutgers New Jersey Medical
School, Newark, NJ, USA
Michael Schulder, M.D. Department of Neurosurgery, Hofstra North Shore-LIJ School of
Medicine, Manhasset, NY, USA
Navesh K. Sharma, D.O., Ph.D. Department of Radiation Oncology, University of Maryland
School of Medicine, Baltimore, MD, USA
Andrew B. Shaw, M.D. Department of Neurological Surgery and Neuromodulation, Wexner
Medical Center at The Ohio State University, Columbus, OH, USA
Jason P. Sheehan, M.D., Ph.D. Department of Neurological Surgery, University of Virginia,
Charlottesville, VA, USA
David M. Shepard, Ph.D. Swedish Cancer Institute, Seattle, WA, USA
Andrew G. Shetter, M.D. Section of Functional Stereotactic Neurosurgery, Division of
Neurological Surgery, Barrow Neurological Institute, Phoenix, AZ, USA
xvi Contributors

Shervin M. Shirvani, M.D. Department of Radiation Oncology, Banner MD Anderson

Cancer Center, Gilbert, AZ, USA
Almon S. Shiu, Ph.D. Department of Radiation Oncology, Keck School of Medicine of USC,
USC Norris Cancer Hospital, Los Angeles, CA, USA
Stephanie L. Da Silva, B.A. Division of Neurosurgery, Children’s Hospital Los Angeles, Los
Angeles, CA, USA
Gabriela Šimonová, M.D., Ph.D. Department of Stereotactic Radioneurosurgery, Hospital
Na Homolce, Prague, Czech Republic
Amit Singla, M.D. Department of Neurosurgery, SUNY Upstate Medical University,
Syracuse, NY, USA
Scott G. Soltys, M.D. Department of Radiation Oncology, Stanford University, Stanford,
CA, USA
Adam M. Sonabend, M.D. Department of Neurological Surgery, Columbia University
Medical Center, New York Presbyterian Hospital, New York, NY, USA
Luis Souhami, M.D., F.A.S.T.R.O. Division of Radiation Oncology, Department of
Oncology, McGill University, Montreal, QC, Canada
Paul W. Sperduto, M.D., M.P.P. Department of Radiation, University of Minnesota Gamma
Knife Center, Minneapolis Radiation Oncology, Waconia, MN, USA
Gary K. Steinberg, M.D., Ph.D. Department of Neurosurgery, Stanford University School of
Medicine, Stanford, CA, USA
Roger Stupp, M.D. Department of Oncology and Cancer Center, University Hospital Zurich,
Zurich, Switzerland
John H. Suh, M.D. Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA
Mohan Suntharalingam, M.D., M.B.A. Department of Radiation Oncology, University of
Maryland, Baltimore, MD, USA
Reinhart A.J. Sweeney, M.D., B.Sc. Department of Radiation Oncology, MVZ Innmed,
Klinik Bad Trissi, Oberaudorf, Germany
Greg Thompson, M.D. Department of Neurosurgery, University of Michigan Hospital
and Health Systems, Ann Arbor, MI, USA
Zulma Tovar-Spinoza, M.D. Department of Neurosurgery, SUNY Upstate Medical
University, Syracuse, NY, USA
Victor C.K. Tse, M.D., Ph.D. Department of Neurosurgery, Kaiser Permanente Medical
Group, Redwood City, CA, USA
Christina I. Tsien, M.D. Department of Radiation Oncology, University of Michigan Hospital
and Health Systems, Ann Arbor, MI, USA
Alain Vighetto, M.D. Service de neurologie, Hospital neurologique, Bron, France
Michael A. Vogelbaum, M.D., Ph.D. Department of Neurosurgery, Cleveland Clinic
Foundation, Cleveland, OH, USA
Lei Wang, Ph.D. Department of Radiation Oncology, Stanford University, Stanford, CA, USA
Michael Y. Wang, M.D. Department of Neurosurgery, University of Miami, Miami, FL, USA
Martin H. Weiss, M.D. Department of Neurological Surgery, Keck School of Medicine,
University of Southern California, Los Angeles, CA, USA
Contributors xvii

David M. Wildrick, Ph.D. Department of Neurosurgery, The University of Texas

M.D. Anderson Cancer Center, Houston, TX, USA
Brian Williams, M.D. Department of Neurosurgery, University of Virginia, Charlottesville,
VA, USA
Richard W. Williamson, M.D. Division of Neurological Surgery, Barrow Neurological
Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA
Yoshiya Yamada, M.D. Department of Radiation Oncology, Memorial Sloan Kettering
Cancer Center, New York, NY, USA
Chun-Po Yen, M.D. Department of Neurological Surgery, University of Virginia,
Charlottesville, VA, USA
Cedric Yu, D.Sc. Department of Radiation Oncology, University of Maryland School of
Medicine, Baltimore, MD, USA
Gabriel Zada, M.D. Department of Neurosurgery, Keck School of Medicine of USC,
University of Southern California, Los Angeles, CA, USA
Jessica Zhou, M.D. Department of Radiation Oncology, University of Michigan Hospital and
Health Systems, Ann Arbor, MI, USA
Zion Zibly, M.D. Department of Neurological Surgery, Center of Neuromodulation, The
Ohio State University Medical Center, Columbus, OH, USA
 Part I
Introduction
 The History of Stereotactic
Radiosurgery
Marina Kushnirsky, Vaibhav Patil, and Michael Schulder
Definition
Since its introduction in 1951, stereotactic radiosurgery
(SRS) has become one of the most important technological
innovations in neurosurgery. Hundreds of thousands of
patients have undergone the procedure, which is now at the
cutting edge of radiation therapy techniques. This modality
originated as the minimally invasive stereotactic application
of various energy sources—ultrasound, orthovoltage, X-rays,
and accelerated subatomic particles—for the treatment of
movement and pain disorders [1]. SRS has since evolved into
a precise, cost-effective, and noninvasive therapy for a wide
range of intracranial and extracranial pathologies. Advances
in imaging enable highly accurate treatment planning, and
radiobiological innovations have improved beam targeting.
The evolution of SRS has allowed for the treatment of an
ever-increasing range of oncological, cerebrovascular, and
functional targets, while simultaneously improving patient
comfort and diminishing harmful side effects.
Stereotactic radiosurgery was first defined in 1951 by the
pioneering Swedish neurosurgeon Lars Leksell, who envi-
sioned it as an alternative treatment during a time when mor-
tality from open neurosurgery was close to 40% [2]. Leksell
saw great potential in a technique that could use a single
heavy dose of radiation to “destroy any deep brain structure
without the risk of bleeding or infection” [3]. His invention
predated advances in technology and radiobiology, which
now enable frameless, fractionated stereotactic localization.
As a result of these advances, the boundary between radio-
M. Kushnirsky, B.A. • M. Schulder, M.D. (*)
Department of Neurosurgery, Hofstra North Shore LIJ
School of Medicine, Manhasset, NY, USA
e-mail: mschulder@nshs.edu
V. Patil, M.D., M.S.
Department of Information Technology,
Commonwealth Care Alliance, Boston, MA, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_1, © Springer Science+Business Media New York 2015
1
surgery and fractionated stereotactic radiotherapy (FSRT)
has become blurred. Sixty-two years since Leksell first
treated a patient with trigeminal neuralgia using an ortho-
voltage dental X-ray tube [4], SRS has changed so radically
that its definition has been reexamined. The argument in the
first decade of the twenty-first century was framed thusly:
the “purists” stated that the unique radiobiological advances
of SRS were lost once fractionation was incorporated, while
the “fractionators” claimed that it was overly rigid to not take
advantage of the ability to fractionate, given the possibilities
opened up by increased computer speed and power.
At a 2005 meeting of the American Association of
Neurological Surgeons Stereotactic Radiosurgery Task
Force, the members attempted to definitively separate
fractionated stereotactic radiosurgery and FSRT. A related
goal was to agree with organized radiation oncology (repre-
sented by ASTRO, the American Society for Therapeutic
Radiation Oncology) on a definition of SRS as opposed to
SRT. They dismissed radiobiological differences between
the two modalities, stating they are unsubstantiated and theo-
retical at best [1]. Instead, the meeting chose to focus on the
intent of treatments as the key distinction between hypofrac-
tionated SRS and FSRT. SRS uses steep radiation dose gra-
dients to ensure that only the target lesion is destroyed while
surrounding tissue is preserved. FSRT employs the differen-
tial responses of tumors and normal tissue to fractionated
ionizing radiation. Thus, dose homogeneity is much more
important for FSRT, in which abnormal and sensitive normal
tissue may be in the same treatment field.
Ultimately, the task force defined SRS as “a distinct disci-
pline 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.
Stereotactic Radiosurgery (SRS) typically is performed in a
single session, using a rigidly attached stereotactic guiding
device, other immobilization technology and/or a stereotac-
tic image-guidance system, but can be performed in a limited
3
4 M. Kushnirsky et al.
number of sessions, up to a maximum of five” [1]. As FSRT’s
conformity and dose falloff improve, it may become neces-
sary to rework the definition of SRS, perhaps including new
information about radiobiological tissue response.
Early Roots
Lars Leksell’s 1951 development of stereotactic radiosur-
gery was preceded by a multitude of technological innova-
tions in both stereotactic surgical fixation and medical
physics. The first stereotactic apparatus was described in
1908 by Sir Victor Horsley and Robert Clarke [5]. It utilized
Cartesian coordinates to locate structures within the brain,
using bony landmarks for reference. Their work also included
the first stereotactic atlas, which contained illustrated cross
sections of the monkey brain registered to distinguishing fea-
tures on the skull. The major issue with Horsley and Clarke’s
system was that intracranial anatomical structures vary sig-
nificantly between individuals in their relationship to bony
landmarks of the skull, making accurate targeting impossi-
ble. Interestingly, one of the engineers who worked on the
apparatus designed a frame for human use. Unable to per-
suade his neurosurgical colleagues to use it, he stored it in a
closet until his family discovered it, almost 60 years later [6].
The first stereotactic device accurate enough for use in
humans was developed in 1947 by Ernest A. Spiegel and
Henry T. Wycis (Fig. 1.1). This new stereotactic frame
Fig. 1.1 Henry T. Wycis holding Spiegel–Wycis stereotactic frame
with Horsley-Clarke frame on the table. From Textbook of Stereotactic
and Functional Neurosurgery. Lozano, Andres M.; Gildenberg, Philip L.;
Tasker, Ronald R. (Eds.) 2nd ed. 2009; used with permission
needed an improved method of intracranial targeting, and by
this time X-ray technology had sufficiently advanced to be
practical and quick enough for use in the operating room.
Spiegel and Wycis employed X-ray ventriculography to
identify where a target lesion was in relation to any cerebral
structure. Imaging techniques combined with advances in
physiology allowed for recognition of select target pathways:
the dorsomedial nucleus for psychosurgery, the lemniscal
system for pain, and the extrapyramidal pathways for move-
ment disorders [7]. In spite of these developments, the
Spiegel–Wycis frame, which consisted of a Horsley–Clarke
device attached to patients’ skulls with a ring secured by a
plaster of Paris cap [5, 8], was not without drawbacks. During
pneumoencephalography, cerebrospinal fluid was drained so
that air would enter the cerebral ventricles and allow for tar-
geting of brain structures using X-rays. The side effects were
so severe that patients were unable to undergo surgery on the
same day their imaging and measurements were taken.
However, when positive contrast became available, the pro-
cedure became more easily tolerated. The Spiegel–Wycis
frame spurred the invention of at least 40 other stereotactic
devices [5], including Leksell’s.
Concurrent radiobiological innovations played an equally
important role as stereotactic ones in the development of
SRS. Ionizing radiation was used for therapeutic purposes
soon after it was discovered; three months after Wilhelm
Konrad Roentgen published his report in 1895, X-rays were
used to treat skin and breast cancers [3, 9]. The discovery of
radioactivity by Becquerel in 1896, and of radium by the
Curies soon after, opened the door for the medical use of
radioisotopes. X-rays were used to treat patients with pitu-
itary tumors as early as 1906, and radium brachytherapy was
applied to treat similar conditions at about the same time [10].
Harvey Cushing, the father of American neurosurgery, had
extensive experience with both X-ray and brachytherapy
treatments, although he remained skeptical of the utility of
either [11]. Dosimetry was poorly understood, and treat-
ments were not standardized. Nonetheless, some neurosur-
geons continued to explore the uses of ionizing radiation,
and new methods continued to be developed through the
1950s.
Emergence of Radiosurgical Practice
Lars Leksell conducted his earliest work with SRS while
serving as head of the neurosurgery department at the
University of Lund [12]. His preliminary work with a 250
kVp X-ray unit attached to a single beam port resulted in the
successful management of pain control in trigeminal neural-
gia patients (Fig. 1.2) [2, 5]. A ceaseless innovator, Leksell
noticed that if he used higher energy radiation, depth dose
and beam definition could be improved, especially in smaller
treatment fields [12]. He then began working with Borje
1 The History of Stereotactic Radiosurgery
Fig. 1.2 First stereotactic instrument for radiosurgery using 280 kV
X-rays, early 1950s. From Textbook of Stereotactic and Functional
Neurosurgery. Lozano, Andres M.; Gildenberg, Philip L.; Tasker,
Ronald R. (Eds.) 2nd ed. 2009; used with permission
Fig. 1.3 Lars Leksell and his physicist colleague, Borje Larsson, pre-
paring a patient for SRS with a particle beam accelerator in 1958.
(Photo courtesy of L. Dade Lundsford, MD)
Larsson, a radiobiologist at the Uppsala University cyclotron
unit, to investigate the use of converging proton beams for
neurosurgery (Fig. 1.3). When these beams proved too com-
plicated and difficult to use in a hospital setting, Larsson and
Leksell began collaborating with Kurt Liden, a medical
physicist at Lund.
After experimenting with particle beams and linear accel-
erators, Leksell and his colleagues ultimately designed the
5
Fig. 1.4 Lars Leksell treating the first case of acoustic neurinoma with
first version of gamma knife, 1968. From Textbook of Stereotactic and
Functional Neurosurgery. Lozano, Andres M.; Gildenberg, Philip L.;
Tasker, Ronald R. (Eds.) 2nd ed. 2009; used with permission
gamma knife (GK), containing 179 cobalt sources in a hemi-
spheric array (Fig. 1.4). The first unit was operational in
1968; Leksell’s first patient was immobilized using a molded
plaster headpiece and treated for a craniopharyngioma [4].
The potential of the GK to treat neoplasms and vascular
anomalies, as opposed to functional targets such as lesioning
for control of pain and movement disorders, was recognized
by Leksell early on. In the precomputed tomography (CT)
era these treatments were mostly limited to patients with
arteriovenous malformations (AVMs) [13] and acoustic neu-
romas, which could be imaged either on angiography or by
polytomography, respectively [3].
At the same time, work was continuing elsewhere with
focused heavy particle irradiation. John Lawrence, whose
brother Ernest won the 1939 Nobel Prize for his invention of
the cyclotron, began experimenting with charged particle
radiation in 1954. He treated patients with pituitary and other
intracranial disorders (Fig. 1.5) [14, 15] using proton and
helium ion beams. He initiated the use of the Bragg peak
principle according to which proton beams deposit their
energy at a distinct point, with minimal exit dose. In practice,
heavy particle beams must be carefully shaped and spread in
order to treat patients with intracranial lesions.
After visiting Stockholm in 1959, Raymond Kjellberg, a
neurosurgeon at the Massachusetts General Hospital, began
the use of Bragg peak proton beam treatments in the USA
[16]. He amassed a large series of patients with arteriove-
nous malformations and pituitary tumors. Similar efforts
were carried out in California with helium ions [17]. For
decades, the expense of building and maintaining a cyclotron
has limited the use of heavy particle SRS to a few centers. In
the last few years, new technology has decreased the size and
cost of proton beam irradiation devices, and the number of
such facilities has grown.
6 M. Kushnirsky et al.
Fig. 1.5 Raymond Kjellberg with a frame for proton beam therapy of
a patient with an AVM. (Photo courtesy of Richard Wilson, Mallinckrodt
Research Professor of Physics, Harvard University)
Acceptance
When SRS was first invented, stereotactic localization relied
on atlases, ventriculography, and angiograms. The advent of
the computerized tomography (CT) scanner in the mid-
1970s, and MRI some 10 years later, opened up the possibil-
ity of direct targeting of tumors and other “soft tissue” targets
inside the skull. Image-guided stereotaxy became available
for brain biopsy, craniotomy, tumor resection, and functional
neurosurgery. Due to this, the 1980s saw the evolution of
SRS from an esoteric technique, available at the original GK
in Stockholm (and as fractionated treatments at the few
heavy particle accelerators around the world), to an emerg-
ing technology of increasing utility.
In 1984, after several years of intense regulatory reviews
and logistical battles, Dade Lunsford and colleagues com-
pleted the installation of the first American GK at the
University of Pittsburgh [18]. This group was instrumental,
via an ongoing series of peer-reviewed publications, in plac-
ing the technique and clinical indications for SRS on a sound
scientific basis. Since then, several new models of GK units
have become available. The most current high-end model,
the GK Perfexion, enables automated collimator changes
and improves access to intracranial targets.
As the potential horizons of SRS broadened, other inves-
tigators were able to adapt linear accelerators (LINACs) for
SRS (Fig. 1.3) LINAC units create X-rays by accelerating
electrons to almost the speed of light, then directing the elec-
tron beams to a heavy metal alloy. The resulting X-ray is
collimated and focused onto a target. Before inventing the
GK, Lars Leksell and his colleagues at the Karolinska
Institute experimented with LINAC, but abandoned the sys-
tem due to low photon energies and mechanical inaccuracy
[4]. However, the ability to use CT imaging for lesion local-
ization and beam targeting greatly increased the accuracy of
LINACs. These systems were a cheaper alternative to GK or
heavy particle accelerators [19] and were quickly adapted.
Working independently, in Buenos Aires and Vicenza, Italy,
respectively, Betti and Colombo reported the successful use
of LINACs for SRS [20, 21] in 1982. Their systems allowed
for the rotation of the LINAC gantry in a single plane.
At about the same time, Winston and Lutz described the
use of a commercially available stereotactic frame for
LINAC radiosurgery [22]. Following in their footsteps,
Loeffler and Alexander demonstrated how a LINAC dedi-
cated to SRS could be a practical alternative to a GK [23]. In
the late 1980s Friedman and Bova elected not to install the
second American GK unit, preferring to develop a new
LINAC SRS system [24]. Other advantages of these LINAC
systems, besides ubiquity and lower cost, included the avail-
ability of collimators in a much greater variety of diameters
than provided with the GK. This allowed for the use of single
isocenters when treating patients whose targets were over
18 mm in diameter, the width of the largest GK collimator.
However, at around the same time several GKs were installed
in several sites around the world.
As clinical experience increased, publications appeared,
indications broadened, and vendors became increasingly
interested, a debate emerged regarding the merits of the
Gamma Knife versus LINAC-based SRS. By now, clinical
and physics studies indicate that SRS can be delivered effec-
tively and accurately with either method [19, 25]. Numerous
reports demonstrating the efficacy of SRS with few if any
short-term complications and lower costs led to the prolifera-
tion of GK and LINAC units around the world.
Fractionation, Extracranial Radiosurgery,
and Other Advances
As the Gamma Knife and LINAC systems continued to
improve treatment outcomes, it became clear that both tech-
nologies had promise for wider application. Rapid advances
in neuroimaging, robotic technology, and beam targeting
soon followed. John Adler, a neurosurgeon who trained at
the Brigham and Women’s Hospital in Boston, spent a
fellowship year with Lars Leksell in 1985 (Adler JR, per-
sonal communication). Excited by his exposure to the GK,
Adler saw the potential of SRS being extended to other areas
of the body. This required a method of delivering focused
1 The History of Stereotactic Radiosurgery
Fig. 1.6 The first Cyberknife treatment, 1994. (Photo courtesy of John
R. Adler, MD)
radiation without a stereotactic frame. Partnering with
engineers at Stanford University and with private financial
backing, the Cyberknife ultimately came into being in 1994
(Fig. 1.6).
The Cyberknife delivers SRS via an X-band LINAC with
an output of 6 MV. It is nonetheless small enough to be
mounted on an industrial robot, allowing for a theoretically
infinite number of beams to be aimed at the target. For treat-
ment of intracranial targets, the patient is immobilized using
a customized, molded plastic mask system that offers a high
degree of reproducibility between multiple fractions.
Treatments are fashioned using an inverse planning method;
to allow for practical computation times, the number of beam
origins (“nodes”) and robot angles are limited. Various other
LINAC-based systems have been developed to improve dose
planning and delivery through beam shaping and intensity
modulation. These systems include XKnife (Radionics),
Novalis (BrainLAB), and Peacock (NOMOS Corporation).
Single fraction SRS technologies have also been evolving; a
rotating Gamma Knife system (RGS), invented in the 1990s,
changes beam diameters during treatment without inter-
changing collimator helmets, which increases the system’s
flexibility and decreases treatment time.
In addition, CT scanners are now being incorporated into
LINAC-based systems. The Tomotherapy Hi-Art system,
invented in the 1990s, provides integrated treatment plan-
ning, patient setup, and CT-guided treatment. The newest
Novalis TX system includes an on-board imaging cone beam
CT scan to improve visualization of soft tissue targets during
treatment and an ExacTrac image-guidance system to adjust
for minute patient movements. These developments allow
for real-time updated imaging during treatment to ensure
positioning accuracy. Perhaps more significantly, this
improves intrafraction targeting accuracy as well. Peer-
reviewed publications have demonstrated the acceptance of
the Cyberknife and Novalis frameless systems [26–29].
7
These and other articles have fostered a useful debate regard-
ing the concept of hypofractionation in SRS and indeed if
such treatments are still “radiosurgical” [30, 31].
Extracranial SRS
With frameless LINAC-based SRS and SRT, it became
possible to further step outside the bounds of traditional
radiosurgery and treat targets outside the brain. The first
radiosurgical moves out of the intracranial compartment
were in the logical direction of the skull base and past that
into the paranasal sinuses, using either GK [32, 33] or
LINAC units [34]. Creative modifications of standard
stereotactic systems, such as the vacuum pillow stabilizer
described by Lax in 1994 [35], were designed to allow for
treatment of targets throughout the body. Hamilton and col-
leagues described the first truly extracranial radiosurgical
unit in 1995. This prototypical system relied on a skeletal
fixation frame and was designed to provide spinal SRS [36].
The need to surgically place a clamp on a spinous process
and to treat the patient in a prone position limited the appeal
of this groundbreaking concept. Non-CNS targets were later
treated using newer stereotactic technologies such as the
Elekta Stereotactic Body frame. However, with the advent of
new frameless techniques and improvements in beam target-
ing, such external devices for rigid fixation and localization
are no longer necessary. Table 1.1 summarizes the historical
landmarks in the development of SRS.
The Role of Industry and Future Advances
The convergence of image-guidance and radiation delivery
technologies initially encouraged the entry of multiple ven-
dors into the SRS marketplace. This reflected the undeniable
advantages of stereotactic localization and the resulting abil-
ity to focus radiation treatments on the smallest possible vol-
ume. While GK was historically the gold standard in SRS, a
variety of frame-based LINAC systems were designed to
provide single fraction SRS beginning in the 1980s. Vendors
included Radionics (X-Knife), Zmed (the University of
Florida system), BrainLab, and Fischer-Leibinger. As radia-
tion oncologists accepted the concept of SRS, and neurosur-
geons accepted fractionation, the industry’s focus shifted
toward frameless systems. As a result, Radionics and
BrainLab adapted their LINAC-based SRS devices for fra-
meless use, and Elekta created a frameless system that can be
used to fractionate GK treatments.
Additional technological advances in stereotactic devices,
imaging modalities such as PET scans, and diffusion tensor
imaging (DTI) are rapidly altering methods for tumor analy-
sis and surgical planning. DTI helps visualize nerve tracts,
8 M. Kushnirsky et al.

Table 1.1 SRS landmarks Table 1.2 Peer-reviewed publication on SRS

Year Author Device/event Year Papers Citations
1947 Spiegel/Wycis First human SRS frame developed 1951–1960 1 7
1951 Leksell Invention of SRS with rotating 1961–1970 0 0
orthovoltage unit 1971–1980 17 402
1954 Lawrence Heavy particle treatment of pituitary 1981–1990 122 4,707
for cancer pain 1991–2000 1,024 20,056
1962 Kjellberg Proton beam therapy of intracranial 2001–2010 1,563 19,051
lesions
2011–present 505 477
1967 Leksell Invention of gamma knife
1970 Steiner GK SRS of AVMs
1980 Fabrikant Helium ion treatment of AVMs of the technique was to touch the desired structure with a
1982 Betti/Colombo LINACs adapted for SRS probe or electrode. Hence, the group chose the word
1984 Bunge Installation of commercial GK “Stereotactic,” a mongrel of the Greek stereo meaning “three
1986 Winston/Lutz LINAC SRS based on common dimensional” and the Latin tact meaning “to touch.”
stereotactic frame Neurosurgeons’ interest in SRS was slow to develop but
1992 Loeffler/Alexander Dedicated LINAC for SRS developed increased exponentially over time. In 1987, the year that the
1993 Mackie First tomotherapy system developed first American GK was installed at the University of
1994 Adler First Cyberknife treatment
Pittsburgh and early work on LINAC SRS had been pub-
1997 DeSalles, Solberg First Novalis shaped beam RS unit
installed
lished, there were no SRS-related presentations at the annual
2011 Sheehan et al. First Gamma Knife extend case studies meeting of the American Association of Neurological
Surgeons (AANS). By 1998 there were 31 such abstracts in
addition to practical course and seminars devoted to the
while PET produces three-dimensional images of processes topic. SRS has remained a key item of interest at the major
in the body. Together with fMRI, these technologies will annual meetings of the AANS and of the Congress of
likely improve the precision of SRS and SRT and may be Neurological Surgeons. In addition, the meetings of the
incorporated into the imaging suites of current units. American and World Societies for Stereotactic and
Nanotechnology, which can be used to detect tumor margins Functional Neurosurgery feature SRS as one of the main
or as a tool for radiation guidance [37], is also a major source topics. The number of peer-reviewed publications on SRS
of excitement in the industry. The advancement of SRS and has grown tremendously as well. From 1981 to 1990, 122
related techniques has been integral in defining the modality such papers were published; in 2011 alone, that number was
as a new standard in patient care. 532 (Table 1.2) [39].
As the field grew more interdisciplinary, the International
Stereotactic Radiosurgery Society (ISRS) was founded in
Organized Radiosurgery 1993 and held its first biannual meeting that year in
Stockholm. At first the papers presented dealt entirely with
Stereotactic societies have been critical in disseminating the treatment of intracranial conditions. As SRS has moved
information about radiosurgical advances. While today’s below the skull base, studies regarding patients with such
organizations host international symposiums with extensive conditions as tumors of the spine, lung, pancreas, and pros-
membership and attendance, their origins are much more tate have been included in the ISRS program. Thus, the
humble. After Spiegel and Wycis created their stereotactic expertise of clinicians in fields completely unrelated to neu-
device, neurosurgeons who were interested in learning the rosurgery is being applied to the study of SRS. Neurosurgeons
technique visited the inventors at their lab at Temple Medical comprise the single biggest specialty group in the organiza-
School in Philadelphia [38]. To facilitate the exchange of this tion, followed by radiation oncologists and medical physi-
information, the International Society for Research in cists. As interest in extracranial and non-neurosurgical SRS
Stereoencephalotomy was created in 1961. inevitably increased, the membership of ISRS will evolve to
Interestingly, the word stereotactic is a relatively recent reflect this. The ISRS publishes a peer-reviewed collection
product of organized neurosurgery. Originally, Horsley and of selected manuscripts from each meeting, entitled The
Clarke labeled their technique “stereotaxic,” meaning “three- Journal of Radiosurgery and SBRT. The growth of SRS and
dimensional arrangement” in Greek. However, when the its widespread acceptance have been such that yet another
International Society for Research in Stereoencephalotomy organization, the Radiosurgery Society, has begun to hold
voted on a new name in 1973, it was decided that the object annual meetings.
1 The History of Stereotactic Radiosurgery
Conclusion
In the 60 years since it was invented, it is clear that stereotactic
radiosurgery has become a mainstream treatment for a wide
variety of conditions. This is not surprising; due to innova-
tions in stereotactic immobilization, imaging, and radiobiol-
ogy, the technique is now extremely precise, noninvasive,
well tolerated, and effective. Invented more than 60 years
ago, SRS is over half the age of its main “parent” special-
ties, neurosurgery and radiation oncology. It is no longer
considered an experimental or new treatment, but rather a
continuously growing and advancing field. Acceptance by
neurosurgeons, surgical specialists, and radiation oncolo-
gists means that as SRS evolves it will not be a technique
for “radiosurgeons,” but one of the methods available to
treat patients.
What remains to be seen is how the field will evolve in
response to developments in imaging and nanotechnology.
SRS has already seen one major revolution: once the genie
of hypofractionation was let out of the radiosurgical bottle,
fractionation became the norm among LINAC users, and
GK created a frameless immobilization device in order to
fractionate treatments. The impetus toward more focused
and less invasive treatments is likely to spur other such
changes in the future. Clinical and technological advances
will continue, and SRS will play an increasingly important
part in the management of patients with a range of tumors
and disorders.
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 Imaging Techniques in Stereotactic
Radiosurgery
Jessica Zhou, Yue Cao, James Balter, Neeraj Chaudhary,
Aditya S. Pandey, Greg Thompson, and Christina I. Tsien
Introduction
Stereotactic radiosurgery (SRS) involves the delivery of a
very precise, focal dose of radiation to a target. Radiologic
imaging is crucial for accurate delineation of the treatment
volume in order to achieve maximal dose to the target and
optimal sparing of the normal surrounding tissue.
Conventional imaging reflects only anatomic rather than
functional properties of the tumor. In contrast, metabolic and
physiologic imaging provides in vivo measures of tumor tis-
sue properties. In this chapter, physiologic MR imaging tech-
niques including proton spectroscopy, blood volume, blood
flow, vascular permeability, diffusion, and diffusion tensor
imaging, as well as metabolic PET imaging, will be described.
Although SRS treatment has been established for many years,
recent advances in modern imaging combined with improved
radiotherapy techniques can provide better target definition,
reduce normal tissue toxicity, and provide better assessment
of treatment response. This chapter describes the role of novel
MR and PET imaging in the treatment planning and posttreat-
ment follow-up of both malignant and benign central nervous
system (CNS) intracranial tumors.
J. Zhou, M.D. • Y. Cao, M.D. • J. Balter, Ph.D.
Department of Radiation Oncology, University of Michigan
Hospital and Health Systems, Ann Arbor, MI, USA
N. Chaudhary, M.D., M.R.C.S., F.R.C.R.
Departments of Radiology & Neurosurgery, University of
Michigan, Neuro-interventional Radiology, Ann Arbor, MI, USA
A.S. Pandey, M.D. • G. Thompson, M.D.
Department of Neurosurgery, University of Michigan
Hospital and Health Systems, Ann Arbor, MI, USA
C.I. Tsien, M.D. (*)
Department of Radiation Oncology, Washington University in
St. Louis, 4921 Parkview Place, Campus Box 8224,
St. Louis, MO 63110, USA
e-mail: ctsien@radonc.wustl.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_2, © Springer Science+Business Media New York 2015
2
Imaging and Treatment Planning
Considerations
Conventional contrast-enhanced computed tomography
(CT) scanning provides anatomic as well as electron density
information with sufficient geometric accuracy to support
stereotactic targeting and to calculate dose. MR contrast-
enhanced T1-weighted and T2-weighted imaging provides
superior soft tissue contrast relative to imaging and has also
been routinely used in target volume definition for SRS of
intracranial tumors.
In order to combine the advantages of MRI and CT, it has
been historically necessary to spatially register these images
within the treatment planning system (Fig. 2.1). Image regis-
tration permits accurate mapping of imaging data from other
modalities to a single coordinate system, typically the treat-
ment planning CT scan [1].
MRI Alone for SRS Simulation and Planning
More recently, MRI has been used as a stand-alone modality
for SRS treatment planning. Traditionally 1.5 T MR scanners
have been used for this purpose. There is increasing interest
now in the use of 3 T MR scanners, which have a higher sig-
nal to noise ratio and consequently higher spatial resolution
and shorter image acquisition time. A recent study by Zhang
et al. showed that the geometric accuracy achieved with 3 T
MRI is comparable to 1.5 T MRI for SRS treatment planning [2].
The advantage of MRI-based planning is that it removes
systematic errors that may occur due to CT-MRI registration and
eliminates radiation exposure from the CT scan. However,
this must be balanced against potential disadvantages of
omitting the CT scan including possible spatial distortion of
the MRI scan due to gradient field nonlinearity and magnetic
field inhomogeneities, the lack of electron density informa-
tion used for dose calculation, and the difficulty in patient
setup verification during treatment delivery [3]. MRI simulation
11
12
Fig. 2.1 Split window display of image registration of MR and CT for a right parietal brain metastasis for SRS treatment planning in the axial
(right image), sagittal (middle image), and coronal (left image) views
may also require a larger bore for patient setup to allow for
appropriate MRI compatible immobilization devices.
Solutions to these shortcomings of MRI-based plans are
being developed. The lack of an identifiable relationship
between MR image values and electron densities has been
addressed in a variety of ways. Early treatment planning
using MRI alone involved assignment of bulk densities (e.g.,
to bone and the rest of the brain), which resulted in a smaller
(1–1.5 %) calculated dose difference between the MRI-based
and a CT-based plans when compared to plans without bulk
density assignment. More recent work has included use of
electron density atlases and statistical modeling of tissue
composition to assign attenuation properties. Recent devel-
opments which may benefit MRI–PET systems as well as
radiation oncology include ultrashort TE (UTE) imaging and
even more sophisticated attenuation models [4, 5]. These
methods may reduce uncertainties of MR planning in most
regions of the brain to a fairly insignificant level in the near
future. One issue of note, however, is the potential for local
distortion effects, e.g., due to air–tissue interfaces, which
may cause displacements of 1–2 mm over very short dis-
tances from the interface (<1 cm) [6].
Radiologic and Anatomic Considerations
During Treatment Planning
The goal of SRS is not only to give a maximal dose of focal
radiation to the target but also to prevent injury to the sur-
rounding normal tissue. Both tumor size and proximity to
surrounding structures need to be taken into consideration
during treatment planning.
Tumor size dictates the feasibility of radiosurgery.
Increasing tumor size results in an exponential increase in
the margin of normal brain tissue irradiated and is potentially
associated with a higher risk of complications. Results from
J. Zhou et al.
the RTOG 9005 trial showed significantly higher CNS toxic-
ity in patients with larger tumor diameters [7]. Tumors with
diameters between 2.1 and 3 cm have a 7.3-fold increased
risk of developing toxicity over tumors with diameters of
2 cm or less. Tumors between 3.1 and 4 cm had a 16-fold
increased risk. In general, SRS is recommended for tumors
less than 4 cm in size [7].
The safety of SRS and the rates of post–treatment com-
plication can also vary based on the location of the tumor
relative to the surrounding cerebral structures. In a review
by Flickinger et al., the rate of symptomatic radiation
necrosis was highest (threefold increased risk) for arterio-
venous malformation (AVM) lesions in the basal ganglia
and the brainstem (pons, midbrain, medulla) [8]. In con-
trast, the risk of radiation injury remained low (even with
increased volumes) for lesions irradiated in the frontal and
temporal lobes.
Similarly, the proximity of critical neuroanatomic struc-
tures to the targeted area is important to consider during SRS
planning. Relative contraindications for SRS include close
proximity or involvement of the optic tract including the optic
nerves and chiasm. The optic apparatus dose is generally lim-
ited to 10 Gy to limit the risk of optic neuropathy [9, 10].
In contrast, the remaining cranial nerves have somewhat
higher dose tolerances [11, 12].
Physiologic MR Imaging and Metabolic
PET Imaging in SRS
Physiologic MR and metabolic PET imaging can add to
information obtained by morphological imaging and serve as
a surrogate marker for specific biologic processes. These
imaging techniques permit in vivo analysis of tumor tissue
properties including chemical composition, tumor vasculature,
perfusion, and tumor cellularity [13].
2 Imaging Techniques in Stereotactic Radiosurgery
Assessing tumor response after SRS can be difficult due
to occurrence of early nonspecific imaging changes that can
represent either recurrent or progressive tumor, or treatment-
related inflammatory and/or necrotic changes such as areas
of contrast enhancement and edema on T1-weighted imag-
ing. Underlying processes of radiation injury cause a tempo-
rary increase in contrast enhancement on MRI, termed
“pseudoprogression,” making the differentiation between
true progression and radiation effects extremely difficult.
Mechanisms that may contribute to radiation-induced neuro-
toxicity include vascular injury, glial and white matter
changes, and immunological mechanisms.
Advanced MR imaging techniques are now becoming
routinely available and will continue to play an increasingly
important role in aiding in the precise definition of at risk
target volumes as well as the assessment of treatment
response [14–16]. In this section, a brief overview of these
imaging techniques will be described.
Dynamic Susceptibility Contrast MRI
Dynamic susceptibility contrast (DSC) T2*-weighted imag-
ing is the preferred method to map whole-brain perfusion
properties [17–19]. Dynamic acquisition of T2*-weighted
MR imaging during intravenous injection of Gd-DTPA
allows estimations of cerebral (tumor) blood volume (CBV),
cerebral (tumor) blood flow (CBF), and mean bolus transit
time (MTT). These parameters can be measured in the
imaged volume by mathematical deconvolution of the arte-
rial input function (from a cerebral artery) and the tissue
response signal. These perfusion parameters provide assess-
ment of tumor viability, tumor vascular properties, and trans-
port kinetics following therapy [13]. Several studies have
shown a correlation between cerebral blood volume and the
histological grade of the tumor [20, 21].
Dynamic Contrast-Enhanced MRI
Dynamic contrast-enhanced (DCE), MR imaging using
T1-weighted imaging provides a method for quantitative
assessment of tumor vascular permeability. DCE MRI is
obtained following dynamic acquisition over several minutes
during intravenous injection of a bolus of Gd-GTPA.
Estimations of vascular permeability with DCE MRI require
the application of pharmacokinetic models with an arterial
input function and therefore are more complex than CBV
estimation. DCE MRI has been shown to be important in
assessment of treatment response following both anti-angio-
genic agents and radiation [22].
13
MR Spectroscopy Imaging
MR spectroscopy is a technique to detect proton metabolites
in tissue, in vivo. This imaging technique provides informa-
tion regarding tumor proliferation, cell membrane break-
down, neuronal activity, and tumor necrosis [15, 23]. Most
commonly detected metabolites include choline-containing
compounds, creatine, lactate, lipid, and N-acetylaspartate.
Spectroscopic images are obtained with either two-
dimensional or three-dimensional means of acquisition. This
is achieved by mapping the concentration of each of the
compounds within voxel sizes of approximately 1 cm3.
Malignant tumors are characterized by an elevated choline to
N-acetyl aspartate (NAA) ratio due to greater cell membrane
phospholipid turnover from increased tumor proliferation as
well as decreased NAA compared to the normal brain [24,
25]. Several studies have demonstrated the utility of MR
spectroscopy in pretreatment evaluation and radiotherapy
planning as well as in differentiating radiation necrosis from
recurrent tumor [26–28].
MR Diffusion and Diffusion Tensor Imaging
Diffusion MRI measures the mobility of water within tissues
at the cellular level and therefore can detect microenviron-
ment changes in tumor tissue. Changes in diffusion can occur
due to cell swelling, necrotic/apoptotic cell death after ther-
apy, or extracellular water space changes as a result of edema
[29]. Changes in tumor such as cytolytic cell death following
successful therapy lead to transient increases in regional dif-
fusion, which may be an important early indicator of treat-
ment response. The extent of directional diffusion can be
estimated with an apparent diffusion coefficient (ADC).
Diffusion has traditionally been analyzed using average
ADC values throughout an entire tumor, which can signifi-
cantly underestimate regional changes following therapy
[30]. The parametric response map (PRMADC) has been
developed as a voxel-wise approach for evaluating ADC
changes and has been found to be an independent, early pre-
dictor of overall survival [31]. ADC maps are largely inde-
pendent of the MRI system, vendor, and field strength.
Therefore, it provides an accurate and noninvasive method of
performing longitudinal studies [32].
Diffusion tensor imaging (DTI) is a diffusion technique
that allows visualization of white matter architecture and has
been increasingly investigated as an imaging biomarker for
detecting physiological changes prior to any changes on con-
ventional imaging [33]. Previous studies have suggested that
changes in diffusion index of normal appearing brain white
14
Fig. 2.2 (a) MR diffusion tensor imaging and tractography illus-
trating a right parietal–occipital mass and the bilateral corticospi-
nal tracts. Peritumoral edema appears to infiltrate and displace the
posterior and superior part of the right corticospinal tract compared
to the left. (b) Quantitative DTI analyses were performed on spe-
cific white matter structures including the posterior cingulate, for-
nix, and corpus callosum. Fractional anisotropy (FA) values in the
matter structures following radiation may also be an indica-
tor for delayed radiation-induced neurotoxicity [34]. These
studies examined changes in diffusion indices including
fractional anisotropy (FA) as an index of fiber integrity, mean
diffusivity (MD) as an index of overall diffusivity, radial dif-
fusivity (RD) as an index of demyelination, and axial diffu-
sivity (AD) as an index of fiber degradation [35]. Surgical
series have demonstrated the utility of DTI in reducing the
risk of morbidity of brain tumor resections near critical
structures. Similar incorporation of DTI tractography imag-
ing in SRS may be valuable with regards to delineation of
normal tissue avoidance structures in treatment planning for
lesions near eloquent regions (Fig. 2.2) [36]. Incorporation
of tractography data in SRS treatment planning has been
shown in studies to lead to decreased dose to critical struc-
tures including the optic tract and pyramidal tracts [37].
Metabolic PET Imaging
With a number of tracer compounds available, PET and
SPECT allow for noninvasive measurements of tumor
hypoxia, proliferation index, and markers of apoptosis [38,
39]. The cellular and physiological information obtained
may be used in combination with MR imaging, which still
has relatively superior spatial resolution, to improve target
volume definition in radiotherapy planning [40].
11C Methionine (MET)-PET visualizes increased radio-
tracer uptake by metabolically active tumor. It is able to detect
increased cellular metabolism in brain tumors involving
J. Zhou et al.
cingulum and fornix show significant decreases compared to the
corpus callosum 1 month following radiation, suggesting increased
radiation sensitivity. Preliminary data showing a correlation
between early diffusivity changes and late decline in verbal recall
suggest that DTI imaging may be a useful biomarker for late CNS
toxicity [34]. Means and standard errors of the percentage decrease
in FA 1 month post-RT are plotted
increased protein transport mediated by L-type amino acid
carriers at the blood–brain barrier level compared with
normal brain tissue [41]. It is able to better differentiate
tumor from background brain signals than 18F-labeled
2-fluoro-2-deoxy-D-glucose (FDG)-PET, which is more dif-
ficult to interpret due to the high level of intrinsic glucose
uptake in the brain.
18F-fluorothymidine (FLT)-PET uses the alternative
tracer FLT, which is a thymidine analogue that is incorporated
exclusively into DNA. This allows measurement of the activ-
ity of cellular thymidine kinase, which increases several folds
as cells enter the S phase and begin DNA synthesis. Therefore,
increased FLT uptake is a direct measure of cellular prolifera-
tion rate and correlates with Ki-67 staining [42].
Imaging Consideration in the SRS
Treatment of Malignant Tumors
Brain Metastases
Whole-brain radiotherapy has been the mainstay of treat-
ment of brain metastasis. However, there has been a recent
shift toward greater use of stereotactic radiosurgery in
patients with a limited number of brain metastases and with
controlled systemic disease in order to increase dose to
tumor and minimize neurocognitive morbidity [43].
SRS target volume definition for brain metastasis is typi-
cally accomplished using conventional thin-cut CT or
T1-weighted MR imaging with contrast enhancement.
2 Imaging Techniques in Stereotactic Radiosurgery
Studies have reported on improved outcomes with the
addition of a 1–2 mm margin to account for microscopic dis-
ease in the SRS treatment of brain metastases [44, 45]. The
additional margin may be necessary to account for possible
infiltrative tumor growth beyond the enhancing border as
well as the limited accuracy of delineation of the enhancing
border based on current imaging methods. A study by
Baumert et al. evaluated specimens from 76 metastatic brain
lesions and found that 63 % of the specimens showed tumor
infiltration beyond the metastases boundary, with small-cell
lung cancer and melanoma showing a maximum depth of
infiltration of >1 mm and other histologies <1 mm [45].
Non-small cell lung cancer, melanoma, and sarcoma also
showed the most number of infiltration zones outside the
boundary. Another study by Noel et al. found that the addi-
tion of a 1 mm margin on MRI to account for microscopic
disease extension for brain metastases improved the 2-year
local control rate from 51 to 90 % [44].
SRS is also frequently used as adjuvant treatment to max-
imize local control following surgical resection, with
reported control rates of approximately 80 % [46]. In plan-
ning treatment in the adjuvant setting, one also needs to take
into consideration changes in the size of the surgical cavity
when delineating the target volume. In a study by Atalar
et al. on 68 lesions, the postresection cavity volume was
smaller than the preresection tumor volume by a median
percent volume change of 29 % [47]. The authors found that
the greatest volume change occurred immediately after sur-
gery during postoperative days 0–3, with no significant
change occurring up to 33 days after surgery. Thus, there
may not be a benefit to an extended waiting period prior to
proceeding with SRS. A planning margin for microscopic
extension has also been shown to improve control in the
adjuvant setting. A study by Soltys et al. analyzed 76 resec-
tion cavities that were treated with radiosurgery [48]. Less
conformal treatment plans with a 2.4 mm margin of brain
tissue around the cavity had a 100 % local control rate, com-
pared with 78 % for a 1.7 mm margin, 52 % for 1.5 mm, and
43 % for 0.8 mm. Toxicity was minimal and therefore the
inclusion of a 2 mm margin to improve local control was
recommended.
Assessment of Treatment Response
Novel imaging techniques in addition to conventional
contrast-enhanced MRI are now more frequently used to
assess brain metastasis response following radiosurgery.
MR diffusion imaging has been used in the evaluation of
SRS treatment response (Fig. 2.3). Several studies have
noted that longitudinal ADC values may be important in
predicting early tumor response to SRS treatment. In a
prospective study by Huang et al., 21 patients with 32 brain
metastases were analyzed. ADCs were measured both prior
15
and following SRS [49]. ADC values for the group showing
radiation-induced central necrosis was significantly higher
than those demonstrating recurrent tumor growth. Similar
results were noted in a prospective trial of 38 patients treated
with gamma knife radiosurgery for brain metastases with
significant increases in mean ADC values indicative of stable
disease and unchanged ADC levels indicative of tumor recur-
rence [50]. The changes in ADC occurred before any defini-
tive change in volume were evident on further imaging
studies. In another study, posttreatment ADC patterns com-
pared with initial diffusion imaging were used to predict ulti-
mate treatment outcomes on serial MR imaging in 25
metastatic tumors [51]. The authors found that the normal-
ized ADC patterns outperformed initial posttreatment tumor
volume in predicting long-term response to treatment.
At the University of Michigan, alterations in vascular vol-
ume and permeability in brain metastases, as measured using
dynamic contrast-enhanced MRI hve been analyzed to pre-
dict subsequent volumetric response following radiation. In
a recent prospective study that evaluated 43 lesions from 20
patients, results showed that the percentage decrease in the
high-CBV-defined subvolumes of the tumor was greater in
the group of responsive tumors than in the group of stable
and progressive tumors (P < 0.007). Perfusion changes were
a significantly better predictor for post-RT response than
changes in the gross tumor volume observed during the same
time interval (P = 0.012), suggesting that physiological
changes occur prior to volumetric changes [52].
PET imaging, including FDG PET, has also been evaluated
for differentiating between recurrence and posttreatment
changes. Studies have shown that areas of radiation injury have
lower glucose metabolism than normal brain tissue due to
lower cellular attenuation [53]. Varying degrees of accuracy of
FDG-PET in detecting tumor recurrence versus radiation
necrosis have been reported. Several retrospective analyses
have shown sensitivity in detection of tumor recurrence
ranging from 80 to 100 % and specificity higher than 80 %;
however, these studies lacked histopathological validation [54, 55].
In a study of 15 patients with a histopathologically confirmed
diagnosis, Thompson et al. showed that FDG-PET was
sufficiently sensitive to differentiate recurrent tumor from
radiation effect in only 43 % of the cases and was least accurate
when the lesion volume was less than 6 cm3 [56].
MET–PET may provide a better method for differentiating
radiation necrosis from recurrent tumor. In 21 patients with
suspected recurrent metastatic brain tumor or radiation
injury, MET-PET scans showed a sensitivity of 78 % and
specificity of 100 % in detecting tumor recurrence [57]. In
another study of 77 patients, a mean SUV ratio of lesion
uptake to contralateral normal gray matter uptake of greater
than 1.41 provided the best sensitivity (79 %) and specificity
(75 %) for metastatic brain tumor and a value of greater than
1.58 provided the best sensitivity (75 %) and specificity
(75 %) for recurrent glioma [58].
16
Fig. 2.3 (a) T1-weighted images (right), ADC map (middle), and
perfusion map (left) are shown at baseline prior to SRS for a right
parietal brain metastases (top row) and 1 month post SRS treatment
(bottom row). Qualitatively, there are significant decreases noted in
tumor volume, diffusion, and perfusion 1 month after treatment. (b)
Mean ADC histogram analyses performed for the normal tissue
Recurrent Gliomas
SRS has been increasingly used as a potential treatment
option for recurrent gliomas in combination with anti-
angiogenic agents following an initial course of standard
fractionation of RT in combination [59].
Novel imaging techniques can be utilized in treatment plan-
ning, especially in cases where there is no tissue confirmation
of recurrent disease (Fig. 2.4). MR spectroscopy has been
J. Zhou et al.
(green), a region of interest corresponding to a brain metastases at
baseline (blue) and 2 weeks after SRS (red ). Quantitative ADC his-
togram analysis demonstrate the fractional tumor subvolume with
low ADC appeared to increase 2 weeks after SRS consistent with a
nonresponsive or progressive tumor confirmed on subsequent fol-
low-up imaging at 4 months
shown to potentially improve target delineation. Areas of con-
trast enhancement on T1-weighted conventional MRI do not
always correspond to the most aggressive areas as reflected by
high choline concentration. The extent of elevated choline has
been found beyond the tumor volume defined by Gd enhance-
ment or hyperintense lesions on T2-weighted or FLAIR
images [60, 61]. Several studies have suggested that elevated
choline peaks correlate with higher tumor grade. In a study of
247 tissue specimens from 31 untreated patients with low- or
2 Imaging Techniques in Stereotactic Radiosurgery
Fig. 2.4 Multimodality MR imaging for target volume definition for a
left temporal glioblastoma. T1 post-gadolinium notes a contrast-enhancing
lesion (far left image) with significant peritumoral edema shown on MR
FLAIR imaging (second image from left). Perfusion map shows areas of
high CBV (red) extending beyond the contrast-enhancing tumor rim as
high-grade glioma, choline peak height normalized to contra-
lateral creatine and choline or ipsilateral NAA significantly
correlated with tumor cell density [62].
The degree of spatial overlap between tumor volumes with
elevated choline and the radiosurgical target volume has been
correlated with clinical outcome. A retrospective study in
patients with recurrent GBMs treated with SRS found an
improvement in survival if the target volume overlapped with
the pretreatment MR spectroscopy metabolic lesion by 50 %
or greater (median OS 15.7 versus 10.4 months, P < 0.01) [63].
Newer imaging techniques are also crucial in posttreat-
ment follow-up of recurrent gliomas as posttreatment
contrast-enhancing lesions often consist of a mixture of
tumor cells and tissue with radiation injury and therefore are
difficult to accurately differentiate noninvasively.
MR spectroscopy is one modality that is being increas-
ingly used to distinguish the two in the posttreatment set-
ting. However, there is currently no consensus in the
literature on which calculated ratios can best differentiate
tumor recurrence from radiation injury. One study of 100
tissue biopsy samples from 44 patients with grade 2-4 glio-
mas, a choline/NAA ratio cutoff threshold of 2.5, was able
to differentiate recurrent tumor from normal, edematous,
and necrotic brain tissue, with an approximate 90 % sensi-
tivity and 86 % specificity [64]. Another study showed the
ability to differentiate tumor recurrence from radiation
injury in 27 of 28 patients by using a cutoff value of 1.8 or
greater for the choline/NAA or choline/creatine ratio repre-
senting tumor recurrence [28].
MR perfusion imaging has also shown its utility in post
SRS treatment evaluation. One study prospectively evalu-
ated 42 image-guided tissue specimens from 13 patients
with high-grade glioma using threshold relative CBV val-
ues to distinguish recurrent tumor from radiation changes
[65]. The authors found that the treatment-related group
17
defined by T1 post-gad (third image from left). This shows the potential
for perfusion MRI to identify aggressive subvolumes in gliomas [11]. C
MET PET (far right image) also provides additional information for tar-
get volume definition compared with conventional MR regarding tumor
extension along the white matter tract
had relative CBV values from 0.21 to 0.71, while the recur-
rent tumor group had CBV values from 0.55 to 4.64. A
threshold value of 0.71 therefore optimized differentiation
between the two groups with a sensitivity of 91.7 % and
specificity of 100 %.
Imaging Considerations in the SRS
Treatment of Benign Lesions
Acoustic Neuroma (Vestibular Schwannomas)
Acoustic neuromas are benign neoplasms derived from
Schwann cells of the myelin sheath that show a predilection
for involvement of sensory nerves. Acoustic neuromas
account for approximately 5–8 % of intracranial tumors and
80–90 % of cerebellopontine angle tumors. Retrospective
data have shown excellent tumor control rates with stereotac-
tic radiosurgery [66]. A University of Pittsburgh study of 216
patients with unilateral acoustic neuromas treated with
Gamma knife (marginal tumor dose of 12–13 Gy) showed a
10 year resection-free control rate of 98.3 %, low toxicity
with good rates of hearing preservation (Robertson–Gardner
serviceable hearing 45 %), and high preservation rates of tri-
geminal and facial nerve function [67].
Contrast-enhanced MRI is used to evaluate treatment
response. Following SRS treatment, clinical data suggest that
acoustic neuromas may temporarily expand in size initially and
then stabilize. Thus, a longer period of follow-up is required
before determining disease progression. A retrospective review
of 75 patients showed that 23 % had evidence of pseudopro-
gression with onset of enlargement at 6 months, of which 9 %
remained larger than initial volume at last follow-up. No fur-
ther progression was seen beyond 24 months for all patients
[68]. Another study involving 87 patients showed that peak
18
tumor volume expansion was observed at 8.6 months after SRS
[69]. At 5 years follow-up, the mean reduction in tumor volume
was 31 %. However, there were still 10 % of tumors that
remained larger than their initial volume.
Considering the potential for pseudoprogression, follow-
up recommendations include posttreatment MR imaging to
establish a baseline and at 24 months, followed by yearly
imaging. In general, salvage therapy is not recommended
before 2 years unless there is clinical deterioration.
Hydrocephalus can also be seen on follow-up imaging, a
potential complication following SRS treatment of acoustic
neuromas. In a retrospective review of 444 patients treated
with radiosurgery, symptomatic communicating hydroceph-
alus developed in 5.6 % of patients, with a median time to
symptom development of 7 months [70]. Patient monitoring
for development of hydrocephalus is recommended follow-
ing SRS treatment for up to 3–4 years.
Trigeminal Neuralgia
Trigeminal neuralgia is a painful syndrome resulting in
intense and often severe episodes of lancinating pain occur-
ring in the distribution of cranial nerve V. Although benign,
trigeminal neuralgia can significantly diminish a patients’
quality of life. Common treatment options include antiepi-
leptics, neuroleptics, opioids, and antidepressant medications.
When medication fails to alleviate the effects of trigeminal
neuralgia, available treatments include microvascular surgi-
cal decompression, ablation, and SRS. SRS has been highly
successful in pain control, with excellent response in
70–90 % of patients [71]. In a prospective clinical trial, 100
patients were treated with Gamma Knife radiosurgery to a
median dose of 85 Gy [72]. Of the total, 83% of the patients
were pain free at a minimum follow-up time of 12 months
and 70 % had stopped taking medications during the study.
Post treatment complications were minimal, with facial par-
esthesia in 6 % and hypesthesia in 4 %.
MRI is of paramount importance for the accurate planning
of SRS treatment of trigeminal neuralgia. Studies have
shown relatively limited use of imaging in predicting effec-
tive treatment outcome because the evidence of treatment
benefit or treatment failure is most often readily apparent
before enhancement occurs. Posttreatment follow-up with
contrast-enhanced MRI taken at 6 months can provide for
target confirmation due to the high prevalence of contrast
enhancement. The posttreatment imaging characteristics of
trigeminal neuralgia were assessed by Massager et al., who
reported that at 6 months post-treatment, contrast enhance-
ment on T1-weighted MRI was seen in 83 % of trigeminal
nerve roots [73]. However, they found no correlation between
the occurrence of focal enhancement of the nerve root and
pain outcome, or development of trigeminal dysfunction.
Repeated serial imaging is generally not considered helpful
J. Zhou et al.
in those patients who did not initially present with radiologic
or neurologic changes on the initial posttreatment scan. Nor
is serial repeat imaging recommended for those patients who
respond well clinically unless neurological deficits emerge.
Imaging may be used for the assessment of potential
radiation-related injury to the brainstem.
Arteriovenous Malformations
Arteriovenous malformations (AVMs) are abnormal commu-
nications between arteries and veins, usually associated with
high blood flow that results in blood vessel remodeling. The
incidence of AVMs is approximately 0.01–0.1 %, and present-
ing symptoms include hemorrhage, seizure, and headaches.
The average annual risk of bleeding is 2–3 %, with a slightly
higher risk if there is a prior history of bleed (2–6 %) and
slightly lower risk if no prior bleed (1–3 %) [74]. AVMs are
graded based on the Spetzler–Martin scale, which reflects the
size and venous drainage, as well as eloquence of the adjacent
brain. Current treatment options include surgery, with opera-
bility depending on AVM location, embolization, and SRS.
Following SRS, clinical studies show obliteration rates of
60–90 % [75, 76]. In one study, 351 patients were treated to
a median dose of 20 Gy, and the rate of obliteration was
73 % by angiography, 86 % by MR alone, and 75 % overall
[77]. A persistent out-of-field nidus was seen in 18 % of pre-
viously embolized and 5 % of nonembolized pts. Data on
larger AVMs show decreasing obliteration and higher com-
plication rates with increasing volume.
Although SRS is noninvasive, one disadvantage of SRS
compared with surgery is the potential for continued risk of
hemorrhage in the 1–3 years after treatment. A retrospective
observational study of 500 patients on the rates of hemorrhage
showed that, compared with the period between diagnosis
and radiosurgery, the risk of hemorrhage decreased by 54 %
during a median latency period of 2 years from treatment to
angiographic evidence of obliteration and by 88 % after
angiographic obliteration [78].
Cerebral Angiography
Cerebral angiography has been the gold standard in the initial
diagnosis and evaluation of AVMs, as part of radiosurgery
treatment planning, and in posttreatment residual AVM moni-
toring [79, 80]. It is a dynamic, real-time study that shows not
only the presence or absence of an AVM but also the vascular
transit time. It provides superior spatial resolution without
overlap of adjacent vascular structures as would be seen on CT
or MRI. The image acquisition on cerebral angiography is
rapid and enables delineation of the arterial and venous phases
of the circulation, which allows better visualization of the
AVM nidus and its shunt components. The potential complica-
tions of the invasive procedure include stroke, arterial dissec-
tion, and reactions to the contrast agent.
2 Imaging Techniques in Stereotactic Radiosurgery 19

Fig. 2.5 (a) University of

Michigan Hybrid CT and biplane
digital subtraction angiography
(DSA) suite; (b) Intra-arterial CT
angiography showing the nidus
of a right-sided basal ganglia
AVM in both the axial (left
image) and coronal plane (right
image). (c) Deep venous drainage
is noted by the white arrow in the
coronal plane (right image)

Even though angiography is useful as a diagnostic tool in
defining the nidus, feeding arteries and draining veins, it is
limited in its use for radiosurgery treatment planning pur-
poses because of its 2D dataset. This can lead to both over-
and underestimation of the AVM nidus in the target volume
[81]. Alternate approaches include obtaining either intrave-
nous CTA or MRI angiography to provide a 3D view of
the nidus [82]. Most recently, hybrid biplane angiography
and CT-on-rails suites have been developed for the safe
placement of endovascular catheters and subsequent capture
of cross-sectional vascular imaging with an intra-arterial
CTA technique [83]. Together, the high spatial and temporal
resolution of biplane angiography can be combined with the
relatively high-contrast soft tissue resolution of CT imaging.
Small cerebral AVMs are often not readily seen on IV-CTA
or MRA and instead may require high-resolution intra-
arterial CTA images that may provide better target volume
delineation for SRS treatment planning (Fig. 2.5).
20
AVM Radiosurgery Treatment Planning
The primary goal of AVM radiosurgery is to develop a plan
with a target volume that conforms closely to the surface of
the AVM nidus while maintaining a steep dose gradient to
minimize the radiation dose to the surrounding brain. More
recently, tractography has been used in the AVM setting to
identify better accuracy areas at risk in the brain that can
cause patient morbidity if compromised [84]. A prospective
study by Koga et al. integrated tractography in 71 AVM
radiosurgery treatments where the tumor was less than
1 cm from fiber tracts including the pyramidal tract, optic
tract, and the arcuate fasciculus. Morbidity as a result of
treatment was minimized, with only one patient experienc-
ing permanent and one experiencing transient pyramidal
tract dysfunction [85].
Post AVM Follow-Up Imaging
MR perfusion imaging has been used to assess response fol-
lowing SRS. In a study by Guo et al., perfusion relative cere-
bral blood volume (rCBV) and cerebral blood flow (rCBF)
maps were assessed in 19 patients before and after radiosur-
gery [86]. Prior to treatment, the ratio of rCBV and rCBF of
the ipsilateral hemisphere to the unaffected hemisphere was
found to be significantly higher in patients with AVM than
those of healthy patients, consistent with a cerebral steal
phenomenon. After treatment, starting at 6 months follow-
up, the ratio of rCBV and rCBF of the AVM nidus to normal
brain gradually decreased to 1.0. Decrease was also seen in
the hemispheric perfusion ratios, reflecting reversal of steal
toward normal perfusion.
Currently, the standard for posttreatment follow-up of
AVMs is MRI every year with cerebral angiography for con-
firmation of obliteration of the nidus. An angiographic cure
requires that no nidus or shunting is identified on the follow-
up imaging study.
Conclusion
Novel functional and metabolic MRI and PET imaging pro-
vides the ability to analyze tumor tissue properties including
chemical composition, vasculature and perfusion, water
mobility, permeability, hypoxia, and tumor proliferation.
These imaging modalities have the potential to improve
radiosurgery treatment planning and posttreatment monitor-
ing, including evaluation of differences in treatment efficacy
between patients and heterogeneity of response within
tumors. Further investigation in randomized studies is war-
ranted to better integrate these imaging techniques into rou-
tine clinical practice.
J. Zhou et al.
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 Techniques of Stereotactic
Localization
Victor C.K. Tse, M. Yashar S. Kalani, and John R. Adler
The word stereotactic stems from the Greek words solid and
arrangement or to order. It describes the ability to locate the
target in a defined three-dimensional space using an estab-
lished coordinate system. Its application to neurosurgery is
credited to Horsley and Clarke at the turn of the twentieth
century [1], but historically, it has been noted that the idea of
using anatomical landmarks as reference points to describe
the locations of deep brain structures precedes Horsley and
Clarke (Fig. 3.1).
History of Stereotaxis
The development of sterotactic localization parallels those of
brain imaging, but the earliest applications of stereotaxis
predate the advent of imaging modalities. Dittmar in 1873
describes a study of the medulla oblongata of cat using a
device to read off the distance from fixed dependable surface
anatomical landmark. Zernov in Russia used a similar
approach in 1890 to locate deep structures in humans [2].
The L’encephalometer was a relatively simple device
anchored onto the meridian of the human skull; it used the
polar coordinate and arc-based angulation system to mark
the trajectory to the designated structures of the brain.
In 1889, it was used to locate the central sulcus of the human
brain for the aspiration of an abscess [3]. Ultimately, its con-
tribution to neurosurgery was overshadowed by the work of
Horsely and Clarke.
Not unlike Zenov’s device, Horsely’s device was
also anchored onto the skull by using a pair of ear bars.
V.C.K. Tse, M.D., Ph.D. (*)
Kaiser Permanente Medical Group, Redwood City, CA, USA
e-mail: Tsevictor@gmail.com
M.Y.S. Kalani, M.D., Ph.D.
Division of Neurological Surgery, Barrow Neurological Institute,
St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA
J.R. Adler, M.D.
Neurosurgery, Stanford University and Chief of New Clinical
Applications at Varian Medical Systems, Stanford, CA, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_3, © Springer Science+Business Media New York 2015
3
The innovation of their device was having a separate base
frame and a headpiece. The base frame fixed onto the skull
rigidly and established the horizontal planes along Reid’s
line, thus allowing the coordinates to be read along the infra-
orbital border to the external auditory meatus. The headpiece
was then incorporated perpendicular onto the basal frame to
adjust the vertical plane. The headpiece carried a micro-
manipulator that was perpendicular to the frame. It was
through this micro-manipulator that the aspiration needle
and stimulating electrode were placed into the deep structure
of the brain. The Horsely–Clarke system was based primar-
ily on a set of predictable measurements available to them
that address the location of deep brain structures in reference
to calvarial landmarks.
In the early part of the 1900s, most stereotatic localization
in clinical use was based on modifications of the Horsley–
Clarke frame with calvarial anatomical landmarks [4]. Later,
several key technical developments, including the introduc-
tion of X-rays, ventriculography, and cerebral angiography,
changed the course of stereotactic localization.
The introduction of the pneumoventriculogram (first
described by Dandy) with air as the contrast agent allowed
Spiegel and Wycis to use intraventricular landmarks to cali-
brate the stereotactic frame [5]. They established the use of
the posterior commissure, the infra-aural plane, and the
Frankfurt line (a straight horizontal line from the top of the
external auditory meatus to the inferior border of the orbit
along either side of the human skull) as reference points.
This approach led to several modifications and refinements
of the published atlas for stereotactic localization. By the
late 1950s, the inter-commissural line joining the anterior
commissure to the posterior commissure (as introduced by
Talairach) was the de facto reference point in defining deep
structures in the brain [6] (Fig. 3.2). The internal structures
of the brain especially those surrounding the ventricles
could be located with a high degree of certainty by reading
off the coordinates from a grid and its companion atlas and
adjusted for the magnification of the X-ray taken during
pneumoencephalography.
25
26
Fig. 3.1 The progression in stereotactic localization from 1906 to the
modern time. (a) A replicate of the horsely and clarke frame (open
source from Google images). (b) A modern leskell frame (image used
with permission from Elekta). (c, d) A frameless system used in the
In the 1930s, visualization of intracranial structures by
X-ray and pneumoencephalography was limited in part by to
poor discrimination of brain tissue density and the over-
shadow effect caused by superimposed structures. Ziedes
Des Plantes suggested that one could eliminate superim-
posed shadows if a single plane was visualized at any one
time. He proposed to move the X-ray source and the detec-
tion plate simultaneously at a fixed distance. This blurred all
images casted by tissue anterior and posterior to the plan of
interest. This proposal led to the principle of tomography
and provided a mean of validating stereotactic localization of
deep structures.
V.C.K. Tse et al.
operating room where the reference fiducial system is attached to the
head-rest and surface anatomical landmarks are co-registered with the
preoperative CT and MRI fused images, thus allowing real-time navi-
gation and target localization
Image-Guided Stereotactic Localization
In 1947, Lars Leksell introduced the arc-based stereotactic
frame, which bears his name and continues to be used today.
The Leksell frame consists of a base frame and a mobile
arc-quadrant headpiece. This design enables the operator to
put the desired target at the arc center and allows the target to
be accessed at various angles. The ability to use the target
center and triangulation fundamentally altered the approach
to localize lesions in the intracranial cavity. Leskell coupled
an X-ray tube to the sterotactic frame so that the trajectory of
3 Techniques of Stereotactic Localization
Fig. 3.2 The incorporation of
ventriculogram in stereotactic
functional neurosurgery. The
AC–PC remains the classical
landmark used by surgeons of
today as it was the de facto
reference point in defining deep
structures in the brain in the days
of Talairach. (Used by
permission by Mark Sedrak, MD)
a treatment probe could be more readily and safely identi-
fied. Extrapolating from his early concept Leksell would
eventually imagine the idea of using a collimated radiation
source instead of a physical probe to allow isocentric target-
centered radiotherapy. By observing this evolution in stereo-
taxy it is clear to see how development of the Leksell frame
eventually resulted in the development of the field of stereo-
tactic radiosurgery [7].
In the early 1960s, Oldendorf elaborated on the tomogra-
phy technique by rotating a radiation source and detector
around an axis in a constant linear manner, to differentiate
tissue density by its radiation absorption. Theoretically, tis-
sue at the point of intersection would have constant radiation
absorption, whereas all other tissues in that plane had vari-
able radiation absorption [8]. Cormack in 1963, used Fourier
transformation and backprojection to provide a mathemati-
cal solution and reconstruct the cross-section of radiographic
images by recapitulating the sum of the radiodensities as line
27
integrals along an X-ray beam path [9]. This laid the ground-
work for the development of CT imaging, which was readily
incorporated into stereotactic localization.
In 1967 Hounsfield envisaged a computational solution to
reconstructing images based on photon transmission when
X-rays were taken in all possible directions around an object
while it was translating along an axis. He deduced that if
X-rays were taken in all directions around an object, when
the data were represented as a series of slices, a mathemati-
cal model based on Fourier transformation could be used to
differentiate the radiodensity of tissue within each individual
slice. Furthermore, in knowing topographical map of the
radiodensity distribution he could regenerate images of
structures within that slice. From this basic concept com-
puted tomography was born. With the support of EMI Inc.,
Hounsfield was successful in building the first CT machine.
Stereotactic surgery in its early years mainly relied on
ventriculocisternography to localize internal structures for
28
Fig. 3.3 The use of a N-localizer (a) to translate two-dimensional coordinates into three-dimensional reference points in the CT images (b).
(c) The localization of the target can then be checked against a phantom base
lesioning, but by the late 1970s, target localization in stereo-
tactic surgery was mainly done by CT imaging. A localizing
plate with vertical fiducial posts filled with radio-opaque
material was fixed to the base of the stereotactic frame. These
posts essentially formed a picket fence around the perimeter
of the stereotactic frame while the patient was being imaged.
The positions of the posts were read as the x–y coordinates in
the CT images and used as reference points. The location of
the target was then triangulated. By late 1970s, the accuracy
of target localization was greatly improved through the inno-
vation of Russell Brown who added a diagonal bar across the
two picket posts to generate an N-localizer. This ingenious
design simplified the conversion of the two-dimensional
coordinates into three-dimensional reference points in the
CT images (Fig. 3.3). The N-localizer allows the colocaliza-
tion of the desired target in both CT and MRI images, and
improves the accuracy of multimodal image fusion. In the
1980s the N-localizer was universally adapted and was
incorporated into the design of the Leskell frame for stereo-
tactic radiosurgery [10–12].
From Frame-Based to Frameless System
As the speed and the computation power of modern com-
puters increased, stereotactic localization started to shift
from a frame-based to “frameless” technology. The
Cartesian coordinate system of computerized volumetric
imaging (initially CT and subsequently MRI) enabled
ready determination of target position within the cranium.
By using common points of reference, the position of this
same head could be accurately determined within the three-
dimensional space of operative tools, thereby making it
possible to perform precision procedures without using rig-
idly attached external frames.
V.C.K. Tse et al.
To facilitate the digitization of surgical space, a series of
externally visible fiducial markers would be attached to dis-
crete skin and scalp locations prior to the acquisition of plan-
ning imaging studies. Upon completing presurgical head
immobilization, most typically in a Mayfield headrest, these
same fiducials could be spatially registered and even tracked
using any number of three-dimensional digitizing devices.
The earliest digitizer used for frameless stereotactic localiza-
tion, was a mechanical arm (wand) consisting of a series of
optically encoded joints that could be read by a computer. By
computationally determining the three-dimensional position
of the scalp fiducials, the digitizer enabled the entire head to
be registered within three-dimensional operative space.
When during actual surgery, calibrated tools were attached to
the same mechanical arm surgeons were able for the first
time to “navigate” through a patient’s anatomy by using the
planning CT (and eventually MRI) as a map, thereby
enabling the emergence of “image-guided surgery.” Over
time further advances in three dimensional digitization tech-
nology translated directly to improved tools for image guid-
ance. These new digitization technologies, each with their
own advantages and disadvantages, utilized acoustic, elec-
tromagnetic, and finally optical tracking concepts [13].
Digital Reconstruction Radiography
Stereotactic frameless radiosurgery is made possible by the
advancement of digital reconstruction radiography and
image fusion algorithms. The digitally reconstructed radio-
graphs (DRRs) are X-ray images mathematically synthe-
sized from the planning CT. DRRs are essentially a series of
ray-line re-constructions through a three-dimension volu-
metric CT data set. A planar transmission image is repro-
duced by ray tracing from the source through the relevant
3 Techniques of Stereotactic Localization
Fig. 3.4 The use of DRR in stereotactic localization: (a, b) The stimu-
lation CT with its selected alignment center is used to generate a pair of
DRR; (c, d): The fusion of two orthogonal X-ray projection images
taken by the tracking system in Cyberknife treatment room and co-
registered with the DRRs. This allows the target position in the three
adjacent CT slices to generate an effective transmission
value at each pixel on the image. DRRs can then be used to
compare to the portal films or their equivalent portal verifica-
tion images. In most stereotactic radiosurgery systems, the
frameless tracking systems use a similar set-up. A simulation
CT is taken according to the constraints of the radiosurgery
machine, an alignment center is selected by the operator
from the planning CT, and a set of DRRs is then generated.
In the treatment room, the target’s location (in reference to
the alignment center) is aligned to the imaging center of the
tracking X-ray source, which has a fixed center in the treat-
ment room. Two orthogonal X-ray projection images taken
by the tracking system are then registered with the DRRs.
The 2D X-ray images are fused with the DRRs, and an auto-
mated gradient correlation algorithm is used to calculate the
2D/3D correction vector that optimizes the translational and
rotational co-registration. This allows the target position in
the three translational and three rotational dimensions (6
degree of freedom) to be compared (Fig. 3.4).
29
translational and three rotational dimensions (6 degrees of freedom) to
be compared. A and C illustrate skull tracking for treating a patient with
trigeminal neuralgia; B and D illustrate spine tracking for treating a
lung lesion
Extracranial Stereotactic Localization
The application of extracranial localization in the nervous
system is generally applied to pathologies of the spinal col-
umn and spinal cord structures. These techniques are pre-
dominantly based on those techniques used in targeting
intracranial lesions. It is based on the premise that the
motion of the spinal cord is relatively small and one can use
the bony landmarks as surrogate marker in tracking the
motion of the cord. Spinal tracking can also be done by
implanting internal fiducials onto the spinous processes,
lamina, or pedicles. Extracranial radiosurgery is also known
as stereotactic body radiation therapy (SBRT), is being
increasingly used for the treatment of prostate, intrinsic
lung, and metastatic tumors. In extracranial stereotactic
localization, specific considerations for organ movement
and subtle movement caused by respiration must be made.
Motion not only makes localization of the target difficult, it
30
introduces an internal marginal error (the probability in both
spatial and temporal dimensions within which the target
may be located) and possibility of causing an error in dose
delivery. To overcome the geometrical uncertainty of target
localization caused by motion, one needs dynamic updating
of the spatial location of the target, the motion of the
patient’s body, and internal organs with respect to time [14].
In other words, one has to track the target in real time either
by following the movement of the target or by tracking some
moving structures that correlates with the movement of the
target. The other approach is to use movement information
to predict the position of the target or its surrogate at a par-
ticular point of a motion cycle such as the inspiration or
expiration motion cycle of the thorax (i.e., gating). In both
cases, this can be achieved by placing infrared reflective
markers onto the patient to allow real time tracking of the
target in reference to the position of the patient. Additionally
internal radio-opaque markers or bony structure can be used
as surrogate markers to tag the target in real time using
X-Ray or stereoscopic CT scanning system. The use of
markers and DRR has been shown to reduce error [15];
however, using bony structures as a surrogate marker runs
the risk of “marker migration” if the target and its reference
bony landmark can move independently to each other.
At the time of treatment planning, both markers are iden-
tified and registered with respect to the planning isocenter
for a chosen phase of motion (i.e., inspiration or expiration
phase of the respiratory cycle). Prior to treatment the patient
is positioned using infrared positioning system in the room
to align the treatment isocenter with the isocenter of the
machine. The motion of the patient is monitored and recorded
to generate a model of the motion cycle. The technician then
sets the acquisition time of the radiographic monitoring sys-
tem to correlate with the body motion and compare the real
time images to that of the DRR.
Immobilization and Target Tracking
Immobilization of the body helps to reduce motion and
increase accuracy. In targeting lesions in the head and neck
region this is commonly done using a facial fixation mask.
In extracranial tracking, devices such as conformal alpha
cradle, Vac-lock bag, and Memorial body cradle have been
used to achieve the same effect. The patient is fitted with
these devices during image acquisition in the planning CT
and during stereotactic radiosurgery treatment. The Memorial
body cradle has its own built-in external fiducial coordinate
system that can be visualized in the planning CT. However, a
built-in fiducial system in the immobiliizing device does not
necessarily improve accuracy.
More recently, the use of real-time “on-board” kilo-
voltage cone beam CT (CBCT) facilitates target localization.
V.C.K. Tse et al.
Unlike conventional CT, CBCT uses a cone-shaped rather
than a fan-shaped beam thus allowing the acquisition of a
three-dimensional image volume during a single rotation of
the X-ray source/detector tandem. These localization vol-
umes can be registered directly with the planning CT for bet-
ter visualization and matching of the target location.
Additionally, it allows one to use soft tissue anatomy and
landmark to track and correct target localization (Fig. 3.5).
To date, Megavoltage CBCT has poor soft tissue contrast
due to Compton scatter and detection efficiency is low result-
ing in high noise levels with high energy photon. In the
future, with advancement of megavoltage cone beam CT one
may even be able to do real-time tracking and correct target
localization in tandem with beam delivery during radiosur-
gery treatment.
The Future of Stereotactic Localization
Over the last generation the field of stereotaxy has evolved
from a small subdiscipline of neurosurgery used only in the
treatment of a handful of functional disorder, to a broad and
growing category of tools and techniques that now impacts
many areas of surgery outside the brain. Moreover, going
forward the ongoing revolution in minimally invasive sur-
gery, which by its nature requires the ever more precise map-
ping of patient anatomic space into operative space, will only
be fully realized by incorporating at increasingly deeper lev-
els all the principles of stereotaxy. Although the idea of using
real-time imaging as a substitute for stereotactic mapping in
open surgical procedures is seductive, e.g., intraoperative
MRI and CT, even here stereotaxy is useful because continu-
ous imaging and perfect patient immobilization prove impos-
sible. In the setting of noninvasive surgical procedures, such
as radiosurgery and high intensity focused ultrasound, the
need for stereotaxy is inescapable. As the importance of such
noninvasive procedures grows, we will see further utilization
of robotic tools to enable dynamic compensation for move-
ment. Meanwhile, other imaging modalities besides X-rays
and MRI can be turned into spatial localization “anatomic”
sensors such as ultrasound and perhaps near infrared. By not
requiring ionizing radiation this approach promises truly
continuous “real-time” “anatomic localization”. It is likely
more specialized tools will be developed to enable specific
clinical applications. As the frontiers of medicine advance
inexorably, and noninvasive procedures subsume nearly all
of surgery, stereotaxy is likely to lose nearly all resemblance
to the stereotactic head frames which introduced the notion
of precision targeted surgery a century ago. Nevertheless the
intrinsic stereotactic principles of organizing the operating
environment into a precisely calibrated three-dimensional
functional space will remain at the heart of such change.
3 Techniques of Stereotactic Localization 31

Fig. 3.5 The use of cone beam

CT in extracranial stereotactic
localization. (a) The stimulation
CT with its selected alignment
center is used to generate the
three-dimensions/volumetric
DRR. (b) The difference in the
bladder filling volume as imaged
by the cone beam CT. (c) The
fusion image from the
positioning cone beam CT and
the DRR using the Trilogy
system by Varian

2. Zernov DN. L´encephalometrie. Rev Gen Clin Ther. 1890;19:302.

References
1. Clarke RH, Horsley V. On a method of investigating the deep gan-
glia and tracts of the central nervous system (cerebellum). Br Med
J. 1906;2:1799–800.
3. Zernov DN. Entsefalometr—ustroistvo dlya lokalizatsii mozgovych
structur u zhivogo cheloveka. Predvaritel’noe soobshenie.
Encephalometer—a device for localising cerebral structures in a liv-
ing man. A preliminary communication. Trudy Fiziko-meditsynskogo
Obshestva Moscovskogo Universiteta 1889; 2:70–80. (Rus).
32
4. Kirschner M. Arch Klin Chir. 1923;176(581):581–620.
5. Dandy WE. Ventriculography after injection of contrast into the
ventricles. Ann Surg. 1918;68(1):5–11.
6. Reichert T, Hassler R. Special method of stereotaxic brain opera-
tion. Proc Roy Soc Med. 1955;48:469–70.
7. Leksell L. The stereotaxic method and radiosurgery of the brain.
Acta Chir Scand. 1951;102:316–9.
8. Oldendorf WH. The quest for an image of brain: a brief historical
and technical review of brain imaging techniques. Neurology.
1978;28(6):517–33.
9. Cormack AM. Representation of a function by its line integrals,
with some radiological applications. J Appl Phys.
1963;34:2722–7.
10. Brown RA, Nelson JA. Invention of the N-localizer for stereotactic
neurosurgery and its use in the Brown-Roberts-Wells stereotactic
frame. Neurosurgery. 2012;70(2 Suppl Operative):173–6.
11. Brown RA, Nelson J. The origin of the N-localizer for stereotactic
neurosurgery. Cureus. 2012;4(8):e55. doi:10.7759/cureus.55.
http://www.cureus.com/papers/the-origin-of-the-n-localizer-
for-stereotactic-neurosurgery/203.
V.C.K. Tse et al.
12. Leksell L. Stereotaxis and tomography, a technical note. Acts
Neurochirurgica. 1980;52:1–7.
13. Reinhardt HF, Zweifel HJ. Interactive sonar-operated device for
stereotactic and open surgery. Sterotact Funct Neurosurg.
1990;54:393–7.
14. Verhey LJ. Immobilizing patients and positioning for radiotherapy.
Semin Radiat Oncol. 1995;5:100–14.
15. Soete G, Van de Steene J, Verellen D, Vinh-Hung V, Van den Berge
D, Michielsen D, Keuppens F, De Roover P, Storme G. Initial clini-
cal experience with infrared-reflecting skin markers in the position-
ing of patients treated by conformal radiotherapy for prostate
cancer. Int J Radiat Oncol Biol Phys. 2002;52:694–8.
Further Reading
Levy M. A Short history of stereotactic neurosurgery. http://www.
neurosurgery.org/cybermuseum/stereotactichall/stereoarticle.html
 Part II
Radiation Biology and Physics
 The Physics of Stereotactic
Radiosurgery
Siyong Kim and Jatinder Palta
Introduction
In radiosurgery, instead of using a surgical knife when treating
a patient, high-energy ionizing radiation is the tool of choice.
To understand the tumoricidal effects of ionizing radiation, it
is important to know how radiation interacts with matter.
This chapter describes general concepts and principles in
radiation physics, including basic physics that are applicable
to stereotactic radiosurgery (SRS). Commonly used delivery
systems are also briefly reviewed. This chapter is written for
non-physics professionals, especially neurosurgeons and
radiation oncologists.
The Radiation Source for Radiosurgery
Ionizing radiation is any electromagnetic or particulate radia-
tion capable of producing ions either directly or indirectly in
its passage through matter [1, 2]. Among the many radiations
we have, the photon, defined as a discrete packet of electro-
magnetic energy, is most commonly used for patient treat-
ment [3, 4]. A photon is called by several different names
depending on its energy level, such as radio waves, infrared,
visible light, ultraviolet, and X-rays in the form of energy as
illustrated in Fig. 4.1. Only the X-ray range of photons is a
form of ionizing radiation, and, though the energy range of
X-rays is fairly wide, only a high-energy range is used for
treatment. Photon treatment beams can be obtained either from
radioisotope sources or from X-ray-generating machines.
Currently, cobalt-60 (60Co) is the most widely used radioisotope
[5–9] for radiosurgery, and the medical linear accelerator
is the most popular X-ray-generating machine [10–14].
S. Kim, Ph.D. (*) • J. Palta, Ph.D.
Department of Radiation Oncology, Virginia Commonwealth
University, Richmond, VA, USA
e-mail: skim2@mcvh-vcu.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_4, © Springer Science+Business Media New York 2015
4
Protons, defined as positively charged particles found in
the nucleus of an atom, are also used for treatment [15–19].
Proton beams can be obtained from particle accelerators
such as cyclotrons and synchrotrons [20], which cost a tre-
mendous amount of money; thus, very few proton facilities
exist worldwide, and there are currently only five in the USA.
Because the majority of radiosurgery treatments are per-
formed with photon beams, emphasis is placed on the photon
beam.
Cobalt-60
Cobalt-60 is the radioactive isotope used as the radiation
source in the Leksell Gamma Knife treatment machine
(Elekta. Nor-cross, GA), which is described later. A radio-
active isotope is an atom with an unstable nucleus that
tries to stabilize itself through a process called radioactive
decay by emitting ionizing radiation such as alpha, beta,
and/or gamma particles. When 60Co undergoes radioactive
decay, it emits beta particles and two strong gamma radia-
tions, one with 1.17 MeV of energy and the other with
1.33 MeV of energy (Fig. 4.2). MeV, a commonly used unit
of energy for particles in the treatment energy range, means
1 million electron volts, where 1 electron volt is the energy
gained by an electron that accelerates through a potential
difference of 1 V. A real treatment beam of Gamma Knife
can include photons of energy different from 1.17 and
1.33 MeV because some photons experience interactions
with 60Co itself and/or its capsulation material and lose a
part of that energy. Therefore, the effective energy of
Gamma Knife is slightly lower than 1.25 MeV (the average
of 1.17 and 1.33 MeV).
Cobalt-60 ultimately decays to nonradioactive nickel. The
half-life of 60Co, that is, the length of time needed for 60Co to
lose half of its radioactivity from decay, is 5.26 years. At the
end of 1 half-life, only 50 % of the original radioactive mate-
rial remains. This means that treatment time after 5 years is
double that at the time of initial installation, and that the
35
36
lower
Energy of -9 -8 -7 -6 -5 -4 -3 -2 -1
photon (eV) 10 10 10 10 10 10 10 10 10
Radio waves
Microwaves
Fig. 4.1 The electromagnetic spectrum is illustrated. Therapeutic X-ray or ionizing radiation is in the energy range of 105 eV and higher. The
energy of photon beams commonly used in radiosurgery are higher than 106 eV
60
Co 5.26 y
27
b 1– (99.8%) 0.313 MeV
b 2– (0.12%) 1.489 MeV
g 1 (99.8%) 1.173 MeV
g 2 (100%) 1.332 MeV
60
Ni
28
Fig. 4.2 For 60Co, most of the disintegrations (99.8 %) are the emission
of a β1− with a maximum energy of 0.313 MeV. This leads to an excita-
tion of 60Ni, which releases its energy quickly by emitting two gamma
rays (1.173 and 1.332 MeV) in cascade. In some disintegration
(0.12 %), a β2− particle with a maximum energy of 1.486 MeV is
released and leads to the lowest excited state of 60Ni
source of Gamma Knife needs to be replaced after a certain
period of time to avoid long treatment times.
X-Ray Production in a Linear Accelerator
One of the interesting characteristics of a fast-moving elec-
tron is that when it interacts with a material, it can produce
an X-ray. A part or whole of the kinetic energy of the elec-
tron is transformed into electromagnetic energy. This prin-
ciple is used to obtain X-rays in most X-ray production
machines in which electrons are accelerated and induced to
hit a target and then generate an X-ray. The amount of
X-ray particles produced increases as the kinetic energy of
the incident electrons increases. Electrons are accelerated by
S. Kim and J. Palta
higher
1 101 102 103 104 105 106 107
Therapeutic
Infrared Ultraviolet X-ray
Diagnostic
Visible
X-ray
potential differences in diagnostic X-ray tubes up to several
hundred kiloelectron volts (keV). The acceleration mecha-
nism in a linear accelerator, however, is somewhat different
because it uses microwave technology similar to that used
for radar to accelerate electrons in a linear tube, often called
an accelerator tube [21]. In linear accelerators, electrons
are usually accelerated to the energy range of 4–25 MeV.
A 6-MeV electron is most often used to create an X-ray for
radiosurgery. When an electron creates a photon, theoreti-
cally, the photon can take any energy from 0 to the same as
the energy of the incident electron. In other words, the pho-
ton beam produced by a 6-MeV electron beam can have an
energy spectrum of 0–6 MeV. The energy of an X-ray pro-
duced in a linear accelerator is denoted MV instead of MeV.
The major components and auxiliary systems of typical
medical linear accelerators are shown in a block diagram
(Fig. 4.3). The role of each part is briefly explained below.
Power Supply
The power supply provides direct current (DC) power to the
modulator.
Modulator
The modulator generates high-voltage pulses lasting a few
microseconds that are simultaneously introduced to the
radiofrequency source and the electron gun.
Electron Gun
The electron gun produces electrons by thermionic emission.
In a conducting material, the electrons exist at or below the
baseline electron energy at low temperatures. As the tem-
perature is increased, some of these electrons have sufficient
energy to pass over the surface–potential barrier between the
material and the vacuum. This process of increasing the tem-
perature of a bulk material to increase the number of elec-
trons that can leave the material is called thermionic emission.
These electrons are pulse-injected into the accelerator tube
according to the signal from the modulator.
4 The Physics of Stereotactic Radiosurgery
Fig. 4.3 The power supply provides DC to the modulator, which
provides a high-voltage pulse to the RF generator and electron gun
simultaneously. The electron gun introduces the electron in pulse to the
accelerator tube. Electron production occurs through the thermionic
process. The RF generator introduces a microwave to the accelerator
Radiofrequency Source
Radiofrequency (RF) is a range of electromagnetic frequencies
above sound and below visible light, generally in the 30 kHz
to 300 GHz range. RF is used for all broadcast transmissions
including AM and FM radio, television, shortwave, micro-
wave, and satellite transmissions. In a linear accelerator used
for radiosurgery, a magnetron is often the RF source. The
magnetron is a diode-type electron tube that functions as a
high-power oscillator to generate microwave pulses. Pulse
duration is several microseconds long, and the repetition rate
is several hundred pulses per second. Following the pulses
from the modulator, microwave pulses are introduced into
the accelerator tube through the waveguide system. The typi-
cal frequency of microwaves used in a linear accelerator is
about 3 GHz.
In some designs, a klystron is used instead of a magnetron.
The klystron is a microwave amplifier rather than a source;
therefore, it requires a low-power microwave oscillator called
an RF driver as an RF source. In general, a klystron produces
microwaves of higher power than the magnetron and is often
used with high-energy linear accelerators (>10 MV).
Waveguide System
The waveguide system is made up of a pressurized rectangular
tube through which microwave pulses generated by either a
magnetron or klystron are transmitted into the accelerator tube.
Accelerator Tube
An accelerator tube consists of many RF resonant cavities.
An RF cavity allows power to be coupled into the particle beam.
In an electron linear accelerator, RF accelerating cavities are
37
tube. The electron and the microwave are timed exactly to be met in the
accelerator tube by the modulator. The accelerator tube accelerates the
electrons via the resonance cavity. As the accelerated electron comes
out of the accelerator tube, the path of the electron is bent through a
bending magnet to hit the target and generates an X-ray
basically microwave resonators. Resonance is a very common
physical phenomenon that can be observed in many types of
systems. Imagine a child on a swing, for example. If the child
pushes the swing at just the right time, the push can make
the swing go higher and higher with very little effort. The
swing has a natural frequency of oscillation. Pushing “at just
the right time” means that energy is put into the system at a
frequency known as the fundamental frequency. Now the
system is said to be in resonance condition.
The amplitude of the motion can increase rapidly with
resonance. An analogous phenomenon can occur in a linear
accelerator with RF resonance, which is generally derived
from an RF cavity that is typically in a right circular cylindri-
cal shape with connecting holes to allow a charged particle’s
beam to pass through for acceleration. Figure 4.4 shows a
typical cylindrically symmetric RF cavity. In a fundamental
RF mode, the electric field is roughly parallel to the beam
axis and radically decays to zero upon approach to the cavity
walls. The pulsed electron particle beam traverses the cavity
through the centered hole, creating an accelerating force
along the axis of the cavity due to the electric field.
Bending Magnet
When an electron moves in a magnetic field, it experiences
force. The direction of the force is at right angles to both the
direction of the magnetic field and the direction of the elec-
tron motion (Fig. 4.5). Using this principle, the path of accel-
erated electrons is controlled so that they can hit the target
normally (note the electron path, bending magnet, and target
in Fig. 4.3). Magnets used for this purpose are called bending
magnets. In certain cases, straight-ahead beam designs can
38
Fig. 4.4 A typical cylindrically symmetric cavity
Fig. 4.5 As the electron travels into a uniform magnetic field, it experi-
ences a downward force. This force causes the electron to travel in a
circular path. The crosses in the figure indicate the uniform magnetic
field pointing into the page
be applied without the bending magnet if the acceleration
structure is short enough to be placed in a vertical direction.
A linear accelerator in straight-ahead beam design is used in
the CyberKnife unit, which will be better described later.
Treatment Head
The major parts of the treatment head are the target (often
called the X-ray target), primary collimator, flattening filter,
ion chamber, and secondary collimators (Fig. 4.6).
Accelerated electrons collide with the target to generate
an X-ray beam. For a given energy of electrons, more X-rays
can be produced if a target material with a higher atomic
number (Z number) is used. Tungsten and gold are com-
monly used as target materials.
The production of an X-ray is based on a process called
bremsstrahlung (meaning “braking radiation”), which is the
result of radiative collisions between a fast-moving electron
and a nucleus. When the electron passes near a nucleus, it can
be deflected from its path by Coulomb forces of attraction
S. Kim and J. Palta
Fig. 4.6 A schematic of the treatment head of a medical linear accel-
erator is illustrated. Initially, as the accelerated electrons hit an X-ray
target, an X-ray beam is generated via the bremsstrahlung process. This
X-ray beam is collimated by the primary collimator. As it exits the pri-
mary collimator, the X-ray beam profile is flattened out by the flattening
filter. Then, it goes through the ion chamber, and, finally, it gets colli-
mated by the secondary collimator. In radiosurgery, generally one more
collimator is added to make a very small field (e.g., circular collimator
or micro-multileaf collimator)
and lose its energy as bremsstrahlung radiation (i.e., an X-ray).
The X-rays are produced in all directions, but high-energy
X-rays are produced in the forward direction (Fig. 4.7).
Therefore, in a linear accelerator, higher photon intensity is
observed in the area close to the central line (i.e., the extended
line following the direction of the incident electron) below
the X-ray target. The X-ray beam is first collimated by the
primary collimator, which has a circular aperture through
which a photon beam can pass to make a radiation field. The
primary collimator is typically made of tungsten.
For patient treatment, a radiation beam with uniform
intensity across the field is desirable, and to create a uniform
photon beam, a conical filter called a flattening filter is used.
The central area of the flattening filter is thicker to attenuate
more photons in the central area. In general, a high-Z-number
material is used for the flattening filter to effectively attenu-
ate photons.
The amount of radiation produced by the linear accelera-
tor is monitored by an ionization chamber, often called a
monitor chamber. The monitor chamber not only controls the
amount of radiation delivered to the patient but also checks
and controls the uniformity of the delivered radiation.
Whereas the primary collimator defines the maximum
aperture of the radiation field, a real treatment field is deter-
mined by the secondary collimator, which defines a rectan-
gular field that fits to each patient treatment in routine
radiation therapy. In radiosurgery, smaller fields are needed.
Thus, an additional collimator system, either a circular col-
limator or micro-multileaf collimator (mMLC) [22], is used.
4 The Physics of Stereotactic Radiosurgery
Fig. 4.7 Schematic illustration of the angular distribution of emission
of bremsstrahlung X-rays around a target. At the kinetic energy of an
electron beam less than 100 keV, X-rays are emitted relatively equally
in all directions. As the kinetic energy of the electron beam increases,
the direction of the bremsstrahlung X-ray emission becomes signifi-
cantly forward. In megavoltage X-ray machines, the transmission
X-rays are therefore used to treat a patient
Flattening Filter Free Mode
As described before, photon beams produced in a conventional
linear accelerator by bombarding a high-Z target with accel-
erated electrons are strongly forward peaked (see Fig. 4.7),
resulting in significant centrally peaked fluence distributions
incident to patients. In the past, such a nonuniform fluence
was considered not suitable for routine clinical applications
and intentionally flattened by a flattening filter (FF) as shown
in Fig. 4.6. However, the rationale that a FF is required to
obtain uniform dose distributions is getting less strong in
modern radiation therapy. An example is the so-called inten-
sity modulated radiation therapy (IMRT), one of the most
significant advancements in modern radiation therapy. In
IMRT, highly inhomogeneous beam fluences are often
applied to achieve extremely conformal dose distributions
even to concave targets, implying no need of flattened beam
in principle. Another example is in case of relatively small
field treatments such as stereotactic radiosurgery (SRS), ste-
reotactic radiotherapy (SRT), and stereotactic body radio-
therapy (SBRT) because there is no significant difference in
beam fluence profile across the field between flattened and
unflattened beams when field sizes are small. Thus, flatten-
ing filter free (FFF) mode is available in several state-of-the-
art commercial linear accelerators nowadays.
The major advantage of a FFF beam is significantly large
dose rate compared to conventional flattened beams [23].
With larger dose rate, treatment time can be reduced and
uncertainty related to patient motion may become smaller.
This feature is very important especially for SRS, SRT, and
SBRT where fractional dose is large. Figure 4.8 shows dose
rate profiles at 10 cm depth of water in several field sizes,
39
4×4 cm2 (a), 6×6 cm2 (b), and 8×8 cm2 (c), for both regular
flattened 6 MV beam and 6 MV FFF beam from a Varian
TrueBeam linear accelerator. As can be seen, dose rates in
FFF mode are larger than those in regular flattened beams by
about two times in 6 MV while profiles are not much differ-
ent. Dose rates in FFF mode become about four times larger
in 10 MV but more nonuniform dose profiles are expected.
A Photon’s Interaction with Matter
The effectiveness of radiation treatment is based on how
much radiation energy is deposited in the tumor compared
with the energy deposited in the surrounding normal tissues.
Energy deposition occurs through interactions between a
radiation beam and the human body at either the atomic or
nuclear level. When photons traverse a material, they reduce
the intensity of the incident photons. The three most com-
mon ways for a photon to interact with matter for energies
above a few keV are photoelectric absorption, Compton scat-
tering, and pair production. These three mechanisms account
for more than 99 % of the interactions between photons and
matter, and the probability of each depends on the energy of
the photon and the material with which it interacts. Because
these interactions are quantum in nature, a specific interac-
tion is never guaranteed. It is simply more or less probable
than the others (depending on the energy and the material).
Photoelectric Absorption
In photoelectric absorption, an X-ray photon is absorbed by
the interacting material and an electron from a shell of the
atom is ejected, leaving the atom ionized, as illustrated in
Fig. 4.9. The ionized atom returns to the neutral state with the
emission of an X-ray, called the characteristic X-ray of the
atom. The kinetic energy transferred to the ejected electron
during the interaction is the same as the incident photon
energy minus the ejected electron’s binding energy to the
atomic nucleus. Photoelectric absorption occurs predomi-
nately at low energies of photons and for high-atomic-number
materials. In water (one of the closest materials to tissue), the
probability of this interaction becomes negligible once pho-
ton energy reaches above 100 keV. Because the effective
energies of photon beams from the Gamma Knife (i.e., 60Co
source) and linear accelerator are of the order MeV, the effect
of photoelectric absorption is not significant in radiosurgery.
Compton Scattering
In Compton scattering, also known as an incoherent scat-
tering, the incident X-ray photon ejects an electron from
an atom, loses some of its energy to the ejected electron,
40
Fig. 4.8 Dose rate profiles at 10 cm depth of water in three field sizes,
4 × 4 cm2 (a), 6 × 6 cm2 (b), and 8 × 8 cm2 (c), for both regular flattened
6 MV beam (denoted as 6 MV) and 6 MV FFF beam from a Varian
Fig. 4.9 In a photoelectric effect, an incident photon striking a bounded
electron is absorbed, and the electron is ejected from the atom with a
kinetic energy equal to the difference between the incident photon
energy and the binding energy of the electron. The probability of the
photoelectric effect increases as the atomic number of the target mate-
rial increases; however, it decreases as the energy of the incident photon
increases. (E is the energy of the incident photon, T is the kinetic energy
of the ejected electron, and BE is the binding energy. Photon energy is
expressed as hν, where h is Plank’s constant and ν is frequency)
and continues to move in a direction different from the initial
direction. The resulting incident photon is called a scat-
tered photon, whereas it is called a primary photon before
S. Kim and J. Palta
TrueBeam linear accelerator. Dose rate scale is arbitrary and as illus-
trated, dose rates in FFF mode are larger than those in regular flattened
beams by about two times while profiles are not much different
the interaction. The energy and momentum are conserved
in this process. Kinetic energy transferred to the electron is
the energy difference between the primary and scattered
photons. The energy of the scattered photon depends on
the direction (i.e., the angle with respect to the direction
of the primary photon). The scattered photon has minimal
energy when it is backscattered (180° from its direction of
travel). If it is scattered in the same direction as the pri-
mary, the scattered photon energy is the same as the primary
photon energy. Compton scattering is important for
low-atomic-number materials and photon energies of
100 keV to 10 MeV. Therefore, Compton scattering is the
most significant interaction for photons used in radiosurgery.
Figure 4.10 illustrates the Compton scattering interaction.
Pair Production
Photons have a quantum of energy but zero mass. In pair
production, the incident photon energy is completely
absorbed in the medium, and an electron and its antiparticle,
a positive electron called a positron, are created. This inter-
action is illustrated in Fig. 4.11. Pair production can only
occur when the energy of the incident photon is greater than
4 The Physics of Stereotactic Radiosurgery
Fig. 4.10 In Compton scattering, the incident photon strikes an elec-
tron and ejects it out of the atom to which it was bound. During this
process, the incident photon energy is transferred to the ejected elec-
tron. The least energy is transferred to the electron when the incident
photon has no scattering (i.e., θ = 0º), and the most energy is transferred
to the electron when the incident photon is scattered backward (i.e.,
θ = 180º). Compton scattering becomes most significant at an energy
range of 100 keV to 10 MeV, and it is almost independent of the atomic
number (i.e., Z value) of the interacting material. Thus, for the radiosur-
gery energy range, Compton scattering is the dominating interaction. (E
is the energy of the incident photon. T is the kinetic energy of the
ejected electron, and E′ is the energy of the scattered photon)
Fig. 4.11 When a photon with energy equal to or higher than 1.02 MeV
comes very close to the nucleus of an atom, it interacts with the nuclear
Coulombic force field and can create a pair of an electron and a posi-
tron. The total kinetic energy of the electron and position is the energy
of the incident photon minus 1.02 MeV. The probability of pair produc-
tion is proportional to the atomic number of the target material and the
incident photon energy
1.02 MeV, which is the minimum energy needed to create an
electron and a positron. Positrons are very short lived and
disappear with the creation of two 0.51-MeV photons each,
a process called positron annihilation. The total kinetic
energy transferred to the electron and positron pair is equal
to the incident photon energy minus 1.02 MeV. Pair produc-
tion is of particular importance when high-energy photons
pass through materials of a high atomic number but plays a
small role in photon beams used for radiosurgery.
41
Fig. 4.12 A photon enters a volume of a medium and transfers a por-
tion of its energy, thus giving the electron a kinetic energy. The electron
will travel a short distance and deposit its energy in a medium. The
original photon will continue to travel within the medium as it transfers
more energy to another electron
Dose and Dosimetry
The physical quantity that is used in radiation therapy to kill
neoplastic cells is the kinetic energy of the incident radiation
beam. Once photons enter a medium, they start to interact with
the medium with the probability of interactions described ear-
lier. Any photon particle loses a part or all of its energy when
it initially interacts with a medium and most of the lost energy
is absorbed by the medium around the interaction point.
Energy absorbed in a unit mass of the interaction medium dur-
ing interactions with a radiation beam is called the dose or,
more specifically, the radiation dose. The commonly used unit
of dose is the gray (Gy), which is equivalent to J/kg (joules per
kilogram), where joule is a unit of energy (1 J is the approxi-
mate energy required to lift 1 kg by 0.1 m assuming gravity
accelerates at 10 m/s2). Depending on the amount of dose, cGy
(centigray, or one-hundredth of a Gy) is also often used.
Dosimetry is either the measuring or calculating of dose.
As you may have noted, the energy absorption mecha-
nism during photon interaction is a two-step process: (1)
energy transfers from the photon to the ejected electron and
(2) energy is deposited from the ejected electron to the
medium (Fig. 4.12). Thus, energy deposition occurs within a
volume around the spot of interaction rather than at a point of
interaction. If the photon still has kinetic energy after the first
interaction (e.g., Compton scattering), it can travel and inter-
act at another point, then cause another energy deposition.
This second interaction is independent of the first interac-
tion, thus, third, fourth, and multiple scatterings are possible.
The energy absorbed from scattered photons is called the
scattered dose, contrary to the primary dose, which is the
energy absorbed in the first interaction. The same thing hap-
pens when a patient is irradiated with a photon beam. Photons
interact with human tissue and deposit energy into the tissue.
42
Fig. 4.13 (a) In the thin line of beam and thin medium, the scattered
photons are out of the medium and never return back to the medium.
There is thus no contribution by the scattered photons to the dose.
Percent depth dose (PDD) is mainly determined by the energy deposi-
tion of the primary photons. (b) On the other hand, in the thick
medium with the thin line of photon beam, the scattered photons can
further interact with the medium and return to the center line of PDD
measurement. In general, however, this effect is insignificant. (c) In the
Radiation therapy’s aim is to kill the target tissue (or cell)
through enough impact from the energy deposition while
minimizing the impact to the normal tissue. In other words,
local control of treatment depends on how much dose is
delivered to the target (and how accurately, too, of course),
and normal tissue complication is dependent on how much
unwanted dose is given to the normal structure.
There are two commonly used dose-calculation methods:
measurement based and model based. Measurement-based
approaches directly use dose distributions measured in phan-
toms. On the other hand, model-based approaches try to cal-
culate the dose from the first principles with limited use of
measured data.
Measurement-Based Dose Calculation
Dose calculation is mainly based on three parameters: per-
cent depth dose (PDD), profile, and output.
Percent Depth Dose
When a photon beam is incident on a medium, it creates a
dose distribution within the medium. Relative dose at any
depth is called the depth dose (DD) and when it is expressed
as a percentile it is called the PDD. Let us assume a certain
number of photons in a hypothetical narrow beam are inci-
dent on a thin medium (Fig. 4.13a). The number of photons
decreases exponentially because some photons interact
with the medium and disappear from the path of the narrow
beam. Now think of energy deposition (i.e., dose) at depth.
The absorbed dose is proportional to the amount of radia-
tion interactions. Energy, however, is deposited by ejected
S. Kim and J. Palta
broad beam and thick medium, the single or multiple scattering of
photons can occur at any line of beam. The broad beam is considered
as a bundle of thin lines of beam. The scattered photons coming from
each beam line to the center line of interest contribute to the total
dose. PDD values beyond the dmax (depth of dose maximum) increase
with field size because there are more line beams for larger fields.
Because most radiosurgery fields are small, radiosurgery beams are
close to case (b)
Fig. 4.14 A typical PDD with a narrow beam is illustrated. The dose is
close to zero at the surface and starts to build up with depth until reach-
ing the maximum. This region is called the build-up region. After the
depth of dose maximum, it then begins to decrease exponentially. Note
that depth dose (DD) is displayed in the “log” scale whereas depth is in
the “linear” scale (i.e., log–linear plot). In a log–linear plot, an expo-
nential decrease is expressed as a line
electrons rather than by photons themselves. Because most
of the ejected electrons lose energy continuously while
traveling through the medium, there is a distance lag
between the photon interactions and the dose. This mecha-
nism also creates a so-called build-up region in the shallow
depth of the medium. Although the number of interactions
is the highest at the surface of the medium, dose is almost
zero (because most ejected electrons move deeper into the
medium). Thus, dose is close to zero at the surface, starts to
build up with depth, and reaches the maximum. Then, the
dose begins to decrease exponentially. Figure 4.14 shows a
typical shape of DD (or PDD) for a narrow beam. In reality,
4 The Physics of Stereotactic Radiosurgery
Fig. 4.15 Comparison of PDD curves for various field sizes. As the
depth gets deeper, PDD increases with field size because of the
increased amount of scatter dose contribution. Note that it is intention-
ally shown in “linear–linear” scale to illustrate that PDD is often drawn
in two ways, “linear–linear” and “log–linear” (see Fig. 4.13)
Fig. 4.16 An ideal dose profile in a plane is illustrated
the target volume is finite in size (Fig. 4.13b). In this sce-
nario, some of the scattered photons can scatter back to the
center of the field and contribute to the dose at depth. This
effect is minimal, however.
The scatter effect is significantly enhanced with a broad
beam (Fig. 4.13c) because more scattered photons can con-
tribute to the dose. The chance of multiple scattered photons
coming to the central line increases with field size because
more scattered photons exist in a larger field, so PDD
increases with field size (Fig. 4.15). In radiosurgery, how-
ever, most fields are relatively small, so the scatter effect is
insignificant. Thus, most radiosurgery beams are similar to
the case shown in Fig. 4.13b, and PDD can be analytically
expressed as a simple exponential function.
Profile or Off-Axis Ratio
Figure 4.16 shows an ideal dose profile, often called the off-
axis ratio (OAR), in a plane where a certain amount of dose
is given uniformly inside the field and no dose is deposited
outside the field. In reality, it is not possible to obtain such a
profile. A typical dose profile in a plane at a certain depth for
a clinical radiation beam is shown in Fig. 4.17a. The dose is
uniform in the central area but starts to gradually decrease as
it nears the field edge. It then drops rapidly at the geometric
43
Fig. 4.17 (a) A typical dose profile is illustrated for a conventional
beam. The region of rapid dose change is called the penumbra. (b) A
typical dose profile for a radiosurgery beam
edge of the field and slowly approaches zero dose (<1 %)
away from the field edge. The region of rapid dose fall-off is
called the penumbra. When a field is large, the flat plateau in
the central area is clearly observed. As the field size becomes
smaller, the plateau disappears as illustrated in Fig. 4.17b,
which is a profile for a typical radiosurgery beam. In radio-
surgery, most radiation fields (<50 mm in diameter) show
either no plateau region or a very narrow plateau region.
Because of the large dose variation within a small region, a
high-resolution measurement detector is required for dose
profile measurement [24–30]. The shape of the individual
radiation field is defined by the collimator system that is spe-
cifically based on the radiosurgery delivery system.
Output
The magnitude of radiation produced by the delivery system
is called the output. In general, this is a relative value that is
normalized to the output of a reference field size. Output var-
ies with field size (or collimator size). Larger field sizes have
higher output.
With the PDD, OAR, and output for a given geometry,
relative dose at any point is simply a multiplication of these
three parameters. Absolute dose is obtained when this value
is multiplied with the machine calibration factor and monitor
units (MU) in the linear accelerator (or calibration dose rate
and treatment time in Gamma Knife).
Model-Based Dose Calculation
Most model-based dose-calculation methods define a kernel,
which is a function that describes how the dose is distributed
within a medium (mostly water). Two commonly used ker-
nels are point kernel and pencil-beam kernel.
Point Kernel
When a photon particle interacts at a point within a medium,
a certain amount of energy is released per mass, which is
called the total energy released per unit mass (TERMA).
A part of this energy is absorbed at the point of interaction
(often called the primary interaction point), but the rest of it
is dispersed around the point. The scattered photon can also
44
travel to any other points, interact, and deposit energy around
the area of interaction. Therefore, a photon interaction can
contribute dose to the whole volume. The point kernel
describes how dose is distributed with respect to the interac-
tion point within the medium, as illustrated in Fig. 4.18.
In general, the distributed dose is expressed as a ratio
between the energy deposited at any point and the total
energy released during the interaction at the primary interac-
tion point. The dose at any point is a summation of kernels
multiplied with the TERMA from all of the primary photon
interactions. TERMA is easily calculated using analytical
expression of interaction mechanisms.
Pencil-Beam Kernel
The pencil-beam kernel includes dose contributions from all
of the primary interactions along a ray instead of at one inter-
action point. Figure 4.19 illustrates a pencil-beam kernel. If
photon energy fluence (the same as the number of photons
times the corresponding energy per area) is known, dose at
any point is simply a summation of kernels multiplied with
energy fluence.
Fig. 4.18 A point kernel is illustrated, which is a distribution of energy
deposited at any point to total energy released at the primary interaction
point
Fig. 4.20 An isodose line connects all points of the same dose. In this figure, absolute isodose lines are displayed in axial, sagittal, and coronal
planes of the CT image
S. Kim and J. Palta
In general, kernel values are preobtained by calculations,
and sometimes the pencil-beam kernel can be extracted from
measurement data.
Isodose Line and Dose–Volume Histogram
Once the dose is calculated in the treatment planning system,
each dose distribution is usually displayed in an isodose line,
which is made up of all the points of the same dose connected
in a line. In radiosurgery, isodose lines are expressed as a per-
centile of the maximum dose. Dose distribution within the tar-
get is much more nonuniform in radiosurgery than in
conventional radiotherapy. The maximum dose is usually
observed in the center of the target, and it is usual to have very
stiff dose fall-offs near the target boundary. Prescription is
assigned to isodose lines of 50–80 % depending on the situa-
tion. A prescription isodose line is higher in the case of a sin-
gle isocenter and lower with multiple isocenters. Figure 4.20
shows isodose lines displayed in absolute value on three (axial,
sagittal, and coronal) planes of tomographic image.
Fig. 4.19 A pencil-beam kernel is illustrated, which is a distribution of
deposited energy from all primary interactions along a pencil-beam line
4 The Physics of Stereotactic Radiosurgery 45

Fig. 4.21 In a dose– Dose Volume Histogram

volume histogram (DVH), 1.0
accumulated volume (i.e.,
histogram) is described 0.9
according to dose for any
particular volume of 0.8
interest (e.g., the target).
In this case, 95 % of the 0.7
volume of the target will

Norm.Volume
get a dose equal to or 0.6
more than 2,000 cGy
0.5

0.4

0.3

0.2

0.1

0.0
0 500 1000 1500 2000 2500 3000
Dose (cGy)

Dose–volume histogram (DVH) describes accumulated

volume (i.e., histogram) according to dose for any particular
volume of interest (e.g., the target) as illustrated in Fig. 4.21.
In Fig. 4.21, 95 % of the volume of the target will get a dose
equal to or more than 2,000 cGy. Although the DVH does not
show spatial information, it is a useful tool for plan evalua-
tion [31, 32]. In radiosurgery, the DVH for the target usually
shows a gentle slope on the high-dose side because of a sig-
nificantly nonuniform dose profile of small fields. With the
lower isodose line selected for prescription, a gentler DVH
slope on the high-dose side is expected. In the case of mul-
tiple isocenters, field overlap causes a significant dose
increase in the central volume of the target, resulting in a
high dose tail in DVH.

Photon Beam Delivery Systems

Gamma Knife
In the late 1960s, Leksell introduced a prototype of Gamma
Knife, which is a dedicated radiosurgery unit [5]. Leksell’s
prototype incorporated 179 60Co radioactive sources placed
over a 60° × 160° sphere. The modern Gamma Knife models
incorporate 201 60Co radioactive sources that converge and
focus on the treatment target at a source-to-target distance of
about 40 cm [6, 7]. Each source contributes a clinically insig-
nificant dose following the beam line. However, when many
beam lines are converged on the focus where the target is, the
therapeutic dose is delivered to the target while the surround-
ing normal tissue dose remains under the limit. Gamma
Fig. 4.22 A photograph of a Gamma Knife unit
Knife mainly consists of the radiation unit, the operating
table and sliding couch, a set of four collimator helmets, and
a control unit. Figures 4.22 and 4.23 show a photograph of a
Gamma Knife unit and a simple schematic diagram,
respectively.
The 60Co radioactive source is in pellet form, and 20 pellets
are encapsulated in a steel capsule. Each steel capsule is 1 mm
in diameter and 2 mm in height. Sources are aligned with three
collimator systems, the precollimator, the stationary collima-
tor, and the final collimator of a helmet. Both the precollima-
tor and the final collimator of the helmet are made of tungsten
alloy whereas the stationary collimator is made of lead.
46 S. Kim and J. Palta

Rear shield Middle shield

Front shield

Central body Upper shielding

Plug door

Treatment table
Couch
Helmet

Position
indicator

Trolley
. . Lower shielding
door

Fig. 4.24 A photograph of a collimator helmet. A properly chosen hel-

met, depending on the target size, is connected to the sliding couch

.. ..
. .

Fig. 4.23 A simple schematic diagram of a Gamma Knife unit

The total activity of the Gamma Knife unit with new 201
sources loaded is of the order 6,000 Ci (2.22 × 1014 Bq, where
Bq is the same as disintegration per second, and Ci is
3.7 × 1010 Bq). The activity of each source is about 30 Ci and
its variation is expected to be within ±5 %. With 6,000 Ci, a
typical dose rate is about 300 cGy/min at the center of the
16-cm-diameter, spherical water phantom. As described ear-
lier, this value drops down to 150 cGy/min (50 % of initial
dose rate) 1 half-life (5.26 years) later.
Four helmets of different collimator sizes, 4, 8, 14, and Fig. 4.25 Picture of a Leksell stereotactic frame. The frame is fixed to
18 mm in diameter, are provided. Figure 4.24 is a photograph the patient’s skull and is connected to the couch
of a collimator helmet. A proper helmet is chosen depending
on the target size and is connected to the sliding couch. The
Leksell stereotactic frame (Fig. 4.25) is fixed to the patient’s directly escapes the unit even with the doors open. When the
skull and connected to the couch. Once the target position is doors are closed, exposure rates by leakage radiation are sig-
aligned to the focus, the sliding couch is pushed into the nificantly reduced.
mechanically set treatment position. Its mechanical spatial Several auxiliary capabilities have been developed lately
accuracy is claimed to be in submillimeters (about 0.3 mm). and they provide software that tracks the patient’s position
In treatment mode, the shielding doors are open, resulting in ten times per second. A robotic automatic positioning system
an increase of scatter dose inside the treatment room. When repositions each isocenter with submillimeter precision
the sliding couch is withdrawn and the shielding doors are without operator intervention.
still open, the scatter dose becomes about 1.3 times higher. The current state-of-art Gamma Knife® unit is called
Because of the unit’s design, however, no primary beam Perfexion™ and it is significantly different from previous
4 The Physics of Stereotactic Radiosurgery
Fig. 4.26 An inner view of the collimator in PerfexionTM unit. There
are eight sectors and 72 holes (3 hole sizes × 24 sub-collimators) in each
sector. (Courtesy of Young-Bin Cho, PMH)
versions in its design. There exist a total of 192 sources and
it has a unique collimator that is a permanent device divided
into eight moveable sectors, each having 24 sub-collimators
arranged in five concentric rings [33]. The collimator holes
are sized as 4, 8, and 16 mm and either one of them or none
of them can be assigned to each sector. Therefore four field
sizes (i.e., 0, 4, 8, and 16 mm) are available for each sector
and automatic change of field size can be made by adjusting
the position of the movable sector. Such design enables effi-
ciently delivering many diverse combinations of beams to
obtain dose distributions conforming to even highly irregular
targets. Figure 4.26 shows an inner view of the collimator. It
can be seen there are eight sectors and 72 holes (3 hole
sizes × 24 sub-collimators) in each sector.
In Princess Margaret Hospital, Canada, a modification
was made on a Gamma Knife® Perfexion™ unit to add a
cone beam CT system as shown in Fig. 4.27.
Radiosurgery using Gamma Knife has been performed
for more than 250,000 patients worldwide during the past 30
years. Many clinical studies with long years of follow-up
have been reported.
Isocentric Linear Accelerator
Most clinical linear accelerators are isocentric, which means
that the gantry, the collimator, and the table can be rotated
with respect to one point in the space called the isocenter. In
reality, the isocenter may not be a point because three
47
Fig. 4.27 The Gamma Knife® PerfexionTM unit in Princess Margaret
Hospital, Canada. A cone beam CT system has been added for better
image-guidance. (Courtesy of Young-Bin Cho, PMH)
rotation axes (gantry, collimator, and table) often do not
intersect at a common point. Instead, they only near each
other within a sphere. The center of this sphere is considered
the nominal isocenter.
The size of the sphere is the key factor in the linear accel-
erator’s spatial accuracy, and the smaller the better. Common
consensus says that the sphere needs to be less than 1 mm in
diameter for radiosurgery based on the fact that the resolu-
tion of modern imaging modalities is around 1 mm. Another
important factor for spatial accuracy is how precisely posi-
tioned the patient is. In a linear accelerator, the patient’s
positioning is usually determined using the treatment room
laser system. Three lasers, one from the ceiling and two from
side walls, are aligned to point to the nominal isocenter. By
matching the laser crosshairs and the desired marks on the
frame attached to the patient’s skull, the target is aligned to
the nominal isocenter. Therefore, laser system accuracy is
significantly important when used for patient positioning.
As described earlier, linear accelerators are equipped with
a so-called secondary collimator system that provides a rect-
angular field for conventional radiotherapy, but rectangular
fields are not considered appropriate for radiosurgery.
Therefore, additional circular collimators are commonly
used as tertiary collimators [10–14]. Circular beams are
superior to rectangular beams for reasons like the sharper
beam, easier dosimetry calculation, more precise beam
delivery, and better field definition for small fields. Because
tertiary collimation happens closer to the patient, the beam is
more accurately aligned and the penumbra is reduced. More
rapid dose fall-off outside the target can therefore be
obtained. Collimator sizes typically range from 5 to 40 mm
to treat a variety of lesion sizes and shapes. Most circular
collimators are made of tungsten alloy or lead and are
48 S. Kim and J. Palta

Fig. 4.28 Several circular collimators in different sizes of diameter (5,

10, 12, 14.20, 24, and 30 mm) used at the University of Florida are
shown

5–10 cm thick. Figure 4.28 shows several circular collima-

tors with different diameters used at the University of Florida.
At the University of Florida, a special device called a
floor stand was developed [34, 35] that improves the accu-
racy of the beam’s focus to the isocenter by adding a set of
bearings to the stereotactic collimator system that accounts
for imperfections in the gantry rotation. A set of bearings is
also attached to the patient and the target area to bypass the
Fig. 4.29 A setup of the floor stand used at the University of Florida is
inaccuracies of the table rotation. It is reported that the floor
shown. The floor stand is mechanically fixed to the holes in the floor
stand can provide mechanical spatial accuracy within
0.2 ± 0.1 mm to define the isocenter [34, 35]. Figure 4.29
shows how the floor stand is set up.
With the introduction of a mMLC, which has many colli-
mator leaves that can be individually moved to conform to
the shape of the target, it is possible to do two-dimensional
conformal radiosurgery for irregularly shaped targets with a
single isocenter (Fig. 4.30). In addition, dynamic conformal
radiosurgery can be performed with the aid of the automatic
field shaping capability while the gantry rotates. It is also
possible to do intensity modulated stereotactic radiosurgery
(IMSR) if the treatment planning system supports the appro-
priate dose optimization [36]. The collimator leaf is usually
made of tungsten. The width of each leaf is an important
parameter related to the conformality and it ranges from 1.5
to 6 mm at the isocenter depending on the manufacturer.
State-of-the-art linear accelerators incorporate a volumet- Fig. 4.30 A photograph of a commercial mMLC. As can be seen, there
ric imaging system referred to as a cone beam computed are many collimator leaves, and each of them can be individually moved
tomography (CT) system. A diagnostic X-ray tube is added to conform to the shape of the target
on a separate gantry at a 90° angle from the treatment gantry,
and a flat panel detector is installed on the opposite side as This advancement opened the door to exploring the possibili-
shown in Fig. 4.31. Volumetric imaging can be obtained in a ties with image-guided radiosurgery using isocentric linear
couple of minutes by recording multiple cone beam geometry accelerators. Improved setup accuracy by virtue of image-
planar images while the gantry rotates. Currently, it is not guidance also encouraged many clinicians to explore frame-
clear whether this capability needs to be used for radiosurgery. less radiosurgery with isocentric linear accelerators [37].
4 The Physics of Stereotactic Radiosurgery
Cyberknife
CyberKnife, developed by Accuray Inc. (Santa Clara, CA) in
collaboration with Stanford University (Stanford, CA), uses
a miniature linear accelerator mounted on a robotic arm as
shown in Fig. 4.32 [38, 39]. The miniature linear accelerator
operates in the X-band RF (9,300 MHz) and provides a
Fig. 4.31 In an advanced linear accelerator, a diagnostic X-ray tube is
added on a separate gantry at a 90° angle to the treatment gantry, and a
flat panel detector is installed on the opposite side. Using an X-ray tube
and cone beam geometry reconstruction software, volumetric images
can be obtained in the treatment room
Fig. 4.32 A CyberKnife
unit uses a miniature linear
accelerator mounted on a
robotic arm. (Courtesy of
Hee Jung Kim, Soon Chun
Hyang University Hospital,
Korea.)
49
6-MV beam. It is much smaller and lighter than a conventional
S-band (2,856 MHz) linear accelerator. CyberKnife incorpo-
rates an image-guided system consisting of two diagnos-
tic X-ray tubes mounted on the ceiling and two detectors
placed on the floor. With this X-ray image-guided system,
CyberKnife continuously and automatically tracks a tumor’s
precise location throughout the procedure, detects any tumor
or patient movement, and makes corrections as needed.
Because of its image-guidance capability, the radiosurgery
procedure is performed without an invasive head frame.
Even without the frame the use of intelligent robotics tech-
nology enables treatments with submillimeter accuracy.
The robot can position the linear accelerator at any point
within a spherical shell of 60–100 cm from the target with a
precision of ±0.5 mm. In principle, the frameless approach
gives more choices in beam-angle selection compared with
radiosurgery with a frame. The robotic arm must, however,
avoid a collision with the patient, table, and imaging system
as well as direct beam incidence into the imaging system.
Another concern is the long treatment time compared with
other delivery systems like the Gamma Knife and the isocen-
tric linear accelerator. A total of 12 collimators from 5 to
60 mm in diameter are provided. Installing the unit would
require a 10-ft ceiling over a 12 × 16 ft2 area.
A variable aperture collimator, called IRIS, has been
introduced recently to allow the field size to be varied during
treatment delivery [40]. The IRIS incorporates twelve 60 mm
tall prism-shaped tungsten–copper alloy segments. They are
arranged in two banks stacked in the direction of radiation
path. The banks are rotated by 30° with respect to each other
to reduce leakage through gaps between segments. With this
variable aperture collimator, treatment time is expected to
significantly decrease.
50
Fig. 4.33 In cyclotrons, protons are injected at the center of two halves
(“dees”) of an electrically powered circular dipole magnet with a con-
stant magnetic field. The proton acceleration occurs within the narrow
gap between the two half-magnets employing a correctly phased alter-
nating electric field. The protons gain energy, twice for each revolution,
while moving in a constant circular path. Accelerated protons with a
fixed energy and a continuous beam current can be extracted
Proton Therapy
Clinical proton beams are produced by injecting hydrogen
atoms with their electron stripped in an accelerating struc-
ture; electric fields accelerate the free protons to the desired
clinical energy. The proton accelerators fall into two broad
categories [20]. Cyclotrons are the classic proton accelera-
tors in which protons are injected at the center of two halves
(called “dees”) of an electrically powered circular dipole
magnet with a constant magnetic field (Fig. 4.33). The pro-
ton acceleration occurs within the narrow gap between the
two half-magnets employing a correctly phased alternating
electric field. The protons gain energy, twice for each revolu-
tion, while moving in a constant circular path. Accelerated
protons with a fixed energy and a continuous beam current of
up to 1 milliampere (mA) can be extracted and transported
into an evacuated tube (beam line). Proton energy is changed
by inserting an energy degrader in the path of the beam
extracted from the cyclotron.
The other type of proton accelerator is the synchrotron,
which allows preaccelerated protons (up to a few MeV) to be
injected into an accelerating chamber equipped with a num-
ber of electromagnets. The protons are accelerated in an orbit
with a constant radius (Fig. 4.34). As the proton energy
increases, the magnetic field strength also increases to keep
them in a stable orbit. The acceleration cycle in synchrotrons
is typically 2 s. Therefore, it is only possible to obtain proton
beams in pulses with a repetition frequency of 30 cycles per
minute and the energy of the protons can be varied from
pulse-to-pulse. Operating the synchrotrons is complex
because it requires rapid magnetic field variations to operate.
S. Kim and J. Palta
Fig. 4.34 In synchrotrons, the protons are accelerated in an orbit with
a constant radius. As the proton energy increases, the magnetic field
strength also increases to keep them in a stable orbit
However, synchrotrons do not require energy degraders, thus
minimizing secondary radiation production in the beam line.
An elaborate beam transport system (BTS) carries the
protons exiting the accelerator to the patient site. The beam
line consists of focusing, bending, and switching magnets
that steer a pencil beam of protons to different treatment
rooms. The length of the beam line can easily exceed 30 m.
A stable and precise BTS is required for reproducible dosim-
etry and patient treatments. The stability of the centroid of
the beam position in the beam line must be better than
1.00 mm. Therefore, the bending and focusing magnets have
to be very stable, mechanically and electrically, during the
operation of the proton machine.
A Proton’s Interaction with Matter
Protons are positively charged elementary particles that con-
tinuously lose energy and go through small-angle deflections
as they travel through matter before they get absorbed. While
the radiation dose deposited by photons drops off exponen-
tially with penetration depth, the dose deposited by protons
increases very slowly for about three-quarters of its range of
travel in the medium before increasing sharply, reaching a
maximum value before rapidly dropping off to 0. The depth
at which the maximum energy is deposited by protons is
called the Bragg peak. Figure 4.35 illustrates a depth dose of
a proton beam showing its Bragg peak. The typical peak to
entrance dose ratio of narrow proton beams is 4 or higher.
4 The Physics of Stereotactic Radiosurgery
Fig. 4.35 The depth dose of a proton beam is almost constant to a
certain depth and starts to increase, then it jumps significantly at the
farthest end of the path. This peak is called the Bragg peak
The peak’s position is proportional to the energy of the
proton beam. The range of 230-MeV protons is approxi-
mately 33.00 cm, which is sufficient to penetrate any part of
the body. The typical range of proton energies used for radio-
surgery is 70–150 MeV (4–15 cm depth).
The clinical target volumes are usually thicker than the
width of the Bragg peaks; therefore, the range of the proton
beam must be modulated to spread out the Bragg peak. By
changing the energy of the incident proton beam with a vari-
able range shifter, the Bragg peaks will “stack” at different
depths. The variable range shifter can be a binary filter, a
double-wedge variable absorber, or a circular wedge.
Scattering foils or active scanning of a narrow beam with
scanning magnets will laterally spread the proton beams to
achieve uniform intensity across the target volume.
Dose Characteristics in Different Modalities
In 1951, Leksell introduced the concept of SRS, and the first
patient was treated with the Gamma Knife prototype in 1967.
Since then, Gamma Knife has only seen improvements with
the establishment of many linear accelerator-based radiosur-
gery programs during the past 20 years. The use of proton
beams for radiosurgery is also increasing. Some research
groups have investigated and compared the dosimetric char-
acteristics of each modality.
The linear accelerator is thought to be able to provide
dosimetric characteristics similar to Gamma Knife when
multiple, noncoplanar arcs are used. In the case of more than
five noncoplanar arcs, the full width at the half maximum
(FWHM) of a 5-mm circular collimator field is very close to
that of Gamma Knife with a 4-mm helmet. The dose fall-off
of the linear accelerator is also almost identical when more
51
than five non-coplanar arcs are used. A recent study for
trigeminal neuralgia treatment reports that compared with
Gamma Knife, linear accelerator-based deliveries exhibit a
flatter top at the high isodose line level (>50 %) and faster
dose-off at the low isodose line levels (<50 %) [41]. The pen-
umbral widths (80 to 20 %) were 1 mm for Gamma Knife
with a 4-mm helmet and 2.1 mm for the 6-MV linear accel-
erator with a 5-mm collimator in another study [42].
Radiosurgery with a proton beam is different from both a
linear accelerator and the Gamma Knife. Proton radiosur-
gery is performed with shaped and fully compensated fields,
widely separated in the entrance angle, and with a single iso-
center based on the characteristics of the proton beam, that
is, the Bragg peak [43].
The proton beam, Gamma Knife, and linear accelerator
have been compared in five clinical cases [3]. The optimal
modality for SRS depends on target size, shape, and location;
however, all modalities are equally good if the target is small
and regular. In the case of trigeminal neuralgia, linear accel-
erator based SRS is effective and can be comparable with
Gamma Knife [42]. Gamma Knife is superior to the linear
accelerator with regard to the conformality. In contrast, the
linear accelerator is superior with regard to the dose fall-off
outer region of the target volume [44]. The linear accelerator
with mMLC can be better than Gamma Knife when hearing
preservation is important during treatment [45].
Quality Assurance
In most conventional radiation therapy treatments, pre-
scribed dose is delivered in many fractions, and dose per
each fraction is relatively small; however, a significantly
large dose is delivered in a single treatment during
radiosurgery. Therefore, the impact of the inaccurate local-
ization of the target or dose delivery in radiosurgery can be
disastrous. To minimize such disasters, SRS quality assur-
ance (QA) should be stringent. Both an international QA
task group and Task Group 42 of the American Association
of Physicists in Medicine (AAPM) have published general
recommendations [46, 47]. The Radiation Therapy Oncology
Group (RTOG) has also published guidelines [48].
In general, radiosurgery QA consists of common QA for
the overall performance of all radiosurgery equipment, valid
for a relatively long term, and specific QA for the calibration
and preparation of equipment on each treatment day.
Common QA
Common QA procedures need to be set to periodically verify
equipment status and performance. It should include target
localization QA, basic dosimetry QA, treatment planning
QA, and output calibration and delivery QA. A detailed QA
52
Fig. 4.36 A sample of a patient-specific QA checklist used for linear accelerator-based radiosurgery at the University of Florida. In this sheet,
checklist items are listed chronologically
Fig. 4.37 An example of verification film. It can be seen that the steel
ball in the calibration jig and radiation beams are well aligned
S. Kim and J. Palta
schedule must be set based on frequency and consequence:
any item that has either high failure rate or severe conse-
quence must frequently be checked.
Overall target localization can be tested using a phantom
containing a target located in the known geometry. Accuracy
of within 1 mm is recommended.
The treatment planning system’s dosimetric and nondosi-
metric conditions should both be checked. Specific items are
well described in the recommendations of the AAPM Task
Group 53 [49].
4 The Physics of Stereotactic Radiosurgery
Dosimetry-related QA procedures are specific to the
delivery system. In the Gamma Knife unit, the following are
periodically verified: dose rate at the center of a 16-cm-
diameter tissue-equivalent sphere at the focus; shutter error:
connections of frame, collimator helmets, and sliding couch;
and leak test on collimator helmets. For linear accelerators,
output is checked daily. If the laser system is used for patient
alignment, its accuracy needs to be verified rigorously. The
most important QA item is the mechanical accuracy of the
nominal isocenter. Less than a 1-mm diameter around the
isocenter sphere is recommended [14, 50]. If an independent
floor stand is used, like at the University of Florida, the accu-
racy is directly dependent on the floor stand. Thus, no addi-
tional QA tests on the laser and linear accelerator isocenter,
other than those for routine conventional radiotherapy, are
required.
Specific QA
The goal of specific quality assurance is to make sure that the
machine is running adequately, that all auxiliary devices are
prepared and working properly, and that treatment parameters
are correctly set just before and during patient treatments.
Before placing the frame into the patient, the treatment
streamline should be checked to minimize unnecessary treat-
ment delay or cancellation after the frame is on. Figure 4.36
shows a sample of a patient-specific QA checklist used for
linear accelerator based radiosurgery at the University of
Florida. As you can see, check items are listed chronologically.
Once the secondary collimator is set as needed, the collimator
drives are physically disconnected to prevent an accidental
change of the secondary collimator. To prevent the treatment
table from accidentally dropping, a mechanical block is
applied to the column of the table. Because the patient’s head
is connected to the floor stand while his or her body is on the
table, an abrupt drop of the table could cause serious prob-
lems as serious as a patient death. For the first isocenter treat-
ment, the accuracy of focusing the radiation fields to the
isocenter is checked by a Winston–Lutz filming test.
A staff member sets the floor stand to the treatment posi-
tion. A steel ball in the calibration jig is set to the isocenter
coordinates independently by another staff member and
attached to the floor stand. Then, the verification film is irra-
diated in four different beam angles with a 24-mm-diameter
circular collimator. If both the floor stand and calibration jig
are set to the isocenter correctly, and beam alignment is
appropriate in all beam angles, images of the ball must be
centered within all the circular fields. Figure 4.37 shows an
example of the verification film. Once the film is confirmed
satisfactory, the patient is moved to the floor. Before the
treatment beam is on, the size of the circular collimator and
the treatment parameters, such as the table angle, gantry start
53
angle, gantry end angle, and monitor unit, are verified. In
subsequent isocenter treatments, the floor stand is set by a
physicist and coordinates are independently double-checked
by two other staff members. Specific QA in the Gamma
Knife unit is relatively less intense. It is basically ready for
treatment in most cases, and only a few safety checks need to
be performed.
Conclusion
SRS is a special radiotherapy technique that holds promise
not only radio-therapeutically but also as a noninvasive
surgical tool. The underlying physics principles for radiosur-
gery are the same as those for conventional radiation therapy;
however, the accuracy requirements in dosimetry and patient
positioning for radiosurgery are at the millimeter level. There
are several dosimetric parameters that must be measured in
tissue-equivalent phantoms such as water including dose
calibration, percentage depth doses, relative dose output fac-
tors, and cross-beam profiles. Radiosurgery treatment fields
are often very small; therefore, the spatial resolution require-
ments for radiation detectors are much more stringent in
radiosurgery.
Glossary
μSv Microsievert, the SI unit for an equiva-
lent radiation dose that accounts for bio-
logical effect.
AAPM American Association of Physicists in
Medicine.
Accelerator A device that accelerates subatomic
charged particles or nuclei to high
energies.
Alpha particle Positively charged particle consisting of
two protons and two neutrons.
Beta particle High-speed electron or positron.
Binding energy Net energy required to remove an atomic
electron from its orbit.
Bq Becquerel, the Système International (SI)
unit of radioactivity equal to one disinte-
gration per second.
Bragg peak Peak can be seen at the end of the depth
dose curve of heavy charged particles
such as a proton.
BTS Beam transport system, a proton acceler-
ator system that carries the protons exit-
ing the accelerator to the patient site.
Cavity A device through which power is coupled
to the accelerating particles in a resonant
mode.
54
Ci Curie, unit of radioactivity equal to
3.7 × 1010 disintegrations per second.
Collimator A device capable of collimating
radiation.
CT Computed tomography.
Cyclotron A particle accelerator in which
charged particles are accelerated in a
circular path by an alternating elec-
tric field in a constant magnetic field.
DD Depth dose, relative dose level
according to the depth of the mate-
rial when the radiation beam is
incident.
Dipole A pair of electric charges or mag-
netic poles.
Dose Energy absorbed per unit mass by
radiation.
DVH Dose–volume histogram, accumu-
lated volume according to dose for a
volume of interest.
FF Flattening filter.
FFF Flattening filter free.
Filter A device used to modify the inten-
sity of radiation.
FWHM Full width at half maximum.
Gamma particle Electromagnetic radiation particle
(photon) emitted by radioactive decay.
Gy Gray, a unit of dose equivalent to
joules per kilogram.
Half-life Length of time needed for a radio-
active substance to lose half of its
radioactivity from decay.
Ionization chamber A chamber for determining the inten-
sity of ionizing radiation by measur-
ing ionization of the enclosed gas.
Ionizing radiation Electromagnetic or particulate radia-
tion capable of producing ions in its
passage through matter.
IMRT Intensity modulated radiation therapy.
IMSR Intensity modulated stereotactic
radiosurgery, a treatment technique
in which radiation intensity is modu-
lated within a field to obtain an opti-
mized dose distribution.
IRIS A variable aperture collimator in
CyberKnife system.
Isocenter A point in the space that is the center
of rotation of the gantry, collimator,
and table of an isocentric medical
linear accelerator.
Isodose line A line made by connecting all points
of the same dose.
Kernel A function that describes how the
dose is distributed within a medium.
S. Kim and J. Palta
keV Kiloelectron volts, a unit of energy of
particles.
Klystron A microwave amplifier.
Linear accelerator A particle accelerator in which the
path of the particles is straight.
mA Milliampere, a unit of electric current.
Magnetron A diode-type electron tube that gen-
erates microwave pulses.
MeV Million electron volts, a unit of
energy of particles.
mMLC Micro-multileaf collimator, a special
collimator consisting of many small
collimator leaves that can be individ-
ually moved to conform to the shape
of the target.
mR Milliroentgen, a unit of exposure.
MV Million volts, a unit of beam quality
of radiation therapy beams produced
in linear accelerators.
OAR Off-axis ratio, relative dose distribu-
tion following a line on a plane nor-
mal to the direction of the radiation
beam, same as profile.
Output Magnitude of radiation produced.
PDD Percent depth dose, relative dose level
in percentile according to the depth of
the material when the radiation beam
is incident.
Photon Quantum of electromagnetic energy
with no mass and charge considered
to be both particle and wave.
Positron Positively charged particle of the
same mass and magnitude of charge
as an electron.
Profile Relative dose distribution following a
line on a plane normal to the direction
of radiation beam, same as the OAR.
Proton Stable and positively charged sub-
atomic particle.
QA Quality assurance.
Radioactive decay Spontaneous disintegration of a
radionuclide followed by the emis-
sion of ionizing radiation in the form
of alpha, beta, or gamma particles.
Radioactivity Capability of radioactive decay.
Radioisotope Naturally or artificially produced
radioactive isotope of an element.
Range Distance charged particles can travel.
Resonance Condition of being resonant in which
an increase in the amplitude of a
physical quantity can occur.
RF Radiofrequency, a range of electro-
magnetic frequencies above sound
and below visible light.
4 The Physics of Stereotactic Radiosurgery
SBRT Stereotactic body radiotherapy.
SRS Stereotactic radiosurgery.
SRT Stereotactic radiotherapy.
Synchrotron A particle accelerator in which
charged particles are accelerated
around a fixed circular path by an
electric field and held to the path by
an increasing magnetic field.
TERMA Total energy released per unit mass,
amount of energy released from radi-
ation to the unit mass of the interac-
tion material.
Z Atomic number; that is, the number of
protons in an element.
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 Radiobiological Principles Underlying
Stereotactic Radiation Therapy
David J. Brenner and David J. Carlson
Since the gamma knife was first conceived in 1968 primarily
for arterial and functional lesions [1], single-fraction stereo-
tactic radiation therapy (SRT)1 often called radiosurgery, has
been widely used to treat a variety of cerebral lesions. By
1985, an alternative modality was available for SRT, using a
linear accelerator (linac) and a stereotactic head frame [5, 6].
More recently, image-guided linac-based radiosurgery is now
in routine clinical practice [7–9], as is the CyberKnife, a fra-
meless robotic system for SRT [10], while proton radiosur-
gery is increasingly used [11, 12]. The initial radiosurgery
concept was developed for intra-cranial lesions, but it is now
increasingly used for other sites, particularly for pulmonary
lesions [13].
In its early use, SRT was always applied in single frac-
tions (i.e., as radiosurgery). More recently, there has been
increasing use of fractionated stereotactic radiotherapy [14–23].
This has been stimulated both by potential biological advan-
tages, as discussed below, and by the development first of
noninvasive relocatable frame systems [24, 25] and subse-
quently of frameless image-guided stereotactic localization
methods [26, 27].
We will review here the radiobiological principles under-
lying SRT, and their applications, to single- or multi-fraction
radiotherapy of the three main types of lesions that might be
treated with this modality, malignant tumors, benign tumors,
and vascular disorders.
1 ponents; the slopes of the two components differing by a
(The term “stereotactic radiation therapy” will be used here to apply
both to single-fraction treatment (often called radiosurgery) and to
multi-fraction stereotactic radiotherapy (often called stereotactic body
radiation therapy when applied to extracranial sites). There is still
debate about the most appropriate terminology [2–4]).
D.J. Brenner, Ph.D., D.Sc. (*)
Center for Radiological Research, Columbia University
Medical Center, New York, NY, USA
e-mail: djb3@columbia.edu
D.J. Carlson, Ph.D., DABR
Department of Therapeutic Radiology, Yale University School
of Medicine, New Haven, CT, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_5, © Springer Science+Business Media New York 2015
5
The Three Rs of Radiobiology:
Reoxygenation, Repair, and Repopulation
These three radiobiological phenomena relate ultimately to
cell killing processes, which is clearly an important (though
not the only, see later in this chapter) mechanism by which
radiotherapy produces tumor control and induces side
effects. We will discuss later in the chapter other potential
mechanisms of radiotherapeutic response, particularly at
high doses.
Reoxygenation
The first radiobiological principle of importance here is that
malignant tumors, even those of limited size, almost always
contain a proportion of hypoxic cells which, because of their
deficiency in oxygen, are highly resistant to killing by X- or
γ-rays [28]. Examples are shown in Fig. 5.1, showing
hypoxic regions in sections of small tumors derived from
human glioma xenograph lines [29].
Figure 5.2 shows a dose–response curve, derived from
the classic studies of Powers and Tolmach [30], illustrating
the fraction of cells surviving in very small tumors in a
mouse irradiated in a single fraction in vivo and subse-
quently assayed by transplantation to other animals. The
cellular survival curve is characterized by two distinct com-
factor of 2–3. Up to doses of several Gy, the response is
dominated by the killing of aerobic cells, while, for higher
doses, the killing of hypoxic cells dominates. It is apparent
that irradiating such tumors with a single large dose of sev-
eral tens of Gy is a futile exercise if the goal is sterilization,
since the hypoxic cells will not be adequately depopulated
with a dose of this magnitude. Figure 5.3 gives rough esti-
mates [31], based on in vitro data, of the single fraction dose
to sterilize a 30 mm diameter tumor, with and without a
hypoxic component.
57
58 D.J. Brenner and D.J. Carlson

100

90

80

70

60

Dose (Gy)
50

40

30

20

10

Fig. 5.1 Hypoxic regions (black) indicated by pimonidazole staining are 0

present even in small tumors. Imaged here is a section of a small tumor

sarcoma

SCLC

melanoma

NSCLC

colo-rectal

medullo

breast

prostate

brain

renal

ovarian

head & neck

derived from a human glioma xenograft line. Adapted from Rijken PF,
Peters JP, Van der Kogel AJ. Quantitative analysis of varying profiles of
hypoxia in relation to functional vessels in different human glioma xeno-
graft lines. Radiat Res. 2002 Jun;157(6):626–32; used with permission

Fig. 5.3 Rough estimate, based on in vitro data, of the single-fraction

100 dose required to sterilize various 30 mm diameter tumors, which are
either fully oxygenated (lower) or contain 20 % hypoxic cells (upper).
response dominated
Adapted from Leith JT, Cook S, Chougule P, Calabresi P, Wahlberg L,
10 –1 by aerated cells
Lindquist C, et al. Intrinsic and extrinsic characteristics of human
tumors relevant to radiosurgery: comparative cellular radiosensitivity
and hypoxic percentages. Acta Neurochir Suppl. 1994;62:18–27; used
10 –2 response dominated with permission from Springer Science + Business Media
by 1–2% hypoxic cells
Surviving Fraction

10 –3
10 –4
10 –5
10 –6
10 –7
0 5 10 15 20 25
Dose (Gy)
Fig. 5.2 Fraction of surviving cells, after a single radiation dose, in
small mouse lymphosarcomas irradiated in vivo. The shallow initial
part of the curve is due to the presence of aerated oxic cells, whereas the
steeper slope at higher doses is caused by the presence of 1–2 % of
hypoxic cells. Reprinted from Hall EJ, Brenner DJ. The radiobiology
of radiosurgery: rationale for different treatment regimes for AVMs
and malignancies. Int J Radiat Oncol Biol Phys 1993; 25:381–385.
Copyright 1993, with permission from Elsevier
However, malignant tumors exhibit a characteristic known
as reoxygenation whereby, between fractionated doses of
x- or γ-rays, tumors tend to reestablish their original pattern
and proportion of oxygenated and hypoxic cells. This prin-
ciple is illustrated in Fig. 5.4 [32]. In a fractionated regime,
therefore, each X- or γ-ray dose predominantly kills aerobic
cells, and the interval between treatments allows hypoxic
cells to reestablish their oxygenated state, thereby reducing
the problem of hypoxic radioresistance. An analysis [33] of
survival data for cervix cancer patients undergoing fraction-
ated external-beam radiotherapy and high dose-rate brachy-
therapy suggests the clinically relevant oxygen enhancement
ratio (OER) for hypoxic tumor subvolumes may be closer to
1.5, substantially lower than the typically reported value of
~3 for in vitro clonogenic survival under anoxic conditions.
An OER of 1.5 agrees with values reported in vitro for
oxygen concentrations of ~5 mmHg (0.66 %). However,
clinically derived OER values are averaged over cells under a
range of oxygen concentrations, so cells irradiated in vivo
under extreme levels of hypoxia, e.g., <0.5 mmHg, may still
have OER values higher than 1.5.
While stereotactic techniques offer valuable physical advan-
tages over conventional radiotherapy, the potential for reoxy-
genation is reduced as the total dose is delivered in a fewer
number of fractions. Hypofractionation may result in decreased
biological effectiveness for hypoxic tumors [34]. The clinical
significance of tumor hypoxia and reoxygenation within the
context of SRT is still a subject of rigorous debate [35].
5 Radiobiological Principles Underlying Stereotactic Radiation Therapy 59

100

0.36
rad/min

Fraction of Initial Colony-Forming

10 –1

Units (3.5 cells/col) Surviving

0.86
rad/min
10 –2

16
rad/min
10 –3

30
10 –4 rad/min
107
rad/min
10 –5
500 1000 1500 2000 2500
Dose (rad)

Fig. 5.5 Illustrating that, as a given single dose is protracted, either by low-
ering the dose rate (as here) or by increasing the number of fractions, the
Fig. 5.4 Schematic illustration of the process of reoxygenation: almost all
biological effect (in this case, cell killing of Chinese hamster cells)
tumors initially contain a mixture of aerated and hypoxic cells. A single
decreases, due to intra-fraction double-strand break (DSB) repair. Based on
radiation dose will kill a larger fraction of aerated oxic cells because they
data from Bedford JS, Mitchell JB. Dose-rate effects in synchronous mam-
are more radiosensitive (see Fig. 5.2). Thus after irradiation, a larger
malian cells in culture. Radiat Res. 1973 May;54(2):316–27. Reprinted
fraction of cells are hypoxic. But after a short time, the tumor tends to
from Hall EJ, Brenner DJ. The dose-rate effect revisited: radiobiological
return to its original proportion of oxic and hypoxic cells, allowing many
considerations of importance in radiotherapy. Int J Radiat Oncol Biol Phys
of the previously hypoxic (but now aerated) cells to be killed by a sec-
1991; 21:1403–1414. Copyright 1991; with permission from Elsevier
ond, and subsequent, dose fractions. Reprinted from Hall EJ, Brenner
DJ. The radiobiology of radiosurgery: rationale for different treatment
regimes for AVMs and malignancies. Int J Radiat Oncol Biol Phys 1993;
25:381–385. Copyright 1993, with permission from Elsevier

Repair

The second radiobiological principle is repair of DNA damage.

It has been well established for many decades that protracting
or fractionating an acute exposure reduces the level of cell kill-
ing. An example is shown in Fig. 5.5. If all tissues were equally
affected by changes in protraction or fractionation, then there
would be no radiotherapeutic significance to fractionation,
beyond the need to increase the dose to compensate for the
increased cellular repair of double-strand breaks (DSBs).
However, there is a wealth of experimental evidence
which indicates that there is a difference in shape between Fig. 5.6 The gamma ray dose–response curve for late responding tissues
the dose–response relationship characteristic of early (e.g., AVM obliteration, cerebral necrosis) has more curvature, i.e., a
small α/β ratio; for early responding endpoints such as tumor control, the
responding tissues and tumors and late responding tissues. dose–response curve is straighter, i.e., the α/β ratio is larger. Consequently
The inference from experiments in animals, which is con- dose fractionation spares late responding tissues more than early respond-
firmed in clinical practice, is that the dose–response relation- ing tissues. Reprinted from Hall EJ, Brenner DJ. The radiobiology of
ship for late responding tissues has more curvature than that radiosurgery: rationale for different treatment regimes for AVMs and
malignancies. Int J Radiat Oncol Biol Phys 1993; 25:381–385. Copyright
for early responding tissues, as shown in Fig. 5.6. 1993, with permission from Elsevier
In mathematical terms, if the dose (D)–survival (S) rela-
tionship is expressed in terms of a linear–quadratic relation,
then the ratio α/β (the dose at which the cell killing by the
S = exp ( -a D - b D 2 ) , (5.1) linear and quadratic terms is equal) tends to be small for late
60
responding tissues (less than ~3 Gy) and larger (greater than
~8 Gy) for early responding tissues [32, 36–40].
The practical consequence of the difference in shape
between the dose–response curves for early and late respond-
ing tissues is a marked difference in the response to fraction-
ation of these two types of tissues. Late-responding tissues
are more sensitive to changes in fractionation than early
responding tissues. The overall outcome is illustrated in
Fig. 5.6. A fractionated regime spares late responding nor-
mal tissues more than a single acute dose, for a given level of
tumor damage.
It is pertinent to ask what exactly constitute “early” and
“late” responding tissues. Probably early responding tissues
contain a large proportion of cycling cells, while late
responding tissues contain large proportions of non-cycling
cells.
Accelerated Repopulation
As a tumor shrinks during radiotherapy, the surviving clono-
gens are stimulated to proliferate at an accelerated rate [41,
42]. For T3 laryngeal cancer, this accelerated repopulation
does not commence for about 30 days after the beginning of
Fig. 5.7 Tumor control probability for T3 laryngeal cancer, as a func-
tion of overall time and overall dose. The data points, at the top of the
dashed vertical lines, are those reported by Slevin et al. [43], and the
surface is the result of a linear–quadratic (with repopulation) fit [42] to
the data, with repopulation effectively starting about 33 days after the
beginning of the treatment. Reprinted from Brenner DJ. Accelerated
repopulation during radiotherapy: quantitative evidence for delayed
onset. Radiat Oncol Invest 1993; 1:167–172. Used with permission
treatment as illustrated in Fig 5.7 [43]. Radiation treatments
of duration longer than about 30 days would therefore need
to increase the total dose to compensate for this clonogen
proliferation. Note that it is unrealistic to categorize almost
any tumor type as one which is not significantly prone to
D.J. Brenner and D.J. Carlson
repopulation—if research in predictive assays has taught us
anything, it is that inter-tumor variation can be large; thus, in
this context, some tumors will grow slowly and some will
grow very quickly. For example, it has been suggested that
the onset to repopulation may be as long as 60 days for
slowly proliferating prostate tumors [44].
How Do These Radiotherapeutic Principles
Apply to Stereotactic Radiation Therapy?
In general these three phenomena control the dose delivery
for cancer radiotherapy as follows:
1. We must fractionate treatment:
• To overcome hypoxia
• For differential response with late effects
2. We would like to prolong treatment:
• To limit early sequelae
3. We would like to shorten treatment:
• To prevent accelerated repopulation
Prima facie, requirements 2 and 3 are mutually exclusive
and so, in most radiotherapeutic situations, the overall treat-
ment time represents a compromise between short treatment
times to minimize tumor repopulation and long treatment
times to prevent unacceptable early complications. In those
protocols that have attempted to utilize shorter overall treat-
ment times, it has been necessary to reduce the overall dose
in order to avoid excessive early complications [45].
By contrast, stereotactic radiotherapy represents a situa-
tion where the contradictory aspects of overall treatment
time can be resolved without the need for compromise.
Because of the excellent dose distributions which can be
obtained using stereotactic radiotherapy, the need for long
overall treatment times to reduce early normal tissue compli-
cations will rarely apply. Specifically, early skin or mucosal
reactions, which are often a limiting factor in radiotherapy,
will not be an issue for intra-cranial stereotactic radiother-
apy. Thus short overall treatment times become a practical
possibility, with their attendant advantages in terms of limit-
ing tumor repopulation.
Inherently, then, SRT is advantageous in terms of repopu-
lation. We discuss here how the remaining two Rs of radio-
therapy (reoxygenation and repair) affect stereotactic
radiotherapy for the three main target lesions, malignancies,
AVMs, and benign tumors.
Malignancies
As we have discussed, it is very unlikely that a single dose
fraction could sterilize even a small tumor which contains
hypoxic malignant cells. Thus there is a clear rationale,
based on the issue of hypoxia, for stating unequivocally that
5 Radiobiological Principles Underlying Stereotactic Radiation Therapy
single-fraction radiotherapy, radiosurgery, is a suboptimal
modality when the target is a malignant tumor [46].
In addition, because of the differential α/β ratio of the
tumor and the surrounding late responding normal tissue
sequelae (such as delayed cerebral necrosis, or optic neu-
ropathy), even in the rare situation when there is minimal
hypoxia, single-fraction treatment of a malignancy would be
expected to give a suboptimal therapeutic ratio between
tumor control and late complications.
Thus an optimal stereotactic radiotherapy protocol for a
large intra-cranial malignancy would involve large numbers of
fractions over a short time period, for example, 20 fractions in
2 weeks might be an appropriate target. For smaller tumors,
where the relative dose to normal tissue surrounding the malig-
nancy is smaller—though still, as always, dose limiting—a
regime consisting of five or ten fractions over 1 week would
combine the clinical advantages of a very short overall time,
the radiobiological advantages of reoxygenation and (partial)
repair of late responding normal tissue damage, and the practi-
cal advantages of a small number of treatments.
It has been argued [47] that, even for malignancies, “when
the treatment volume is small and contains little functioning
brain tissue, the need for fractionation may not apply.”
However, the dose-limiting factor of any radiotherapeutic
treatment of a malignancy must always be the normal tissue
tolerance, so fractionation should always allow a greater
tumoricidal dose.
Of course one of the potential advantages of radiosurgery is
that it may be able to overcome the radioresistance of tumors
such as metastases from melanomas or renal-cell sarcomas.
However, by keeping the number of fractions low (perhaps to
five or six), the radioresistance of such tumors will still be
adequately addressed while maintaining the other biological
advantages of fractionation that have been outlined here.
The arguments presented here do not exclude the fact that
good results may be obtained using radiosurgery for brain
malignancies. Indeed there are reports of good results with
this technique. Rather, for any given situation, better
results—in terms of therapeutic ratio between tumor control
and complications—would always be expected by fraction-
ating than can be obtained with a single fraction—an impor-
tant consideration in the treatment of cerebral malignancies.
Arteriovenous Malformations
In treating AVMs, the goal is to produce progressive luminal
closure through an inflammatory reaction in the vessel walls
of the malformation, by irradiating the constituent epithelial
cells [48–51]. This is a classic “late” response, occurring
weeks to months after the radiation treatment and thus, prima
facie, one would expect a relevant α/β ratio similar to that for
other late responding tissue.
61
Fig. 5.8 Linear–quadratic fit to combined long-term AVM obliteration
data from Paris [57] and Pittsburgh [58]. The estimated α/β ratio from
this analysis is 5.2 Gy, consistent with a recent estimate of 3.5 Gy by
Kocher et al. [59], based on most currently available data, which is in
turn consistent with a typical α/β value for a late responding tissue
The issue here is that the dose-limiting side effect of the
treatment, generally delayed cerebral radionecrosis, is, of
course, also a late response [52–56]. Thus, in the treatment
of AVMs, the tissue which it is desired to damage and the
surrounding normal tissue that it is desired to spare are both
of the same radiobiological type, i.e., they are both late
responding tissues. Consequently one would expect that
nothing is to be gained by a fractionated course relative to a
single dose. In other words a change in fractionation pattern
will not preferentially produce more damage in the AVM
than in the surrounding normal tissues. The ratio of damage
between the AVM and the surrounding normal tissue would
be the same whether the dose is delivered in a single or in
multiple exposures. Given that the issue of hypoxic cells is
not relevant here, this is a strong rationale for radiosurgery,
i.e., a single, highly localized radiation treatment.
In fact, there have been few estimates of α/β ratios reported
in the literature corresponding to the end point of AVM oblit-
eration, as few dose–response data have been established. An
early estimate [46] of 0.6 Gy (range 0.2–5 Gy) was reported
based on limited dose–response results for complete AVM
obliteration after stereotactic irradiation with helium ions.
Using the more recent dose–response data from Touboul
et al. [57] and Flickinger [58], we estimated values of 5.2 Gy
from long-term obliteration data and 2.4 Gy [range 0.9–8 Gy]
from short-term obliteration data (see Fig. 5.8). A recent
analysis by Kocher et al. [59] of most available data resulted
in an overall best estimate of 3.5 Gy and an estimate of 4.6–
6.4 Gy for small AVMs. All these values are consistent with
those of a classic late response.
62
In summary, in the treatment of AVMs there is probably
nothing to be gained by a fractionated course relative to a
single dose. Thus, the optimal treatment for AVMs is
expected to be single-fraction stereotactic radiotherapy or
radiosurgery, i.e., a single, highly localized radiation treat-
ment at, of course, the appropriate dose.
Benign Tumors
Less is known about the sensitivity to fractionation of
benign tumors. It is less likely that hypoxia will be a signifi-
cant role here [60]; one estimate of the α/β ratio for benign
parasellar meningiomas is 3.3 Gy [61], similar to that for
late responding normal tissues. For benign tumors as with
AVMs, the most likely scenario is that both the target and
the surrounding normal tissue respond in a similar way to
fractionation, like that of a late responding normal tissue,
suggesting that there is little to be gained from fractionation.
For example, if the dose-limiting late sequelae were
radiation-induced optic neuropathy, which is caused by
damage to the arteries supplying the optic nerve, this almost
certainly responds to changes in fractionation like a classic
late responding tissue [62, 63].
In summary, in the treatment of benign tumors there is
probably nothing to be gained by a fractionated course, rela-
tive to a single dose. However, we certainly do not have ade-
quate data for a variety of benign tumors to consider this
conclusion definitive.
Mechanistic Models of Radiotherapeutic
Response
Why are we interested in mechanistic models to describe
radiotherapeutic response? There are really two reasons:
First, we need some model for calculating isoeffect doses
when alternate fractionation schemes are considered. Second,
mechanistic models are a useful tool for understanding
mechanisms—if a model based on given mechanisms is
inconsistent with the data, then we can conclude that the
assumed mechanism is either wrong or not the dominant one.
The tool most commonly used for quantitative predictions
of dose and fractionation dependencies is the linear–qua-
dratic (LQ) formalism [37, 38, 64–66]. In radiotherapeutic
applications, the LQ formalism is now almost universally
used for calculating isoeffect doses for different fraction-
ation/protraction schemes.
In contrast to earlier methodologies, such as CRE, NSD,
and TDF [67, 68], which were essentially empirical descrip-
tions of past clinical data, the LQ formalism has become the
preferred tool largely because it has a somewhat more biologi-
cal basis, with tumor control and normal tissue complications
D.J. Brenner and D.J. Carlson
specifically attributed to cell killing. By contrast, descriptive
empirical models can go disastrously wrong if used outside
the dose/fractionation range from which they were derived—
as when NSD was applied to large doses per fraction [69, 70].
Mechanistic Basis
of the Linear–Quadratic Model
The standard model is that both tumor control and complica-
tions result primarily from cell killing [38, 71, 72]—and the
LQ is a mechanistic model of cell killing (though see below
for discussions of possible alternate mechanisms). In Eq.
(5.1), αD can be interpreted as the quantity of lethal DNA
lesions formed by a single radiation track, i.e., unrejoinable
DSBs, lethally misrepaired or fixed DSBs, and lethal intra-
track exchange-type chromosome aberrations, while βD2 can
be interpreted as the quantity of lethal DNA lesions formed
by two radiation tracks, i.e., lethal inter-track exchange-type
chromosome aberrations formed through binary misrepair of
two separate DSBs [66, 73]. Underlying the application of
the LQ to fractionation and protraction effects is the pairwise
misrepair of primary lesions such as DSBs or base damage
formed by separate radiation tracks (hereon in, we shall refer
to the DSB as the primary lesion, but base damage sites may
well also be relevant here [74]). As schematized in Fig. 5.9,
cell killing can occur via chromosome aberrations such as
dicentric aberrations [75], formed when pairs of nearby
Fig. 5.9 Examples of binary misrepair: (a) shows two chromosomes;
each has one double strand break (DSB), shown as a gap. Centromeres,
which are needed for proper transmission of chromosomes to daughter
cells at mitosis, are shown as black constrictions. Most DSB are cor-
rectly restituted, but a few undergo binary misrepair. (b) Binary misre-
pair can result in a dicentric chromosome aberration, which generally
destroys the clonogenic viability of the cell. In about half the binary
misrepair events, the two DSBs shown in (a) lead to a translocation (c).
Translocations involve large scale rearrangements and can cause poten-
tially precarcinogenic alterations in cellular phenotype but most do not
impair cellular survival. Reprinted from Brenner DJ. The linear–qua-
dratic model is an appropriate methodology for determining isoeffec-
tive doses at large doses per fraction. Semin Radiat Oncol. 2008; 18:
234-239. Used with permission
5 Radiobiological Principles Underlying Stereotactic Radiation Therapy
DSBs wrongly rejoin to one another [76]. Protracting the
exposure time potentially allows the first DSB to be repaired
before the second is produced, and the LQ approach quanti-
fies this effect [66]. Nowadays, this binary DSB misrepair
model is the most usual way to motivate the standard LQ
approach, but different biological rationales for the same
mathematical formalism have also been given, as we will
discuss.
It is important to stress here that the standard LQ formal-
ism, as applied to time–dose relationships, is not merely a
truncated power series in dose. Its key feature here is a spe-
cific mechanistically based functional form for the protrac-
tion factor, usually designated by G, which takes into account
dose protraction or fractionation. Expressions for special
cases of the time factor, G, were derived by Lea and
Catcheside [65, 77]; a general form was subsequently derived
[78] and has since been rederived from several different
points of view [70]. We refer to this general form of the time
factor, given explicitly in Eq. (5.5), as the generalized Lea–
Catcheside time factor, G.
The LQ Formalism
The LQ model, in its most usual current version, describes
cell killing in terms of the following mechanisms:
1. Radiation produces many types of clustered DNA lesions,
including the DSBs, proportional to absorbed dose up to
several hundred Gy for low- and high-LET radiation
[79–82]. Experiments such as these imply that single-
track mechanisms are responsible for the induction of
DSBs and all other types of clustered DNA damage.
2. These DSBs can be repaired, with first-order rate con-
stant λ(=ln 2/T½, where T½ is the repair halftime).
In practice, there may be more than one class of DSB
which may be repaired with different rate constants; the
LQ formalism can be simply extended to take this into
account.
3. In competition with DSB repair, binary misrepair of pairs
of DSBs produced from different radiation tracks (i.e.,
different photons) can produce lethal lesions (often iden-
tified as predominantly dicentric chromosomal aberra-
tions), the yield being proportional to the square of the
dose (see the quadratic term in Eqs. 5.2 and 5.4). The two
independent radiation tracks can occur at different times
during the overall regimen, allowing repair of the first
DSB to take place before it can undergo pairwise misre-
pair with the second; it is this phenomenon which is the
heart of the fractionation/protraction dependence in the
LQ formalism.
4. In addition, single radiation tracks can produce lethal
lesions, possibly by a variety of mechanisms, the yield
being linearly proportional to the dose.
Overall, in the LQ formalism, the yield (Y) of lethal
lesions and the corresponding survival (S) equation are
63
Y μ a D + Gb D2 . (5.2)
(Note that the biologically effective dose, biological effec-
tive dose (BED), is defined as Y/α [37].) Then, assuming the
lethal lesions are Poisson distributed from cell to cell, the
surviving fraction will be
S = exp ( -Y ) , (5.3)
and thus
S = exp éë - (a D + G b D 2 ) ùû . (5.4)
In Eqs. (5.2) and (5.4), G is the generalized Lea–Catcheside
time factor, which accounts quantitatively for fractionation/
protraction; it is important to note that G acts only on the
quadratic component, as described in Point 3 above. The
generalized time factor has the form [78]
¥ t
- l (t -t )
G = ( 2 / D 2 ) ò D ( t ) dt ò e D ( t ¢ ) dt ¢ .
¢
(5.5)
-¥ -¥
Here D ( t ) describes the variation in dose rate over the entire
course of the radiotherapy, and λ is a characteristic damage
repair rate. Generically, the term after the second integral sign
refers to the first of a pair of DSBs required to produce a lethal
lesion—the exponential term describing the reduction in num-
bers of such DSB through repair; similarly, the term after the
first integral sign refers to the second DSB, which can interact
with DSBs, produced earlier, that still remain after repair.
The time factor, G, can be calculated for any fractionation/
protraction scheme and systematically accounts for the effects
of protracting the dose delivery in any way. G can take values
from zero to one, with G = 1 for a single acute dose, leading to
the simplest single-fraction LQ formalism shown in Eq. (5.1).
The interpretation of G < 1 is a reduction in cell killing due to
intra-fraction DNA repair which occurs during protracted
radiotherapy. Two special cases, which illustrate the main fea-
tures of the general expression for G, are: (1) for irradiation
with n short fractions, each separated by a time T [83]:
G = éë 2q / (1 - q ) ùû éë n - (1 - q n ) / (1 - q ) ùû , (5.6)
where θ = exp(−λT). When the time between the short frac-
tions is very long, then
G = 1/ n, (5.7)
and the most simple LQ model for well-separated fraction-
ated exposures becomes
S = exp éë - D (a + b D / n ) ùû . (5.8)
Different fractionation/protraction schemes have different
time factors, G, any of which can be calculated [64, 84] from
64
Eq. (5.5). Even for high dose rates, dose protraction effects
may have a significant impact on cell killing and, ultimately,
treatment effectiveness [85, 86].
The LQ model can further be used to relate cell death to
clinical endpoints of interest. The tumor control probability
(TCP) model quantifies the response of a group of patients to
a specific radiotherapy treatment and is essential in the anal-
ysis of clinical data for local control. The TCP model relates
the tumor volume (or number of tumor cells) and the radia-
tion dose to the probability of tumor cure, i.e., the probability
that no tumor cells survive the radiation treatment. The most
commonly used TCP algorithm [87, 88] is based on Poisson
statistics:
TCP = exp éë - N × S ( D ) × eg (T -Tk ) ùû , (5.9)
where N is the initial number of tumor clonogens, S(D) is the
surviving fraction of cells predicted by the LQ model, T is
the overall treatment time, and Tk is the lag time before
accelerated tumor repopulation begins. The repopulation rate
of tumor cells, γ, is conveniently expressed as γ = ln(2)/Td,
where Td is the effective tumor doubling time. The TCP for-
malism can also be modified to include interpatient variabil-
ity in radiosensitivity [89].
How Well Does the LQ Model Work,
At Low and High Doses?
The goal here is to be able to make equi-effect regimen
extrapolations from standard regimes, typically with
1.8–2 Gy per fraction, to hypofractionated regimes. Possible
hypofractionated doses per fraction are, for example, up to
about 7 Gy for prostate [90], and up to about 15–20 Gy for
non-small cell lung cancer (NSCLC) [91]. For fractionated
stereotactic radiotherapy, we are interested in extrapolating
in the opposite direction, from single-fraction doses as high
as 18 Gy to hypofractionated exposures with lower doses per
fraction [92].
So the general question is whether the LQ formalism
described in the previous section describes radiotherapeuti-
cally relevant dose–responses in the dose-per-fraction range
from, say, 1.8 to 20 Gy. For many situations, such as prostate
cancer hypofractionation, the dose-per-fraction range of
interest is probably about 1.8–7 Gy.
We have previously argued that the LQ model does pro-
vide an appropriate methodology for determining isoeffective
doses at large doses per fraction [93]. Below, we discuss
some in vitro and in vivo experimental data to address the
question, and then discuss some alternate mechanistic mod-
els to the LQ equations, and their potential impact, relative to
LQ-based predictions.
D.J. Brenner and D.J. Carlson
In Vitro
It is not easy to generate precise, accurate measurements of
cell survival at high radiation doses. One recent approach to
this problem is to use DNA flow cytometry for counting cell
numbers, rather than colonies. This approach can produce
very high statistics data and establish precise survival curves.
Figure 5.10 shows such survival data for irradiated CHO
cells [94], where it can be seen that the standard errors can be
made very small with this approach. The single-fraction
LQ-model fit (Eq. 5.1) to these data clearly fits very well,
indicating that it can predict the pattern of dose–responses
over the key 1.8–7 Gy dose range.
Similar results have recently been reported by Garcia
et al. [95], using a more standard colony assay to measure
cell survival. In this case, surviving fractions in the dose
range from zero to 16 Gy were measured. In order to esti-
mate dose regions where the single-fraction LQ model
(Eq. 5.1) did/did not fit the data, the authors fitted the data
from 0 to 4 Gy, and then from 0 Gy to progressively larger
doses, each time assessing the goodness of fit of the model to
the data. Typical results are shown in Fig. 5.11, where it can
be seen that the quality of fit to the LQ model does not
decline significantly until doses above 15 Gy are included.
In Vivo
There are a fairly wide range of quantitative in vivo end-
points for which it is possible to test concordance with the
LQ predictions in the 1.8–20 Gy range [96]. Figure 5.12, for
Fig. 5.10 Survival of x-irradiated CHO cells, determined by flow
cytometry population counting, 5 days after treatment [94]. The curve
is the corresponding LQ model fit. Reprinted from Brenner DJ. The
linear–quadratic model is an appropriate methodology for determining
isoeffective doses at large doses per fraction. Semin Radiat Oncol.
2008; 18: 234-239. Used with permission
5 Radiobiological Principles Underlying Stereotactic Radiation Therapy
Fig. 5.11 Goodness of fit of LQ model to measured cell-survival data,
as a function of the dose range which was fitted [95]. The quantity plot-
ted is χ2 per degree of freedom; hence, smaller values represent better
fits to the LQ model. For example the left-most point represents a good
fit of the LQ model to cell-survival data in the dose range from 0 to
4 Gy and the right-most point represents a less good fit of the LQ model
to cell-survival data in the dose range from 0 to 16 Gy. Reprinted from
Brenner DJ. The linear–quadratic model is an appropriate methodology
for determining isoeffective doses at large doses per fraction. Semin
Radiat Oncol. 2008; 18: 234-239. Used with permission
example, shows some isoeffect results from Van der Kogel
[97] for late responding damage to the rat spinal cord, from
Douglas and Fowler [98] for acute damage in mouse skin
and from Peck and Gibbs [99] for early and late damage to
the murine small intestine. The form of the plot, the so-called
reciprocal-dose Fe plot [96, 98], is such that, if the LQ for-
malism applies, the data would fall on a straight line.
Although the reciprocal-dose plot approach is not an optimal
methodology for parameter estimation [100, 101], it does
provide a visual indication of how well in vivo data agrees
with the LQ model, in the dose range of interest. All the
quantitative in vivo endpoints in Fig. 5.12 are consistent with
the LQ model, over a wide range of doses per fraction,
including those of interest in hypofractionation. Extensive Fe
plot analyses by Barendsen [96], using 12 normal tissue
response endpoints, reached the same conclusion. While
more sophisticated methods are available for assessing
agreement with the LQ model [102], given the inherent
uncertainties in the data, it is clear that all these data, includ-
ing those for single fractions of ~20 Gy, are consistent with
the LQ model.
Clinical outcome data for local tumor control can also be
used to test the validity of the LQ model over different dose
ranges and fractionations. The application of TCP models to
local control data for early-stage NSCLC and the validity of
this LQ-based approach at high stereotactic doses are further
discussed below.
65
Fig. 5.12 Isoeffect data for late response from three (open square,
open circle, open triangle) different regions of the rat spinal cord [97],
for acute skin reactions (filled diamond) in mice [98], and for early
(filled circle) and late (⊕) murine intestinal damage [99]. The data are
plotted in a “reciprocal-dose Fe” form [98] such that, if they follow a
linear–quadratic relationship, the points fall on a straight line. Reprinted
from Brenner DJ. The linear–quadratic model is an appropriate meth-
odology for determining isoeffective doses at large doses per fraction.
Semin Radiat Oncol. 2008; 18: 234-239. Used with permission
Is the LQ Model Correct?
We have shown that the LQ model is reasonably predictive of
dose–response relations, both in vitro and in vivo, in the dose
per fraction range of 1.8–15 Gy. Of course it goes without
saying that no mechanistic model describing dose–time pat-
terns can be fully complete or correct, so we discuss here
some of the main perceived mechanistic uncertainties associ-
ated with the LQ model.
Pairwise Production of Chromosome
Aberrations Is Not the Only Mechanism
Mediating Cell Killing
Again it is argued that cell killing is the dominant process
mediating radiotherapeutic response [38, 71, 72], both for
early and late effects, including vascular effects. But not
all cell killing is mediated through chromosome aberra-
tions produced by pairwise misrepair. However, other
cell killing mechanisms—such as apoptosis and induction
of small mutations—are dose-rate independent [103].
66
The LQ incorporates both dose-rate-independent mecha-
nisms such as these (in the linear term) and dose-rate-depen-
dent mechanisms (in the quadratic term). Assuming LQ
correctly models the mechanisms involved in the dose-rate-
dependent term, then with appropriate parameters (α/β actu-
ally is the ratio of the dose-rate-independent term to the
dose-rate-dependent term), LQ should be adequate predict-
ing fractionation/protraction effects.
There Are Other Mechanistic
Models Describing Pairwise Production
of Chromosome Aberrations, as Well as LQ
It has been known for some time that, in addition to the LQ
model, various other binary misrepair models lead to the
same generalized Lea–Catcheside time factor, G, in an appro-
priate approximation, and thus predict virtually the same
time–dose relations as does the LQ approach. This result was
demonstrated by several authors [73, 83, 104–107] for the
repair–misrepair (RMR) model [108], lethal–potentially
lethal (LPL) model [105], the repair–misrepair–fixation
(RMF) model [73], and more general binary misrepair
models. In light of the conceptual similarities between the
LQ model and other binary misrepair models, the fact that
the corresponding formalisms make virtually equivalent
predictions for dose–time relationships is not, in retrospect,
particularly surprising.
Lethal Lesions Are Not Poisson Distributed
from Cell to Cell
This Poisson assumption, embodied in Eq. (5.3), is used in
all models which calculate the fraction of inactivated cells
from the average yield of lethal lesions. It is certainly the
case that, based on microdosimetric considerations, this dis-
tribution is not exactly Poisson [109]. For densely ionizing
radiations such as heavy ions or neutrons, this point is well
taken and important. But for sparsely ionizing radiation such
as X- or γ-rays, below ~50 Gy per fraction, deviations from
a Poisson distribution are quite minor [66, 110].
Repair Mechanisms Saturate at High Doses
Various high dose saturable repair (SR) models have been con-
sidered [111–115], all having in common the notion that per-
lesion repair rate decreases as the dose—and the production of
initial damage—increases. This might arise, for example, if
repair enzymes can be overloaded. Such a change in repair
rates with increasing dose might in principle result in different
dose–response relations at high doses, compared with the LQ
approach where repair rates are dose independent.
D.J. Brenner and D.J. Carlson
In fact there is no, as yet, strong evidence that saturable
repair mechanisms are important at the doses and dose rates
of relevance to radiotherapy [116]. However, since SR mod-
els appear, prima facie, to be mechanistically different from
binary misrepair models, there is the possibility that they
could make significantly different predictions of fraction-
ation/protraction effects, casting doubt on the validity of
LQ-based isoeffect dose calculations. In fact, the formalisms
describing most SR models also lead, in an appropriate
approximation, to the same time–dose relations as does the
LQ formalism [104]. This comes about because these SR
formalisms reduce to the specific form of the generalized
Lea–Catcheside time factor, G, which describes protraction
effects in the LQ approach.
Different Mechanisms at High Single Doses?
One additional aspect of the use of large dose fractions is the
possibility that tumor cell death might be enhanced by addi-
tional biological processes resulting in tumor cell killing
[117], such as rapid endothelial cell apoptosis in tumor ves-
sels or systemic abscopal effects. Garcia-Barros et al. [118]
have reported that vascular endothelial cell apoptosis occurs
at doses greater than ~8 to 10 Gy. Recently published clinical
data showing a high rate of short-term local control for
patients with metastatic spinal cord tumors treated with large
single doses have been attributed to this phenomenon [119].
Provocative data on the stimulation of antitumor immunity
for melanoma treated with stereotactic body radiation ther-
apy (SBRT) have also been reported [120, 121]. There
remains a need, however, for more preclinical and clinical
studies before this novel “high dose” biology should be
accepted as a new mechanism for the effect of high dose
fractions [122]. In addition, evidence presented below still
suggests that the LQ model provides a good description of
local control data at high doses per fractions despite these
possible additional biological mechanisms that are not
captured in the model.
The Success of Stereotactic Radiation
Therapy: Better Dose Distributions,
Not Better Biology
While other radiobiological mechanisms at high doses per
fraction have been shown in the laboratory, there is to date no
clinical evidence of their relevance to SRT response, and the
LQ model appears to be appropriate for use at all the doses
and fractionation schemes of relevance to SRT. Rather than
new biological mechanisms, recent analyses of clinical data
suggest that the great success of SRT is primarily related to
its improved conformal dose delivery that permits significant
escalation of the biologically effective doses [123, 124].
5 Radiobiological Principles Underlying Stereotactic Radiation Therapy
Prima facie, single-fraction radiotherapy appears to rep-
resent a major paradigm shift from the practice of radiother-
apy that has developed over the past 90 years. Specifically,
essentially all non-stereotactic treatment plans to date involve
significant volumes of normal tissue receiving doses close to
the prescribed tumor dose. It follows that the goal in such a
scenario is to maximize tumor response for an acceptable
level of normal tissue damage probability—and the primary
tool that radiotherapists have used to maximize this thera-
peutic ratio has been fractionation. The benefit of dose frac-
tionation is supported by an abundance of animal and human
data generated over many decades.
SRT can ignore this classic fractionation paradigm, yet
still be remarkably successful, because of technical advances
brought about by image-guided robotic technology or multi-
leaf collimated beams: these techniques can deliver large
tumor doses with very small margins, thereby minimizing
large doses to large volumes of normal tissue. For many
tumor sites, such as tumors in the periphery of the lung, this
has reduced the concern about unacceptable normal tissue
injury and allowed considerable dose escalation.
It is hardly surprising that additional biological processes
(described above) would come into play when tumor doses
are increased so markedly. The important question is whether
any or all of these processes, colloquially termed a “new
biology” [122], need to be invoked to explain the high local
control rates obtained with SBRT. Since most successful
SBRT regimens deliver very high BEDs to the tumor, is the
impressive efficacy of SBRT the result of “new biology” or
simply the high BEDs delivered to the tumor?
Mehta and colleagues [125] recently reviewed the avail-
able clinical TCP data for SBRT and 3D conformal radio-
therapy (3D-CRT) for early-stage NSCLC. Figure 5.13 is a
replot of the NSCLC TCP data as a function of BED. It is
clear there is a monotonic relationship between TCP and
BED for SBRT—as the delivered BED to the tumor increases,
so does the probability of local control. This conclusion is
consistent with the results from 3D-CRT studies of NSCLC,
which consistently use lower BEDs and consistently demon-
strate lower TCPs—though the different dose distributions
involved here make comparison harder to interpret.
Based on these two observations that (1) TCP increases
monotonically with BED and (2) the TCP vs. BED relation
is the same whether single or multiple fractions are used, we
can say with some confidence that the great success of SBRT
is due to the fact that the new stereotactic radiotherapy tech-
nologies provide dose distributions that permit the clinician
to prescribe BEDs of 100 or more Gy [126]—tumor BEDs
that are simply unreachable with conventional dose distribu-
tions. A “new biology” is therefore not necessary to explain
the high cure rates for NSCLC. They are simply a result of
the much higher delivered tumor doses. This does not mean
that different radiobiological mechanisms do not exist at the
high doses associated with SBRT, and it would be surprising
67
Fig. 5.13 Tumor control probability (TCP) as a function of biological
effective dose (BED) for stage I NSCLC. Symbols show crude local
control rates (≥2 years) from a pooled analysis reported by Mehta et al.
[125] with different symbols distinguishing 3D-CRT and SBRT regi-
mens. Solid line shows an LQ-based fit to the available data
if there were none at these very high BEDs. However, these
potential new mechanisms seem unlikely to be contributing
to clinical response more than the standard biological mech-
anisms that dominate in conventional radiotherapy.
Conclusions
For malignant tumors:
• Radiobiological and clinical arguments, based on the
need to overcome hypoxia, and the potential for a differ-
ential response between the tumor and the surrounding
normal tissue, strongly suggest that fractionation will
result in improved outcome.
• For most malignancies, even when good dose distribu-
tions can be obtained, single-fraction radiation therapy
has not been in general use for more than 70 years.
• For most sites, only a few fractions (5–10) would be
optimal for treating malignant tumors.
• Modern technology has made fractionated stereotactic
radiotherapy practical and often logistically advantageous.
For AVMs:
• The arguments in favor of fractionation probably do
not hold, and single-fraction treatment is generally
optimal.
• There is no hypoxic cell issue to overcome, and both the
AVM and the surrounding normal tissue probably respond
the same way to changes in fractionation.
For benign tumors:
• There is some evidence that benign tumors respond to
fractionation like a late responding normal tissue, in
which case fractionation would not improve outcome,
unless hypoxic cells were an issue.
68
• Overall, the radiobiological evidence is probably insuffi-
cient to make recommendations on appropriate fraction-
ation schemes for benign tumors.
For calculations of biologically effective dose with the lin-
ear–quadratic model:
• The mechanistically based LQ approach appears to be
appropriate for use at all clinically relevant doses and
fractionation schemes.
• While novel radiobiological mechanisms at high doses
have been shown in the laboratory, there is to date no evi-
dence from the clinic of their relevance.
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 Treatment Planning for Stereotactic
Radiosurgery
David M. Shepard, Cedric Yu, Martin J. Murphy,
Marc Bussière, and Frank J. Bova
Introduction
This chapter provides an introduction to treatment-planning
procedures for stereotactic radiosurgery (SRS). A brief
history of SRS planning is provided in section “Background
on SRS Planning.” The basic steps followed in the develop-
ment of an SRS treatment plan are described in section
“Basic Steps in Developing an SRS Treatment Planning”
including imaging, contouring, selection of plan parameters,
and evaluating treatment plan quality. Section “Gamma
Knife” focuses on treatment planning for the Gamma Knife.
Sections “Linac-Based SRS with Circular Cones” and
“Linac-Based SRS with Multileaf Collimators” discuss lin-
ear accelerator-based SRS, and the final two sections (sec-
tions “CyberKnife” and “Proton SRS”) cover planning for
the CyberKnife and proton radiosurgery.
D.M. Shepard, Ph.D. (*)
Department of Radiation Oncology, Swedish Cancer Institute,
Seattle, WA, USA
e-mail: david.shepart@swedish.org
C. Yu, D.Sc.
Department of Radiation Oncology, University of Maryland
School of Medicine, Baltimore, MD, USA
M.J. Murphy, Ph.D.
Department of Radiation Oncology, Virginia Commonwealth
University, Richmond, VA, USA
M. Bussière, M.Sc.
Department of Radiation Oncology, Massachusetts General
Hospital, Boston, MA, USA
F.J. Bova, Ph.D.
Department of Neurosurgery, University of Florida,
Gainesville, FL, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_6, © Springer Science+Business Media New York 2015
6
Background on SRS Planning
Over the past three decades, radiosurgery has been trans-
formed from a curiosity available at a single institution to a
routinely used therapy available at medical facilities through-
out the world. During this increase in utilization, radiosurgi-
cal planning and delivery techniques have undergone
significant technical improvements including: (1) availabil-
ity of true three-dimensional (3D) image data, (2) improved
plan delivery techniques, and (3) increased sophistication of
planning algorithms.
The most critical improvements have come about through
the availability of true three-dimensional image data pro-
vided primarily through computed tomography (CT) and
magnetic resonance imaging (MRI) scanning techniques.
Today’s practicing radiosurgeon has the advantage of view-
ing target and nontarget tissues with increased contrast reso-
lution and with dramatically improved spatial resolution.
Clinician has also benefited from the development of tools
for registering or fusing single and multimodality datasets.
The second area that has undergone significantly improve-
ment is that of plan delivery. For several years, the only
radiosurgical device available was the Gamma Knife. The
Gamma Knife has now been joined by several designs that
use linear accelerators as the radiation source. While the ini-
tial linear accelerator (linac)-based systems were less accu-
rate than the Gamma Knife, devices were developed in the
late 1980s that provided significant improvement in the
delivery accuracy of linac-based radiosurgical units. Recent
years have seen additional advancements in basic linac tech-
nology resulting in highly accurate base linear accelerators.
These devices provide efficient radiosurgical delivery, and
have made it possible to extend the benefits of radiosurgery
to targets outside the cranium.
The third area of technological advancement in radiosur-
gery has been the increased sophistication of the planning
algorithms that has been made possible by the tremendous
increase in computer processing power over the past three
73
74 D.M. Shepard et al.

decades. The ability to process images, register images, and a large number of beam paths are required to concentrate the
develop plans has gone from a process that required many dose in the target and create steep dose gradients. It is impor-
hours to one that can be accomplished in a matter of seconds. tant to note that as new SRS delivery techniques emerge, cli-
This has allowed radiosurgical teams to not only develop and nicians must examine the impact on dose conformity as
evaluate their first best guess at a plan but to iterate through compared with historical SRS delivery techniques using the
many different plans in order to arrive at a more optimal Gamma Knife or linac-based delivery with circular collima-
plan. tors. A loss in dose conformity may force the user to adopt a
While these planning and delivery tools help provide treatment schedule that deviates from basic radiosurgical
improved treatment plans, the basics principles set forth by principles and begins to depend more upon radiological prin-
Lars Leksell in the 1950s remain the foundation for radiosur- ciples. While this may be appropriate in certain clinical situ-
gery [1–4]. Leksell’s basic idea was to place the target tis- ations, a cautious approach is warranted.
sues in the center of a large number of beams of radiation.
The beams arrangement was designed so that the beams only
intersected over the target issues and they quickly diverged Basic Steps in Developing an SRS Treatment
from the target in all directions. Planning
The majority of clinical data published on radiosurgery is
based upon a planning technique known as sphere packing. The basic steps followed in radiosurgery treatment planning
This technique was initially developed by Leksell and con- are illustrated in Fig. 6.1.
stitutes the basis of the Gamma Knife planning process. It
has also been used in conjunction with many of the linac-
based delivery systems. In this technique, a set of beams are Stereotactic Localization
aimed at a point in space, known as the isocenter. The beams
are selected so that they approach and leave the isocenter Because SRS involves the delivery of a very high dose of
through unique paths, providing both geometric concentra- radiation in either a single delivery or a small number of
tion and a high-dose gradient. Much of the accuracy dis- fractions, it is essential to achieve a high degree of dose
cussed in the radiosurgery literature is a measure of the conformity and accurate patient positioning. This critical
delivery systems’ ability to precisely target radiation beams
at this “point” in space. The resultant dose distribution is
approximately spherical and therefore provides a reasonable
plan for spherical target volumes. For more complex target
shapes, a technique known as sphere packing is employed. In
this technique, the planner places the initial dose sphere
inside the target volume. The initial dose sphere is typically
selected to be the largest sphere that the system can produce
and that can fit “inside” the target volume. The planner then
continues to pack the target volume with spheres of equal or
smaller diameter until adequate target coverage is achieved.
An advantage of linear accelerator-based system over the
Gamma Knife is the ability to produce larger spheres and
therefore pack a specific volume with fewer total spheres or
isocenters. These spheres of dose are created using beam sets
that deliver radiation from a large number of beam angles.
The Gamma Knife makes use of 192 (or 201) individual
beams while multiple arcs are used in the linear accelerator
systems. It has been shown that in order to produce the con-
centration and gradient, which is responsible for a vast major-
ity of all published radiosurgical clinical outcomes, at least 15
beams must be spread over approximately 2π space [5].
In recent years, SRS delivery techniques have expanded
beyond the Gamma Knife and linac-based delivery using cir-
cular collimators to include the CyberKnife, tomotherapy,
and the adaptation of linacs with mini multileaf collimators
(MLC). While each of these systems offers the radiosurgeon
special features, they are all bound by the same principle that Fig. 6.1 The basic steps in SRS treatment planning
6 Treatment Planning for Stereotactic Radiosurgery 75

Fig. 6.3 (a) The fiducial indicator box for CT imaging. (b) The patient
is imaged with a fiducial box attached to the frame (Photos courtesy of
Elekta)

Fig. 6.2 Gamma knife coordinate frame (Photo courtesy of Elekta)

dosimetric requirement is accomplished by stereotactically

focusing many convergent radiation beams on the target. By
cross-firing a large number of beams, a high dose is delivered
in the region of intersection with a rapid falloff in dose out-
side of the target.
One approach to accurate stereotactic localization is
achieved with fixation frames such as the frame shown in
Fig. 6.2. On the day of the procedure, this fixation frame is
fixed to the patient’s skull under local anesthetic. The frame
serves two important purposes. First, it provides a rigid fixa-
tion system that ensures that the patient cannot move during
the delivery. Secondly, it provides a frame of reference
whereby the tumor location can be determined relative to the
frame and relative to the delivery unit.
One approach for facilitating the registration of the patient
images is to attach a fiducial box (see Fig. 6.3) to the stereo- Fig. 6.4 The fiducial marks appear as white dots on this MRI image of
tactic head frame before patient imaging. The box includes a Gamma Knife patient (Photo courtesy of Elekta)
tubes filled with a high-contrast solution that provides easy
to delineate fiducial marks on each of the patient’s images invasive nature of fixation frames makes them a less viable
(see Fig. 6.4). option. Fractionation radiosurgery, known as stereotactic
After the imaging is complete, the patient images are radiotherapy (SRT), is commonly delivered to patients where
loaded into the planning system. The images are registered the likelihood of late toxicity makes it inadvisable to treat a
with respect to the fiducial marks. The markings on the fidu- large target volume in a single high-dose fraction [7, 12–14].
cial box provide a coordinate system that makes it possible to
precisely determine the position of the treatment volume
with respect to the stereotactic head frame. Patient Imaging
In addition to the fixation frames described above, frame-
less SRS techniques have been developed that maintain a The three primary imaging techniques for SRS are MRI, CT,
highly precise delivery [6–12]. Frameless SRS is typically the and planar angiography. MRI is an excellent technique for
preferred option in fractionated radiosurgery where the imaging soft tissue contrast. MRI, however, does not provide
76
Fig. 6.5 One approach to image registration
attenuation coefficients, and must be fused with CT images
if one wishes to correct for to make appropriate heterogene-
ities in the dose calculation. It should be noted that in most
MRI units the spatial uniformity of the images degrades as
the radius of the images increases. Because most fiducial
systems place the fiducial markers at the outermost extent of
the MRI image volume, the accuracy obtained in mapping
the imaged voxels to stereotactic space can be compromised.
This is one of several reasons some radiosurgical practitio-
ners have opted for image fusion technologies as opposed to
direct stereotactic MRI scanning (see Fig. 6.5).
CT imaging provides inferior soft tissue contrast as com-
pared with MRI scanning. However, the spatial resolution of
CT is extremely reliable. CT also provides attenuation coef-
ficients that make it possible to make accurate heterogeneity
corrections in the dose calculation.
Planar angiography is an imaging option that can be used
for imaging patients with arteriovenous malformations
(AVMs). While plane film angiography was the gold stan-
dard for AVM nidus identification, cut films have almost
been fully replaced by electronically derived images. For the
past few decades, the primary mode of electronic image
acquisition has been the image intensifier. While this device
is known for its excellent image contrast, it is equally known
for its poor spatial accuracy. Most image intensifiers have
multiple levels of image distortion. More recently, solid-state
image acquisition systems have been developed. These sys-
tems have all but eliminated concerns regarding spatially
nonuniform images.
An additional problem with angiography is that while plane
film angiography can provide images in multiple planes, the
basic image set that the clinician has to work with is two
dimensional. This two-dimensional image dataset can lead to
inaccuracies in the target definition. It is for this reason that
most targeting for vascular radiosurgery targets are obtained
either through CT angiography, MRI angiography, or both.
Registering the Images
The general planning procedure starts with the acquisition of
three-dimensional image information and the import of
D.M. Shepard et al.
patient images into the treatment-planning system via a
computer network or data storage media. On the planning
computer, these images are typically displayed in two-dimen-
sional slices along the axial, sagittal, or coronal planes [15].
A screen capture from the GammaPlan system is shown
in Fig. 6.4 that illustrates the process of aligning the fiducial
marks in the SRS planning system. The planning system
must be able to accurately identify the fiducial marks and
have internal mechanisms for validating their consistency.
Once the fiducial markers are identified, the patient anatomy
shown on the images is placed in the coordinate system
defined by the stereotactic localization device.
Some systems use fiducial markers that fully define the
stereotactic reference system while others require specific
information from the scanner. For example, a fully defined
system does not require information on the axial slice posi-
tion. This is because it can derive this information from the
actual scan image. Consequently, this approach eliminates
the need for QA measurements to guarantee accurate scanner
information such as linearity of table movement or degree of
gantry tilt.
Frameless systems also need to be able to map the three-
dimensional dataset into a rigid and definable coordinate sys-
tem. To achieve this, stereotactic systems have been designed
that incorporate surrogate fiducial markers into the CT or
MRI scans. These markers can also be referenced at the time
of therapy through mechanical, electrical, or optical means.
A critical feature of frameless systems is the ability to demon-
strate that the reference can in fact be reliably and precisely
fixed to the patient. Many systems offer testing only at the
time of design and development. These tests are usually at the
hands of the developer, an expert with extensive experience.
It is critical for a repeat fixation system to also provide a
methodology of testing its accuracy for each patient.
Shows the RadioCameras™ Treatment Guidance System
(Varian, Palo Alto, CA). This system provides patient-specific
statistics on the device’s ability to be precisely reapplied.
Two basic approaches are used in the registration of
images. The first is to use direct stereotactic MRI and CT
scanning. In this procedure, fiducial markers are incorpo-
rated into both image datasets and each dataset is indepen-
dently mapped into stereotactic space. In the second
approach, stereotactic CT scanning is performed using a
fiducial system when acquiring the images. Non-stereotactic
MRI scans are also obtained (see Fig. 6.5). The MRI scans
are then mapped into stereotactic space by registration of the
MRI dataset to the CT dataset. In most cases, rigid registra-
tion techniques are used. Typically, the clinician visually
inspects the results of the registration to verify the quality of
the fit. An advantage of this second approach is that it allows
the MRI scan to be obtained prior to the placement of any
stereotactic ring. Consequently, the clinician can exam the
actual scan that will be used for scanning prior to deciding
that radiosurgery is the appropriate mode for treatment.
6 Treatment Planning for Stereotactic Radiosurgery
Fig. 6.6 Skull-scaling device used with the Gamma Knife to provide
mapping of the skull (Photo courtesy of Elekta)
Contouring Structures
After the images have been imported into the planning sys-
tem and the fiducial marks have been registered, the target to
be treated is then identified. To aid target delineation, fusion
of images from different imaging modalities is possible with
many SRS planning systems. While some planning systems
may not require the users to outline the target and critical
structures, contouring is required if plan evaluation tools
such dose-volume histograms (DVHs) are to be used.
Contouring is also required by systems that employ inverse
planning.
The patient’s external contour can either be manually
contoured or identified automatically by the planning system
based on grayscale information from the images. For Gamma
Knife planning, the skin contour or scalp of the patient’s
head is measured with a skull-scaling device (see Fig. 6.6).
The location of the surface is important for computing the
penetration depth for each beam during the dose calculation.
The skull-scaling device used for Gamma Knife planning
makes it possible to know the penetration depth for each
photon beam even if the entire skull has not been imaged.
Defining the Prescription
The dosimetric characteristics of the treatment plan vary
from one delivery approach to another. With the Gamma
77
Knife and linac-based SRS using cones, the use of multiple
isocenters means that multiple spherical isodose distribu-
tions have to be packed into the target volume. Overlaps of
such high-dose spheres are inevitable. As a result, the dose is
highly nonuniform in the target. The isodose surface that
encloses the target (which is often taken as the prescription
dose) is typically 50 % of the maximum dose in the target.
For linac-based SRS using an MLC, the target dose is
highly uniform when a single isocenter is used. The isodose
line that encompasses the target can be greater than 80 % of
the maximum dose in the target. In SRS, the prescription
dose is normally set to the dose level that conforms to the
target, or the minimum target dose. As compared with frac-
tionated radiation treatments, radiosurgery treatment plans
have significantly less normal tissue included in the prescrip-
tion isodose volume. For this reason, the typical restrictions
on dose uniformity (a foundation of fractionated radiation
therapy) do not apply in radiosurgery cases. The radiosur-
geon is more concerned with the dose to normal tissue out-
side the target volume. Consequently, the goal in treatment
planning is to achieve maximum normal tissue sparing rather
than maximum target dose uniformity.
The radiosurgeon can minimize the dose to normal tissue
by designing a plan where the isodose that just covers the
target surface is along the steepest portion of the dose gradi-
ent. It can be shown that for single-isocenter plans, this
places the optimal dose prescription at the 80 % isodose sur-
face [16]. This is because the dose gradient falls off most
quickly, between the 80 and 40 % isodose surfaces. Therefore,
prescribing to the 80 % isodose line minimizes the integral
dose to all normal tissues, the tissues outside the target vol-
ume. For multiple isocenter plans, this optimal surface shifts
to the 70 % isodose surface and at time can be extended to
isodose surfaces as low as the 50 % dose surface, as is often
the case in Gamma Knife plans.
Designing the Treatment Plan
For optimal planning, the neurosurgeon, radiation oncolo-
gist, and physicist or dosimetrist should perform the treat-
ment planning as a team and bring all aspects of expertise to
bear on the problem. After the images have been imported
and registered and contouring of structures has been com-
pleted, one can proceed with the task of formulating a treat-
ment plan that meets the dosimetric requirements specified
by the physician. The planning steps that are followed differ
from one delivery technique to the next. For the Gamma
Knife and for linac-based SRS with circular collimators, the
task of planning is to find a set of isocenter locations, the size
of the collimators to use for each location, and the weights of
the isocenters. Multiple isocenters are commonly used in a
Gamma Knife treatment plan due to the limited number of
collimator sizes to choose from and the relative efficiency
78
with which each isocenter can be delivered [17–24]. For
linac-based SRS with circular collimators, the planner strives
to minimize the number of isocenters in a plan to compen-
sate for the relative inefficiency of the beam delivery [25,
26]. Linac systems, however, have the advantage of a much
wider range of collimators usually extending from 5 to
50 mm in diameter.
For linac-based SRS with MLCs, only one isocenter is
used [25, 27–37], and the planning methods are similar to
those used for external beam radiation therapy. The selection
of beam directions and field shapes is aided by the use of
tools such as beam’s-eye-view (BEV) visualization and digi-
tally reconstructed radiographs (DRRs).
Dose Calculation
A variety of dose calculation techniques have been employed
for SRS treatment planning [38–48]. Simple empirical dose
calculation methods were employed with many of the earlier
SRS planning systems [17]. For Gamma Knife radiosurgery,
a standard set of beam data is included with the system, and
the user verifies the dose profiles of an individual beams for
each of the focusing helmets. The use of a standard dataset is
possible because all Gamma Knife systems use the same
design with only slight variations in the single beam dosim-
etry. The dose distribution in the patient is calculated by
adding the dose distributions for all 192 beams [20]. For
linac-based SRS with circular collimators, the tissue-
maximum ratios (TMRs) and dose profiles can be measured
for each collimator size as a function of depths. For a given
arc, the mean TMR for all beam directions is calculated and
the total dose contributed by the arc can be calculated. Dose
distributions can be computed by approximating an arc as a
series fixed beams and summing the dose distributions from
all of the beams.
For intracranial SRS, heterogeneity corrections are
generally not applied in the dose calculation. Corrections
to account for variations in the attenuating properties of
tissue, bone, and air are not needed because of the simple
geometry that is employed [44, 49]. The magnitude of the
resulting error can be estimated by assuming that the aver-
age beam passes through 5 mm of skull with an average
density of 1.2 g/cc. Assuming an attenuation of 4 %/cm for
a 6 MV beam, the maximum error in absolute TMR that
would result from ignoring heterogeneity corrections is
less than 1 %. However, when SRS is extended to extracra-
nial applications, traditional empirical dose calculation
methods are no longer adequate for accurate dose calcula-
tions due to the presence of bone and air. Therefore, many
treatment-planning systems designed for planning extra-
cranial SRS employ 3D pencil beam dose calculation
methods.
D.M. Shepard et al.
Forward Versus Inverse Planning
Forward planning is the most common planning approach
for SRS. With forward planning, the treatment plan is devel-
oped through an iterative trial and error approach. From one
iteration to the next, the planner attempts to determine a set
of parameters (such as beam angle, beam weights) that give
an acceptable plan. The iterative process is usually stopped
when the planner is no longer able to make noticeable
improvements in the plan quality.
With inverse treatment planning, the user begins by out-
lining the target and any sensitive structures. A series of
treatment goals are then defined, and an optimization algo-
rithm determines the plan parameters that provide a plan that
best satisfies these goals. The quality of the plan is scored
using an objective function and constraints. An objective
function reduces an entire treatment plan into a single
numerical value. The job of the optimizer is to either mini-
mize or maximize the value of the objective function.
Typically, an optimization will also include one or more con-
straints. A constraint is a condition that must be satisfied in
order for a solution to be considered feasible. The most basic
constraint in any radiotherapy optimization is that the beam
weights must be nonnegative.
As compared with forward planning, inverse planning
provides two potential advantages. First, the time required
for planning can be reduced because much of the trial and
error is removed. Secondly, inverse planning should lead
to improved plan quality due to the ability of the optimizer
to consider thousands of plan configurations in selecting
the optimal plan. Unfortunately, the quality of inverse
planning tools for SRS varies significantly from one deliv-
ery technique to the next and one planning system to the
next. Users of some systems will find that an experienced
planner using forward planning techniques produces the
highest quality plans.
Evaluation of Plan Quality
The most common tool for evaluating plan quality is the
visualization of isodose curves superimposed on the patient’s
anatomical images. Figure 6.7a shows a typical isodose plot
for a Gamma Knife patient. In this case, the isodose curves
are plotted as a percentage of the maximum target dose.
Isodose curves can also be plotted as a percentage of the pre-
scribed dose or as absolute dose lines. When evaluating plan
quality, it is common practice to visualize isodose curves in
the axial, sagittal, and coronal planes. Some systems can also
display three-dimensional dose clouds that make it possible
to quickly assess the quality of the dose coverage.
DVHs also serve as an important tool for analyzing plan
quality. A DVH plot from a Gamma Knife patient is shown
6 Treatment Planning for Stereotactic Radiosurgery
Fig. 6.7 (a) A Gamma Knife isodose plot with the target outlined in red, the 50 % isodose line in yellow, and the 30 % isodose line in green. (b)
Dose-volume histogram for target in this case
in Fig. 6.7b. For each structure, the DVH plots the fraction of
the volume covered by each dose level. Both the dose and the
volume can be expressed as either absolute or relative values.
DVHs are particularly useful because they reduce a three-
dimensional treatment plan into an easy to read two-
dimensional plot. The comparison of multiple plans is also
simplified by overlying DVHs on the same plot. The disad-
vantage of DVHs is the lack of spatial information. A DVH
will indicate the presence of hot or cold spots, but it does not
provide specify where in the structure of interest this under-
dosage or underdosage is located. Consequently, slice-by-
slice evaluation of a plan is critical in making a final decision
regarding a treatment plan.
Additional parameters have been defined to score both
dose conformity and target coverage for SRS treatment plans
[50–58]. The most commonly used parameter for scoring
dose conformity is the conformity index defined in the radio-
surgery quality assurance guidelines of the Radiation Therapy
Oncology Group (RTOG) [52]. The RTOG defined the con-
formity index as the volume of the prescription isodose sur-
face divided by the target volume. For a perfectly conformal
plan where the prescription isodose line exactly matches the
target volume, the conformity index would equal 1. A case is
considered to be per protocol if this ratio falls between 1.0
and 2.0. A shortcoming of this index is that it does not con-
sider the degree of overlap between the prescription isodose
curve and the target. A plan with a complete geometric miss
of the target could still give a perfect conformity index. As an
alternative, Lomax and Scheib have suggested a conformity
index defined as “the ratio of the volume within the target
irradiated to at least the prescription isodose over the total
volume enclosed by the prescription isodose” [55].
Consequently, this value ranges from 0 (no conformity) to 1.0
(for perfect conformation, where the prescription isodose is
79
identical to the target volume). As a planning goal, Lomax
and Scheib suggest a conformity index of 0.6 or higher.
The RTOG has also defined a homogeneity index that is
equal to the maximum dose in the treatment volume divided
by the prescription dose. A case is considered per protocol if
this ratio is less than or equal to 2.0. In terms of target cover-
age, the RTOG considers a case to be per protocol if the iso-
dose line equal to 90 % of the prescribed dose completely
encompasses the target. Lomax and Scheib suggest an alter-
native volumetric definition of coverage where target cover-
age is defined as the percentage of the target volume covered
by the prescription [55].
Gamma Knife
Gamma Knife Unit
The first Gamma Knife was built in 1967 under the direction
of Lars Leksell of the Karolinska Institute in Stockholm,
Sweden. Currently, there are over 300 units worldwide with
approximately 60,000 patients treated annually [59]. Over
the years, there have been a number of advances and updates
to the Gamma Knife. Two models of the Gamma Knife are
currently offered by Elekta, the 4C (introduced in 2004) and
the Perfexion (introduced in 2006).
Gamma Knife 4C
Inside of the shielded treatment unit of the Gamma Knife 4C
(Fig. 6.8), the beams from 201 radioactive sources are
focused so that they intersect at a single location. The result
is an elliptical region of high dose with a rapid falloff in dose
80
Fig. 6.8 A patient positioned for treatment on a Gamma Knife model
4C (Photo courtesy of Elekta)
outside of the boundaries of the ellipse. Each exposure to an
elliptical region of high dose is referred to as a “shot” of
radiation.
For each exposure, the focusing helmet dictates the size
of the high-dose region. A focusing helmet incorporates a
separate collimator for each of the 201 Co-60 sources (see
Fig. 6.9a). The four focusing helmets provided with the
Gamma Knife can be used to produce a shot of radiation that
is 4, 8, 14, or 18 mm in diameter (see Fig. 6.9b). Within each
helmet, individual collimators may be plugged to provide
further shaping of the dose distribution. The benefits of plug-
ging are illustrated in Fig. 6.9.
Figure 6.10a shows the isodose curve for a single 4 mm
shot for a trigeminal neuralgia patient. In Fig. 6.10b, a plug-
ging pattern has been used to lower the dose to the brainstem.
The plugging pattern is shown in Fig. 6.10c.
After the imaging is complete, the patient images are
loaded into the Gamma Knife’s treatment-planning system
(GammaPlan). The images are registered with respect to the
fiducial marks, and the treatment volume is outlined by a
physician.
At the time of treatment, the patient lies on the couch of
the treatment unit, and the appropriate focusing helmet is
affixed to the table. The patient’s stereotactic head frame is
then attached to the focusing helmet, and the x, y, and z coor-
dinates are adjusted to place the center of the planned shot of
radiation at the focal point of the 201 beams of radiation.
After, the personnel leave the room, the exposure time is pro-
grammed, the door of the shielding unit is opened, and the
D.M. Shepard et al.
Fig. 6.9 The four focusing helmets dictate the size of each shot of
radiation (Photo courtesy of Elekta)
couch is advanced into the high radiation field. Next, the
treatment couch is docked, and the shot of radiation is deliv-
ered. After the exposure is complete, the couch retracts and
the door closes. If more than one shot of radiation is to be
delivered, the process is repeated with the appropriate focus-
ing helmet and x, y, and z positioning. The model 4C Gamma
Knife provides an automated positioning system in which
the shot positions and exposure times are directly transferred
to a record-and-verify system, and the machine sets the coor-
dinates in an automated fashion.
The treatment planning for the Gamma Knife 4C is rela-
tively straightforward for small spherical targets. For exam-
ple, Fig. 6.11 shows a case where the treatment volume is
relatively spherical and approximately 6 mm in diameter. An
8 mm shot of radiation was placed so that it covers the entire
tumor volume.
The treatment-planning process becomes more complex
when the tumor volume is large or irregularly shaped. These
cases typically require several shots of radiation. Through an
iterative process, the planner must determine the number of
6 Treatment Planning for Stereotactic Radiosurgery
Fig. 6.10 The isodose curves for a trigeminal neuralgia patient before (a) and after (b) plugging. (c) The plugging pattern. 35 of the 201 sources
have been blocked (blocked collimators are shown in black)
Fig. 6.11 A single shot treatment plan for a Gamma Knife treatment.
The target outlined in blue, the 50 % isodose line in yellow, and the
30 % isodose line in green
shots of radiation that are required along with the size, the
location, and the weight that should be assigned to each.
In Fig. 6.12, a simple 2D bean-shaped target is used to
illustrate the general planning procedure [22]. Each frame
illustrates the dosimetric impact of an added shot of radia-
tion. In this case, five shots of radiation provide a conformal
treatment plan. Note that three different shot sizes were used
in creating this plan.
During the process of treatment planning, the plan quality
is evaluated through the use of isodose plots and DVHs.
81
In the GammaPlan system (the Gamma Knife specific
treatment-planning system), users typically normalize to the
maximum dose and seek to cover the target with the 50 %
isodose line.
Gamma Knife Perfexion
In 2006, Elekta introduced the Gamma Knife Perfexion
which includes a significant redesign of the Gamma Knife.
The most critical change in the Perfexion is the new collima-
tor system. The new system replaces the multi-helmet colli-
mator setup with a single integrated permanent collimator
system that incorporates openings for 4, 8, and 16 mm treat-
ment beams.
The collimator is partitioned into eight independently
moveable sectors each delivering 24 beams of radiation
meaning there is a total of 192 Co-60 sources. The beam size
can be changed dynamically by sector, and individual sectors
can be blocked to provide further shaping of each shot of
radiation. For each shot, an ellipsoidal shot of radiation can
be delivered by utilizing the same sized beams from each of
the eight sectors. More sophisticated shaping of the dose dis-
tribution can be obtained by mixing beams of various sizes
and/or blocking individual sectors. Unlike with the model 4C
where it is necessary to manually block individual beams to
shape the dose distribution, the Perfexion makes it possible
to simply move individual sectors into the off position to
block the beams that pass directly through a particular criti-
cal structure.
In addition to the updated collimator design, the Perfexion
introduces a number of other changes to the Gamma Knife.
One change is in the positioning system design. The
Perfexion positions the patient by moving the couch rather
than moving patient’s head. Rapid transition times are
82 D.M. Shepard et al.

a b c
5 100 5 1 5 1
90 0.9 0.9
80 0.8 0.8
centimeters

70

centimeters
0.7

centimeters
0.7
60 0.6 0.6
2.5 50 2.5 0.5 2.5 0.5
40 0.4 0.4
30 0.3 0.3
20 0.2 0.2
10 0.1 0.1
0 0 0
2.5 5 2.5 5 2.5 5
centimeters centimeters centimeters
d e f
5 1.2 5 5
1.2 1.2
1.0
1.0 1.0
centimeters

centimeters

centimeters
0.8 0.8 0.8
2.5 0.6 2.5 2.5
0.6 0.6
0.4 0.4 0.4
0.2 0.2 0.2
0

Fig. 6.12 (a) A bean-shaped target. (b–f) The process of adding shots to create a treatment plan is illustrated

achieved moving from one shot of radiation to the next
because there is no need to change focusing helmets and the
beams are simply moved into the off position during the tran-
sition. This ability to quickly switch from one shot of radia-
tion to the next facilitates the treatment of larger tumors as
well as patients with multiple brain metastases.
The Perfexion provides improved patient comfort due the
increased space inside the collimator body. The larger colli-
mator size also eliminates the need for eccentric frame posi-
tioning, and makes it possible to treat most peripheral lesions.
The Perfexion is also the first Gamma Knife model that
offers a stereotactic frame with a vacuum-assisted bite block
(the Extend system) that makes it possible to deliver frame-
less fractionated treatments.
Linac-Based SRS with Circular Cones
Initial developments in the use of linear accelerator-based
SRS techniques were centered on the use of multiple con-
verging arc treatments delivered with circular collimators.
For each treatment plan, the user must select the number of
arcs, the angular arrangement of each arc, the weight
assigned to each arc, and the number of isocenters. When
one isocenter is used, the high isodose levels at the isocenter
are nearly spherical. A variety of arc arrangements have been
reported [26, 60]. As compared with the Gamma Knife, a
greater number collimator sizes is available with circular
collimators. By adjusting the weightings of the arcs or
through an asymmetric arc arrangement, ellipsoidal instead
of spherical isodose distributions can be created.
For tumors that are small and convex in shape, it is often
possible to treat with only one isocenter. When one isocenter
is used, the dose uniformity in the target is high and the dose
can be prescribed to a high isodose level. When the target
volume is large or it deviates from a sphere or an ellipsoid,
multiple isocenters are typically required to achieve adequate
target dose conformity. The spherical high-dose regions must
overlap in order to avoid leaving a cold spot in the target.
Consequently, one must accept a decreased target dose uni-
formity as compared to plans using a single isocenter. To
date, no negative clinical consequences have been reported
as a result of the lack of dose uniformity seen in Gamma
Knife and linac-based circular collimator treatments.
When multiple isocenters are used, the treatment-planning
problem is similar to sphere packing problem of the Gamma
Knife [61], where spherical dose distributions are packed
together to achieve a composite dose distribution conform-
ing to the target volume. Because the setup and delivery time
per isocenter is typically longer for linac-based radiosurgery
as compared with Gamma Knife-based radiosurgery, it is
generally desirable to deliver a limited number of isocenters.
However, the greater selection of collimator sizes and the
availability of larger collimator sizes as compared with the
Gamma Knife reduce the need for the use of a large number
of isocenters. Overall, the Gamma Knife centers and linac-
based SRS centers have reported similar cure rates and com-
plication levels.
6 Treatment Planning for Stereotactic Radiosurgery
Linac-Based SRS with Multileaf Collimators
An MLC is a field-shaping device that uses movable leaves
made out of a highly attenuating material such as tungsten in
order to generate arbitrary field shapes (see Fig. 6.13). The
first MLCs designed for routine external beam delivery typi-
cally had leaf widths that projected to 1 cm at isocenter.
These MLCs lacked the geometric precision for shaping
small irregularly shaped fields such as those in commonly
encountered in SRS.
Interest in the use of MLCs for radiosurgery increased
when vendors introduced micromultileaf collimators
(mMLCs), a type of MLC where each leaf projects to a width
of between 2 and 5 mm at isocenter. mMLCs are suitable for
SRS applications, because they are capable of shaping small
irregular fields with acceptable geometric error. Typical
mMLCs have between 20 and 80 leaves, arranged in pairs.
The maximum field size of mMLCs generally varies from 8
to 20 cm, much greater than those available with traditional
circular collimators. As a result, extracranial SRS and stereo-
tactic body radiation therapy (SBRT) can be delivered.
Additionally, vendors now offer MLCs designed for
both conventional treatments and radiosurgery. For exam-
ple, Elekta’s Agility MLC has 160 leaves of projected
width 0.5 cm at isocenter and offers field sizes up to
40 × 40 cm. Varian offers their HD 120™ MLC, a 120 leaf
MLC which can deliver field sizes up to 22 × 40 cm with
2.5 mm leaves (projected at isocenter) across the central
8 cm of the field.
Due to their ease of use and wide range of possible appli-
cations, the advent of MLCs has led to a decline in popular-
ity of SRS delivery using circular collimators.
As compared with Gamma Knife and linac-based SRS
with circular collimators, the use of an MLC and a single
Fig. 6.13 A photo of Varian’s high definition multileaf collimator
(HD-MLC) (Varian Medical System, Inc. All rights reserved.)
83
isocenter can lead to plans that are less conformal with a less
steep dose gradient at the target edge. The decreased dose
gradient is in part the result of the use of larger beams and
fewer unique beam paths. As mentioned previously, a routine
Gamma Knife plan will involve as many as 201 beams and a
typical plan for a linac-based cone-beam treatment would
include five arcs each covering approximately 100° of gantry
rotation. By contrast, a typical micromultileaf plan may have
as few as six beams.
Target size is a second issue that impacts one’s ability to
create a conformal treatment plan using an MLC. For small
targets, such as in the treatment of trigeminal neuralgia, high
precision in target localization and positioning is required.
MLCs may not be suitable for target sizes significantly less
than one centimeter due to the undulating field edges caused
by the finite leaf width. For larger targets, MLC can provide
efficient beam delivery and dose uniformity due to the use of
a single isocenter [50]. However, the dose to surrounding
structures increases as the size of the target increases [50].
As a result, the dose to normal structures may exceed the
acceptable limits if one attempts to treat a large tumor with a
single fraction.
Generally multileaf collimators (including mMLCs) can
be used for four delivery approaches: (1) fixed-field confor-
mal delivery; (2) dynamic conformal arc delivery; (3) fixed-
field intensity-modulated radiation therapy (IMRT); and (4)
volumetric modulated arc therapy (VMAT).
Fixed Fields: 3D Conformal Delivery
With MLCs, three-dimensional (3D) conformal therapy
treatment-planning techniques can be applied to SRS plan-
ning. If there are a sufficient number of MLC-shaped beams,
the dose distribution quality can rival that obtained using
with multiple arcs using circular collimators and multiple
isocenters. This is especially true when the targets are larger
and non-spherical in shape. Because only one isocenter is
needed, the dose uniformity created with MLCs is generally
better than that achieved with the use of circular collimators
and multiple isocenters. With the exception of the need for
stereotactic reconstruction from stereotactic frames and
markers, the planning method for SRS essentially matches
that for 3D conformal therapy. Each non-coplanar field is
shaped based on the BEV of the target with additional mar-
gins to account for the width of the beam penumbra, which is
wider than the penumbra from circular collimators and
increases with leaf width.
The use of fixed fields delivered with an MLC is best
suited for convex target shapes. With fixed fields, there is
only a limited ability spare normal tissues in the center of a
concave volume.
84
Dynamic Conformal Arcs
In dynamic conformal arc delivery, the shape of the field
changes continuously to conform to the BEV of the target
during arced beam delivery. Dynamic conformal arc delivery
combines the dosimetric advantages of arcs (reduced hot-
streaks of dose through the patient) with the dose conformity
that is possible with MLC beam shaping. Additionally, this
approach only requires a single isocenter. With the use of
three or four non-coplanar arcs, a uniform high-dose volume
can be created that conforms to the target.
Treatment planning for dynamic conformal arcs requires
the delineation of the target and critical structures. The planner
must determine the number of arcs, their length, and their
arrangements. For planning and delivery control, each arc is
approximated as a series of fixed fields. The shapes are
typically set based on the beam’s eye view (BEV) of the target
and critical structures. For example, one can set each field
shape contained within an arc to match the BEV of the target
plus a 3 mm margin. Additionally, one may choose to use the
BEV of a critical structure to design field shapes that block
that structure throughout the arc path. If the gantry of the
accelerator rotates with a constant speed and maintains a con-
stant dose rate during rotation, one must assign the same num-
ber of monitor units to each beam angle within a given arc.
The dose calculation for conformal arcs is more compli-
cated than that for conventional arcs due to fact that the field
shapes changes while the beam is on. The planning system
must calculate the dose contributions from a large number of
irregularly shaped fields. In determining the angular spacing
of the fixed fields, one must balance the need for accuracy
with the desire for a reasonably quick dose calculation time.
When an arc is approximated with fields spaced more than 5°
apart from one another, the lack of sufficient field overlap
results in undulating features in the lower isodose lines away
from the focal region. These features are not reflected in the
actual delivery. Finer spacing of the beams will reduce such
artifacts in the displayed isodose lines.
In some treatment-planning system, a long arc can also be
broken into multiple sub-arcs. The weights of these sub-arcs
can be optimized based on the user-defined dose-volume con-
straints [62]. During delivery, each of these sub-arcs is treated
as a separate beam. Generally, this technique works best on
convex targets and less well on targets with concave surfaces.
Fixed-Field Intensity-Modulated Fields
With fixed-field IMRT, a modulated intensity pattern is deliv-
ered from each beam direction. Consequently, radiation can
be delivered to the target through preferred locations within
each beam. From each beam direction, the dose delivered to
the target is nonuniform. However, all of the beams in combi-
D.M. Shepard et al.
nation produce a highly conformal dose distribution. For both
external beam radiation therapy and SRS, IMRT improves
dose conformity as compared with the use of conventional
unmodulated beams [63]. It should be noted that for small
intracranial targets, IMRT delivered with an MLC may be
unable to achieve the dose conformality obtained using sphere
packing due the fact the width of the leaves of the MLC are
on the order of the size of the targets to be treated.
The IMRT planning problem is modeled by subdividing
each beam into a grid of beamlets. The weight, or intensity,
of each of the beamlets is then determined. Because of the
complexity of determining the appropriate beamlet weights
inverse (automated) planning techniques are employed.
IMRT planning for SRS and IMRT planning for external
beam radiation therapy share the same general procedures.
The user defines a series of treatment goals, and an optimiza-
tion algorithm determines the plan parameters that lead to a
plan that best satisfies those goals.
Volumetric Modulated Arc Therapy
Volumetric modulated arc therapy (VMAT) also known as
intensity-modulated arc therapy (IMAT) is a rotational
approach to the delivery of IMRT making use of a conven-
tional linear accelerator and a conventional MLC. The gantry
speed, dose rate, and MLC leaf positions are all varied
dynamically while the gantry rotates about the patient. The
degree of intensity modulation is determined by the number
of arcs as well as the number of aperture shapes included
within each arc. The ability to modulate the intensity of radi-
ation can provide significant dosimetric advantages relative
to dynamic conformal arc therapy.
In 2007, Varian and Elekta each introduced delivery con-
trol systems capable of delivering VMAT. Since that time,
VMAT has become a widely adopted delivery technique. A
key advantage of VMAT is the highly efficient nature of the
delivery. This is particularly beneficial when delivering the
large doses utilized in radiosurgery treatments. The effi-
ciency can be further increased when VMAT is combined
with flattening filter-free delivery, a technique where the
beam is delivered without a flattening filter thereby permit-
ting very high-dose rates.
CyberKnife
Overview
The CyberKnife (see Fig. 6.14) is a fully integrated radio-
surgery system that uses a pair of kilovoltage imaging
devices to locate the treatment site and direct the external
treatment beam [64]. The treatment beam is provided by a
6 Treatment Planning for Stereotactic Radiosurgery
Fig. 6.14 A CyberKnife (Figure courtesy of Accuray, Inc.)
linear accelerator (linac) mounted to a robotic arm that is
capable of maneuvering and pointing the linac with nearly
complete freedom within the treatment workspace (with the
exception of the angles blocked due to the interposing of the
linac between the diagnostic X-ray source and the amor-
phous silicon imaging panels located in the floor).
During treatment, the imaging system repeatedly acquires
planar images using a pair of amorphous silicon imagers and
compares the coordinates to the structures to be tracked
(either implanted fiducial markers or visible anatomical
structures) with those in the reference DRRs that are
generated from the planning CT images. After a rapid image
comparison process (taking a few milliseconds), the updated
coordinates of the beams are supplied to the robot and the
position of the robot is updated to compensate for the any
movement of the target. This enables the system to maintain
alignment of the beam with the target even if the patient
moves [11, 65].
The maneuverability of the beam, unconstrained by an
isocenter, combined with the capacity to adjust alignment
during treatment, endows the CyberKnife with unique dose
delivery capabilities. These capabilities enable (1) the deliv-
ery of highly conformal dose distributions to irregular target
volumes, (2) the delivery of fractionated SRT treatments, and
(3) the treatment of extracranial sites that are not amenable to
localization and/or fixation using conventional stereotactic
frames. They are exploited in a treatment-planning system
that has been designed specifically for the CyberKnife.
85
Beam Characteristics
The treatment beam is provided by a 6 MV X-band linear
accelerator that does not employ a flattening filter. The beam
is collimated to a circular cross section by one of a set of
twelve interchangeable collimators. At a source-to-surface
distance (SSD) of 80 cm, these collimators provide a beam
diameter that ranges from 5 to 60 mm. The SSD of the beam
can be varied from 60 to 100 cm. A continuous range of
beam diameters can be achieved by varying the collimator
size and SSD. In 2008, Accuray introduced the Iris variable
aperture collimator. The Iris incorporates two stacked banks
of six tungsten segments that in combination create a
12-sided variable aperture. The variable aperture automati-
cally replicates the sizes of the 12 fixed collimators. The key
benefit of the Iris aperture is that it reduces treatment time by
facilitating the efficient combination of varying beam sizes
within a single delivery.
Treatment Sites, Planning Scenarios,
and Imaging Requirements
All treatment planning for the CyberKnife is based on a CT
study used alone or in conjunction with supplemental diag-
nostic imaging such as MRI. As with most radiosurgical and
SRT systems, the CT study is utilized for both target delinea-
tion and dose calculation. However, with the CyberKnife, the
86
Fig. 6.15 Optimized plan for a spinal lesion
CT also plays a critical role in the image guidance aspect of
the delivery process. If MRI images are to be used to enhance
anatomical delineation, then the MRI study must be fused to
the CT study prior to beginning the planning process.
The integrated image guidance system allows the
CyberKnife to target any treatment site that can be located
via radiographic landmarks. Targeting is achieved by regis-
tering the landmarks in the kilovoltage (kV) alignment
images with their counterparts in DRRs derived from the
treatment-planning CT study.
For treatment sites that maintain a rigid relationship with
bony landmarks that can be easily visualized on planar
images (such as intracranial lesions), target localization can
be achieved by measuring the position of the skeletal fea-
tures in the treatment room. For treatment sites in soft tissue,
a common localization strategy is to make use of fiducial
markers implanted near the lesion in a manner similar to
those being employed by other extracranial systems. Accuray
has also introduced the Xsight Spine tracking system that
uses advanced image-registration tools to automatically
track lesions or targets in or near spinal structures. Accuray’s
Xsight Lung tracking system automatically compensates for
the tumor motion without the need for implanted fiducials.
These targeting capabilities enable the user of the
CyberKnife to plan treatments for central nervous system
(CNS) lesions in the cranium and anywhere along the spine,
as well as soft tissue sites in the thorax, abdomen, and pelvis.
Although the general treatment-planning procedure is not
site specific, each site introduces some distinctive elements
to the planning process.
The important role that the planning CT study plays in
target localization and beam alignment during treatment
D.M. Shepard et al.
places additional demands on its spatial resolution. To
achieve optimal targeting accuracy [66], it is recommended
that the CT slice thickness not exceed 1.25 mm [67]. While
this slice thickness is commonly used for intracranial lesions,
it is a higher spatial resolution than is typically used for rou-
tine diagnostic studies of extracranial sites.
CNS lesions, including tumors and AVMs, are the most
commonly treated sites. As examples of CNS applications,
we take note of two specialized treatment-planning prob-
lems: trigeminal neuralgia and spinal lesions. The trigeminal
nerve is visualized for planning using CT cisternography
[68]. The patient is scanned over the full head in the
Trendelenburg position. Typically, 64 cGy is prescribed to
the 80 % isodose line, encompassing approximately 8 mm of
nerve, and is delivered in one fraction. Beam alignment and
tracking during treatment is based on the position of the cra-
nium visualized in the treatment room radiographs.
Treatments of lesions along the spine are delivered in 1–5
fractions. Targeting is based on typically based on automated
tracking of skeletal structures. The planning CT study (see
Fig. 6.15) is set up to visualize the region in and around the
lesion with the patient lying supine in an alpha cradle. The
typical treatment dose is 1,200–2,000 cGy prescribed to the
80 % isodose line. Dose to the cord is limited to 800 cGy.
Experience from numerous treatments has shown that
patients resting supine in an alpha cradle move less than
3 mm over the course of a 30 min treatment fraction [9]. The
image guidance system detects and corrects for intra-fraction
movement.
In addition to CNS sites, the CyberKnife has been used
to treat pancreatic, lung, prostate, and other soft tissue
tumors.
6 Treatment Planning for Stereotactic Radiosurgery
The Planning Process
The CyberKnife treatment-planning process combines a
variety of user-managed and automatic planning operations
to arrive at satisfactory deliverable plans. The planning sys-
tem uses a CT study as the primary planning resource. The
dose calculation process makes a coarse accommodation of
anatomical inhomogeneities by distinguishing air, tissue,
and bone based on the Hounsfield number.
The robotic manipulator has a great deal of flexibility in
positioning and aiming the treatment beam. This makes it
possible to deliver both isocentric and non-isocentric dose
distributions. To utilize the full benefit of this flexibility and
at the same time make planning calculations tractable, the
planning system works with a discrete set of linac positions
(called nodes) and a discrete set of pointing directions at
each node analogous to a multitude of isocenter-gantry-table
positions in routine radiosurgery planning. During the deliv-
ery process the robotic manipulator moves the linac from
one node to another. At each node, the robot stops, aims the
linac in the selected directions, and delivers dose increments
in a “stop and shoot” sequence. The beam is not on while the
robot is in motion.
A typical treatment plan has at its disposal a set of up to
110 nodes distributed approximately uniformly over about
one half of a sphere centered on the treatment site. For each
plan, these nodes are selected from a total of more than 300
possible linac positions. For non-isocentric delivery, the
planning system defines up to 12 discrete pointing directions
(vectors) at each node. These pointing vectors are aligned to
designated points within the treatment volume to produce a
set of overlapping beams designed to optimally cover the tar-
get volume while avoiding critical structures. The combina-
tion of nodes and pointing vectors provides altogether a set
of 1,320 “beams” from which to construct a plan. The plan is
developed by selecting beams (i.e., nodes and pointing vec-
tors) from among the 1,320 available and assigning them
“weights” corresponding to the amount of dose each beam is
to deliver.
The planning process consists of a sequence of planning
choices by the clinician combined with a set of constraints
on the dose actually delivered by the plan. The first step is to
identify the treatment site. Because each anatomical location
is optimally treated by a particular configuration of nodes,
the planning system has predetermined groups of nodes that
are considered the best choices for each treatment site. These
groups of nodes are called “paths.” There are 80–110 nodes
in each path, chosen from among 300+ possible linac posi-
tions. When the clinician designates the treatment site, the
planning system selects the appropriate path.
In the second step, the clinician chooses to construct
either a single-isocenter, a multi-isocenter, or a non-isocentric
plan. While the isocentric option is reasonable for compact
87
semispherical lesions, the non-isocentric technique is most
commonly employed due to its greater flexibility.
The third step is to choose either forward or inverse plan-
ning. Non-isocentric plans are difficult to design using for-
ward planning and so inverse planning is typically used. It
will be assumed from this point on that the clinician is inter-
ested in inverse planning.
One or more collimators can be employed in a plan.
Typically, for isocentric plans, the collimator diameter is
matched to the diameter of the lesion. In non-isocentric
delivery, the clinician has more freedom in selecting the col-
limator diameter(s). Typically, the collimator diameter is
chosen to be approximately 60 % of the lesion’s smallest
projected cross section. This makes it possible to obtain
acceptable dose conformality, dose homogeneity, and dose
falloff at the boundary of the target without unduly lengthen-
ing the treatment time. As mentioned above, the beam diam-
eter can be fine-tuned by adjusting the SSD away from its
nominal distance of 80 cm. The Iris variable aperture colli-
mator has simplified the use of multiple collimator diameters
within a single plan.
Inverse planning works within a set of constraints to find
the best deliverable plan. The clinician specifies a minimum
target dose and a maximum dose to each critical structure
that can potentially be transited by a beam. Additionally the
planner can create artificial dose constraint structures to fur-
ther influence the plan. These structures can be used to atten-
uate or block beams so as to shield critical structures. They
can also be used to modulate the dose reaching the lesion.
The effective use of artificial constraints is a valuable
acquired skill.
In the contouring process, the clinician outlines the target
volume, all relevant critical structures, and any artificial
structures needed to help manage the dose distribution. Part
of this step involves identifying up to 12 locations within the
target lesion that serve as endpoints for the pointing vectors
at each node.
After the contouring is complete, the planning system has
up to 1,320 beams to choose from when optimizing the plan.
The inverse calculation then selects from among the avail-
able beams to get optimal target coverage and critical struc-
ture avoidance. The optimizer then assigns beam weights
that meet the dose constraints. If constraints applied in an
inverse planning formulation are too strict, the system may
be unable to find a plan that simultaneously satisfies all of the
constraints. Experienced CyberKnife planners have found it
most effective to begin by defining minimum target doses
combined with fairly generous maximum doses to the criti-
cal structures. If the system can find a solution for this first
approximation, the clinician then reduces the maximum
doses to the critical structures until either the necessary con-
straints are met or a solution is no longer possible. If the
obtainable solutions cannot quite meet the original critical
88
structure constraints, then the clinician must decide if the
best obtainable solution is good enough. After an optimized
plan has been calculated, the clinician has an opportunity to
fine-tune it in a pseudo-forward planning step by selectively
turning individual beams on and off.
The final decision made in the planning process is whether
the original fractionation scheme should be modified in light
of the achievable dose limits to the target volume and critical
structures. This is an important consideration for spine treat-
ments because there is incomplete knowledge of the spinal
cord’s tolerance of single-fraction doses.
Proton SRS
Introduction
In recent years, there has been a steady growth in the number
of proton therapy centers worldwide [69]. The upfront costs
of a new proton therapy center (frequently in excess of
$100 M) as well as the high operational costs have been a
limiting factor in the routine clinical adoption of proton ther-
apy. Of those centers offering proton therapy, fewer than half
have an active radiosurgery program. By comparison there
are approximately 300 Gamma Knife centers worldwide [59]
and a much larger number of linac-based SRS programs.
The major advantage of high-energy protons and other
heavy charged particles is the characteristic distribution of
Fig. 6.16 (a) The STAR (Stereotactic Alignment Radiosurgery) iso-
centric patient positioning device designed and built by Product Genesis
Inc. [82] and used by the MGH (Massachusetts General Hospital,
Boston) group in conjunction with horizontal fixed proton beamlines.
The patient can be rotated enabling any portal combination aimed from
D.M. Shepard et al.
dose with depth. As the beam passes through tissue, the dose
initially remains approximately constant. Near the end of the
range, however, the dose quickly increases to its peaks value
then rapidly falls off to near zero dose. The region of high dose
at the end of the particle range is called the Bragg peak [70].
By adjusting the incident energy of the beam, the position of
the Bragg peak can be controlled to match the depth of the
lesions being treated. This is, however, a case of too much of a
good thing. The Bragg peak is usually much narrower than the
span of the average target. This in turn requires that the peak
be “spread out” or modulated. The effect of this modulation is
an increase the surface dose of the entrance beam.
Proton delivery systems are not compact like conven-
tional linacs or Gamma Knife units (see Fig. 6.16). Until
recently, proton facilities that were originally designed for
nuclear research used retrofitted equipment to bring the radi-
ation to the patients. This meant using fixed beamlines and
innovative methods to deliver fields from various directions.
Modern proton facilities designed and built for radiation
therapy have incorporated gantry systems making their use
similar to linacs [71, 72].
Dose Modeling
Doses from proton beams are clinically described in Cobalt
Gray Equivalent (CGE). The CGE represents the equivalent
biological dose to achieve the same cell-kill as 60Co gamma
the top cranial hemisphere. (b) A 110-Ton isocentric gantry and 6-axis
robotic patient positioner designed and built as a collaborative effort
between General Atomic Inc. [83] and Ion Beam Application Inc. [84]
and used for proton SRT and SRS at the NPTC (Northeast Proton
Therapy Center, MGH, Boston)
6 Treatment Planning for Stereotactic Radiosurgery
rays. The ratio of the physical to biological dose is called the
radiobiological effectiveness (RBE). Clinical applications of
protons assume an RBE of 1.1 relative to 60Co [73, 74]. This
means that 10 % less physical dose is required when deliver-
ing proton beams compared to X-rays.
The Bragg peak measured for a single energy beam is
referred to as a “pristine” Bragg peak. The width of a pristine
Bragg peak as measured from the proximal to distal 90 %
dose varies with energy. The width is narrower for shallow
fields and broader for deeper fields; however, a typical width
is around 0.5 cm. In order to treat larger lesions, multiple
pristine Bragg peaks are combined to create a spread out
Bragg peak (SOBP). The SOPB 90–90 % width (also known
as the modulation width) can be customized to the thickness
of any lesion by varying the depth and weight of each pris-
tine peak.
It is important to note that the relative weights and depth
pullbacks of the individual pristine peaks needed to generate
a flat SOBP are dependent not only on the 90–90 % width
but also on their entire depth dose profile. The pristine peak
shape is also affected by the field diameter. Therefore, for a
specific beamline, both the energy and the field diameter
must be modeled in the treatment-planning algorithm to
properly generate the desired SOBP. An SOPB can be gener-
ated by delivering the dose from each pristine Bragg peak
separately or by using beam spreading devices such as spin-
ning absorber wheels or ridge filters [75].
The lateral dose penumbra of proton beams depends on
the inherent beam source geometry as well as individual
treatment field settings. Beamlines designed to treat large
fields generally use a double scattering system which can
results in a 5 cm FWHM source size. When this source size
is combined with a source-to-axis distance (SAD) of 220 cm
that is typical for a proton gantry system, the result is a
80–20 % isocenter plane penumbra of 2.8 mm for a range of
8 cm and 6.3 mm for a range of 16 cm. In a small-field single
scattering system with an SAD of 450 cm, the source size is
around 1 cm FWHM, and the penumbra is reduced to 2.3 mm
for a range of 8 cm and 5.3 mm for a range of 16 cm.
Treatment-planning systems with integrated proton beam
algorithms, such as Elekta’s XiO planning system, must be
able to model both the lateral and depth dose profiles based
on as many clinical variables as possible. This is achieved by
using pencil beam algorithms which model multiple
Coulomb scattering within beam modifying devices as well
as the patient [76, 77].
Pre-planning Consideration
As compared with linac and Gamma Knife delivery, protons
result in a lower integral dose to the patient due to the sharp
dose fall off beyond the Bragg peak. Larger lesions benefit
89
the most from the reduction of dose to normal brain from
protons as compared with other modalities. Protons also
make it possible to deliver a uniform target dose even with
large lesions. This may be considered an advantage when
treating AVM where the target and normal brain are inter-
twined. However, additional clinical results are needed to
demonstrate this conclusively.
The immobilization hardware and alignment techniques
used for linac SRS can be applied to proton radiosurgery
particularly when a gantry-based beamline is used. In fixed
beamlines, the need to rotate the patient can lead to torque
on the patient’s head that can result in slight shifts of the
head relative to an external reference frame. In such cases, it
would be unwise to rely on conventional stereotactic exter-
nal reference frames. The insertion of three 1/16″ diameter
316LVM grade stainless steel spheres in the outer table of
the patient’s skull used in conjunction with diagnostic qual-
ity X-ray treatment alignment system provides a reliable
reference coordinate system [78]. A benefit of using an
internal marker system is the flexibility to image, plan, and
treat on different days. This is an important consideration
for proton facilities that have significant overhead due the
need to fabricate custom beam shaping devices, which
require pretreatment QA/QC and possibly dosimetric verifi-
cation. Patients also benefit from not having to wear a ste-
reotactic frame while waiting for their treatments as is
necessary with same day CT-Plan-Treat schedules. Using
internal alignment markers does not necessarily preclude
the use of stereotactic bony fixation for CT imaging and/or
the treatment. It does however provide the flexibility to use
stable noninvasive immobilization devices as assessed on an
individual patient basis.
Treatment planning for proton therapy requires CT
imaging because the dose algorithms convert the pixel den-
sities to proton stopping power. The stopping powers are
used to calculate the penetration of the protons inside the
patient. When required, secondary imaging studies such as
PET, MRI and angiography can be fused or merged with
the primary planning CT as is done with conventional treat-
ments [79, 80]. Because of the proton penetration conver-
sion from CT densities and the sharp dose fall off beyond
the Bragg peak special precautions are necessary to ensure
that the planning CT’s densities are not artificially altered.
This means that if a CT requires contrast for target and nor-
mal structure delineation it may be necessary to first obtain
a non-contrast CT to be used for treatment planning. A sec-
ondary scan performed with contrast is used for structure
delineation and fused to the non-contrast planning CT. This
is especially important when treating vascular lesions,
where using the contrast CT scan to calculate the proton
stopping powers would overestimate the required proton
range and modulation and result in an increased treatment
volume.
90
Fig. 6.17 A custom brass
aperture and Lucite compensator
used to ensure a conformal
proton beam
Relative Dose (%)
Clinical Treatment Planning
Proton arc therapy is not feasible nor is it necessary to gen-
erate conformal plans. Three to five static ports are gener-
ally sufficient to obtain satisfactory target dose conformity.
Using BEV (beams-eye-view) projections, the user deter-
mines the best combination of ports to optimize the dose
conformality. When practical, the use of orthogonal beams
minimizes overlap regions between fields. Brass apertures
are custom milled to the shape of the lesion’s BEV projec-
tion (see Fig. 6.17). The expansion of the aperture openings
accounts for the penumbra of the specific portal. Blocking
of specific critical structures is made easy using the BEV
approach. Custom lucite range compensators are fabricated
to enable dose shaping to conform to the distal edge of the
target.
Although the beam directions are determined on a case-
by-case basis, an effort is made to use standard beam arrange-
ments. Pituitary adenomas are located in and around sella
and have similar dose constraints. A standard approach at the
Massachusetts General Hospital (MGH) for pituitary lesions
has been to use four fields (RL, LL, ASO, PSO) (Fig 6.18).
The lateral fields avoid the optic structures and brainstem
while passing through the temporal lobes; the PSO avoids
the optic structures and temporal lobes while passing through
the brainstem; and the reduced weight ASO avoids the tem-
poral lobes and brainstem while passing through the optic
structures.
Another standardized approach is used to treat acoustic
neuromas using 3–4 fields (L/RPO, L/RAO, L/RSO,
L/RPSO). This field combination limits the dose to the brain-
stem, cerebellum, and temporal lobe while avoiding bone
heterogeneities as much as possible. In other cases such as
AVMs, the variability in location, shape, and size makes
standardization difficult (see Fig. 6.19). In order to maximize
D.M. Shepard et al.
Photon & Proton Depth Doses
190 MeV Photons
100 170 MeV Photons
150 MeV Photons
75 130 MeV Photons
6 MeV Photons
50
25
0
0 5 10 15 20 25
Depth in Water (cm)
dose uniformity across targets, it has been the MGH practice,
for proton SRS, to avoid truncating a target so as to treat it
using abutting or patch fields [81]. These techniques are reg-
ularly used when treating fractionated proton SRT to improve
dose conformality of very irregular targets; however they
create small local high-dose points within the treatment
volume.
Patient demographics are dependent on the practice refer-
ral patterns as well as the facility’s ability to offer alternative
treatments. Proton facilities that do not have an alternative
modality option are likely to have a significant fraction
(~25 %) of patients with metastatic disease compared to very
few if an alternative such as linac SRS is available. At the
MGH, 47 % of PSRS patients are AVMs, 19 % pituitary or
cavernous sinus lesions, 13 % acoustic neuromas, 11 %
meningiomas, 4 % extracranial, and 6 % are miscellaneous
other disease.
Other Considerations
When considering the overall advantage of protons for SRS,
one should compare the dose gradient relative to standard
Gamma Knife or linac-based systems. As with any such
treatment device there exist unique planning situations at
which it will excel. However when one considers that
Gamma Knife or linac-based system routinely produce plans
that expose as little as 5–10 % of normal nontarget tissues in
the prescription isodose shell while providing dose gradients
that drop the dose from the prescription dose to half of the
prescription dose in 2.5–4 mm, the margin for improvement
is relatively small. The image guidance techniques available
with linac-based systems such as cone-beam CT could also
impact the degree of the advantage seen with proton therapy
for SRS and SBRT.
6 Treatment Planning for Stereotactic Radiosurgery
Fig. 6.18 A standard 4-field pituitary beam combination used for
PSRS. The first image shows a 3D view of the ports and the structures
of interest. Typical doses are 18–20 CGE @ 90 % to the target with
constraints of 8 and 12 CGE to the surface of the optic structures and
brainstem, respectively
91
Summary
The technological advances in recent years have created a new
array of options for SRS. The dosimetric advantage of SRS
has also been gradually extended to extracranial sites. The
introduction of mMLCs, IMRT, and inverse planning into SRS
gives us more control in shaping the high-dose volume to con-
form to the target. Online or real-time image guidance also
provides a new alternative to the use of traditional stereotactic
frames. With these advances, fractionated treatments can now
be reliably administered. Although the dosimetric goals and
basic principles of SRS planning have not changed, the means
of achieving the dosimetric goals has shifted more towards
automation and computer optimization.
Glossary
Conformity index Defined by the RTOG as the volume of
the prescription isodose divided by the target volume.
Constraint A condition that must be satisfied during inverse
treatment planning for a plan to be considered feasible.
The most basic constraint is that all beam weights must
be nonnegative.
Dose-volume histogram (DVH) A plot of the volume ver-
sus dose used to analyze the dose distribution on a struc-
ture by structure basis.
Forward treatment planning An iterative approach to
planning where the user manually changes each of the
plan parameters until an acceptable plan is obtained.
Homogeneity index Defined by the RTOG as the maximum
dose in the treatment volume divided by the prescription
dose.
Inverse treatment planning An automated approach to
planning where the user defines the treatment goals and
an optimization algorithm is run that determines the
parameters that best meet the goals.
Micromultileaf collimator (mMLC) A device attached to
or incorporated into the head of a linear accelerator used
to define field shapes. As compared with a conventional
multileaf collimator (MLC), the leaves of an mMLC
are less wide and project to 5 mm or less in width at the
isocenter.
Objective function A scoring function that reduces the
entire treatment plan into a single numerical value that is
to be either minimized or maximized.
92
Fig. 6.19 6-field PSRS
radiosurgery isodose plan for a
9.6 cc right thalamic AVM in a
17-year-old patient. The
treatment was delivered in two
sessions, separated by 2 weeks,
each delivering 8 CGE @ 90 %
for a total of 16 CGE @ 90 %.
Three fields (LL, RPO, ASO)
were delivered on the first session a
and three different fields (RL,
LAO, LSO) were delivered on 90
the second session
Relative Dose (%)
45
20
Depth in Water (cm) 13
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 Designing, Building, and Installing
a Stereotactic Radiosurgery Unit
Lijun Ma, Andrew Hwang, and Arjun Sahgal
Introduction
Stereotactic radiosurgery (SRS) units are fundamentally
based on delivering a high dose of “ablative” ionizing radia-
tion to small targets within the brain localized in three dimen-
sions. The treatments require an overall delivery precision in
the order of 1–2 mm and delivery of highly conformal radia-
tion with steep dose gradients beyond the target edge.
The term brain stereotaxy simply refers to a method for
locating points within the brain using an external 3D frame
of reference usually based on the Cartesian coordinate sys-
tem. Although the use of stereotactic instruments have been
reported in the literature as early as the 1800s [1], the first
definitive brain SRS unit was designed and built by the
Swedish neurosurgeon Dr. Lars Leksell in the 1950s [2].
Without modern 3D imaging like CT and MRI, Lars Leksell
achieved stereotaxy by designing a rigid head fixation device
attached to the patient’s cranium. The frame incorporated the
required Cartesian coordinate system and, therefore, the
ability to pinpoint any location within the frame space to
guide the radiation beams [3–7].
Since that time, a large number of different techniques
have been used to deliver SRS. These include dedicated
SRS units such as the Gamma Knife and Cyberknife in
addition to linac-based systems. In this chapter, we provide
an overview of the design principles of various SRS units.
L. Ma, Ph.D. (*)
Department of Radiation Oncology, University of California
San Francisco, San Francisco, CA, USA
e-mail: lijunma@radonc.ucsf.edu
A. Hwang, Ph.D.
Department of Radiation Oncology, Alta Bates Summit
Medical Center, Oakland, CA, USA
A. Sahgal, M.D.
Department of Radiation Oncology, University of Toronto,
Toronto, ON, Canada
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_7, © Springer Science+Business Media New York 2015
7
In addition, basic aspects of shielding and radiation safety
are described, as well as installation, acceptance, and qual-
ity assurance testing.
Design Principles
Common types of ionizing radiation used for SRS include
high-energy gamma rays (e.g., 60Co), high-energy X-rays,
and charged particles such as protons. Photon-based (X-rays
and gamma rays) and ion-based (protons and heavy charged
particles) SRS units use fundamentally different design prin-
ciples. The basic principle of photon-based SRS units is to
converge a large number of beams at the isocenter in order to
produce rapid dose fall off beyond the focal area. The beams
are created using radioactive sources (60Co) or high-energy
electron linear accelerators. In contrast, ion-based units tend
to use a limited number of beams, or points, in order to
spread the Bragg peak across the target volume. The rapid
dose fall off is largely created at the distal end of the Bragg
peak [8–13]. Charged particles such as protons, helium ions,
and carbon ions are accelerated using high-energy cyclotrons
or synchrocylotrons. In this chapter, we will focus on photon-
based SRS units as these units are dominant in current clini-
cal practice for both intracranial and the current extrapolation
to extracranial body sites. State of-the-art photon-based SRS
units currently include the Gamma Knife Perfexion,
Tomotherapy, Cyberknife, and linac-based systems that
sprouted from the dedicated Novalis brain radiosurgery units
(for example, the Varian and Elekta brand systems).
One of four basic design schemes for radiation delivery is
generally applied in building a SRS unit:
1. Fix the source of radiation and fix the patient position
2. Move the source of radiation and fix the patient position
3. Move the source of radiation and move the patient position
4. Fix the source of the radiation and move the patient
The first principle is applied in Gamma Knife and most
proton and heavy-ion units, the second principle is used in
the majority of linac-based SRS units and the Cyberknife
95
96 L. Ma et al.

unit [14], the third principle is used in Tomotherapy [15] and

linac-based simultaneous gantry and couch rotating units
[16], and the fourth principle is uncommon but has been
reported in the rotating chair SRS unit [17].
When applying these principles, recent technological
developments have been intensely focused on designing not
only accurate but more efficient and safer SRS units in a
turnkey type of solution. For example, repeat patient posi-
tioning during beam-off periods can now be automated via
computer controls with minimal user interventions; a large
amount of radiation with three- to fourfolds of conventional
dose rate can be now delivered in a matter of minutes; and
notably, full integration of online imaging capability that
facilitates patient setup in full six degrees of freedom. Some
of these features are still work in progress but highlight an
expansion in the design paradigm of building an SRS unit.
With respect to clinical developments, SRS has surpassed its
role in treating a small target with a single fraction to treating
multiple targets simultaneously (even up to 20–30), large tar-
gets and hypofractionation.

Components and Functions

Gamma Knife

The Gamma Knife (GK) is a teletherapy 60Co unit specifi-

cally designed for intracranial SRS treatments [18–21]. The
latest GK unit is named the Perfexion (PFX) and contains
192 60Co sources fixed on the exterior surface of a conical
collimator. Each source delivers gamma rays of 1.25 MeV in
mean energy. The center of the collimator is the “isocenter.”
The initial activity of the individual source is approximately
3.0 Ci. Therefore the total initial activity in each unit exceeds
5,000 Ci. This activity typically produces a dose rate of
approximately 300 cGy/min at the isocenter. Because radio-
active 60Co decays with a half-life of 5.3 years, the dose rate
will be reduced by 50 % after 5.3 years thus making refuel-
ing a necessary consideration for the system.
The source-to-isocenter distance for all GK units is on
the order of 40 cm. This distance is significantly shorter than
the 100 cm source-to-axis distance (SAD) of the standard
linear accelerator. Short source-to-focal distance is a hall-
mark design characteristic of the GK unit. This not only
improves the required total activity of the sources (inversely
square law), the geometric penumbra (linear divergence) but
also facilitates high mechanical precision near the isocenter.
For example, if a minor milling error occurs in the primary
collimator, the projected penumbra would be significantly
narrower at a short source-to-isocenter distance than at a
large source-to-isocenter distance.
The high level of activity of the GK unit demands heavy
density materials for proper shielding. With shielding and
Fig. 7.1 The original model U GK unit as installed in the USA in the
late 1980s. (a) The side view of the unit and couch; (b) the helmet col-
limator with a head phantom docked onto the helmet via the attached
stereotactic frame
collimators, a GK unit weighs about 20 tons. A heavy and
robust supporting structure, precise beam collimation via
high-Z materials such as tungsten, and a short source-to-
focal distance are major contributing factors for the sub-
millimeter mechanical accuracy of the GK unit.
Historically, there have been several models of GK
[Models U, B (B1 & B2), and C, and now the PFX]. In the
USA, the original GK Model U was installed at the University
of Pittsburgh in 1987. An illustration of the Model U unit is
given in Fig. 7.1. After the FDA approval of later models
(Model B, C, and PFX), the Model U has been gradually
phased out of service. Major differences between the origi-
nal U and the later B and C models include the couch driving
mechanism (hydraulic vs. electrical), patient positioning
assembly (manual vs. automatic), collimator design, and
source arrangement pattern. However, the key components
7 Designing, Building, and Installing a Stereotactic Radiosurgery Unit
Fig. 7.2 The redesigned PFX unit as released by Elekta in 2006. Note
the absence of helmet collimator and the universal collimator design as
compared with the original Model U of Fig. 7.1
remained nearly identical for these GK models (models U,
B, and C), which include a shielded source head ball housing
201 60Co sources, a movable couch, four tertiary helmet col-
limators (18, 14, 8, and 4 mm in beam aperture), removable
plug collimators (201 for each helmet), a separate console
control unit, patient positioning devices, audio/video moni-
toring devices, and a dedicated treatment planning system.
The patient positioning device consists of the Leksell frame
(pinned to the patient skull) and its attachments to the helmet
of the GK. The frame is attached manually via either a pair
of bars (i.e., trunnions) or the automatic positioning system
(APS) device.
In 2006, Elekta introduced a new GK unit called Perfexion
(PFX). The PFX (Fig. 7.2) transforms and significantly
improves upon the design of previous GK models. One dis-
tinct feature is the use of a single collimator where three
sizes of collimation apertures (16, 8, and 4 mm) are drilled
directly into a single piece of tungsten shaped like a speaker
cone. The radioactive 60Co sources are placed inside metal
housings called sectors that slide linearly on the outer sur-
face of the collimator to align themselves with these pre-
drilled apertures, to create confocal radiation beams of 16, 8,
and 4 mm of approximate full width half maximum (FWHM).
Because the sectors are driven by independent stepper
motors, beams of different aperture sizes can be mixed from
different directions at the focus point. The total number of
configuration for variable beam apertures at the isocenter is
given as 48 − 1 = 65,535. This is because at each isocenter, a
total of four beam aperture sizes (0 mm or blocked, 4, 8, and
16 mm) can be directed from eight equally spaced directions,
i.e., 45° separation between two neighboring sectors sur-
rounding the universal collimator. The overall beam preci-
sion is dependent upon the precise drilling of >500 apertures
and the precise alignment of the sliding sectors. Therefore,
manufacturing the universal collimator and sector housing
comprises a major cost in building the PFX unit.
97
Besides elimination of the tertiary helmet collimators with
a single universal collimator, the new PFX design also trans-
forms the automatic patient positioning system (APS) via the
introduction of a single integrated translational couch.
Therefore, independent patient positioning devices such as
the tertiary trunnion bars and add-on APS units have been
eliminated. The translational couch enables the patient’s head
frame to be docked onto the end of couch and then entire
patient body plus the head frame is shifted automatically to
align with the treatment delivery. The maximum tolerance
level for the accuracy of the translational couch is less than
0.3 mm, which is comparable to the previous models.
The elimination of the tertiary collimator has also signifi-
cantly extended the maximum traveling distance achievable
for the PFX as compared to the previous models. For exam-
ple, the overall reachable volume via the automatic couch
has been extended more than 300 %. Now the majority of
intracranial lesions can be readily treated with the stereotac-
tic frame placed in the central position, this greatly eases the
effort of frame placement.
This new design of the Gamma Knife PFX has resulted in a
simple turn-key solution for most treatment indications
including complex multiple metastatic brain lesion treatment
with significant improvements in the range of locations in the
brain that can be treated, radiation safety, and patient comfort.
In addition to the above hardware design improvements,
the treatment planning system for the PFX has also been
updated from the previous models. The salient features of the
system as well as the 3D dose calculation algorithms are cov-
ered in another chapter.
Linear Accelerator-Based SRS Units
Historically, linac-based SRS units were built upon standard
linear accelerators with add-on collimation systems and couch
stabilization devices [16, 22–32]. The majority of these SRS
units employed tertiary cones, or add-on micro- or mini-mul-
tileaf collimators, to deliver noncoplanar converging arc
beams at the isocenter. The arrangement of these noncoplanar
arc beams aims to deliver an elliptical dose distribution similar
to that of a single shot in Gamma Knife delivery. In general,
the tertiary cones are made from high-Z materials and are
intended to extend the source to diaphragm distance to sharpen
the beam penumbra at the isocenter. Note that the source to
isocenter distance is typically 100 cm, which is more than two
times of the source-to-isocenter distance of the GK unit.
Unlike GK units where the isocenter is mechanically
aligned with the beam focus, traditional linac-based SRS
units predominantly rely on wall-mount lasers and special
localizer boxes attached to the stereotatic frame for defining
the target coordinates. Therefore, the accuracy of the laser
system is critical in ensuring the treatment accuracy for
linac-based SRS units. As a general practice, a pretreatment
98
Fig. 7.3 Example of isocenter test tools: (a) an automatic diode scanning tool; (b) a film holder with central prick pin for marking the film before
exposure with the radiation
isocenter alignment check must be carried out for each
patient delivery.
Figure 7.3 illustrates the isocenter alignment devices for
the PFX unit. In using the isocenter alignment check tool, the
beam profile is first scanned via small-volume detector such
as diode (Fig. 7.3a) across axis directions. A film is pricked
with a pin at the isocenter set by the mechanical device
(Fig. 7.3b). Then the film is exposed and pinprick mark is
compared with the center of the beam profile to determine
agreement between the mechanical and radiation isocenters
[5, 25, 30, 33, 34].
For linac-based SRS units, the most commonly used iso-
center alignment check is the Winston–Lutz test method
[28, 32]. For the test, a metallic spherical ball is first aligned
with the isocenter using wall-mount lasers or a front-pointer.
A series of port films are then exposed downstream for a
“dry-run” of actual beam deliveries. Typically, the film is
placed on a special holder attached to the gantry port extend-
ing underneath the ball. If the linac is equipped with high-
resolution electronic portal imager (EPID) [35], the image
can be taken with that device in lieu of the film. Once
exposed, the projected ball image is compared with the edge
field to detect any deviations in the isocenter. The Winston–
Lutz test is especially useful for linac-based SRS because it
not only checks the isocenter alignment but also detects any
collisions among the gantry, couch, and tertiary collimators
during the patient delivery.
Example isocenter measurement results for a Gamma
Knife unit and a linac-based SRS unit are given in Fig. 7.4.
Once the alignment between the laser and mechanical iso-
centers is verified, the target coordinates for the linac-based
SRS treatments are set via a laser-based localizer. A picture
of the setup localizer is shown in Fig. 7.5. To facilitate the
alignment of the isocenter, the localizer can be adjusted in
L. Ma et al.
six degrees of freedom (x, y, z translation, and pitch, yaw,
and roll) to correct for non-flat couch top and minor setup
errors. The coordinates on the localizer is commonly set in
positive numbers in order to minimize misreading in setting
up the stereotactic coordinates.
With the recent advent of onboard imaging devices, the
isocentric process has been gradually replaced by automatic
image-based setups. An example of such a new generation
linear accelerator is shown in Fig. 7.6. Some of the features
of this type of linear accelerator include digital control
boards, an onboard imager (OBI), high dose rate delivery
without flattening filter attenuation as used for conventional
radiotherapy. With an improved digital control system, such
a linear accelerator is able to deliver arc beams with a high
dose rate while being able to adjust the speed of gantry rota-
tion and MLC leaf motions for beam intensity modulation,
as well as collecting 2D and 3D onboard kV images during
the process. As a result, patient treatment setup does not
need to be referenced to the isocenter setup and verifications,
but can solely rely on direct online image studies via OBI for
direct planar or volumetric match of the patient position with
that defined in the reference CT image studies during the
treatment planning process. However, the imaging device
must be carefully calibrated so that its reference center coin-
cides with the linear accelerator isocenter, so that any shift in
patient position detected from the online imaging process
can be reliably compensated using changes in couch position
or beam alignment (i.e., MLC shifts).
Once the patient is aligned, linac-based SRS commonly
uses either noncoplanar converging fixed beams or dynamic
arc beams. In dynamic rotation delivery, the gantry rotates
while the couch can be either fixed or rotates at the same
time. The advantage of the dynamic arc-beam delivery is that
only a single treatment setup is required and parallel-opposed
7 Designing, Building, and Installing a Stereotactic Radiosurgery Unit
Fig. 7.4 Results of radiation and mechanical alignment tests for (a)
GK unit and (b) linac-based SRS unit. (a) Used the smallest circular
field of 4-mm in diameter and (b) used a square field of 4 × 4 cm2. The
Fig. 7.5 A typical linac-based SRS treatment setup and illustrated beam arrangements
beams can be avoided during the entire delivery to produce a
better entrance and exit dose for a treatment plan.
With the ubiquitous adoption of high-definition MLC sys-
tems, fixed-cone collimator-based SRS delivery is fast being
replaced by MLC-based SRS delivery. From the beginning,
these high-resolution MLCs were able to shape the beam
aperture conformally in the beam’s eye view during the gan-
try rotation for linac-based SRS delivery; therefore, the tech-
nique is termed shaped-beam SRS delivery in contrast to the
traditional fixed-beam cone SRS delivery [27, 29, 31,
36–38]. Recent advances in MLC technology have resulted
in leaf size on the order of even 2.5 mm which allows for
even small targets <1 cm to be treated.
For the majority of treatments, MLC-based SRS is capa-
ble of delivering the full treatment regardless of a single or
multiple targets with a single isocenter. With optimized beam
99
agreement between the pinpricked center and full width half maximum
(FWHM) field edge was found to be within 0.5 mm for both cases
weights and intensity modulated arc beam delivery (IMAT or
VMAT), MLC-based SRS may also be able to deliver even
better dose distributions for complex targets as compared to
the conventional fixed-field approach [31]. A picture of a
dedicated MLC-based SRS linear accelerator is shown in
Fig. 7.7. The unit is considered as a stereotactic unit because
it possesses a high-definition MLC with a slightly restricted
maximum field size of 22 × 40 cm2, as compared to the
40 × 40 cm2 maximum field size typical of conventional lin-
ear accelerators. In addition, this particular unit also pos-
sesses the capacity to perform online near real-time image
guidance via a ceiling and floor-mounted kV X-ray imaging
system. The mechanical accuracy of the unit has been
reported to be on the order of 0.5 mm [39], and notably
treated small targets such as the trigeminal nerve root entry
zone for the treatment of trigeminal neuralgia [38].
100
Fig. 7.6 A digitally controlled linear accelerator capable of high dose
rate stereotatic radiosurgery, hypofractionated body radiotherapy, and
conventional radiotherapy delivery as released by Varian Medical
Systems in 2009
Fig. 7.7 A dedicated linear accelerator unit Novalis (Brainlab
Company) with a built-in high-definition 2.5 mm leaf width at isocenter
MLC, for shaped-beam SRS delivery
Cyberknife SRS Unit
The Cyberknife consists of a compact linear accelerator
mounted onto a robotic arm. The accelerator is collimated
using fixed cones that range from 5 to 60 mm in nominal
diameter. In newer units, an optional variable diameter col-
limator (Iris) can be used. Treatment is primarily guided
using a pair of orthogonally mounted planar X-ray imagers,
although the system also has an optional optical tracking sys-
tem that can be used in conjunction with the X-ray imager.
L. Ma et al.
Fig. 7.8 Illustration of the Cyberknife SRS unit with integrated kV
imaging system
Considering the principles of the design, Cyberknife is
a unique SRS system in that the majority of the treatment
beams are non-isocentric (Fig. 7.8). The largest circular
field size for the Cyberknife is 6 cm in diameter so the
system is by design a dedicated SRS unit. However like
dedicated linac-based systems, cross firing and fast over-
lapping of multiple beams of variable field sizes allow
the Cyberknife to treat larger target volumes such as the
prostate.
Unlike those isocentric systems previously discussed,
several unique factors contribute to the successful operation
of the Cyberknife [1]. The linear accelerator operates in the
X-band microwave frequency which allows for a signifi-
cantly shorter waveguide length and a compact design of the
linear accelerator head such that it can be mounted onto a
robotic arm. This facilitates non-isocentric beam delivery
and, more importantly, precision handling of the linear
accelerator to achieve the necessary accuracy required for
SRS delivery [2]. The stereoscopic ceiling mount kV X-ray
tubes provide sufficient fast 2D imaging to monitor the
patient positioning, not only during the setup but also
throughout the treatment, to constantly guide or correct the
individual beam direction from the linear accelerator head
beam to irradiate a target [3]. In-room kV X-ray images are
able to match accurately (<0.1 mm) with digitally recon-
structed images (DRRs) from a conventional CT scan to
generate a virtual image center, which the robotic arm uses
for guiding the individual beam directions. In essence, the
image center is the heart and soul of Cyberknife delivery,
and it can be placed anywhere in space as long as the robotic
arm knows where it is. This is fundamentally different from
all other SRS units, where the image center must reference
to the mechanical isocenter of the linear accelerator and not
vice versa.
7 Designing, Building, and Installing a Stereotactic Radiosurgery Unit
Tomotherapy Unit
Tomotherapy is an integrated unit that is capable of deliver-
ing SRS using intensity modulated radiation therapy treat-
ments based on a helical fan beam geometry analogous to
modern CT scanners [15, 40]. In design, one can think of the
Tomotherapy unit as a CT unit that also delivers therapeutic
high-energy X-rays. The unit has a compact Siemens 6 MeV
S-band linac mounted on a rotating slip ring gantry with a
source–axis distance of 85 cm. The linac has neither a bend-
ing magnet nor a flattening filter and operates at a nominal
dose rate of approximately 900 MU/min. The bore of the
unit is >80 cm, and there are a series of individual binary
(either open or shut) collimators that produce a fan-beam
X-ray across the gantry. The binary MLC leaves open and
close to modulate the beam direction in the transverse
direction.
The size of the field in the longitudinal direction (parallel
to the bore) is defined by a pair of jaws. The field size cur-
rently in the longitudinal direction is 1, 2.5, or 5 cm. During
delivery, the patient is transported through the bore of the
gantry as the fan-beam rotates around to form a spiral trajec-
tory around the patient. The Tomotherapy unit is also
equipped with 738 xenon detectors that enable online CT
scanning of the patient using MV photons using the treat-
ment beam. The unit is shown in Fig. 7.9. With binary colli-
mation and online imaging capabilities, Tomotherapy
delivers SRS treatments similar to the shaped-beam linac-
based SRS treatments except the target volume is irradiated
in a slice-by-slice fashion. The physical accuracy of the unit
is on the order of 0.5–1.0 mm.
For the specific application of high dose intracranial
SRS treatments, one challenge for the Tomotherapy unit has
Fig. 7.9 Tomotherapy unit with built-in fan-beam megavoltage X-rays
and online megavoltage CT capability for image guidance
101
been immobilization of the patient to correctly match that
of reference position during the CT simulation process.
Although patient roll angles can be corrected by changing
the delivery angles, any significant rotational error in pitch
and yaw in the patient setup must be corrected manually
before the treatment. In addition, the existing Tomotherapy
system does not have the ability to detect patient motion
during delivery. Longer treatments can therefore be broken
down into smaller sub-fractions to allow imaging to detect
potential motion.
Overall Accuracy
Treatment accuracy has been the key characteristic of all
SRS units. The mechanical accuracy is reported to be less
than 0.3 mm for Gamma Knife, 0.5–1.0 mm for dedicated
SRS linac units, 0.5–1.0 mm for Cyberknife and Tomotherapy
units, and approximately 1.0 mm for linac-based non-
dedicated SRS units. To evaluate the overall procedural
accuracy of a SRS treatment (unless for a simple treatment
geometry such as trigeminal neuralgia where mechanical
accuracy can dominate), other sources of uncertainties must
be carefully considered. These include (1) uncertainties in
the diagnostic imaging studies and image fusion when appli-
cable, (2) dose calculation uncertainties, and (3) target
motion and setup errors. In general, the imaging resolutions
of CT and MR studies and the spatial distortions in the imag-
ing acquisition process are the major source of uncertainties
intrinsic to all SRS units. For example, irregularities in the
gradient field and the magnetic susceptibility from the ste-
reotactic frame could cause significant spatial errors for the
MR studies in SRS treatments. For dose calculations, the
acceptance level of a SRS dose algorithm is <2 % or <1 mm
in the high dose gradient regions.
Table 7.1 summarizes the estimated error levels for SRS
deliveries.
Overall, the imaging studies and setup variations can be
the major sources of uncertainties in most SRS deliveries
[41] but, nonetheless, the overall procedural accuracy can be
conservatively estimated to be on the order of 1–2 mm or
better.
Table 7.1 Estimated uncertainties in intracranial SRS deliveries in
terms of a peripheral isodose surface conforming to a clinically defined
target surface
Source of errors Standard deviation (mm)
Imaging studies (resolution and distortions) 0.5–1.5
Mechanical alignment and setup errors 0.3–1.0
Tissue/target motion 0.5–1.0
Treatment planning 0.5–1.0
Overall (quadrature) 1.3−2.2
102
Potential Issues and Challenges
Over the past decade, image-guided or image-based SRS
delivery such as Cyberknife and linear accelerator systems
have created a significant driving force to deliver more pre-
cise treatments with greater efficiency and patient through-
put. One common challenge for existing image guidance
solutions is to ensure that the imaging process is sufficiently
fast. This is important not only for the purposes of treatment
efficiency and patient comfort but also to ensure that any
observed patient shifts can be corrected in a timely fashion
before and during the beam-on delivery. However, frequent
imaging via the current kV or MV X-ray beams has raised
concerns with respect to excessive imaging dose and risks of
secondary malignancies, particularly for young patients. One
potential development is in the area of imaging modalities
such as online MR-guided teletherapy treatment devices.
Future studies will confirm whether such new developments
would improve the overall accuracy and more importantly
clinical outcome of such devices over the traditional SRS
deliveries.
Shielding Design
One of major tasks in building and installing a SRS unit is to
design a bunker room and to enforce radiation protection
rules. There are two aspects of source shielding and radiation
protection for SRS delivery: (1) to reduce extrafocal radia-
tion that contributes to dose deposition outside of the target
volume and (2) to reduce radiation exposure to the operators
and the general public outside of the room.
The radiation to be shielded is generated from the primary
beam directly hitting outside of the target, scattered radia-
tions, and leakage radiation from the head of the radiation
source. For extrafocal radiation irradiating the patient
internally, the concern is secondary malignancy risk, particu-
larly in the treatment of young patients and patients with
benign diseases or functional conditions to which radiation
is being applied. Measurements have been carried out to
document such doses for both GK and linac-based SRS units
[5, 42]. As a percentage of the target dose, GK and linac-
based units result in ~0.4 % to blood forming organs, ~0.5 %
to the thyroid, ~0.04 % to the gonads, and ~0.05 % to the
breast or thorax region. One difference between the GK and
the linac-based units is the dose to the lens. Since the dmax for
60
Co is 0.5 cm while for 4–6 MV is in the range of 1.0–
1.5 cm, the lens dose is estimated to ~2.5 % of the target
dose. Such a percentage could be important for treatment
involving a large dose of delivery such as that for trigeminal
neuralgia where the target dose ranges from 70 to 90 Gy.
L. Ma et al.
C
storage
EARTH BELOW GRADE
B Computer
Room Treatment
a Room
CONSOLE
A
SRS
Unit
D Alley E
Fig. 7.10 A sample floor plan for installing a dedicated SRS unit. The
designated points (A, B, C, D, E) are selected calculation points for
barriers transmissions
For room shielding, the bunker design depends on numer-
ous factors that include the machine load, how frequently a
particular wall is irradiated, and the distance between the
wall and the isocenter. To ameliorate requirements for pri-
mary irradiations, it is often advantageous to construct a
bunker in the basement and direct the primary beam toward
the underground earth. Figure 7.10 shows a sample floor
plan hosting a SRS unit. As an illustration, we present here
an example calculation for shielding design of the floor plan
in Fig. 7.10.
A simple equation for shielding design calculations is
given as follows:
R = WUT ´ ( d 0 / d ) ´ 10( - t /TVL ) ´ S ,
2
where R is the exposure per week, W is the work load (i.e.,
maximum delivered dose per week), U is the use factor (i.e.,
fraction of the time beam is directed or scattered toward the
barrier, U = 1 if scattered radiation is considered), T is the
occupancy factor (i.e., fraction of the time a person is present
at the point), d0 is the reference dose calibration distance
(e.g., 100 cm for linac-based SRS unit), t is the thickness of
the barrier materials, TVL is the tenth-value layer of the bar-
rier material, and S is the scatter factor (e.g., S = 1 if primary
is used, S = 0.001 if scatter radiation is considered).
If we need to calculate the required wall thickness near
the console operator at point A, the following parameters
are first determined as follows: W = maximum 5 patients
per day × 5 days per week × 5,000 cGy per treatment =
125,000 cGy/week; TVL = 13.5 in. for the concrete of the
wall; d0 = 1 m and d = 4 m; U = 1; T = 1 and S = 1 for the case;
and the exposure limit is 0.002 rad/week. We have
R = 125, 000 ´ 1´ 1´ (1 / 4 ) ´ 10( - t /13.5) ´ 1 £ 0.002.
2
7 Designing, Building, and Installing a Stereotactic Radiosurgery Unit
Solving for t from the above equation, we have t ≥ 89 in.
This means that the minimum concrete wall thickness at point
A should be about 7.5 ft in order to meet the exposure limit.
It is clear that either increasing source to barrier distance or
adding high-density shielding materials such as lead in the
wall (reducing TVL value) will significantly reduce the wall
thickness and increase room size. If necessary, the workload
can also be restricted to maintain the exposure level to a sat-
isfactory level.
Note that the above calculations represented the simplest
form of open-field single beam shielding calculations. When
considering specialized units such as intensity modulated
shaped-beam SRS, Cyberknife, and Tomotherapy treat-
ments, additional factors such as the so-called IMRT factor
should be considered. This is because traditional linear
accelerators are normally calibrated to deliver 1 cGy per
monitor unit at approximately 100 cm source-to-isocenter
distance, but units such as Cyberknife and Tomotherapy are
calibrated differently. To deliver 1 cGy generally requires a
significantly more monitor units and, in general, a conserva-
tive multiplicative factor such as 15 is currently assumed for
the purpose of shielding calculations. This in effect increases
the R value of the above equation for the leakage radiation
shielding by a factor of 15 assuming 100 % treatments are
IMRT type. The actual percentage of IMRT cases can be
adjusted according to the individual clinical practices.
Shielding design is covered in detail in National Council on
Radiation Protection and Measurements (NCRP) report
number 151 (http://www.ncrppublications.org/Reports/151).
In addition, a number of publications describe shielding for
specific modalities [43–45].
Radiation Safety Program
Before building or installing a SRS unit, an institutional radi-
ation safety committee should be formed to implement a
radiation safety program. The goal of the program is to main-
tain the radiation exposures to all employees and individual
members of the public to be “as low as reasonably achiev-
able” (ALARA). This is commonly referred to as ALARA
principle.
To implement the program, a general rule is to monitor
the radiation level that is significantly below the regulated
legal dose limits (e.g., a factor of 10). In general, film badges
are used to monitor the radiation exposure to all SRS opera-
tors and visitors. A radiation safety officer (RSO) should be
designated for the SRS treatments. The key responsibilities
of RSO are to oversee the radiation exposure reports (e.g.,
monthly) and to provide refresher radiation safety training to
the users (e.g., annually). The RSO needs to be responsive to
emergency situations and serve as a person of contact
between the institution and federal and state agencies. For
103
some states, the RSO is required to be a qualified operator of
the SRS unit.
In case of pregnancy, the RSO needs to determine whether
it is appropriate for the worker to continue to operate. In gen-
eral, a declared worker may work as long as the total expo-
sure to the embryo or fetus is maintained within the ALARA
dose limits.
Installation and Acceptance
Installation and acceptance a SRS unit requires extensive
tests of the functionality of the unit. Common to all SRS
units, three categories of tests should be performed: (1) dose
rate calibration and radiation survey; (2) radiation and
mechanical isocenter alignment; and (3) imaging acquisition
and treatment planning process.
The phantoms in Fig. 7.11 are sometimes also used for
regular quality assurance measurements or serve as the scat-
tering medium for radiation survey tasks. As an example, the
absolute dose rate for a newly installed GK SRS unit should
be measured at least at 300 cGy/min using the 16- or 18-mm
helmet. This is important because this not only affects the
delivery efficiency but also ensures adequate source life
before the next reloading is needed. The dose calibration
geometry should be measured using tissue-equivalent phan-
toms of standard shapes as illustrated in Fig. 7.11.
Another important specification that needs to be tested is
the radiation and mechanical isocenter alignment. This is
performed using the special mechanical alignment tool for
the GK unit and the Winston–Lutz test methods for linac-
based units as previously described. In general, the smallest
field size should be measured to ensure maximum accuracy.
The most important test in installing a SRS unit is to
ensure the delivered dose profiles match the prescribed ones.
As a general practice, the beam profiles along all major axes
of a single-isocenter delivery should be compared with the
calculated profiles. The agreement should satisfy the mini-
mum manufacturer specifications such as 2 % at the central
axis and 2 mm in the dose gradient region. For accurate
delivery using small collimators (e.g., 4–5 mm in diameter),
the requirements can be more stringent such as 1 % or 1 mm
in the dose profiles. The dose profiles can be measured using
radiochromic films with the insert pieces fit into the standard
calibration phantoms as illustrated in Fig. 7.11. The exposed
radiochromic films should be scanned using the laser densi-
tometer with a resolution of 100 μm or better. An example
result for the measured dose profile is given in Fig. 7.12.
Besides the major tests described above, additional accep-
tance tests may be carried out to meet federal, state regula-
tions, and institutional protocols for installing a SRS unit.
Most of these tests are also part of quality assurance program
in using the SRS unit. Detailed tasks are recommended in the
104 L. Ma et al.

Fig. 7.11 Example of customized calibration phantoms for SRS units: (a) an acrylic for linac-based SRS units; (b) the ABS plastic phantom used
for GK, (c) the solid-water phantom for the PFX released in 2009, and (d) the solid-water phantom for the Tomotherapy unit

110 audio–video monitoring and communication circuits. The

100 Measurements report by the AAPM task group TG-148 provides recom-
Reference mended QA tests for the Tomotherapy unit [46], and AAPM
90
task group TG-135 provides recommendations for robotic
RELATIVE DOSE (%)

80
70 radiosurgery (Cyberknife) [47].
60 One important but often neglected test in accepting a SRS
50 unit is to check imaging quality and accuracy. To carry out
40
such task, a standard MR/CT phantom with precalibrated
grid pattern should be scanned (preferably with fiducial
30
localizer box) and imported into the treatment planning sys-
20
tem to validate image resolution and detect any spatial dis-
10
tortion for the studies. One test phantom is shown in
0
85 90 95 100 105 110 115 Fig. 7.13. In general, it is recommended that an anthropo-
Z-AXIS morphic head phantom should be scanned for all imaging
modalities including CT, MR, and angiogram during the
Fig. 7.12 Measured dose profiles as compared with the calculated pro- acceptance of a SRS unit.
file in accepting a GK SRS unit. The agreement was found to be within
1 % and 1 mm requirements for the 4-mm helmet shown here

Service and Maintenance

AAPM task group TG42 report [5]. Additional basic tests
include timer, or monitor chamber accuracy, and linearity Proper functioning of a SRS unit is only as good as its weak-
tests; radiation survey; wipe tests (for Gamma Knife units); est link. To maintain high performance quality, routine ser-
emergency beam-off switch; door interlocks; and patient vice and maintenance is important. Before building and
7 Designing, Building, and Installing a Stereotactic Radiosurgery Unit 105

Fig. 7.13 The grid phantom for detecting MR versus CT spatial distor-
tion of the SRS imaging studies

Fig. 7.14 Source loading unit with opened unit head for handling a
Table 7.2 The servicing period for major components of the SRS units high activity of 60Co sources
Recommended
check and
Major components servicing frequency Most of the service and maintenance jobs listed in
Couch motion mechanism (all units) Annually
Table 7.2 are performed in the treatment room except for the
APS (GK) Annually
source loading and reloading task specific to the GK. Since
Microswiches (GK) Monthly
the unit requires manipulation of >1,200 Ci of 60Co sources,
Source activity (GK) Every 7–10 years
the radiation exposure is significantly higher than the design
Stereotactic frames and fiducial boxes (all units) Weekly
Alarm and interlocks (all) Daily
limit of a treatment room. Typically, a special hot cell bunker
Audio/video system (all) Annually is constructed for carrying out such tasks.
Laser systems (LB, TU, CK) Daily The hot cell should be large enough to accommodate the
Gantry rotation (LB, TU) Annually source head and the source loading unit. An illustration of
X-ray camera systems (LB, CK) Weekly the source manipulator with the open unit head is shown in
Robotic arms (CK) Quarterly Fig. 7.14. The door of the hot cell should be also shielded to
GK Gamma Knife, LB linac-based units, CK Cyberknife, TU tomo- allow operation of the robotic arms by an operator from out-
therapy unit side. Lead bricks are typically used to shield the doors.

installing a SRS unit, it is recommended that a comprehen-
sive probable risk analysis (PRA) should be carried out. The
goal of PRA is to assign priorities or possible risk factors to
the individual components and steps or sequences of the SRS
unit operations. This aims to eliminate potential cause lead-
ing to unrecoverable or disastrous events.
For example, a relative low priority can be assigned to
the functionality of the skull surface measurement device,
while a high priority should be given to the functionality of
the isocenter alignment tool such as the laser systems or
patient positioning device. Since the skull surface measure-
ment can be visually checked versus the patient imaging
studies, the chance of operation error and malfunction is
small. Potential errors can be reversed and corrected with-
out significant risk of injuring the patient. However, mal-
functions in the laser system and patient positioning device
would directly affect the shot coordinates and may produce
unrecoverable gross delivery errors. Therefore, regular test-
ing and servicing of such major components of the SRS units
is required (Table 7.2).
Personnel Training and Qualifications
Operation of the SRS units require qualified users. The quali-
fications and the training of the personnel should follow the
practice guideline from the American College of Radiology
(ACR). The minimum requirements for the key members of
team are summarized in Table 7.3 [48].
All core team members should receive basic operation
instructions and radiation safety training (physicians, physi-
cists, therapists, dosimetrists). Other ancillary SRS team
members may include nursing staff, neuroradiologists, and
anesthesiologists in cases where pediatric patients are treated.
Quality Control, Quality Assurance,
and Quality Management
Quality control is the process to validate whether a SRS unit
is compliant to the design requirements. Once a SRS unit is
built and installed, a series of tests needs to be performed to
106
Table 7.3 Minimum requirements of a qualified user for performing
SRS treatments
Member of the team Qualifications
Radiation oncologist • Certification (e.g., American Board
of Radiology or equivalent)
• SRS training either in residency or
in attending
Neurosurgeon • Certification (e.g., American Board
of Neurological Surgery)
• SRS training either in residency or
in attending
Qualified physicist • Certification (e.g., American Board
of Radiology or equivalent)
• SRS physics training and unit
operations and quality assurance
Radiation therapist • State Licensing and Certification
(e.g., American Registry of
Radiological Technologists (ARRT)
• Unit operation training
ensure initial quality of the unit. Quality control processes
governs all the manufacturing tests involved in testing the
quality of the unit.
Because SRS units are medical devices, FDA regulates
the manufacturing quality control process. For the unit to be
used for human treatments in the USA, the manufacturers
need to submit proper documentations showing good manu-
facturing practice (GMP) in designing and manufacturing
process of the device.
Similar to a teletherapy unit, GK and linac-based SRS
units involve moving components such as gantry, couch, and
patient positioning devices. A strict quality assurance pro-
gram should be enforced. The quality assurance program can
be separate into routine quality assurance and patient-specific
quality assurance procedures. The routine quality assurance
procedures include daily, monthly, and semiannual/annual
quality assurance procedures, user refreshing training, and
emergency procedures. Patient-specific quality assurance
procedures include quality management program (QMP)
checks, pretreatment checks such as dry-run [49] and the
Winston–Lutz tests. The routine quality assurance for SRS
deliveries generally includes unit functionality, safety inter-
locks, radiation monitor, and functionality and accuracy of
imaging studies.
In addition to general procedures, qualified operators
must carry out unit-specific quality assurance tests. For
example, the GK uses radioactive 60Co sources, and the
Nuclear Regulatory Commission (NRC) regulations (or
agreement state regulations) mandate additional tests for
operating GK units. For example, annual wipe tests of all the
helmets are typically required to ensure no source leakage.
A QMP is also required for most SRS deliveries. Major
components of such a program include documentation of
patient identification by at least two methods (name, photo,
etc.), and the treatment plan and delivery follows a written
L. Ma et al.
directive without deviation. In case of deviations, the reporting
level for misadministration and variance is narrow for SRS
deliveries. Typically, the misadministration of single fraction
SRS delivery is defined as when the delivered dose differs
from the prescribed dose by 10 % or higher. Because of strin-
gent criteria, small deviations from the standard protocol are
likely to result in misadministrations to be reported.
Therefore, most SRS programs require qualified physicists
to supervise all QA tasks of the procedure. In-treatment
checks, such as validations of target coordinates matching
the treatment plan, need also be carried out. Redundant QA
checks by another team member are also recommended.
All qualified SRS users should receive regular refresher
training. The training should cover radiation safety instruc-
tions and reporting requirements for radiation workers as
well as quality assurance chart reviews. One important train-
ing aspect is reviewing emergency procedures so that users
can respond quickly and appropriately to major equipment
failures or medical emergencies.
Cost and Budget
Budgeting for a SRS unit is a complex issue. Historically, the
add-on option to an existing linear accelerator has been
appealing because the accelerator is already in place for con-
ventional radiation therapy treatments. However, it is a gross
misconception that any conventional linear accelerator can
be used for SRS delivery. Physically, the requirement in the
isocenter alignment is a factor of two or three higher for SRS
deliveries as compared with standard fractionated treat-
ments. In addition, SRS demands high dose rate with a large
number of monitor units being delivered regularly. Wear and
tear on the expensive linear accelerator components such as
the klystron (or the magnetron) and the microwave guide
could also be substantial for these treatments.
For linac-based SRS delivery, the gantry speed in MU/
degree should be at least 5 MU/degree and preferably
10 MU/degree or higher for efficient deliveries. Extra con-
siderations need to be paid to pretreatment QA effort,
machine scheduling, patient flow logistics, and room design.
Today, many centers opt to purchase a dedicated SRS unit in
order to maximize the capabilities of SRS treatments.
The estimated startup costs for different SRS units are
summarized in Table 7.4.
In general, the acquisition and the ownership cost are
significantly higher for dedicated SRS units as compared
with standard radiation therapy equipment. Aside from
operation logistics, patient care and patient quality of life
should be the driving factor for purchasing a SRS unit. It is
clear that the patients themselves are most likely to go for a
SRS option when it provides better results compared to
those standard radiotherapy practices of the past, such as
whole brain radiotherapy.
7 Designing, Building, and Installing a Stereotactic Radiosurgery Unit 107

Table 7.4 Total estimated acquisition cost of different SRS units

Units Estimated cost in million dollars (M)
Gamma Knife 3.0–5.0 M (include source units, planning software, bunker, service contracts, and
training); additional 0.5–1.0 M for source reloading with 1–2 weeks down time
Dedicated or combo linac-based unit 3.0–5.0 M (include dedicated accelerator, treatment planning system, bunker,
add-on collimators, service contract, and training)
Tomotherapy unit 3.0–4.0 M (including compact S-band accelerator units, online-CT, treatment
planning system, service, and training)
Cyberknife 3.0–4.0 M (including X-band accelerator units, bunker, imaging devices, service
contract, and training)

Conclusions
Specialized equipment is needed to successfully deliver
SRS. This is accomplished using a number of different
methods. However, all radiosurgery equipment must
deliver highly conformal doses of radiation with steep
dose gradients to small targets precisely localized within
3D space. This equipment must be properly installed,
serviced, used, and tested to ensure safe and effective
patient treatments.
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 Part III
Stereotactic Radiosurgery Techniques
 Gamma Knife Radiosurgery
Ajay Niranjan, Greg Bowden, John C. Flickinger,
and L. Dade Lunsford
Historical Review
Professor Lars Leksell first coupled an orthovoltage X-ray
tube with his first-generation guiding device to focus radia-
tion on the Gasserian ganglion to treat facial pain. He subse-
quently investigated cross-fired protons as well as X-rays
from an early-generation linear accelerator (linac) for radio-
surgery [1]. In the 1960s, he became dissatisfied with the
cumbersome nature of cross-fired proton beams and the poor
reliability and wobble of then-existing linear accelerators.
Leksell and Larsson finally selected cobalt-60 as the ideal
photon radiation source and developed the Gamma Knife [2, 3].
They placed 179 60Co sources in a hemispherical array so
that all gamma rays (radiation from the decay of 60Co) were
focused on a single point thereby creating cumulative radia-
tion isocenters of variable volume depending on the beam
diameter. The first Gamma Knife created a discoid-shaped
lesion suitable for neurosurgical treatment of movement dis-
orders and intractable pain management.
Clinical work with the Gamma Knife began in 1967 in
Sweden [4]. By 1975, a series of surgical pioneers at the
Karolinska Hospital, Stockholm, began to use a reengineered
Gamma Knife (spheroidal lesion) for the treatment of intra-
cranial tumors and vascular malformations. The third and
fourth units created were placed in Buenos Aires and
Sheffield England in the early 1980s. Lunsford et al. intro-
duced the first clinical 201 source Gamma Knife unit to
North America (the fifth gamma unit worldwide). Dr.
Lunsford performed the first Gamma Knife radiosurgery in
August 1987 at University of Pittsburgh Medical Center.
A. Niranjan, M.D., M.B.A. (*) • G. Bowden, M.D., M.Sc.
Department of Neurological Surgery, University of Pittsburgh,
Pittsburgh, PA, USA
e-mail: niranjana@upmc.edu
J.C. Flickinger, M.D. • L.D. Lunsford, M.D.
Department of Radiation Oncology, University of Pittsburgh,
Pittsburgh, PA, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_8, © Springer Science+Business Media New York 2015
8
In the USA, based on the available published literature,
arteriovenous malformations (AVMs) and skull base tumors
that failed other treatments were considered the initial indi-
cations for radiosurgery [3]. A cautious approach was
adopted while waiting for increased scientific documenta-
tion. The encouraging results of radiosurgery for benign
tumors and vascular malformations led to an exponential rise
of radiosurgery cases and sales of radiosurgical units
(Table 8.1). The research rate continues to escalate with hun-
dreds of papers being published on this technology annually
in the last several years [5]. Currently, metastatic brain
tumors have become the most common indication for radio-
surgery, comprising 30–50 % of radiosurgery cases at busy
centers (Table 8.2). A wide variety of brain and body disor-
ders are now treated with radiosurgery [6]. Gamma Knife
radiosurgery is an example of a disruptive innovation in neu-
rosurgery as a wide variety of brain disorders are now treated
with radiosurgery [7].
The Evolution of Gamma Knife: Models A, B, C,
and PERFEXION
The Gamma Knife has evolved steadily since 1967. In the
first models (model U or A), 201 cobalt sources were
arranged in a hemispherical array. These units presented
challenging 60Co loading and reloading issues. To eliminate
this problem, the unit was redesigned so that sources were
arranged in a circular (O-ring) configuration (models B, C,
and 4C) (Fig. 8.1).
Gamma Knife radiosurgery usually involves multiple iso-
centers of different beam diameters to achieve a treatment
plan that conforms to the irregular three-dimensional vol-
umes of most lesions. The total number of isocenters may
vary depending upon the size, shape, and location of the tar-
get. Each isocenter has a set of three x, y, z stereotactic coor-
dinates corresponding with its location in three-dimensional
space as defined using a rigidly fixed skull stereotactic frame.
In terms of actual dose delivery, this means several changes in
111
112 A. Niranjan et al.

Table 8.1 Number and location of active Table 8.2 Brain disorders treated worldwide by gamma knife
Gamma Knife sites worldwide [6] radiosurgery by December 2011 [6]
Continent Country Units Category Indication Total
Africa Egypt 2 Malignant tumors Chondrosarcoma 957
Morocco 1 Nasopharyngeal carcinoma 1,770
Australia Australia 1 Other malignant tumor 10,400
Asia China 16 Malignant glial tumor (grade III and IV) 30,874
India 7 Metastatic tumor 252,372
Indonesia 1 Total 296,373
Iran 1 Benign tumors Hemangiopericytoma 1,533
Korea 15 Glomus tumor 2,335
Japan 48 Chordoma 2,395
Jordan 1 Other schwannoma 2,645
Pakistan 1 Hemangioblastoma 2,652
Philippines 1 Trigeminal schwannoma 4,139
Singapore 1 Pineal region tumor 4,420
Taiwan 7 Craniopharyngioma 5,107
Thailand 1 Benign glial tumors (grade I and II) 5,990
Vietnam 1 Other benign tumor 6,865
Europe Austria 2 Pituitary adenoma (nonsecreting) 19,575
Belgium 1 Pituitary adenoma (secreting) 31,226
Croatia 1 Vestibular schwannoma 63,797
Czech Rep. 1 Meningioma 90,761
France 3 Total 243,440
Germany 4 Vascular disorders Aneurysm 348
Greece 1 Other vascular disorder 5,325
Italy 5 Cavernous angiomas 6,128
Netherlands 1 AVM 71,566
Norway 1 Total 83,367
Poland 1 Functional OCD 193
Portugal 1 disorders Intractable pain 707
Romania 1 Other functional disorders 1,444
Russia 2 Parkinson’s disease 1,715
Spain 1 Epilepsy 2,731
Sweden 1 Trigeminal neuralgia 43,402
Switzerland 1 Total 50,192
Turkey 5 Ocular disorders Other ocular disorders 238
UK 5 Glaucoma 314
South America Argentina 1 Uveal melanoma 2,084
Brazil 2 Total 2,636
Chile 1 Total 676,008
Columbia 2
Venezuela 1
North America Canada 3 Center in March 2000. This technology combined advances
Dominican Rep. 1
in dose planning with robotic engineering and uses a submil-
Mexico 2
limeter accuracy automatic positioning system (APS)
USA 111
(Fig. 8.2). This technology obviates the need to manually
Puerto Rico 2
Total 269
adjust each set of coordinates in a multiple isocenter plan.
The robotic positioning system moves the patient’s head to
the target coordinates defined in the treatment plan. The robot
eliminates the time spent removing the patient from the hel-
the patient’s head position within the helmet. In 1999, the met, setting the new coordinates for each isocenter, and repo-
model C Gamma Knife was introduced. The first model C in sitioning the patient in the helmet. This has significantly
the USA was installed at the University of Pittsburgh Medical reduced the total time spent to complete the treatment and
8 Gamma Knife Radiosurgery
Fig. 8.1 Schematic diagram of model 4C Gamma Knife unit (Courtesy of Elekta AB, Stockholm, Sweden.)
Fig. 8.2 Gamma Knife 4C automatic positioning system, docking and
4 mm collimator (Courtesy of the University of Pittsburgh Gamma
Knife Facility, 2013.)
also increases accuracy and safety [8–13]. Because the treat-
ment time is shortened, a precise three-dimensional (3D) plan
can be generated using multiple smaller beams achieving
volumetric conformality. Such an approach results in a
steeper dose fall-off extending beyond the target (higher
selectivity). The other features of the model C unit include an
integral helmet changer, dedicated helmet installation trol-
leys, and color-coded collimators. In 2005, the fourth-
generation Leksell Gamma Knife, model 4-C, was introduced
113
(Fig. 8.3). The first unit was installed at the University of
Pittsburgh in January 2005. The model 4-C is equipped
with enhancements designed to improve workflow, increase
accuracy, and provide integrated imaging capabilities. The
integrated imaging, powered by Leksell GammaPlan, offers
the ability to fuse images from multiple sources. The plan-
ning information can be viewed on both sides of the treatment
couch. The helmet changer and robotic APS are faster and
reduce total treatment time.
The Gamma Knife PERFEXION unit is the latest inception
of this technology (Fig. 8.4). This system was developed in
response to input from expert neurosurgeons, radiation oncol-
ogists, and medical physicists. This resulted in a list of critical
features that included unlimited cranial reach, full automation
of the treatment protocol, improved patient and staff comfort,
radiation protection, and best dosimetry performance. The
first unit became active in 2006 and one was installed at the
University of Pittsburgh in 2007. The PERFEXION unit has
192 60Co sources arranged in a cylindrical configuration in five
concentric rings (Fig. 8.5). This differs substantially from the
previous hemispherical arrangements of the other units. The
tungsten collimator array ring eliminates the need for collima-
tor helmets with PERFEXION [9, 11]. Three collimators are
available for the PERFEXION system: 4, 8, and 16 mm. The
tungsten collimator array is subdivided into eight identical but
independent sectors, each containing 72 collimators (24 colli-
mators for each of the three collimators). Each sector with 24
sources can be moved independently into five different posi-
tions: (1) sector in home position when system is standby, (2)
4 mm collimator, (3) 8 mm collimator, (4) 16 mm collimator,
and (5) sector off position (blocking). This revolutionary
change allows the ability to form composite shots using differ-
ent beam diameters.
114 A. Niranjan et al.

Fig. 8.3 Gamma Knife 4C unit

(Courtesy of the University
of Pittsburgh Gamma Knife
Facility, 2013.)

Fig. 8.4 Gamma Knife

PERFEXION unit
(Courtesy of the University
of Pittsburgh Gamma Knife
Facility, 2013.)

The radiation cavity has been increased by more than
300 % compared to previous models. The increase in the vol-
ume of the radiation cavity allows for a greater mechanical
treatment range in X/Y/Z. It is (160/180/220 mm) for the
PERFEXION system compared to (100/120/165 mm) for
other Gamma Knife models. This provides virtually unlim-
ited cranial reach, so crucial in the care of patients with mul-
tiple brain metastases [4]. The APS used in the C units was
replaced by the patient positioning system (PPS). Rather
than just the head, the whole bed moves into preselected ste-
reotactic coordinates (Fig. 8.6). This provides better patient
comfort and allows complete of the majority of radiosurger-
ies in one single run, and has repeatability better than
0.05 mm. Docking of the patient into the PPS is done
by means of an adaptor that attaches to the standard stereo-
tactic Leksell G frame. The redesigned hardware of the
PERFEXION unit has had significant impact on the planning
software Leksell GammaPlan PFX (LGP PFX), a new
version of the LGP running on a PC platform with the
Linux operating system. The PERFEXION unit provides the
8 Gamma Knife Radiosurgery 115

Fig. 8.5 Diagrams of Gamma Knife PERFEXION collimator system. (a) Cross section of PERFEXION radiation unit. (b) Independently moving
sectors can be modified for varied shot compositions. (c–e) Sector position in 8, 4, and 16 mm collimator (Courtesy of Elekta AB, Stockholm, Sweden.)

The Radiosurgery Procedure

Following are the basic steps of Gamma Knife radiosurgery:

1. Daily quality assurance of the radiosurgery system
2. Application of the stereotactic guiding device to the
patient’s head
3. Stereotactic brain imaging using magnetic resonance
imaging (MRI), computed tomography (CT), and/or an
angiogram
4. Quality assurance of images
5. Determination of target volume(s)
6. Conformal radiosurgery dose planning by the radiosur-
gery team
7. Stereotactic delivery of radiation to the target volume by
positioning the patient’s head inside a collimator helmet
or docking system
8. Removal of stereotactic guiding device

Fig. 8.6 Docking mechanism of PERFEXION patient positioning system Daily Quality Assurance of the Radiosurgery
(Courtesy of the University of Pittsburgh Gamma Knife Facility, 2013.) System

potential to increase the spectrum of treatable indications Gamma Knife quality assurance testing is performed by an
including multiple brain metastasis, access to the upper authorized medical physicist every morning. The medical
cervical spine, and other pathologies of the head and neck. physicist ensures that the system tests required by US Nuclear
116
Regulatory Commission (NRC) regulations are performed
and functioning properly. These tests include the perma-
nently mounted radiation monitor and its remote indicator,
handheld radiation monitor, patient viewing and communica-
tion systems, door interlock, timer termination of exposure,
emergency stops, beam status indicators, availability of the
release rods for the emergency removal of a patient, test run
of the automatic patient positioning unit, microswitch test,
and function of the helmet hoist. Assessing the PERFEXION
unit is very similar but includes a sector positioning check to
verify proper functioning of the automatic collimator setup.
Additionally, the patient docking and positioning system is
assessed using a diode test tool and focus precision check.
Apart from daily quality assurance tests, monthly and annual
quality assurance is also performed in addition to preventa-
tive maintenance of the Gamma Knife unit.
Application of the Stereotactic Guiding Device
For Gamma Knife radiosurgery, appropriate stereotactic
frame placement is the initial critical aspects of the proce-
dure. Subtle changes to the positioning of the frame can be
the difference between a simple treatment plan, complicated
patient positioning, or even inability to proceed without
changing the frame. These issues are greatly reduced in the
PERFEXION system but the principles remain imperative to
best patient care. Prior to frame placement, the radiosurgery
team should review the preoperative images and discuss
optimal frame placement strategy. The preoperative images
should be kept in plain view while applying the head frame.
An effort should be made to keep the lesion as close to the
center of the frame as possible. The possibility of collision
by the frame base ring, the posts/pins assembly, or the
patient’s head with the collimator helmet during treatment
should also be considered prior to the frame application.
Furthermore, significant angulation should be avoided as it
may affect collisions, planning integration, and patient com-
fort when fixed in place for treatment. The authors use the
following strategies to avoid collisions and obtain optimal
frame placement. To target lower lesions (skull base tumors,
acoustic tumors, cerebellar lesions), the frame is positioned
lower by placing the ear bars in the top holes of the earpieces
on the Leksell G frame. For higher lesions (sagittal sinus
meningioma, metastases high in the frontal or parietal lobe),
the frame is positioned higher by placing the ear bars in the
bottom holes of the earpieces. For anterior targets (anterior
frontal lobe tumors, cavernous sinus tumors, sellar lesion
and lesion anterior to sella, and anterior temporal lesions),
the frame is shifted forward by placing earpieces posteriorly
on the base ring of the frame. The posterior edge of the ear-
piece is kept at 90 to 75 mm on the y-dimension of the head
frame (instead of 95–100 mm) depending upon the shift that
A. Niranjan et al.
is needed to bring the lesion closest to the center of the frame.
For anterior target, short posterior posts are preferred to
avoid collision of the posterior post/pin assembly with the
collimator helmet. To target posterior lesions (occipital lobe
tumors, transverse sinus tumors, cerebellar lesions), the
frame is shifted backward by positioning the earpieces for-
ward. The posterior edge of the earpiece is kept at 110–
125 mm instead of 95–100 mm. The anterior posts are
positioned as low as possible on the supraorbital region to
avoid collision of the frontal post/pin assembly with the col-
limator helmet. For radiosurgery planning, a higher gamma
angle (120–140°) is used if a potential collision is detected at
the default angle of 90°. To reach lateral targets (lateral
metastases, convexity tumors, far lateral tumors), the frame
is shifted laterally (right or left) toward the lesion. While
shifting the frame laterally, it is important to make sure that
there is enough space on the contralateral side to allow posi-
tioning of the fiducial box on the base ring of the frame. The
MRI or CT fiducial should be tried on the frame prior to
sending the patient to the MRI unit. If the fiducial box does
not fit on to the frame due to excessive shifting of the frame,
the frame will have to be repositioned.
The frame adaptor (which attaches the frame to the table)
is checked for fit. If the frame is shifted too anteriorly and the
back of head ring is too close to the neck, adaptor may not fit
and consequently treatment cannot be carried out. Tight fit-
ting of the adaptor may cause neck discomfort to patient espe-
cially during a long treatment. The frame cap check provides
information about geometry of all stereotactic frame parts
including posts and screws and also information about patient
head geometry to the treatment planning system. This infor-
mation is needed for the prediction of potential collisions or
close contact with the gamma knife unit collimator system. If
frame cap does not fit then the exact post and screw measure-
ments must be given to the treatment planning system.
Stereotactic Brain Imaging Techniques
Aside from the frame application, the next most important
aspect of radiosurgery is accurate imaging of the target. MRI
is the preferred imaging modality. CT is used when MRI is
not possible. Angiograms are used in conjunction with MRI
for AVM radiosurgery.
Stereotactic MRI
The critical aspects of stereotactic imaging include optimal
contrast between normal and abnormal tissues in addition to
high spatial resolution, short scan time, and thin slices so that
accurate target localization can be achieved. The use of MRI
in stereotactic planning has enhanced accurate targeting of
lesions that are usually not adequately defined by any other
imaging modality. Some physicians prefer the fusion of
8 Gamma Knife Radiosurgery
magnetic resonance and CT images for stereotactic guidance,
as they believe that in certain types of scanners, distortion may
affect the accuracy of target localization in MRI. For the initial
2 years, the authors used both MRI and CT for stereotactic
planning. Significant target coordinate differences were not
observed using the Leksell stereotactic system. Since 1993,
MRI has been used for stereotactic radiosurgery planning in
almost all eligible cases using a 1.5-T unit.
At our institution, high-resolution, gadolinium-enhanced
3D localizer (T2* images) image sequence is used first to
localize the tumor in axial, sagittal, and coronal images [14].
This sequence (3-mm-thick slices 2 mm apart) only takes
45 s for 11 axial, 11 sagittal, and 11 coronal slices. Using the
axial images, the fiducials can be measured and compared
with the opposite side to exclude the possibility of magnetic
resonance (MR) artifacts and to confirm that there is no
angulation or head tilt. Alternatively, T1-weighted sagittal
scout images (3-mm-thick slices with 1 mm) using spin echo
pulse sequence can be obtained for lesion localization. The
average time for this sequence is approximately 1.5 min. For
stereotactic imaging of most lesions, a 3D volume acquisi-
tion using fast spoiled-GRASS (gradient recalled acquisition
in steady state) sequence at 512 × 256 matrix and two NEX
(number of excitations) covering the entire lesion and sur-
rounding critical structures are preferred. To define the radio-
surgery target, this volume is displayed as 1- or 1.5-mm-thick
axial slices. The field of view (FOV) is kept at 25 cm × 25 cm
in order to visualize all fiducials. The approximate imaging
time for this sequence is 6–8 min.
We generally prefer 3D spoiled-GRASS sequence for
most lesions. Additional sequences are performed when more
information is needed. Pituitary lesions are particularly diffi-
cult to image especially if there has been prior surgery. A half
dose of paramagnetic contrast is usually given to image pitu-
itary adenomas. For residual pituitary tumors, after trans-
sphenoid resection, a fat-suppression SPGR sequence is
recommended in order to differentiate tumor from the fat
packed in the resection cavity. For cavernous malformations,
an additional variable echo multi planar (VEMP) imaging is
obtained to define the hemosiderin rim. For thalamotomy
planning, an additional fast inversion recovery sequence is
performed to differentiate basal ganglia from white-matter
tracts. Brain metastases patients receive a double dose of con-
trast agent, and the entire brain is imaged by 2 mm slices to
identify all of the lesions. Before removing the patients from
the MR scanner, the images must be checked for accuracy.
Stereotactic CT Imaging
When using CT imaging instead of MRI, it is advisable to use
short posterior posts to avoid artifacts from the posts and
pins. Care should also be taken in deciding the optimal place
for the pins because they cause artifacts on CT. An effort
should be made to keep the lesion away from the pin artifacts.
117
With modern CT scanners, 1- or 2-mm-thick slices (depending
upon the size of the lesion) without any gap can be obtained
in 4–5 min. Before removing the patients from the CT
table, accuracy checks are performed to make sure that
images would be accepted by the planning system and the
lesions have coordinates that are achievable in the Gamma
Knife unit.
Stereotactic Angiography
Angiography is the gold standard for AVM radiosurgery
planning. It should be used in conjunction with MR or CT
imaging to provide the third imaging dimension. The tech-
nique of angiography differs slightly from the conventional
digital angiography as the stereotactic angiographic images
are used not only for AVM nidus definition but also to guide
radiation to the target. The orthogonal images (instead of
oblique or rotated) are preferred but are not necessary. For
AVM nidi that are not properly visualized in orthogonal
planes, a rotation of up to 10° in two dimensions or aspects
can be used without compromising the accuracy of radiation
delivery. Before removing the angiography catheter, the
images should be reviewed to make sure that all the fiducials
are seen on the images. Digital subtraction techniques, despite
a potential radial distortion error, have proved satisfactory.
Quality Assurance of Images
Regular quality control checks of the MR unit are performed
in order to maintain accuracy of images. With a properly
shimmed magnet, regular servicing, and strict quality assur-
ance on the unit as well as on the images, MRI provides high-
resolution images with accurate target localization. A special
frame holder is used in order to avoid head movement during
MRI. Accuracy of images is checked for each image sequence
by comparing the known frame measurement with image
measurements in addition to the distance from the posterior
fiducials to the middle fiducials. The images are exported
from Imaging Suite via the Ethernet. Images are defined
using Leksell GammaPlan software (LGP) after the images
are transferred to the LGP computer. The measurements are
again checked and compared with the known frame measure-
ment and also the distance to the middle fiducial in order to
check for any distortion during image transfer.
Determination of Target Volume(s)
Target determination is an important step in order to make a
conformal plan. Target volume can be outlined using the LGP
software (manual or semiautomatic mode). Experienced sur-
geons can create conformal dose plans without outlining the
target; however, for new centers especially where physicists
118
assume the initial responsibility for planning, target definition
and outlining by surgeon or oncologist becomes an important
step. The surgeon’s input is required to define radiosurgery
targets for patients with AVMs, tumors, and functional neuro-
surgery as used by some centers. Defining the target volume
also helps in calculating conformality index.
Techniques of Conformal Dose Planning
This area will focus primarily on the 4C and PERFEXION
units. In the process of treatment planning, several strategies
can be used. The model C allows treatment using robotic
automatic patient positioning system (APS mode), manual
positioning (trunnion mode), or mixed treatment (some iso-
centers in APS mode and some in trunnion mode). A differ-
ent approach would be used if only a trunnion treatment plan
was possible versus an APS treatment plan. Universally, in
LGP one can start planning from the middle of the target and
then move to the top and bottom of the target. Another
approach is to start at the bottom or top and build from the
starting point. Some surgeons prefer to outline the target vol-
ume before planning the treatment volume. Beginners can
also use the inverse dose-planning algorithm to create a plan
and then optimize it manually. When planning a treatment
using trunnions only, one might tend to use larger collima-
tors (especially for larger lesions) to reduce the time and
maximize coverage of the target. For example, for a medium-
size acoustic tumor, in trunnion mode, one might use a few
14 mm collimators for the majority of the tumor and a few
4 mm collimators for the intracanalicular portion of the
tumor. In APS mode, however, one would most likely use
multiple 8-mm isocenters for the majority of the tumor and
4 mm isocenters for the intracanalicular portion because the
total time spent would be less. There would be no need to go
into the treatment room to set each isocenter. As long as the
isocenters are in close proximity to one another, the software
would automatically put them into the same treatment run
and the patient would move from one set of coordinates to
the next until all isocenters of one collimator size were
treated. The conformal dose planning is enhanced by the use
of multiple small collimators.
There are other tricks to use in planning; for example,
using a steep (125°) gamma angle for posterior lesions (cer-
ebellar or occipital) to avoid frame collisions. Another tech-
nique available for single isocenter lesions is to match the
gamma angle to the angle of the target. In APS mode, during
the set up phase of planning, the idea is to try to group as
many isocenters in the same run as possible, even if it means
changing all of the isocenters to high docking or a different
gamma angle than the default 90°. If a different gamma angle
is used, the plan must be rechecked for accuracy and adjusted
if necessary. In the current version of LGP, multiple targets
A. Niranjan et al.
(multiple tumors) can be treated using different isodose pre-
scription and different central doses with the use of multiple
matrices.
PERFEXION offers additional options to provide a con-
formal dose plan. Three different approaches are available:
• The use of a classical combination of shots including 4, 8,
and 16 mm collimators to cover the entire target volume.
• The automatic dynamic shaping ability, which is a new
feature in the treatment planning, introduced for the
PEREFXION system. This procedure will provide solu-
tions to block selected sectors to protect volumes defined
as critical structures.
• The use of single isocenters composed of different beam
diameters or blocked sectors. Any pattern of sectors
including 4, 8, 16 mm collimators and blocks can be gen-
erated. This can aid significantly for shaping dose distri-
bution especially for irregular volumes.
Techniques of Stereotactic Radiation
Delivery Using Gamma Knife
The model C Gamma Knife allows radiation delivery using
trunnion mode (manual patient positioning) or APS mode
(robotic positioning) or a combination of the two (mixed
treatment). In trunnion treatment, the x, y, and z of each iso-
center are set manually and double-checked to avoid errors.
The same coordinates and the time obtained from LGP are
entered into the control console, and radiation is adminis-
tered. The APS plan is transferred directly from planning
computer to control computer. The operator selects the run (a
combination of isocenters of same beam diameter) that
matches the collimator helmet on the Gamma Knife unit.
The APS is moved to the dock position, and the patient’s
head frame is fixed into the APS. The accuracy of the dock-
ing position is checked. The system prompts the user to per-
form clearance checks first for all those planned isocenters in
which the pins, posts, frame, or patient’s head would be less
than 12 mm away from the inner surface of the collimator
helmet (even though they may not match with the collimator
size that is being used for first run). The clearance check is
performed by moving the patient to those positions under
APS manual control and by checking the risk of collision
with the collimator helmet. After the clearance check, the
system prompts the surgeon to carry out position checks. In
the position checks, all the isocenters using the same helmet
are checked, one by one, by moving the patient’s head to
these positions using APS manual control.
The team moves out after the position checks are com-
pleted, and the radiosurgical dose is administered. The APS
moves the patient to all the planned positions, one by one,
until the isocenters using that size of collimator helmet are
completed. The team monitors the patient and the coordinates
8 Gamma Knife Radiosurgery
of different isocenters on the control computer. If other runs
using a different gamma angle but using the same helmet are
planned, then the patient is taken out, the next run is selected,
APS is moved to the dock position, and the patient’s head is
again fixed in the APS using the planned angle (72, 90, 110,
or 125°). Position checks are performed, and procedure is
begun. Similarly, if additional runs using different helmets
are planned, the helmet is changed, the patient’s head is posi-
tioned in the APS, and the position checks for all the isocen-
ters for that helmet and gamma angle are performed.
Radiosurgery with the LGK PERFEXION is a fully auto-
mated process for all aspects of the procedure including set
up of the stereotactic coordinates, setup of different sector
positions defining collimator size or blocked beams, and
setup of exposure times. All treatment data are exported to
the operating console. The only manual part of the procedure
is the positioning of the patient’s head in the docking
device and adjustment of the couch height for optimal
comfort. After confirmation of the patients’ identity, most
PERFEXION radiosurgeries are administered in one single
run (95 %). Rarely a clearance check is needed. For this, a
special test tool simulating the shape and dimensions of the
inner collimator is attached and rotated around patient’s
head. Once radiosurgery begins, the team monitors the
patient and the setup of coordinates, exposure times, and sec-
tor setup of different isocenters on the control computer of
operating console. The system allows audiovisual communi-
cation with the patient during irradiation and the process can
be interrupted at any time if needed.
Conclusion
In the past 25 years, we have witnessed dramatic improve-
ments in the stereotactic radiosurgery technologies. Gamma
Knife radiosurgery now offers better image handling, faster
and more compact platforms that make the calculations
almost real time. The advent of PERFEXION allows for
expanded indications and accessibility to lesions that were
challenging with previous systems. Furthermore, the ability
to mix collimators within a single shot adds to the surgeons’
119
ability to conform to the target. The APS has also had a
significant impact in reducing the risk of human error and
increasing the rate of treatment. In the future as these
and many other modifications become more utilized,
it should provide better treatments, resulting in better
patient outcomes.
References
1. Leksell L. The stereotaxic method and radiosurgery of the brain.
Acta Chir Scand. 1951;102:316–9.
2. Ammar A. Lars Leksell’s vision—radiosurgery. Acta Neurochir
Suppl. 1994;62:1–4.
3. Lunsford LD, Flickinger J, Lindner G, Maitz A. Stereotactic radio-
surgery of the brain using the first United States 201 cobalt-60
source gamma knife. Neurosurgery. 1989;24:151–9.
4. Leksell L. Cerebral radiosurgery. I. Gammathalanotomy in two
cases of intractable pain. Acta Chir Scand. 1968;134:585–95.
5. Niranjan A, Lunsford LD. Radiosurgery: where we were, are, and
may be in the third millennium. Neurosurgery. 2000;46:531–43.
6. International Leksell Gamma Knife Society. Indications treated
1991–2011. 1996. http://www.lgksociety.com.
7. Niranjan A, Madhavan R, Gerszten PC, Lunsford LD. Intracranial
radiosurgery: an effective and disruptive innovation in neurosur-
gery. Stereotact Funct Neurosurg. 2012;90:1–7.
8. Goetsch SJ. Risk analysis of Leksell Gamma Knife Model C with
automatic positioning system. Int J Radiat Oncol Biol Phys.
2002;52:869–77.
9. Lindquist C, Paddick I. The Leksell Gamma Knife Perfexion and
comparisons with its predecessors. Neurosurgery. 2007;61:130–40;
discussion 140–1.
10. Niranjan A, Novotny Jr J, Bhatnagar J, Flickinger JC, Kondziolka
D, Lunsford LD. Efficiency and dose planning comparisons
between the Perfexion and 4C Leksell Gamma Knife units.
Stereotact Funct Neurosurg. 2009;87:191–8.
11. Novotny J, Bhatnagar JP, Niranjan A, Quader MA, Huq MS,
Bednarz G, et al. Dosimetric comparison of the Leksell Gamma
Knife Perfexion and 4C. J Neurosurg. 2008;109(Suppl):8–14.
12. Regis J, Hayashi M, Porcheron D, Delsanti C, Muracciole X,
Peragut JC. Impact of the model C and Automatic Positioning
System on gamma knife radiosurgery: an evaluation in vestibular
schwannomas. J Neurosurg. 2002;97:588–91.
13. Yu C, Jozsef G, Apuzzo ML, MacPherson DM, Petrovich Z. Fetal
radiation doses for model C gamma knife radiosurgery.
Neurosurgery. 2003;52:687–93; discussion 693.
14. Niranjan A, Maitz AH, Lunsford A, Gerszten PC, Flickinger JC,
Kondziolka D, et al. Radiosurgery techniques and current devices.
Prog Neurol Surg. 2007;20:50–67.
 LINAC: Past, Present, and Future
of Radiosurgery
Maryam Rahman, Gregory J.A. Murad, Frank J. Bova,
and William A. Friedman
Introduction
Modern neurosurgery has witnessed a surge of new technol-
ogies and minimally invasive techniques that attempt to min-
imize tissue damage and patient recovery times from
neurosurgical interventions. With improving accuracy of
imaging techniques, neurosurgeons are capable of delivering
targeted treatment that causes little damage to surrounding
tissues without compromising efficacy. The search for mini-
mally invasive neurosurgical treatment has led to the devel-
opment of the operating microscope, endovascular treatment,
and endoscopic surgery. One of the most exciting discoveries
made during this search is the use of targeted, high-dose
radiation for neurosurgical disorders.
Radiosurgery is any method for stereotactically focusing
multiple beams of radiation on a target [1]. Initially described
with the Gamma Knife, stereotactic radiosurgery (SRS) is
now commonly delivered by linear accelerators (LINACs).
To deliver SRS, modifications were made to LINACs for
radiosurgical use [2]. The LINAC is now the most frequently
used device for delivery of conventional radiotherapy
and SRS.
Radiosurgery is truly minimally invasive, delivering ther-
apeutic energy to an accurately defined target without an
incision. It has been used to treat a wide variety of pathologic
conditions including benign and malignant brain tumors,
vascular lesions such as arteriovenous malformations
(AVMs), and pain syndromes such as trigeminal neuralgia.
The last 50 years has produced a tremendous amount
M. Rahman, M.D., M.S. (*)
Assistant Professor, Department of Neurosurgery, Preston A. Wells
Jr Center for Brain Tumor Therapy, University of Florida,
PO Box 100265, Gainesville, FL, USA
e-mail: mrahman@ufl.edu
G.J.A. Murad, M.D. • F.J. Bova, Ph.D. W.A. Friedman, M.D. (*)
Department of Neurosurgery, University of Florida,
Gainesville, FL, USA
e-mail: friedman@neurosurgery.ufl.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_9, © Springer Science+Business Media New York 2015
9
of knowledge about both targeting the lesion and radia-
tion delivery. This review covers the history of the develop-
ment of LINACs, the modifications necessary to deliver
radiosurgery, and current and future applications of LINAC
radiosurgery.
Radiosurgery
Regardless of the source of radiation, radiosurgical funda-
mental concepts include the following [3]:
1. A very high dose of radiation is delivered (usually in one
treatment).
2. A steep dose gradient is achieved with minimal dose to
surrounding structures.
3. The target is localized stereotactically.
4. Computerized dosimetry planning is employed.
5. The radiation delivery system is very accurate.
Radiosurgery refers to a single session surgical procedure
that delivers ionizing radiation to a target volume with accu-
rate preplanning of three-dimensional (3D) isodose surface
contours [4, 5]. These concepts require precise knowledge of
both the target volume and the behavior of the therapeutic
energy beam [6].
The basis for SRS was conceived over 60 years ago by Lars
Leksell [1]. His team’s implementation of these concepts cul-
minated in the development of the Gamma Knife. The modern
Gamma Knife employs cobalt radiation sources in a fixed
hemispherical array, such that all photon beams are focused
on a single point. The patient is stereotactically positioned in
the Gamma Knife so that the intracranial target coincides with
the isocenter of radiation. Using variable collimation, beam
blocking, and multiple isocenters, the radiation target volume
is shaped to conform to the intracranial target.
An alternate radiosurgical solution is use of the linear
accelerator (LINAC). Most LINAC radiosurgical systems
rely on the same basic paradigm: a collimated X-ray beam is
focused on an intracranial target. The development and mod-
ification of LINAC for radiosurgery will be discussed.
121
122 M. Rahman et al.

collimated by a set of secondary and tertiary collimators [9].

The Early LINAC
Photon beam radiation was proposed by Swedish physicist
Gustav Ising and subsequently developed by Rolf Wideroe, a
Norwegian physicist working in Switzerland in 1928
(Table 9.1) [7, 8]. He described a series of co-linear tubes
connected to a high-frequency generator. This apparatus
became widely used in experimental physics for heavy par-
ticles, where increase in velocity is modest. However, elec-
tron velocity increased so rapidly due to the small size of
electrons, the tubes could not be long enough and the system
was impractical for medical applications [8].
World War II drove the need for microwave technology
for military radar equipment. Innovation in this field led to
the development of the modern LINAC. LINACs produce
photon beams very differently from the Gamma Knife.
Instead of decay of cobalt, LINACs use a microwave genera-
tor to accelerate electrons within a waveguide. The wave-
guide bunches the electrons onto a portion of the wave,
where they can be efficiently accelerated up to 99.9 % of the
speed of light. Once the electrons reach their full accelerat-
ing potential, they collide with a heavy metal target. The
energy generated from this collision is mostly lost as heat.
However, a small percentage of the electrons pass near the
large nuclei of the metal target, are deflected, and undergo a
change in acceleration. This interaction results in the emis-
sion of a photon from the electron, i.e., electromagnetic radi-
ation [9]. “Bremsstrahlung,” German for “braking radiation,”
is used to describe the production of radiation from deceler-
ating or “braking” electrons.
Once the photon beam is produced, it is limited by a pri-
mary collimator, passes through a flattening filter to improve
the spatial uniformity of the beam, passes through two inde-
pendent monitoring ionization chambers, and can then be
The photon then transfers energy and ionizes atoms within
tissue. These ionizing events lead to molecular changes.
Photon beam radiotherapy differs from particle beam radia-
tion which propagates particles such as protons, neutrons,
pions, and heavy charged particles through tissue. These
charged particles directly disrupt the atomic structure of the
material they are traversing and thereby cause biological
change [10]. The expense of particle beam units has partly
driven the development of LINACs for radiosurgery.
In 1938, William Hansen at Stanford described the con-
cept of accelerating electrons by passing them repeatedly
through a resonant microwave cavity, gaining velocity on
each pass. He called this a “Rhumbatron” [11]. It was only
improvements of microwave generators, necessitated by
World War II, that enabled this concept to become a reality.
These discoveries, along with Harry Boot and John Randall’s
creation of the “magnetron” in the UK and the Varian broth-
ers’ development of the “klystron” in the USA, both in 1939
[8], led to the development of microwave LINACs in both
the UK and the USA by 1945 [12]. All of these devices
worked similarly to accelerate electrons. The groups led by
Don Fry at the Atomic Energy Research Establishment and
Hansen at Stanford both described clinically workable
LINACs. Interestingly, the groups had little knowledge of
each other’s work until the late 1940s [8].
LINAC and Radiosurgery
Shortly after World War II, Leksell first used the term radio-
surgery [1]. This concept sprouted from an idea Leksell had
discussed with Sir Hugh Cairns at the first Scandinavian neu-
rosurgical meeting in Oslo after the war. He discussed his
concerns about then-available neurosurgical techniques and

Table 9.1 Early history of LINAC radiosurgery

Date Primary author Location Event
1928 R. Wideroe Baden, Switzerland Developed photon beam radiation with high-frequency generator
1938 W. Hansen Stanford, USA Description of “rhumbatron” using a resonant microwave unit to accelerate electrons
1939 H. Boot & J. Randall Birmingham, UK Creation of “magnetron” using resonant microwave for radar during WWII
1939 R. & S. Varian Stanford, USA Creation of “klystron” using resonant microwave for radar during WWII
1948 W. Hansen Stanford, USA Development of microwave LINAC
1953 C.W. Miller, D.W. Fry Great Malvern, UK Development of micowave LINAC
1957 L. Leksell Stockholm, Sweden Treatment of patients with Gamma Knife
1983 O. Betti & V. Derechinsky Buenos Aires, Argentina LINAC radiosurgery with Talairach stereotactic localization
1984 M.D. Heifetz Los Angeles, USA Description of high-dose radiation with LINAC to small targets in the brain
1984 F. Colombo Vicenza, Italy Description of stereotactic LINAC radiosurgery system
1985 G.H. Hartmann Heidelberg, Germany Modified stereotactic localization to deliver multiple arc radiosurgery treatments
1985 M.S. Ginsberg Miami, USA First description of LINAC radiosurgery in the USA
1988 K. Winston & W. Lutz Boston, USA LINAC radiosurgery with phantom target device to check accuracy
1989 W.A. Friedman & F. Bova Gainesville, USA High-precision bearings to control patient and gantry movements to improve beam
accuracy to 0.2 ± 0.1 mm
9 LINAC: Past, Present, and Future of Radiosurgery
his plans to mechanically direct a probe or narrow beam of
X-ray or ultrasound into the brain to ablate pathways for pain
alleviation. Cairns gave him a positive response and Leksell
began systematically investigating ionizing beams [13]. He
and his colleagues tested an orthovoltage X-ray tube and pro-
ton beam produced by the cyclotron in Uppsala, calling pro-
ton radiosurgery “stralkniven” (ray knives) [14]. They also
considered LINAC as a potential radiation source. Ultimately,
they constructed the “Gamma Knife” using cobalt radiation
[15]. Leksell began treating patients in 1957 [3, 14]. Other
investigators worked with particle beam radiosurgery sys-
tems in Berkeley and Boston [16, 17].
Early radiosurgery researchers were aware of the poten-
tial for LINAC in delivering targeted radiation. Larsson, the
head physicist in the collaborative group at Uppsala
University with Leksell, wrote in 1974, “The choice between
the two alternatives, e.g., roentgen or gamma radiation,
should be based on technical, clinical and economical rather
than physical considerations. If radiation surgery will reach
a position as a standard procedure, improved electron accel-
erators for roentgen production, adapted for the purpose,
would seem a most attractive alternative” [18].
The initial LINACs developed in the UK and the USA
used traveling-wave technology [8]. They were limited by
relatively low beam energy, low radiation output due to inef-
ficient waveguide design and limited microwave power, and
restricted range of movement. These systems were also
large, with the top of the gantry being approximately 4 m off
the floor, to accommodate the accelerating waveguide. The
next generation of devices achieved full isocentric rotation
by mounting the accelerating structure to a gantry, allowing
the radiation source to be rotated in a vertical plane about a
single point. Also, by mounting the waveguide horizontally
with magnetic beam deflection (beam bending), the next
generation of LINACs had more manageable heights. The
next major improvement came in 1968 when Knapp et al.
developed the side-coupled standing wave structure which
improved shunt impedances so that the total length of the
accelerating structure was greatly reduced [19]. This devel-
opment did away with the need for beam bending (which had
its own problems) and still allowed for full isocentric rota-
tion at a practical height [8]. Currently, the US and Japanese
manufacturers use standing-wave technology, while the UK
manufacturers continue to use traveling-wave technology.
All LINAC radiosurgery systems focus a collimated X-ray
beam on a stereotactically identified target. The gantry of the
LINAC rotates over the patient, producing an arc of radiation
focused on the target. The patient couch is rotated in the hori-
zontal plane and another arc is performed. In this manner,
multiple noncoplanar intersecting arcs of radiation are pro-
duced. Like the Gamma Knife, the intersecting arcs produce
a high target dose, with minimal radiation to the surrounding
brain [3]. Along with the LINAC rectangular collimator, a set
123
of secondary circular collimators of varying size are used to
conform the beam [20].
Modifications of LINACs were necessary to perform
radiosurgery including a system to rotate the couch in syn-
chrony with the gantry, collimator development, and stereo-
tactic localization [21]. Several factors made LINAC
desirable for radiosurgery delivery. LINACs were used
widely in the USA for conventional radiotherapy, and modi-
fying the LINAC for radiosurgery was much more cost-
effective than purchasing a Gamma Knife. Gamma Knife
units at the time were only capable of delivering radiosurgery
and could not deliver conventional radiotherapy when not
being used for radiosurgery. Additionally, extracranial radio-
surgery treatment was believed to be more feasible using
LINACs. The theoretical benefits of LINAC discussed by
radiosurgery leaders in the past have now become a reality.
Within 10 years of LINAC development, reports appeared
on the use of external beam radiation for radiosurgery [12].
In 1983 Oswaldo Betti and Victor Derechinsky reported the
development of a multibeam LINAC coupled with a Talairach
stereotactic localization system in Buenos Aires [12, 22].
They used circular collimators that could be oriented in mul-
tiple coronal planes of a patient sitting in a moveable chair
while attached to a rotating head frame [6, 22, 23]. Their
system uniquely had the patient in a sitting position [3].
In 1984, a standard LINAC with small modifications was
used by Heifetz et al. (with Marilyn Wexler’s physics contri-
butions) to deliver high-dose radiation to small targets spar-
ing normal brain, similar to Leksell’s Gamma Knife [24].
Simultaneously, a neurosurgeon, Federico Colombo, and a
group of physicists led by Renzo Avanzo in Vicenza, Italy,
reported their stereotactic LINAC radiosurgery system [25].
They wrote about radiosurgical dose schemes of 40–50 Gy
over two fractions separated by 8–10 days for various intra-
cranial targets of 2–4 cm in diameter [26, 27]. The dose gra-
dient achieved compared well with Gamma Knife data [27, 28].
Hartmann et al. in Heidelberg, Germany, followed these
achievements with the description of a modified stereotactic
localization and positioning system to deliver multiple arc
radiosurgery treatments [29]. They modified a Riechert–
Mundinger stereotactic device, using laser lights to position
the frame within the isocenter.
The first published work on LINAC radiosurgery in the
USA came from the University of Miami in 1985 [30].
However, their system relied on the jaws of the treatment
machine for beam collimation instead of the secondary col-
limation system described by Larsson et al. [18]. Their tech-
nique was regarded as fractionated, rather than single fraction.
One of the first solutions for the requirement to spread out the
radiation entrance path and minimizing treatment delivery
time was described by Ervin Podgorsak at McGill University
[31]. He and his colleagues modified a LINAC using extra
collimators to define small circular fields and simultaneous
124
Fig. 9.1 Conformal dose. Nonspherical lesions can be treated with
minimal dose to surrounding structures. The colored lines are as fol-
lows: red = 70 % isodose, green = 50 % isodose, yellow = 20 % isodose
gantry and couch rotations. Additionally, the couch and
gantry were monitored from the control area, eliminating the
need to enter the room during treatment [32]. Due to increased
error rates with simultaneous gantry and couch rotation, most
institutions have not adopted this system.
Concerned with error and quality control, Winston and
Lutz published their work on multiple arc LINAC SRS in
1988 [33]. Their system included a phantom target device
that could easily be used to check the accuracy of each patient
treatment as well as to evaluate sources of error. They found
a mechanical accuracy of their system of 0.5 ± 0.2 mm. They
suggested that the major error in any radiosurgery system
was the error of localization and not mechanical error [3]. In
1989, Friedman and Bova reported on LINAC radiosurgery
system at the University of Florida [34]. A portable add-on
stereotactic devise was coupled to the LINAC, and high-pre-
cision bearings in the device controlled all patient and gantry
movements. As a result, the radiation beam accuracy was
improved to 0.2 ± 0.1 mm. The accuracy of treatment deliv-
ery was further increased with imaging software improve-
ments and the ability to fuse CT and MRI images [34].
As LINAC radiosurgery became more prevalent, increas-
ingly larger and more complex lesions were being treated
(Fig. 9.1). The circular collimators were still useful for these
types of lesions using a sphere packing technique (Fig. 9.2).
An alternative approach to sphere packing was first described
by Dennis Leavitt who built the first dynamic field shap-
ing collimator for radiosurgery in 1989 [35]. The circu-
lar collimators were supplemented with independent
rectangular vanes that “trimmed” the circular radiation field.
M. Rahman et al.
Fig. 9.2 Sphere packing technique. Dose planning has traditionally
used the sphere packing technique originally developed by Lars Leksell.
In this technique, sets of beams of radiation are aimed at the isocenter.
The beams are selected to reach the isocenter via unique paths. The
resultant dose distribution is spherical. To cover the entire target vol-
ume, the initial dose sphere is the largest sphere that fits inside the target
volume. The target volume is then “packed” with equal or smaller
diameter until adequate target coverage is achieved
This and other discoveries eventually led to the development
of a micromultileaf collimator from Varian and BrainLAB
[36]. These collimators have changed treatment delivery
from multiple noncoplanar arcs to fixed static fields and
dynamic arcs and allow for treatment of larger and more geo-
metrically complex lesions.
LINACs are continuously being modified to improve
radiosurgery delivery. For example, John Adler and Richard
Cox at Stanford University reported the development of an
industrial robot combined to a LINAC, called the Cyberknife®
(Accuray Inc., Sunnyvale, CA) [37]. This system can posi-
tion a circularly collimated beam of X-rays to a target from a
range of positions and angles. Moreover, the Cyberknife®
uses room-mounted imaging to localize the treatment isocen-
ter before treatment [38]. Other systems such as the Trilogy™
(Varian Medical Systems, Inc., Palo Alto, CA) also localize
the isocenter prior to treatment (Fig. 9.3) [39]. Real-time
imaging of patients can be used to readjust beam coordinates
for the target, making treatment of extracranial sites such as
spine and abdomen possible [12, 20]. Spinal radiosurgery is
being implemented for benign and malignant tumors, over-
coming the tremendous difficulty of target localization in an
area with movement of multiple joints [40–43]. In addition to
modifications to collimation and target localization, LINACs
have been modified to deliver SRS with intensity modulated
radiation therapy (IMRT) [12]. LINACs provide tremendous
possibilities for unique approaches to treatment. These sys-
tems demonstrate the versatility of LINAC for radiosurgery.
9 LINAC: Past, Present, and Future of Radiosurgery
Fig. 9.3 The Trilogy™ system. This system includes inline CT
for target localization prior to treatment allowing for extracranial
radiosurgery targeting
Radiosurgery for Benign Tumors
SRS has proved useful for the treatment of a variety of
benign intracranial neoplasms. These tumors commonly
arise from the skull base, where their dramatic impact on
quality of life belies their benign histology and small size.
Despite progressive improvement in microsurgical tech-
niques, outcomes for patients with these difficult tumors
continue to be less than optimal [44–46]. A significant
amount of experience has been accumulated using SRS in
the treatment of schwannomas and meningiomas. We will
focus on each of these tumor types in turn.
Vestibular Schwannomas
Among benign intracranial tumors, vestibular schwannoma
(acoustic neuroma) has been one of the most frequent targets
for SRS. This common tumor (representing approximately
10 % of all primary brain tumors) is a benign proliferation of
Schwann cells arising from the myelin sheath of the vestibu-
lar branches of the eighth cranial nerve. These tumors are
slightly more common in women, present at an average age
of 50 years, and occur bilaterally in patients with neurofibro-
matosis (NF) type 2.
Leksell first used SRS to treat a vestibular schwannoma
in 1969 [47]. SRS is a logical alternative treatment modality
for this tumor for several reasons. A vestibular schwannoma
125
is typically well demarcated from surrounding tissues on
neuroimaging studies. The sharp borders of this noninvasive
tumor make it a convenient match for the characteristically
steep dose gradient produced at the boundary of a radiosurgi-
cal target. This allows the radiosurgeon to minimize radia-
tion of normal tissue. Excellent spatial resolution on
gadolinium-enhanced MRI facilitates radiosurgical dose
planning. These tumors typically occur in an older popula-
tion that may be less fit for microsurgical resection under
general anesthesia. Finally, the location of these tumors at
the skull base in close proximity to multiple critical neuro-
logic structures (i.e., cranial nerves, brain stem) leads to
appreciable surgical morbidity and rare mortality even in
expert hands. This makes the concept of an effective, less
invasive, less morbid alternative treatment that can be per-
formed in a single day under local anesthesia quite attractive.
Whether or not radiosurgery fits this description has been
extensively debated.
Certainly, the role of radiosurgery is limited by its inabil-
ity to expeditiously relieve mass effect in patients for whom
this is necessary. The radiobiology of SRS also requires
lower, potentially less effective doses for higher target vol-
umes in order to avoid complications. This limits the use of
SRS to the treatment of smaller tumors. Despite these limita-
tions, there is substantial literature demonstrating radiosur-
gery is a safe and effective alternative therapy for acoustic
schwannomas.
Spiegelmann et al. have reported their experience in 44
VS patients treated with LINAC SRS from 1993 to 1997
[48]. CT scanning was selected as the stereotactic imaging
modality for target definition. A single, conformally shaped
isocenter was used in the treatment of 40 patients; two or
three isocenters were used in four patients who harbored
very irregular tumors. The radiation dose directed to the
tumor border was the only parameter that changed during
the study period: In the first 24 patients who were treated the
dose was 15–20 Gy, whereas in the last 20 patients the dose
was reduced to 11–14 Gy. After a mean follow-up period of
32 months (range, 12–60 months), 98 % of the tumors were
controlled. The actuarial hearing preservation rate was 71 %.
New transient facial neuropathy developed in 24 % of the
patients and persisted to a mild degree in 8 %. Radiation
dose correlated significantly with the incidence of cranial
neuropathy, particularly in large tumors (≥4 cm3).
Fractionated stereotactic radiation therapy (FSRT) has
been used as an alternative management for vestibular
schwannomas. This method is proposed as a way of exploit-
ing the precision of stereotactic radiation delivery to mini-
mize dose to normal brain while employing lower fractionated
doses in an effort to minimize complications. Litre et al.
recently reported on their experience with 155 VS patients
treated with fractionated LINAC SRS [49]. The patients
received five fractions of 1.8 Gy weekly for a total central
dose of 55 Gy. Local tumor control rates were 99.3 % at
126
Fig. 9.4 Pretreatment MRI scan shows left-sided vestibular schwannoma
3 years, 97.5 % at 5 years, and 95.2 % at >7 year follow-up.
Tinnitus (70 %), vertigo (59 %), imbalance (46 %), and ear
mastoid pain (43 %) greatly improved post SRS.
Complications included facial numbness (3.2 %), facial
weakness (2.5 %), worsened tinnitus (2.1 %), and need for
ventriculoperitoneal shunt (2.5 %). Thus far, most radiosur-
geons feel that optimal results can be achieved with highly
conformal single-fraction radiosurgery while sparing the
patient the inconvenience of a prolonged treatment course.
Friedman et al. performed an analysis of 390 VS patients
treated with LINAC SRS at University of Florida (UF) from
July 1988 to August 2005 [50]. With a median follow-up of
32 months for the entire group, most tumors were unchanged
or smaller (Figs. 9.4 and 9.5), and only 11 (4 %) tumors were
larger. The 1- and 2-year actuarial control rates were both
98 %, and the 5-year actuarial control rate was 90 %. Four
patients (1 %) required surgery for tumor growth. Seventeen
patients (4.4 %) reported facial weakness and 14 patients
(3.6 %) reported facial numbness after SRS. The risk of these
complications rose with increasing tumor volume or radio-
surgical dose to tumor periphery. Since 1994, when doses
were deliberately reduced to 1,250 cGy, only 2 patients
(0.7 %) experienced facial weakness and only 2 patients
(0.7 %) developed facial numbness. Based on this and previ-
ous studies, the authors currently recommend a peripheral
dose of 12.5 Gy for almost all acoustics as that dose most
likely to yield long-term tumor control without causing cra-
nial neuropathy.
Recently, van de Langenberg et al. described 37
VS patients treated with LINAC SRS with a 4-year probabil-
ity of no additional intervention of 96.4 % ± 0.03 [51].
M. Rahman et al.
Fig. 9.5 Four years after treatment, the MRI scan shows the schwan-
noma of Fig. 9.4 to be much smaller
Median follow-up was 40 months and 65 % patients demon-
strated tumor shrinkage, 22 % had stable VS size, and 13 %
had growth. In 54 % of all patients, transient tumor swelling
was observed.
LINAC SRS is a well-described effective treatment for
smaller VS tumors and has a lower complication rate com-
pared to surgery.
Meningiomas
Meningiomas are the most common benign primary brain
tumor, with an incidence of approximately 7/100,000 in the
general population. Surgery has long been thought to be the
treatment of choice for symptomatic lesions and is often
curative. Many meningiomas, however, occur in locations
where attempted surgical cure may be associated with mor-
bidity or mortality, such as the cavernous sinus or petroclival
region [52, 53]. In addition, many of these tumors occur in
the elderly, where the risks of general anesthesia and surgery
are known to be increased. Hence, there is interest in alterna-
tive treatments, including radiation therapy and SRS, either
as a primary or as an adjuvant approach.
Simpson, in a classic paper, described the relationship
between completeness of surgical resection and tumor recur-
rence [54]. A grade I resection, which is complete tumor
removal with excision of the tumor’s dural attachment and
involved bone, has a 10 % recurrence rate. A grade II resec-
tion, complete resection of the tumor and coagulation of its
9 LINAC: Past, Present, and Future of Radiosurgery 127

dural attachment, has up to a 20 % recurrence rate. Grade III

resection is complete tumor removal without dural resection
or coagulation. Grade IV resection is subtotal, and grade V
resection is simple decompression. Recurrence rates in
grades IV and V groups basically reflect the natural history
of the tumor, with high rates of recurrence over time.
Unfortunately, some common meningioma locations, such
as the cavernous sinus or petroclival region, are not readily
amenable to a complete dural resection or coagulation strat-
egy because of location and the proximity of vital neural and
vascular structures. In addition, relatively high complication
rates have been described for meningioma surgery in some
locations and in the elderly.
Pollock and colleagues recently analyzed 198 patients
with meningiomas less than 35 mm in diameter treated with
either surgical resection or Gamma Knife radiosurgery [55].
Tumor recurrence was more frequent in the surgical
resection group (12 % vs. 2 %). No statistically significant
difference was detected in the 3- and 7-year actuarial pro-
gression-free survival rate between patients with Simpson
grade 1 resections and those who underwent radiosurgery. Fig. 9.6 A patient with known breast carcinoma presented with symp-
Progression-free survival rates with radiosurgery were supe- tomatic pontine lesions. She was treated with radiosurgery (16 Gy to
the 80 % isodose line)
rior to Simpson grades 2, 3, and 4 resections. Complications
were lower in the radiosurgery group.
Multiple LINAC SRS series have been published [56–59].
Hakim and colleagues described one of the largest such
series, and the only one to report actuarial statistics [60]. One
hundred twenty-seven patients with 155 meningiomas were
treated. Actuarial tumor control for patients with benign
tumors was 89.3 % at 5 years. Six (4.7 %) patients had per-
manent radiation-induced complications.
The University of Florida report on LINAC SRS treat-
ment of meningiomas is one of the largest yet published [61].
Two hundred and ten patients were treated from May 1989 to
December 2001. All patients had follow-up for a minimum
of 2 years, and no patients were lost to follow-up. Actuarial
local control for benign tumors was 100 % at 1 and 2 years
and 96 % at 5 years (Figs. 9.6 and 9.7). Actuarial local con-
trol for atypical tumors was 100 % at 1 year, 92 % at 2 years,
and 77 % at 5 years. Actual control for malignant tumors was
100 % at 1 and 2 years but only 19 % at 5 years. Permanent
radiation-induced complications occurred in 3.8 %, all of
which involved malignant tumors. These tumor control and
treatment morbidity rates compare well with all other pub-
lished series. Fig. 9.7 Three years later, the site of the lesion of Fig. 9.6 is barely visible
We found that reliance on imaging characteristics rather
than surgical pathology did not yield a high incidence of Han et al. recently compared LINAC SRS to fractionated
missed diagnoses. During the time interval of this study, only radiation in the treatment of skull base meningiomas. A total
two patients were treated as presumed meningiomas and of 220 skull base meningiomas were treated using SRS
later found to have other diagnoses. One had a dural-based (n = 55), hypofractionated stereotactic radiation therapy
metastasis that was surgically excised when it enlarged. The (hFSRT) (n = 22), and FSRT (n = 143). Median follow-up
other had a hemangiopericytoma of the lateral cavernous was 32 months, and the median tumor volumes were 2.8 cm
sinus that was surgically excised when it enlarged. for SRS, 4.8 cm for hFSRT, and 11.1 cm for FSRT.
128
The median treatment doses were 1,250 cGy in one fraction
for SRS, 2,500 cGy in five fractions for hFSRT, and 5,040 cGy
in 28 fractions for FSRT. Radiographic control was achieved
in 91 % of SRS patients, 94 % of hFSRT patients, and 95 %
of FSRT patients. The authors concluded that there was no
differences in clinical or radiologic response to the different
radiation strategies, although these data are limited due to
variability of patients within each group and the slow growing
natural history of skull base meningiomas [62].
One of the advantages of LINAC SRS is the flexibility of
the system to treat systemic lesions. Increasingly, radiosur-
geons are reporting on their experiences with treating spinal
meningiomas with SRS. Recently, Gerszten et al. described
the treatment of 45 benign spine tumors with LINAC SRS
and CT for target localization [63]. They treated 14 cervical,
12 thoracic, 14 lumbar, and 5 sacral tumors. The majority of
the tumors (91 %) were intradural. The mean maximum dose
to the tumor volume was 16 Gy (12–24 Gy) given in a single
fraction in 39 cases. Median follow-up was 32 months. Of
the 19 (42 %) patients who had pretreatment pain, 15 had
significant improvement after SRS. Of the 15 patients with a
neurologic deficit pretreatment, four motor deficits were
stable, one motor deficit worsened in patients with NF 1, 10
sensory deficits improved, and one sensory deficit worsened
in a patient with NF 1.
Longer follow-up in these patients will be necessary for
an accurate assessment of the efficacy of SRS for spinal
benign tumors.
Radiosurgery for Malignant Tumors
Malignant tumors are radiobiologically more amenable to
fractionated radiotherapy than benign lesions. Malignancies
tend to infiltrate surrounding brain, resulting in poorly defin-
able tumor margins. A priori, these two traits of cerebral
malignancies would seem to make SRS an unattractive treat-
ment option. Nevertheless, SRS has proved to be a useful
weapon in the armamentarium against malignant brain tumors.
The most common applications of SRS to malignant tumors
are the treatment of cerebral metastases and the delivery of an
adjuvant focal radiation “boost” to malignant gliomas.
Cerebral Metastases
Metastatic brain tumors are up to ten times more common
than primary brain tumors with an annual incidence of
between 80,000 and 150,000 new cases each year [64].
Fifteen percent to 40 % of cancer patients will be diagnosed
with a brain metastasis during the course of their illness.
Once a brain metastasis has been diagnosed, the median life
expectancy is less than 1 year; however, in many patients,
M. Rahman et al.
aggressive treatment of metastatic disease has been shown to
restore neurologic function and prevent further neurologic
manifestations. Debate exists concerning the optimum treat-
ment for metastatic brain disease.
In autopsy series, brain metastases occur in up to 50 % of
cancer patients [65]. Approximately 30–40 % of patients
present with a solitary metastasis. Brain metastases fre-
quently cause debilitating symptoms that can seriously
impact the patient’s quality of life. With no treatment or ste-
roid therapy alone, survival is limited (1–2 months). Whole-
brain radiotherapy (WBRT) extends median survival, but the
duration of survival is typically low (3–4 months). Several
randomized trials have suggested that, when possible, sur-
gery followed by WBRT is superior to WBRT alone. Patchell
et al. reported a randomized clinical trial involving 46
patients with a single metastasis and well-controlled sys-
temic disease [66]. They found a significant improvement in
survival (40 vs. 15 weeks) and local recurrences in the CNS
(20 % vs. 52 %) for patients in the surgery plus WBRT arm
of the study. Likewise, Noordijk et al. randomized 66 patients
and found a significant survival advantage (10 vs. 6 months)
for the combination therapy arm [67]. In contrast, Mintz
et al. studied a group of 84 patients and did not show an
advantage of surgery plus radiotherapy over radiotherapy
alone [68]. It has been suggested that the inclusion of a
higher percentage of patients with active systemic disease
and lower performance scores did not allow the benefit of
improved local control to affect survival in this series.
Haines points out that survival and quality of life are the
most important outcome measures in evaluating a clinical
treatment for cancer [69]. Surrogate end points, like local
control, are inherently unreliable, especially when the defini-
tion of local control is changed. This applies to a comparison
of SRS with surgery for brain metastasis. In surgical series,
local control means no visible tumor on follow-up scans. In
SRS series, local control means no growth (or sometime
minimal growth) on follow-up scans. These end points are
unlikely to be equivalent.
In addition, comparison of current results to historical con-
trols is fraught with hazard to selection bias. This issue led to
erroneous conclusions about the efficacy of brachytherapy for
malignant gliomas and to overly optimistic reports regarding
the efficacy of intraarterial chemotherapy. Of equal import is
the difficulty and variability of reporting standards for local
control. Few series provide actuarial local control. They simply
provide a “raw” number at an arbitrary point in time. Less
commonly appreciated is the difficulty in documenting local
control. Many of these patients die away from the medical
center where radiosurgery was performed. It is frequently
impossible to determine from family or local physician tele-
phone interview whether the proximate cause of death was
loss of local control, new intracranial disease (loss of regional
control), or systemic disease. Most radiosurgical series have
9 LINAC: Past, Present, and Future of Radiosurgery
assumed that, unless an MRI was performed documenting
local loss of local control prior to death, local control was
maintained. This assumption may lead to a systematic overes-
timation of local control rates.
Sturm [70–72], Black [73, 74], and Adler [75–77] pub-
lished early reports on linear accelerator radiosurgery for
brain metastases. Alexander reported on 248 patients [73].
Median tumor volume was 3 cm3 and median tumor dose
was 15 Gy. Median survival was 9.4 months. Actuarial local
control was 85 % at 1 year and 65 % at 2 years. Auchter et al.
reported a multi-institutional study of 122 patients [78].
Actuarial 1- and 2-year survivals were 53 % and 30 %,
respectively. Local control was 86 %.
As radiosurgery has emerged as a treatment option, clini-
cians have attempted to define prognostic factors, which may
help to define patient populations most likely to benefit from
radiosurgical treatment. Multiple factors have been discerned
from retrospective analysis and include Karnofsky perfor-
mance scale score, status of systemic disease, histology,
number of metastases, volume of metastases, time interval
between the diagnosis of the primary lesion and the meta-
static lesion, pattern of enhancement [79, 80], the Radiation
Therapy Oncology Group (RTOG) recursive partitioning
categories [81], and radiation dose.
At the University of Florida 619 patients treated with SRS
for 1,569 brain metastases have been described [82]. Median
dose to target periphery was 1,750 cGy (range 1,000–
2,250 cGy). Median survival was 7.9 months. Actuarial local
control was 84.3 % (Figs. 9.6 and 9.7). The 1- and 2-year
actuarial control rates were 0.82 and 0.72. Melanoma histol-
ogy predicted poorer survival. Recursive partitioning analy-
sis (RPA) class I or II were associated with improved
survival. Female sex, younger age, higher Karnofsky perfor-
mance status (KPS), controlled primary tumor, absence of
systemic metastases, asynchronous presentation, fewer brain
metastases, smaller total tumor volume, surgery prior to
SRS, and multiple SRS treatments were also associated with
improved survival.
Malignant Gliomas
Current conventional treatment for malignant gliomas
involves a combination of surgery, radiation, and, often, che-
motherapy. The prognosis in these patients remains poor.
The majority of recurrences occur within 2 cm of the enhanc-
ing lesion as seen on initial imaging. Gross total excision
may be associated with prolonged median survival in patients
with malignant gliomas. Radiosurgery is an attempt at fore-
stalling local recurrence by aggressive local therapy.
Malignant gliomas account for approximately 40 % of the
17,000 primary brain tumors diagnosed annually in the
USA. The prognosis for long-term survival remains poor.
129
More than 80 % of recurrences are found within 2 cm of the
original tumor site. Many attempts have been made to
improve long-term survival by improving local control. Such
therapies include aggressive surgical removal, brachyther-
apy, chemotherapy wafers, and radiosurgery.
A number of linear accelerator radiosurgery series have
been published. Shrieve and colleagues reported on 32
patients receiving interstitial brachytherapy and 86 patients
receiving radiosurgical boost [83]. They found similar sur-
vival rates between the two groups and recommended radio-
surgery because of its outpatient, noninvasive nature. Hall
and colleagues reported 35 patients and believed that radio-
surgery did confer a survival advantage, with fewer compli-
cations than brachytherapy [84]. Masciopinto and colleagues
[69] reported on 31 patients so treated and found that the
“curative value of radiosurgery is significantly limited by
peripheral recurrence [85].”
A recurring theme in all retrospective studies of brain
tumor therapies is the question of selection bias influencing
the results of therapy more than the therapy itself. In an
attempt to control for selection bias in retrospective treat-
ment trials for malignant gliomas, Curran [74] developed the
RPA categories [86], and Sarkaria and colleagues used this
methodology to analyze 115 patients from three institutions
treated with linear accelerator radiosurgery [87]. They found
that patients treated with radiosurgery had a significantly
improved 2-year and median survival compared with RTOG
historical controls. The improvement was seen predomi-
nately in the worst prognostic classes (3–6 classes).
At the University of Florida, we have retrospectively
reviewed 100 patients with WHO grade III and IV malignant
gliomas who received SRS boost therapy for residual or
recurrent enhancing disease [88]. The patients in our study
were divided into RPA classifications for comparison with
historical controls. Class III and IV patients had median sur-
vival times very similar to the historical controls. Class V
patients demonstrated an increase in median survival (15.6
vs. 8.9 months) and 2-year survival rate (12.5 % vs. 6 %)
compared with historical controls. Eloquent location corre-
lated with poorer survival. This may be due to the selection
of less aggressive therapies for this group of patients.
Recurrence at time of radiosurgery was associated with lon-
ger survival. Very probably, this reflects the fact that patients
judged “eligible” for radiosurgery at time of recurrence are
already selected for longer survival than the average patient
treated up front. However, it remains possible that radiosur-
gery at time of recurrence is truly more effective than upfront
radiosurgery.
What about drawbacks of the recursive partitioning tech-
nique? The RTOG classes used are broad and do not include
all known prognostic variables, most notably tumor size. In
addition, important linear variables like age, mental status,
and KPS are converted into binary ones. This approach,
130
therefore, is flawed, as are all attempts at retrospective analy-
sis. Irish and colleagues, in an analysis of 101 consecutive
malignant glioma patients, have shown that those “eligible”
for radiosurgery have a median survival of 23.4 months,
compared with 8.6 months for “ineligible” patients [89].
Likewise, Curran found a marked survival advantage in
radiosurgery “eligible” vs. “ineligible” patients [90].
The only complete solution to the issue of selection bias
affecting outcome is a prospective randomized study. Such a
study has been performed and the results published in 2004.
RTOG Study 93-05 randomized patients with glioblastoma
into two treatment arms [91]. One received postoperative
radiosurgery, followed by conventional radiotherapy and
BCNU chemotherapy. The other arm received radiotherapy
and chemotherapy without radiosurgery. At a median follow-
up time of 61 months, the median survival in the radiosurgery
group was 13.5 months compared with 13.6 months in the
standard treatment arm. There were no significant differences
in 2- or 3-year survival, patterns of failure, or quality of life
between the two groups. Notably, RTOG 93-05 did not
address the use of radiosurgery for recurrent malignant glio-
mas. The main limitation of this study is that SRS was deliv-
ered prior to systemic therapy, and since the completion of
this trial, standard therapy for glioblastoma has become radia-
tion and temozolamide due to the seminal paper in 2005 [92].
Arteriovenous Malformations
Patient Selection
Open surgery is generally favored if an AVM is amenable to
low-risk resection (e.g., low Spetzler–Martin grade, young
healthy patient) or is believed to be at high risk for hemor-
rhage during the latency period between radiosurgical treat-
ment and AVM obliteration (e.g., associated aneurysm, prior
hemorrhage, large AVM with diffuse morphology, venous
outflow obstruction). Radiosurgery is favored when the AVM
nidus is small (<3 cm) and compact, when surgery is judged
to carry a high risk or is refused by the patient, and when the
risk of hemorrhage is not believed to be extraordinarily high.
Endovascular treatment, although rarely curative alone,
may be useful as a preoperative adjunct to either microsur-
gery or radiosurgery. The history, physical examination, and
diagnostic imaging of each patient are evaluated and the
various factors outlined above are weighed in combination to
determine the best treatment approach for a given case. The
decision about optimal AVM treatment is best made by a
multidisciplinary team composed of experts in operative,
endovascular, and radiosurgical treatment.
Stereotactic Image Acquisition
The most problematic aspect of AVM radiosurgery is target
identification. In some series, targeting error is listed as
the most frequent cause of radiosurgical failure [93, 94].
M. Rahman et al.
The problem lies with imaging. Although angiography very
effectively defines blood flow (feeding arteries, nidus, and
draining veins), it does so in only two dimensions. Using the
two-dimensional data from stereotactic angiography to rep-
resent the three-dimensional target results in significant
errors of both overestimation and underestimation of AVM
nidus dimensions. Underestimation of the nidus size may
result in treatment failure, and overestimation results in the
inclusion of normal brain within the treatment volume. This
can cause radiation damage to normal brain, which—when
affecting an eloquent area—may result in a neurologic defi-
cit. To avoid such targeting errors, a true three-dimensional
image database is required. Both contrast-enhanced CT and
MRI are commonly used for this purpose.
We use contrast-enhanced, stereotactic CT as a targeting
image database for the vast majority of AVMs. Our CT tech-
nique employs rapid infusion (1 mL/s) of contrast while
scanning through the AVM nidus with 1-mm slices. The
head ring is bolted to a bracket at the head of the CT table,
ensuring that the head/ring/localizer complex remains immo-
bile during the scan. This technique yields a very clear three-
dimensional picture of the nidus. Alternative approaches use
MRI/MRA as opposed to CT. Attention to optimal image
sequences in both CT and MRI is essential for effective
AVM radiosurgical targeting.
Dose Selection
Various analyses of AVM radiosurgery outcomes have eluci-
dated an appropriate range of doses for the treatment of
AVMs. We prefer to deliver a dose of 20 Gy to the periphery
of the AVM nidus whenever possible. Larger AVMs, or those
in critical locations, may require a lower dose—but this will
reduce the chances of complete obliteration.
Follow-Up
Standard follow-up after AVM radiosurgery typically con-
sists of annual clinic visits with MRI/MRA to evaluate the
effect of the procedure and monitor for neurologic complica-
tions. If the patient’s clinical status changes, he/she is fol-
lowed more closely at clinically appropriate intervals.
Each patient is scheduled to undergo cerebral angiogra-
phy at 3 years after radiosurgery, and a definitive assessment
of the success or failure of treatment is made based on the
results of angiography. If no flow is observed through the
AVM nidus, the patient is pronounced cured and is dis-
charged from follow-up. If the AVM nidus is incompletely
obliterated, appropriate further therapy (most commonly
repeat radiosurgery on the day of angiography) is prescribed,
and the treatment/follow-up cycle is repeated.
The University of Florida Experience
From May 18, 1988 to March 22, 2005, 544 patients with
AVMs were treated at the University of Florida. The mean
age was 40 (range, 4–78 years). The median treatment
9 LINAC: Past, Present, and Future of Radiosurgery
volume was 7 cm3 (range, 2–45.3 cm3). Many patients early
in the series were treated with single isocenters (259), but in
recent years an effort has been made to produce highly con-
formal plans by employing multiple isocenters. The median
radiation dose to the periphery of the AVM was 1,750 cGy
and the mean follow-up duration was 31 months.
Presenting symptoms included the following: headache/
incidental (188), seizure (227), hemorrhage (179), progres-
sive neurological deficit [23]. Spetzler–Martin scores were
as follows: (1) 29; (2) 188; (3) 228; (4) 98. AVMs were fur-
ther delineated into four nidus volume categories: (a) <1 cm3;
(b) 1–4 cm3; (c) 4–10 cm3; (d) >10 cm3. Angiographic/MRI
cure rates were as follows: (a) 92 %; (b) 79 %; (c) 64 %; and
(d) 36 %. There was a dramatic increase in cure rates when
the peripheral dose was raised to a least 15 Gy. There was a
dramatic decrease in cure rate when AVM size exceeded
10 cm3 (size D).
In 2003, we determined which factors were statistically
predictive of radiographic and clinical outcomes in the radio-
surgical treatment of AVMs [95]. The computerized dosim-
etry and clinical data on 269 patients were reviewed. The
AVM nidus was hand contoured on successive enhanced CT
slices through the nidus, to allow detailed determination of
nidus volume, target miss, normal brain treated, dose confor-
mality, and dose gradient. In addition, a number of patient
and treatment factors, including Spetzler–Martin score, pre-
senting symptoms, dose, number of isocenters, radiographic
outcome, and clinical outcome were subjected to multivari-
ate analysis.
None of the analyzed factors were predictive of perma-
nent radiation-induced complications or of hemorrhage after
radiosurgery in this study. Eloquent AVM location and 12 Gy
volume correlated with the occurrence of transient radiation-
induced complications. Better conformality correlated with
a reduced incidence of transient complications. Lower
Spetzler–Martin scores, higher doses, and steeper dose gra-
dients correlated with radiographic success.
When AVMs are not cured, current practice frequently
involves a “retreatment,” usually 3 years after the original
treatment. We reviewed the cases of 52 patients who under-
went repeat radiosurgery for residual AVM at our institution
between December 1991 and June 1998 [96]. In each case,
residual arteriovenous shunting persisted beyond 36 months
after the initial treatment. The mean interval between the first
and second treatments was 41 months. Each AVM nidus was
measured at the time of original treatment and again at the
time of retreatment, and dosimetric parameters of the two
treatments were compared. After retreatment, patients were
followed, and their outcomes evaluated, according to our
standard post-AVM radiosurgery protocol. Definitive end
points included angiographic cure, radiosurgical failure
131
(documented persistence of AVM flow 3 years after retreat-
ment), and death. The mean original lesion volume was
13.8 cm3 and the mean volume at retreatment was 4.7 cm3,
for an average volume reduction of 66 % after the initial
“failed” treatment. Only two (3.8 %) AVMs failed to demon-
strate size reduction after primary treatment. The median
doses on initial and repeat treatment were 12.5 and 15 Gy,
respectively. To date, 25 retreated patients have reached a
definitive end point. These include 15 (60 %) angiographi-
cally documented cures, nine (36 %) angiographically docu-
mented failures, and one fatal hemorrhage. A single
permanent radiation-induced complication occurred among
52 (1.9 %) patients, and 1 patient experienced a transient
deficit that resolved with steroid therapy. Two hemorrhages
(one fatal) occurred during a total of 130 patient-years at
risk, resulting in a 1.5 % annual incidence of posttreatment
hemorrhage. If one includes retreatments in the analysis of
radiosurgical success, the results are as follows: (a) 100 %;
(b) 92 %; (c) 85 %; (d) 82 %.
Ten (1.8 %) patients sustained a permanent radiation-
induced complication. Seventeen (3.1 %) had a transient
radiation-induced complication. These problems usually
resolved within several months of steroid therapy. Most
importantly, 42 patients suffered hemorrhages after radiosur-
gical treatment, and 8 were fatal. Hemorrhage during the
latent period after radiosurgery is the major drawback of this
procedure. Only surgery at this point can immediately elimi-
nate the risk of hemorrhage in patients with AVMs.
Conclusion
Modifications of LINACs for radiosurgery have led to close
collaboration between neurosurgeons, medical physicists,
and radiation oncologists. Such collaborations have increased
cross fertilization for each of these fields. Increasing use of
LINAC for radiosurgery has contributed to neurosurgeons
gaining a more in depth understanding of radiotherapy and
the challenges of delivering radiation to patients, and SRS has
now become an essential part of neurosurgical education.
The development of LINAC has led to widespread avail-
ability of radiotherapy for patients. LINACs are found in
almost every major medical center in the USA With afford-
able modifications to LINACs, radiosurgery is also now
widely available to patients. LINACs are currently the most
common devices used to deliver radiotherapy and radiosur-
gery. LINAC radiosurgery is being used to treat patients for
brain tumors, vascular malformations, pain syndromes, and
functional indications. LINAC technology is continually
being improved and will continue to play a major role in
clinical delivery of radiosurgery for patients.
132
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 Charged Particles in Stereotactic
Radiosurgery
Shervin M. Shirvani and Joe Y. Chang
Introduction: The Rationale for Charged
Particle Radiation for SRS
The majority of radiotherapy delivery systems worldwide
use photons generated from either a radioactive isotope such
as Cobalt-60 or from a linear accelerator. Photon radiation
has many advantages including its wide availability, cost-
effectiveness, and track record of controlling malignancies
originating from a multitude of tissues. Nonetheless, photons
are not without their disadvantages, and over the last several
decades, radiation oncologists and medical physicists have
investigated alternative radiotherapy modalities which cir-
cumvent the limitations of photons. Among these alterna-
tives, charged particle radiotherapies such as proton and
carbon ion beams have received special attention because of
their favorable physical characteristics.
Charged particles have an energy transfer pattern that is
fundamentally different from photons. In the case of photon
radiation, dose deposition and resultant ionizations in mat-
ter are characterized by a shallow peak dose followed by a
smooth fall-off. Consequently, adjacent normal tissue
located both shallow and deep to the target receives signifi-
cant radiation exposure. Unlike photons, charged particles
deposit their energy sparingly until a certain depth is
reached, at which point a very large deposition of energy
occurs. Beyond this depth, called the “Bragg peak,” there
are no further ionization events attributable to the charged
particle (though a small number of ionizations due to nuclear
scatter may still occur when larger nuclei like carbon ions
are used). The clinical consequence of the charged particle
depth–dose distribution is that the effects of radiotherapy
S.M. Shirvani, M.D.
Department of Radiation Oncology, Banner MD Anderson Cancer
Center, Gilbert, AZ, USA
J.Y. Chang, M.D., Ph.D., M.S. (*)
Department of Radiation Oncology, The University of Texas
M.D. Anderson Cancer Center, Houston, TX, USA
e-mail: jychang@mdanderson.org
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_10, © Springer Science+Business Media New York 2015
10
are mostly limited to the tissue before or at the Bragg Peak.
Organs beyond this depth are spared the toxic effects of
radiation. This difference between photons and charged
particle radiation is illustrated in Fig. 10.1.
Stereotactic radiosurgery (SRS) and charged particle radio-
therapy are not mutually exclusive. SRS is conceptually
defined as the delivery of large, hypofractionated doses of
radiation to precise targets. This definition is not limited to any
particular radiation modality, and charged particles can be
used in place of photons for stereotactic treatment, provided
that the essential processes of SRS—including accurate dose-
modeling, image-guidance, and quality assurance—can be
achieved. In fact, combing the radiobiological and dose esca-
lation advantages of hypofractionation with the tissue-sparing
characteristics of charged particle radiation can be an elegant
way to maximize the therapeutic index.
Until 2001, there were only two proton therapy centers in
the USA. Since then, the attractive properties of charged par-
ticles have encouraged the construction of eight additional
centers with four more to be completed soon. This sudden
acceleration in proton center availability will likely fuel
active investigation into the use of charged particle radiation
in a variety of clinical settings, including radiosurgery. This
chapter will review the physics and radiobiology of charged
particle radiotherapy as well as published clinical outcomes
to date in the hypofractionated, stereotactic setting.
Physical and Technical Considerations
For therapeutic radiation, charged particles are first produced
by applying an electric field to a gas of the desired particle to
separate the nucleus from its electrons. Acceleration of the
nucleus-derived charged particle is then achieved via a
cyclotron or a synchrotron. These machines operate by
accelerating particles around a round cavity while subjecting
them to electric and magnetic fields. In a synchrotron, both
the electric field and the magnetic field vary in time to accel-
erate a particle while also keeping it along a defined circular
135
136
Fig. 10.1 Comparison of dose-distribution curves of photons and pro-
tons. The high entrance dose and tail of exiting dose are avoided by the
use of charged particles
track as it accelerates. In a cyclotron, the particle starts in the
center of a cylindrical cavity and accelerates in a spiral, mov-
ing centripetally with time. In this case, the electric field
alternates with a constant frequency to accelerate the particle
during each revolution, but the magnetic field is kept uniform
to achieve the spiral movement.
When the particle achieves the desired energy, it is ejected
from the synchrotron or cyclotron. In the case of protons, this
is usually 150–250 MeV which results in 25–30 cm of
penetration into tissue. After ejection from the accelerator,
the particle is then guided by magnetic fields to the treatment
gantry. A nozzle at the gantry directs the beam to the prop-
erly positioned and immobilized patient. Worldwide, proton
and carbon ion cyclotrons are the most commonly used sys-
tems for charged particle therapy. Other charged ions includ-
ing helium, neon, argon, and silicon nuclei have been
explored in research settings but are not currently in wide-
spread use.
A monoenergetic beam of charged particles results in a
narrow Bragg peak, which has limited clinical utility for
treating typical tumor widths. Therefore, two different modes
of delivery have been developed to adequately cover the
dimensions of a typical target. The most common method of
delivery is via passive scattering. In this system, the particle
beam is scattered and flattened to create a beam of desired
width and intensity. The monoenergetic beam can also be
modulated with a range shifter to generate a polyenergetic
beam; the resulting depth–dose curve of the polyenergetic
beam is a superposition of the depth–dose curves of the con-
stituent Bragg peaks. It is characterized by a nonzero entrance
dose which rises to a plateau region before falling to zero at
the depth of the most distal constituent Bragg peak
(Fig. 10.2). The range shifter can customize the width of this
“spread-out Bragg peak” so that the tumor is adequately cov-
ered by the high-dose plateau.
To maximize conformality to the target’s three-
dimensional shape and to avoid normal tissues, additional
S.M. Shirvani and J.Y. Chang
SOBP (4cm) E=214.2MeV, Weight=8.7%
100
E=221.8MeV, Weight=47.4% E=211.6MeV, Weight=7.1%
E=219.3MeV, Weight=13.6% E=209 MeV, Weight=6.4%
E=216.7MeV, Weight=12.6% E=206.3MeV, Weight=5.0%
80
Dose (%)
60
40
20
0
0 5 10 15 20 25 30
Depth (cm)
Fig. 10.2 Depth–dose curve for a spread-out Bragg peak (SOBP) with
its constituent pristine Bragg peaks also shown. The gray area repre-
senting the target is encompassed by the width of the SOBP plateau
region
shaping of the radiation field in passive scattering systems is
usually necessary. Either apertures or collimators are used to
shape the perimeter of the beam, while customized compen-
sators placed in the beam path after the aperture can be used
to finely modulate the field’s distal edge [1, 2]. Importantly,
the materials used for these devices must provide adequate
attenuation without producing harmful particles through
scatter interactions. For example in the case of proton ther-
apy, brass or tungsten apertures are often used.
Because passive scattering planning is similar to 3D con-
formal radiation, complicated dose distributions and tight
conformation of dose around curved lesions are difficult to
achieve. However, with proper resources and skilled dosim-
etry, these challenges are usually surmountable. Dosimetric
studies of passive scattering proton therapy in the thorax
have shown that, with proper planning, their dose distribu-
tions are superior to photon-based treatments (3D conformal
photon or photon IMRT) in most cases [1, 3].
The second mode of delivery is a scanning beam system.
In this mode, the charged particle is subjected to an electro-
magnetic field prior to exiting the gantry. This electromag-
netic field modulates the energy and direction of the particle
beam so that the particles exiting the gantry deposit their
energy at a specific plane (“uniform scanning”) or voxel
(“spot scanning” or “pencil beam scanning”) within the
tumor [4]. In these systems, all the planes or voxels that con-
stitute the target are treated in turn, usually starting at the
most distal areas, until the entire volume of the tumor has
been irradiated. Among the voxel-based modes, spot scan-
ning delivers dose to each voxel in a step-and-shoot fashion
while pencil beam scans and treats each voxel in a continuous
fashion. In both cases, the dose that each voxel receives can
be independently modulated, and therefore treatment planning
for these techniques is typically done using inverse-planning
algorithms. Because of this similarity with photon-based
10 Charged Particles in Stereotactic Radiosurgery
intensity-modulated radiotherapy (IMRT), these techniques
are often called intensity-modulated proton therapy (IMPT).
Scanning beam delivery has two important advantages.
First, compensators and apertures are not needed, and there-
fore, contaminant scatter from these objects and the risk of
secondary malignancy is reduced. Second, scanning modes
result in greater conformality and are especially useful for
eccentric tumors or tumors located near sensitive structures.
A disadvantage, on the other hand, is that this approach is
less forgiving when intra- and interfraction tumor and organ
motion occurs [5–9]. To address intrafractional motion, it is
imperative that tumor motion be accounted for during simu-
lation, treatment planning, and dose delivery. In the chest, for
instance, tumors’ position can change significantly over the
course of respiration. Investigators at MD Anderson have
demonstrated that the creation of a four-dimensional, inter-
nal gross tumor volume (“4D-iGTV”) based upon the maxi-
mal intensity projection of the tumor on axial CT slices
throughout the entire respiratory phase is an accurate method
for minimizing the risk of a geometrical miss due to tumor
motion [10]. For interfraction changes due to an early tumor
response, adaptive planning can be considered [8, 9].
Radiobiologic Advantages of Charged
Particle Therapy
Charged particle radiotherapy is directly ionizing because,
by virtue of their charge, the accelerated particles can inter-
act with atomic electrons through Coulombic forces.
Consequently, charged particles, unlike photons, are asso-
ciated with high linear energy transfer (LET). Their inter-
action with tissues is characterized by (1) direct damage to
cellular DNA and (2) a dense mobilization of secondary
electrons along the particle track, resulting in a high local
concentration of free radicals which also cause DNA dam-
age. In clinical systems that utilize a SOBP, cellular dam-
age is considered to be nearly constant across the plateau
phase of the depth–dose curve, but in reality, there may be
variations over the course of the particle track. This is dis-
cussed in more detail in section “The Challenges of Particle
Therapy”.
Though different nuclei used in charged particle therapy
may have similarities with respect to the general shape of
their depth–dose curve, their ultimate radiobiological effects
is dependent upon the specific LET of the particle that is
used. Said differently, the shape of the SOBP is useful for
determining the distribution of dose, but the extent of bio-
logical damage that is done to the target tumor is dependent
on a different property: relative biological effectiveness
(RBE). This quantity is defined as the ratio of the dose of
photons to the dose of charged particles necessary to achieve
the same biological effect in a specified test system. If the
137
RBE for a specific particle is high, then that particle exerts a
significant amount of damage per absorbed unit of energy
and is said to have high “quality.”
RBE is related to LET in a bell-shaped distribution: RBE
rises until an LET of approximately 100–150 keV/μm and then
falls at higher LET values. The reason for the peak in RBE at
100 keV/μm is that the likelihood of a single-particle track
causing a DNA double-strand break is maximized at this level.
Because each charged particle has a different LET, we expect
RBE to be different among them. For instance, protons in the
250 MeV range have an RBE of approximately 1.1, whereas
carbon-ions have an RBE in the 2–3 range [11, 12]. This means
that protons are radiobiologically similar to photons, offering a
10 % improvement in radiation quality, whereas heavy nuclei
cause considerably higher biological effect.
Two other radiobiological phenomena deserve mention
with regard to the relative advantages of charged particle
radiation. In photon radiobiology, the radiosensitivity of a
tumor cell can be diminished by the absence of oxygen or by
the cell’s position in a radioresistant phase of the cell cycle
(such as the S phase). In both cases, the altered radiosensitiv-
ity is attributable to the cell’s capacity for repair of
radiation-induced DNA damage, which is enhanced by
hypoxia and the presence of sister chromatids and DNA-
repair enzymes in certain cell-cycle phases. However, the
single-track, double-strand break described in the previous
paragraph is a subtype of DNA injury that is difficult to
repair even in the presence of these radiobiological modifi-
ers. Because high quality particles (such as heavy nuclei
such as carbon ions) are more likely to induce this type of
injury, the oxygen and cell cycle effects become less impor-
tant. This ability of heavy ion particle radiation to overcome
these intrinsic mechanisms of radioresistance is a major the-
oretical advantage over photons. In fact, this difference in
radiobiology is the main distinguishing feature between
heavy nuclei ions and protons, whose radiological quality is
similar to photons.
Particle Radiosurgery: Early Clinical
Outcomes
As stated in section “Introduction: The Rationale for Charged
Particle Radiation for SRS”, there is no a priori reason that
stereotactic hypofractionation cannot be combined with par-
ticle radiotherapy so that patients can benefit from the advan-
tages of both. However, highly reproducible patient
immobilization devices (such as the Gamma Knife frame)
and image-guidance technologies (such as cone-beam com-
puted tomography) have not been traditionally been avail-
able in proton or heavy-nuclei gantry systems. Fortunately,
newer systems have circumvented these limitations by
incorporating customized vacuum molded masks and frames
138
for immobilization, four-dimensional simulation for treat-
ment planning, and on-board imaging systems such as fluo-
roscopy, CT imaging, and fiducials for image-guidance.
Nonetheless, “particle radiosurgery,” as loosely defined by
the combination of charged particle radiotherapy with large
fraction sizes, is still a young concept whose preliminary evi-
dence is limited to a handful of single-institution series in the
context of treating early-stage lung cancer. Still, despite their
limitations, these experiences provide proof of principle of
the efficacy and organ-sparing characteristics of particle
radiosurgery.
Non-small Cell Lung Cancer
Rationale for Particle Therapy in the Thorax:
Anatomy and Dose
SRS advances for non-small cell lung cancer in the last
decade have largely relied on photon techniques. These early
experiences were successful in safely ablating peripheral
tumors but also resulted in considerable toxicity when used
for centrally located tumors [13–17]. Life-threatening com-
plications including radiation pneumonitis, great vessel rup-
ture, esophageal ulceration, and spinal cord myelopathy have
been reported when central tumors have been treated with
ablative dose regimens [18, 19]. This difference in therapeu-
tic ratio was especially stark in an early phase II study of 70
patients with both peripherally and centrally located tumors
treated to 60–66 Gy in three fractions [20]. In this cohort,
2-year freedom from severe toxicity was 83 % for those with
peripheral tumors compared with only 54 % for patients with
perihilar or central tumors.
Fig. 10.3 Comparison of passively scattered proton therapy (right panel) and 3D conformal photon therapy (left panel)-based stereotactic ablation
of a lung tumor close to critical structure brachial plexus. The proton plan results in a diminished dose to the brachial plexus
S.M. Shirvani and J.Y. Chang
These anatomically challenging cases are one circum-
stance where particle-based radiotherapy may provide valu-
able synergy to hypofractionated treatment. Provided that
proper beam angles are used, particles such as protons and
carbon ions should significantly reduce the integral dose to
the lung and minimize incidental irradiation of nearby organs
including the heart, esophagus, spinal cord, bronchial tree,
major vessels and brachial plexus (Fig. 10.3). Providing evi-
dence of this principle, dosimetric studies at the Mayo Clinic
and MD Anderson Cancer Center have confirmed that the
Bragg peak characteristics of proton therapy can be used to
deliver ablative doses of radiation to early stage tumors as
effectively as photon SRS while significantly reducing the
dose to surrounding normal tissues.
In the MD Anderson study, proton plans compared to pho-
ton-based SBRT plans significantly reduced the mean total
lung dose from 5.4 to 3.5 Gy (p < 0.001) and 2.8 Gy (p < 0.001)
and reduced the total lung volume receiving 5, 10, and 20 Gy
(p < 0.001). Moreover, for cases where the PTV was within
2 cm of the critical structures, the proton plans resulting in sig-
nificantly reduced mean maximal dose to the aorta, brachial
plexus, heart, pulmonary vessels, and spinal cord [21].
Similarly, the Mayo Clinic study found that proton-based tech-
niques resulted in significantly reduced total lung mean and V5
dose; other normal tissues including heart, bronchial tree
(including trachea), esophagus, and spinal cord lower were also
found to receive less dose with protons [22]. Interestingly, in
both studies, better dose distributions were achieved with scan-
ning beam methods than with passively scattered protons.
A second rationale for particle radiotherapy is the con-
verse of the first: While the goal described above is to mini-
mize normal tissue effects given a specified target dose, the
10 Charged Particles in Stereotactic Radiosurgery
other potential use of particle therapy is to escalate the dose
delivered to the tumor given prespecified thresholds for adja-
cent organs. In radiosurgery for non-small cell lung cancer,
this second rationale is particularly relevant because of the
observation that higher BED is more likely to achieve cure
[13–16, 23–32]. This phenomenon was underlined in a retro-
spective study by Onishi and colleagues who demonstrated
that among different photon SRS regimens, patients who
received a BED greater than 100 Gy had much better 5-year
local control (92 % vs. 74 %) and overall survival (88 % vs.
69 %) than those who received a lower BED [23]. In light of
these findings, particles may be a powerful tool for achieving
100 Gy BED when adjacent organs-at-risk prevent dose
escalation of photons to these levels.
Outcomes for Highly Hypofractionated Regimens
Thus far, seven experiences using hypofractionated particle
therapy for non-small cell lung cancer have been reported,
four with proton therapy and three with carbon ion therapy
(Table 10.1). Each of these studies has unique technical and
image-guidance procedures. The earliest study was per-
formed by Bush et al. at Loma Linda. At this center, 68
patients were treated to 51–60 cobalt-60 Gray equivalents
(CGE) in ten fractions. Real-time fluoroscopy was used for
verification of patient and tumor position, and notably, this
study did not include any compensatory actions for respira-
tory motion [33]. Nonetheless, 3-year local control and
cause-specific survival rates were 74 % and 72 %, respec-
tively, over a median follow-up of 30 months. With regard to
toxicity, no cases of acute radiation pneumonitis were
observed nor were there any grade 3 early or late esophageal
or cardiac toxicities.
Nihei and colleagues used three-dimensional CT simula-
tion, respiratory gating, and real-time digital radiographs for
position verification. With these more modern techniques, 37
patients were treated to a total dose of 70–94 CGE using frac-
tion sizes of 3.5–4.7 CGE, which resulted in a local control
rate of 80 % at 24 months [34]. Hata and colleagues in Japan
Table 10.1 Highly hypofractionated proton or carbon ion for T1-T2 N0 non-small cell lung cancer
Study Dose (CGE)/no. of fractions
Proton therapy
Westover et al. [37] (2012) 42–50/3–5
Iwata et al. [36] (2010) 80/20 or 60/10
Hata et al. [35] (2007) 50–60/10
Nihei et al. [34] (2006) 70–94/20
Bush et al. [33] (2004) 60/10
Carbon ion therapy
Iwata et al. [36] (2010) 52.8/4
Miyamoto et al. [39] (2007) 52.8–60/4
Miyamoto et al. [38] (2007) 72/8
139
utilized 50 or 60 CGE in ten fractions to treat a cohort of 21
patients with stage I NSCLC [35]. All but one of the patients
(95 %) experienced durable local control following this treat-
ment. Two-year overall and cause-specific survival rates were
74 and 86 %. As in the Bush study, the toxicity profile was
favorable with no grade 3 or greater reactions observed. Other
hypofractionated proton regimens used in Japanese proton
centers have demonstrated similar results [36].
The Massachusetts General Hospital reported outcomes
for 15 patients with 20 tumors treated with proton SBRT to
42–50 CGE in 3–5 fractions between July 2008 and
September 2010. Only one grade 3 or higher toxicity was
observed (grade 3 pneumonitis in a patient with severe
chronic obstructive pulmonary disease), and the 2-year over-
all survival and local control rates were 64 % and 100 %,
respectively, with a median follow-up of 24.1 months [37].
The National Institute of Radiological Sciences (NIRS) in
Chiba, Japan, has reported three trials of hypofractionated
radiotherapy using carbon ions. The first, a phase I/II study
of 50 patients treated to 72 CGE in nine fractions, resulted in
a 5-year local control rate of 95 % with no grade 3 toxicities
observed [38]. A second study followed 76 patients with T1
and T2 tumors treated to 52.8 CGE in four fractions and
60 CGE in four fractions, respectively [39]. At 3-year fol-
low-up, local control for T1 tumors was 98 % and for T2
tumors was 80 %. Again, no grade 3 toxicities were observed.
Finally, a dose escalation study in which patients receive
single-fraction regimens from 28 to 44 CGE is ongoing at
NIRS. Preliminary results showed no grade 3 or greater tox-
icities at any of the dose levels during a follow-up period of
16 months [40]. The local control and survival outcomes of
this cohort are yet to be reported.
Outcomes for Modestly Hypofractionated
and Conventionally Fractionated Regimens
In addition to the studies above, more modestly hypofrac-
tionated regimens using proton therapy have been reported
for non-small cell lung cancer (Table 10.2). While strictly
Local control Overall survival
100 % (2 years) 64 % (2 years)
81 % (3 years) 73 % (3 years)
95 % (2 years) 74 % (2 years)
80 % (2 years) 84 % (2 years)
74 % (3 years) 44 % (3 years)
86 % (2 years) 87 % (2 years)
98 % (3 years) 78 % (3 years)
95 % (5 years) 50 % (5 years)
140
Table 10.2 Modestly hypofractionated proton radiotherapy for non-small cell lung cancer
Dose (CGE)/
Study no. of fractions Chemotherapy
Early stage
Chang et al. [41] (2010) 87.5/35 N/A
Shioyama et al. [42] (2003) 76a/22a N/A
Locally advanced
Chang et al. [45] (2011) 74/37 Carboplatin/paclitaxel
Nakayama et al. [43] (2011) 67.1–91.3/33 None
a
Median values
speaking these fall outside the realm of radiosurgical abla-
tion, they are nonetheless instructive with regard to the high
doses that can be achieved with the depth–dose characteris-
tics of particle radiotherapy: Targeting the subset of patients
with centrally or superiorly located Stage IA–II non-small
cell lung cancers, Chang et al. conducted a Phase I/II pro-
spective study of proton radiation with a total dose of
87.5 CGE at 2.5 CGE per fraction [41]. At initial reporting of
outcomes with a median follow-up time of 16.3 months, the
most common adverse effects were Grade 2 dermatitis
(67 %), Grade 2 fatigue (44 %), Grade 2 pneumonitis (11 %),
Grade 2 esophagitis (6 %), and Grade 2 chest wall pain
(6 %). No grade 4 or 5 toxicities occurred, and the local con-
trol rate was 88.9 %. Similarly, Shioyama and colleagues
reported 28 patients with Stage I NSCLC treated with proton
therapy to a median total dose of 76 CGE in median 3 CGE
fractions (range, 2–6 CGE) [42]. The 5-year local control
rate was 89 % for patients with Stage IA disease with one
case of Grade 3 acute toxicity observed.
Interestingly, the outcomes achieved in the Chang and
Shioyama studies with modest hypofractionation were com-
parable to photon-based ablative approaches. This suggests
that, in certain settings, the radiobiological advantages of
high LET radiation can substitute for the radiobiological
advantages of hypofractionation, while still allowing for the
interfractional recovery of normal tissues. In cases where
normal tissue toxicity is not a major concern, it stands to
reason that combining ablative hypofractionation with
charged particle radiotherapy would result in maximal
efficacy.
Finally, in the locally advanced setting, several studies
have confirmed the utility of using charged particles, specifi-
cally protons, to increase the radiation dose while sparing
normal tissue (Table 10.2). Though these results also do not
reflect a stereotactic approach, they are nonetheless instruc-
tive for demonstrating the advantages of proton therapy for
treating large volumes in the thorax. Especially notable are
the low rates of severe toxicity observed despite the use of
S.M. Shirvani and J.Y. Chang
Local control Overall survival
89 % (2 years) 54.5 % (2 years)
T1A—89 % (5 years) T1A—70 % (5 years)
T1B—39 % (5 years) T1B—16 % (5 years)
80 % (1 year) 86 % (1 year)
66 % (2 years) 59 % (2 years)
high radiation doses and/or concurrent chemotherapy in this
setting. Nakayama et al. retrospectively reviewed 35 patients
with stage II or III NSCLC who were medically inoperable or
who refused surgery and instead were treated with proton
therapy without concurrent chemotherapy [43]. The median
proton dose delivered was 78.3 CGE (range, 67.1–91.3 CGE).
The overall and local progression-free survival rates were
81.8 % and 93.3 %, respectively, at 1 year and 58.9 % and
65.9 %, respectively, at 2 years, and incredibly, no grade 3 or
higher toxicity was observed. Similarly, Sejpal et al. pub-
lished a retrospective analysis of 62 patients with locally
advanced NSCLC who were treated with proton therapy and
concurrent platinum- or taxane-based chemotherapy and
compared their outcomes with those of patients treated in ear-
lier eras with photons [44]. The median total radiation dose
was 74 CGE for the proton group and 63 Gy for the photon
group. The proton patients had lower rates of pneumonitis,
esophagitis, and hematologic toxicity than those observed in
patients in the photon cohort despite the fact that the proton
dose was, on average, higher. Finally, Chang et al. completed
a phase II study of 44 patients with stage III NSCLC who
received 74 CGE via conventional fractionation (2 CGE per
fraction) with weekly concurrent carboplatin and paclitaxel
[45]. Despite the very high intensity of this treatment course,
grade 3 toxicities were minimal: 5 had grade 3 esophagitis, 5
had grade 3 dermititis, and only 1 patient had grade 3 pneu-
monitis. No grade 4 or 5 toxicities were observed. Eighty per-
cent local control and 29 months overall survival were
achieved. The concept about combining stereotactic radio-
therapy and hypofractionated radiotherapy using intensity-
modulated proton-based integrated boost and/or dose painting
has been proposed to further improve the therapeutic ratio
and improve cure rate in stage III NSCLC.
Summary
While the studies above demonstrate promising tumor con-
trol after the use of charged particles in the setting of lung
cancer, an important caveat is that these experiences are
10 Charged Particles in Stereotactic Radiosurgery
characterized by considerable heterogeneity with respect to
doses, fractionation schemes, and techniques for positioning,
immobilization, respiratory compensation, and geometric
verification. Nonetheless, they uniformly demonstrate proof
of principle that charged particles achieve high local control
while limiting normal tissue effects in the thorax. Whether
the costs of charged particle radiation are justified by these
advantages, however, is controversial until a prospective ran-
domized study can be completed. Fortunately, a trial at MD
Anderson Cancer Center is underway to compare stereotac-
tic proton and photon treatments in centrally located stage I,
selective stage II, and recurrent NSCLC using a dose regime
of 50 Gy in four fractions. The results of this study will shed
light on whether the financial cost of proton therapy, specifi-
cally, is justified by improved clinical outcomes.
Hepatocellular Carcinoma
Rationale for Particle Therapy for Hepatic Tumors
The liver is a parallel organ and, as such, is particularly sen-
sitive to the toxic effects as more functional subunits are irra-
diated. Therefore, photons’ integral dose distribution
presents challenges when high doses are desired for a target
within the liver. In point of fact, hepatocellular carcinoma
often arises in the background of chronic hepatic insuffi-
ciency, making the dosimetric characteristics of charged par-
ticles even more appealing for sparing still-functioning
hepatocytes. Additionally specific patient populations may
garner additional benefit. For patients with liver transplants,
the ability to reduce integral dose with charged particles may
have important ramifications for reducing secondary malig-
nancy in a population characterized by an immunocompro-
mised state [46]. For those with portal venous thrombosis a
large volume of liver often requires treatment and, often, the
size and location of the carcinoma and thrombosis preclude
conventional photon radiotherapy at higher doses [47, 48].
In light of these clinical considerations, charged particles
present significant theoretical advantages for radiotherapy of
hepatic tumors. In the conventionally fractionated setting,
dosimetric comparison studies have shown that protons
result in better sparing of the fractional liver volume receiv-
ing more than 30 Gy [49]. Improvements in the mean liver
dose, V45 for the stomach and duodenum, V40 and V50 for
the heart, and the maximal dose to the spinal cord were also
observed. As with lung tumors, treating hepatic malignan-
cies with radiation involves addressing issues related to
tumor motion secondary to diaphragmatic movements.
Multiple techniques including implantable fiducial markers,
four-dimensional simulation, daily cone-beam CT, abdomi-
nal compression, and a combination thereof can be used to
guide particle therapy directed at liver tumors [47].
141
Clinical Outcomes
Hypofractionated proton therapy for liver tumors has been
studied extensively by the University of Tsukuba Proton
Medical Research Center. Among the first reported experi-
ences was a series of 162 patients for hepatocellular carci-
noma with regimens utilizing fractions in the 3.5–5 CGE
range for total doses between 50 CGE (ten fractions) and 84
CGE (24 fractions). Notably, 72 patients (44 %) had Child-
Pugh class B and C cirrhosis. At a median follow-up interval
of 31.7 months, the 5-year local control rate was 86.9 %, and
the overall survival rate was 23.5 %. The acute side effects
were limited primarily to elevation in liver enzymes (9.7 %)
and only 5 patients (3 %) had grade 2 or higher late toxicity.
Several other studies by the Japanese group showed similar
outcomes for patients with difficult to treat hepatic tumors
[48, 50–52]. A more recent prospective study employing a
regimen of 66 CGE in ten fractions using proton radiotherapy
was reported by Fukumitsu [53]. In this trial of 51 patients,
overall survival and local control rates at 3 years were 49.2 %
and 94.5 %, respectively. Only 3 patients experienced late
sequelae of Grade 2 or higher.
In the USA, Bush et al. conducted a phase II trial of hypo-
fractionated proton therapy in which 34 patients with unre-
sectable HCC were treated to 63 CGE in 15 fractions [54].
The 2-year overall survival was 55 % with local control rates
of 75 %. Fewer than 10 % of these patients experienced a
gastrointestinal bleed, and only mild acute liver toxicity was
observed. Of interest, 2 of these patients were observed to
have complete pathologic response upon examination of
their explanted livers (they were among 6 patients who had
gone on to receive liver transplant after proton therapy).
Studies employing carbon ion therapy for hepatic tumors
have mainly been performed at the National Institute for
Radiological Science (NIRS) in Chiba, Japan. The main eligi-
bility criterion for carbon ion treatment at NIRS was that other
therapies had to be considered ineffective. Dose-escalation
studies were implemented with various fractionation schemes
from 15-fraction to single-fraction regimens. At the more
extreme end of hypofractionation, 69 patients treated with
52.8 CGE in four fractions. Therapy-related impairment in
hepatic function was minimal and the 5-year local control and
survival rates were 81 % and 33 %, respectively [55].
Interestingly, toxicity rates were no different whether the tumor
was within 2 cm of the main portal vein or beyond [56]. An
even shorter regimen of two fractions in 2 days was employed
in a dose-escalation study, in which a total of 117 patients were
treated to doses ranging from 32.0 to 45.0 CGE. Thus far, there
have been no therapy-related deaths or severe adverse events,
and the patients receiving a higher dose appear to have better
local control and survival [57, 58].
The main difference between the proton regimens at
Tsukuba and the carbon ion regimens at Chiba are the degree
142
of hypofractionation. In the carbon ion studies, dose regi-
mens more closely resembled what would be considered
radiosurgery. Promising results from these studies should
prompt increased interest around the world for employing
stereotactic particle therapy for hepatic malignancies.
Central Nervous System Tumors
As in the thorax, dose to tumors in the central nervous sys-
tem is often limited by their proximity to multiple radiosen-
sitive structures including the optic chiasm, brainstem,
hypothalamus, and spinal cord. Therefore, considerable
investigation has focused on whether high doses of radiation
can be delivered through particle therapy to achieve better
dose distributions than photon-based treatments. However,
although research into the role of charged particle radiation
for CNS tumors has been ongoing for over 50 years, most
centers have focused on conventionally fractionated or mod-
estly hypofractionated regimens [59]. With the construction
of multiple proton therapy centers in the USA, there has been
renewed interest in combining the dosimetric advantages of
particles with radiosurgery for the treatment of intracranial
and spinal tumors. Phase I–II studies investigating this
approach are anticipated. For now, retrospective reviews of
patients treated at the Harvard Cyclotron provide prelimi-
nary insight into the role of particle radiosurgery—specifi-
cally proton radiosurgery—for treating CNS tumors in the
contemporary era. Patients with a variety of central nervous
system tumors have been treated stereotactically with proton
therapy during the last decade. For image-guidance and
localization, the Harvard Cyclotron relied on implantable
skull fiducials; patients were immobilized using either skel-
etal pin cranial fixation or a modified relocatable frame with
dental fixation [60]. These experiences are reviewed here.
Acoustic Neuroma
Excellent tumor control was reported at the Massachusetts
General Hospital in their experience using proton radiosurgery
for acoustic neuromas with a median marginal dose of 12 CGE
to the tumor was delivered to the tumor, and implanted skull
fiducials were used for stereotactic positioning [61, 62]. Five-
year tumor control was 94 %, while the trigeminal and facial
nerve preservation rates were both around 90 %, respectively.
More recently, a South African group retrospectively reported
on 51 patients with large acoustic neuromas treated with hypo-
fractioned proton therapy to a dose of 26 CGE (isocenter) in
three fractions [63]. A noninvasive stereophotogrammatic
patient support and positioning system utilizing the markers
on the mask, video cameras, and a computerized adjustable
treatment chair was used for stereotactic positioning. The
5-year local control was 98 %. Hearing preservation was
42 %. Facial and trigeminal nerve preservation rates were
90.5 % and 93 %, respectively.
S.M. Shirvani and J.Y. Chang
Arteriovenous Malformations
Fifty nine patients at Massachusetts General Hospital with high
risk high-risk cerebral arteriovenous malformations (AVMS)
received two-fraction proton radiosurgery [60]. The majority of
these patients had undergone prior therapies, and different
radiosurgery doses were used, with 16 CGE in two fractions
prescribed to the 90 % isodose line being the most common. At
a median follow-up of 56.1 months, 9 patients (15 %) had total
and 20 patients (34 %) had partial obliteration. Five-year actu-
arial rate of hemorrhage was 22%, and 14 % (8 patients) even-
tually suffered fatal hemorrhage. One patient developed a
Grade 2 generalized seizure disorder and two had mild neuro-
logic deficits. Although the total obliteration rate was low, the
low toxicity rate observed in this study suggests that higher
doses could be considered in future studies.
Meningioma
Halasz et al. retrospectively reviewed 50 patients with 51
histologically proven or image-defined, presumed-benign
meningiomas treated between 1996 and 2007 [64]. The
series included patients undergoing primary treatment as
well as those with residual or recurrent tumor following sur-
gery. The median dose delivered was 13 CGE (range, 10.0–
15.5 CGE) prescribed to the 90 % isodose line. With a
median follow-up of 32 months, the 3-year actuarial tumor
control rate was 94 %. Symptoms were improved in 47 % of
patients. Potentially permanent adverse effects after proton
radiosurgery occurred in 3 patients. These results compare
favorably with historical outcomes using conventional
fractionation.
Pituitary Tumors
Twenty-two patients with acromegaly who failed transsphe-
noidal resection underwent proton radiosurgery to a median
dose of 20 CGE (range, 15–24 CGE) delivered in one frac-
tion [65]. With a follow-up of 6.3 years, complete or partial
response was observed in 21 of 22 patients (95 %). A com-
plete response defined as sustained (≥3 months) normaliza-
tion of insulin-like growth factor-I without medical
suppression was attained in 13 patients (59 %). Therefore,
the majority of patients were able to attain a durable bio-
chemical response without medication. Eight patients (38 %)
eventually had new pituitary deficits. A different series of 38
patients with corticotrophin adenomas were treated with
single-fraction proton radiosurgery to a median dose of
20 CGE (range, 15–20) [66]. Complete response (defined as
sustained (≥3 months) normalization of urinary free cortisol
off medical therapy or normalization of plasma corticotro-
phin) was achieved in 23 patients.
In both of the above pituitary series, no visual complica-
tions, seizures, clinical evidence of brain injury, or secondary
tumors were observed. However, 38 % of the patients in the
first study and 52 % of the patients in the second developed
new pituitary deficits during follow-up.
10 Charged Particles in Stereotactic Radiosurgery
Future Directions for CNS Tumors
Currently, most centers employing charged particles for
CNS tumors rely on conventionally fractionated or modestly
hypofractionated treatment regimens. Nonetheless, the expe-
rience at the Harvard Cyclotron demonstrates proof of prin-
ciple that CNS tumors can be targeted for true radiosurgical
treatment within a charged particle gantry. As more proton
and carbon ion centers come online, integrated systems for
achieving immobilization, positioning, and image-guidance
will be needed to enable stereotactic treatment and thus
improve the therapeutic ratio for patients.
The Challenges of Particle Therapy
Three major challenges to charged particle therapy are cost,
motion/modeling uncertainties, and potential nuclear frag-
ment contamination. With regard to cost, charged particles
entail considerably higher investment than linear accelera-
tors used for generating photons and electrons [67]. Because
of their large mass, protons and heavy nuclei require large
cyclotrons and high energy inputs to achieve acceleration of
the therapeutic particle to the necessary energy for medical
use [68]. The total cost to build a proton center has histori-
cally been between $120 and $200 million. A general rule of
thumb is that the required size of the cyclotron or synchro-
tron is directly related to the size of the charged particle.
Therefore, heavy nuclei gantries entail even greater capital
investment [69].
Newer technologies that generate high energy protons in
more compact systems are emerging and may provide a more
affordable avenue for introducing particle therapy to every-
day practice [70]. Systems employing a single-room gantry
may cost as little as $20 million. Still, whether charged par-
ticles are cost-effective when compared to photon-based
alternatives remains a controversial subject among radiation
oncologists [67, 68, 71].
Several planning uncertainties also present a challenge to
the widespread adoption of charged particle radiotherapy.
First of all, proton dose distribution is very sensitive to
motion/anatomy changes [9, 10]. In addition, the conversion
of CT Hounsfield units to charged particle stopping party is
not as straightforward as the case in photon radiation [72].
Particle therapy treatment modeling systems are variably
effective in predicting the precise depth of the Bragg peak,
and this uncertainty in spatial resolution can be exacerbated
when the particles traverse air cavities [73]. Finally, though
most treatment planning systems assign a constant RBE for
converting photon doses to charged particle doses, the true
RBE is likely to be dynamic along the range of the charged
particle. Additionally, the RBE can vary for different cancer
histologies and for different dose/fractionation regimens [74,
75]. For practical reasons, treatment modeling has not cur-
143
rently taken these RBE variations into account. However,
with increased use of particle therapy in the coming years, it
may be necessary to account for this variability in specific
circumstances.
Proton therapy can generate neutron contaminants via the
collision of protons with the gantry system as well as the
patient himself. These secondary neutrons have high LET
and can travel beyond the proton’s Bragg peak to induce
DNA damage in normal tissue structures. This may result in
late toxic effects or the development of secondary malignan-
cies [76]. Heavier nuclei can likewise generate neutrons and
other nuclear fragments through interactions with atomic
nuclei. These fragments, like neutrons, are capable of caus-
ing cellular damage beyond the primary particle’s Bragg
peak. However, it is important to note that the incidental irra-
diation attributable to these fragments may ultimately be less
carcinogenic than the low-dose bath of radiation seen in con-
formal photon radiotherapy. In fact, preliminary evidence in
pediatric patients suggests that the overall risk of secondary
malignancy is lower when particles are used in place of pho-
tons [77].
Though these uncertainties in charged particle therapy
should inspire caution, the best strategy is to test the assump-
tions, approximations, and algorithms used in charged parti-
cle treatment through prospective trials. Similarly, the impact
of cost and nuclear contamination should not deter the use of
charged particle therapy unless it can be shown, prospec-
tively, that these limitations outweigh the beneficial effects
of particle radiation. Ultimately, randomized controlled trials
are needed to fully assess both the comparative efficacy and
cost-effectiveness of charged particle therapy. Though no
true randomized trials have been completed thus far, promis-
ing trials comparing proton and photon radiation in several
cancer sites have fortunately been opened.
Conclusion
Charged particle radiotherapy has distinct advantages over
photon radiation in terms of dose distribution and radiobiol-
ogy. The characteristic Bragg peak of charged particle radi-
ation results in minimal dose delivery beyond the treatment
volume and, consequently, relative sparing of organs-at-
risk. Recent advances in patient positioning, immobiliza-
tion, and image-guidance have allowed investigation into
the combination of particle therapy with a hypofractionated,
stereotactic treatment approach. This approach, “particle
radiosurgery,” has resulted in promising local control, sur-
vival, and toxicity outcomes in multiple tumor sites.
Randomized controlled trials will determine whether the
degree of improved efficacy and reduced morbidity follow-
ing particle radiosurgery justifies its use over photon tech-
niques despite higher financial costs.
144
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 CyberKnife
Carolina E. Fasola, Lei Wang, John R. Adler,
Scott G. Soltys, Iris C. Gibbs, Albert C. Koong,
and Daniel T. Chang
Introduction of CyberKnife Stereotactic
Radiosurgery
The CyberKnife (Accuray Inc., Sunnyvale, CA) was devel-
oped as a tool to deliver large and highly conformal doses of
ionizing radiation to well-defined targets with steep dose
gradients to spare surrounding tissue. It was initially used in
the 1990s for the treatment of intracranial lesions, both
benign and malignant. Prior to the development of
CyberKnife, radiosurgery was frame based and largely cen-
tered on the Gamma Knife (Elekta AB, Stockholm, Sweden)
system as well as conventional linear accelerator (linac)-
based systems. In contrast to the frameless CyberKnife, both
Gamma Knife and linac-based systems require the applica-
tion of an invasive frame to the patient’s head to achieve the
desired accuracy.
With the advent of radiation devices capable of improved
accuracy and superior organ motion management over the
past decade, prolonged courses of conventional radiation
therapy can be quickly shortened to span a few high dose
treatments. While frame-based stereotactic techniques were
already able to provide high dose radiation in as few as one
treatment, the necessity of skeletal fixation using a head frame
was uncomfortable for patients and, at the same time, limited
treatment to intracranial sites of disease. The CyberKnife
image-guided localization system emerged with advances in
imaging and computer technology, providing precise target
delineation and replacing the need for a rigid stereotactic
frame for immobilization. The CyberKnife became a nonin-
C.E. Fasola, M.D. • L. Wang, Ph.D. • S.G. Soltys, M.D.
I.C. Gibbs, M.D. • A.C. Koong, M.D., Ph.D. • D.T. Chang, M.D. (*)
Department of Radiation Oncology, Stanford University,
Stanford, CA, USA
e-mail: dtchang@stanford.edu
J.R. Adler, M.D.
Neurosurgery, Stanford University, Stanford, CA, USA
Varian Medical Systems, Stanford, CA, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_11, © Springer Science+Business Media New York 2015
11
vasive alternative to surgery and frame-based stereotactic
techniques. Additionally, in contrast to the frame-based tech-
nology, high dose treatments with CyberKnife could be
divided into more fractions to reduce normal tissue dose, thus
minimizing toxicity from treatment. The concept of stereotac-
tic body radiotherapy was first described in 1994 by investiga-
tors in Sweden [1, 2]. With its ability to deliver image-guided
treatments, the Cyberknife was uniquely suited to explore
some of the earliest applications of stereotactic treatments in
the body. Initially beginning with organ motion management
by gated breath-hold, the CyberKnife’s efficiency of treating
lesions throughout the body improved dramatically with the
addition of the Synchrony™ respiratory tracking system to
the platform, thus broadening the scope of clinical application
to include a wide variety of tumors. In this chapter, we
describe the CyberKnife and some of its more unique clinical
indications.
CyberKnife Technology
The CyberKnife system consists of a lightweight and com-
pact 6-MV linac mounted on a robotic arm (robotic manipu-
lator) with six axes of movement, allowing the linac to point
virtually any direction (Kuka GmbH, Augsburg, Germany),
shown in Fig. 11.1. The robotic manipulator is guided with a
computerized localization system consisting of two paired
kilovoltage X-ray sources fixed on the ceiling, two silicon
image detectors installed in the floor on each side of the
patient with a live field size of 20 cm × 20 cm, and a couch
with six degrees of freedom. The high-resolution orthogonal
digital images acquired with the patient on the couch are reg-
istered to digitally reconstructed radiographs (DRRs) derived
from the planning computed tomography (CT) scan
(Fig. 11.2), which is used for patient setup and patient motion
correction during delivery.
The system uses a large number of narrow circular beams
emanating from a wide array of directions that accumulate
within the predefined target volume, thus allowing more than
147
148 C.E. Fasola et al.

Fig. 11.1 The main components of the CyberKnife system. (Modified image used with permission from Accuray Incorporated)

Fig. 11.2 A library of digitally reconstructed radiographs (DRRs) is generated from the treatment planning CT. Each of these images, which
approximates an oblique projection, emulates a unique pose of the patient’s anatomy

100 non-isocentric, noncoplanar beams to be used during the
process of designing a treatment plan and creating a dose
distribution that conforms to even irregularly shaped target
volumes (Fig. 11.3). In contrast, frame-based isocentric
radiosurgery systems (e.g., Gamma Knife and linac-based
systems) construct spherical dose distributions around a dis-
crete isocenter, and irregular targets require multiple spheres
to ensure adequate dose coverage.
Recent developments in hardware and software have sig-
nificantly enhanced the delivery efficiency to reduce patient
treatment times. The newer CyberKnife G4 system is capa-
ble of a dose rate up to 1,000 MU per minute in up to 1,600
beam directions. The newly designed RoboCouch™ aligns
patients quickly from the control room with a high degree of
accuracy in six degrees of freedom so that setup time can be
reduced. The IRIS variable collimator system is capable of
11 CyberKnife 149

Fig. 11.3 (a) With standard

radiosurgery dispersed isocentric
beams, all beams intersect a
common region (light gray).
Because multiple spherical
volumes are needed to cover
irregular lesions, the resulting
dose distribution tends to be
inhomogeneous.
(b) Non-isocentric beams from
various directions. Beams do not
all cross in a single point and
dose need not be inhomogeneous

Fig. 11.4 The IRIS collimator

includes two banks of tungsten
segments capable of rapidly
manipulating beam geometry to
deliver up to 12 beam sizes from
each position

changing the collimator size during delivery (Fig. 11.4). In
combination, these features have been able to significantly
reduce treatment time. For brain and spine cases, the typical
treatment time in the current G4 system ranges from 15 min
to 1 h depending on the complexity of the treatment sites,
with an average of approximately 30 min.
CyberKnife Treatment Planning
Treatment planning with CyberKnife is similar to frame-based
technology in that it is developed on CT image data with other
imaging modalities such as MRI, fMRI, and PET scans coreg-
istered for target volume delineation. For lesions of the brain,
head, and neck, a thermoplastic head mask is fabricated for
immobilization. For body lesions, a custom vacuum body
mold may be used. In order to generate high-resolution DRRs
for image guidance during delivery, the planning CT is
acquired at 1.0–1.5 mm slice thickness.
The CyberKnife treatment planning system is capable of
generating both isocentric and non-isocentric treatment
plans. Non-isocentric treatment delivery marks a stark con-
trast to earlier technology and is particularly useful in treat-
ing irregularly shaped targets. The total system accuracy is
similar to previously published results from frame-based
radiotherapy and is less than 1 mm [3, 4]. The CyberKnife
uses 12 secondary collimators to shape cylindrical beams
with diameters ranging from 5 to 60 mm. While other treat-
ment planning systems may use forward planning, in which
beam angles and weights are adjusted manually by the phys-
icists or dosimetrists, all the CyberKnife planning is done
using an inverse approach. For more complex and irregu-
larly shaped tumors, robotic radiosurgery provides an enor-
mous range of possibilities for placing beams and beam
arrays. In designing plans for these targets, the goal of the
CyberKnife planning algorithm is to find a beam arrange-
ment that returns a maximally conformal distribution for a
given shape of target [5, 6].
150
The optimization process is based on a set of goals and
dose constraints specified by the user. The treatment plan-
ning system determines the directions and activation dura-
tions for each non-isocentric, noncoplanar beam (selected
from a universe of approximately 2,000 beam directions)
such that the user’s specifications are met. A typical plan uti-
lizes more than 100 beam directions in a single treatment.
The sequential optimization algorithm was introduced in
newer planning systems to improve the efficiency of the
planning process [7]. Unlike the standard optimization pro-
cess, which optimizes on a set of clinical objectives at the
same time, the sequential optimization option is composed
of a series of individual optimization steps, which are per-
formed in a defined sequence in the order of priority. Each
step corresponds to a clinical objective. The solution of each
prior step is maintained or relaxed by a user-defined value
when the next step is optimized. The process closely mimics
the clinical decision making of a physician in designing a
treatment plan. The steps and user-defined constraints com-
prise a script that can be saved so that the treatment planning
process with similar targets can be standardized, thus reduc-
ing planning time for subsequent plans.
The use of multiple collimators can improve plan confor-
mality and reduce the treatment time [8]. The introduction of
the IRIS variable collimator, which provides an aperture size
ranging from 5 to 60 mm, has made it practical and feasible
to use more collimator apertures in treatment planning. The
IRIS collimator is designed with two sets of tungsten colli-
mator banks, each of which forms a hexagonal shape rotated
30° apart to form a semicircular shape (Fig. 11.4). In the cur-
rent implementation, the IRIS beam apertures are incremen-
tal to match the fixed collimator set.
Previously, the raytracing algorithm (pencil-beam-based
algorithm) was used exclusively in the CyberKnife treatment
planning system. Since 2008, the Monte Carlo (MC) calcula-
tion option has been available for CyberKnife treatment
planning. The CyberKnife MC calculation is a Monte Carlo
simulation with modifications to improve calculation speed
[9, 10]. This calculation algorithm more accurately predicts
dose in inhomogeneous areas such as the lung as evidenced
by a study by Wilcox et al., who compared the traditional
raytracing calculation with the MC calculation in lung
tumors for the CyberKnife system and showed that the ray-
tracing calculation consistently overestimated doses in low-
density structures (the maximum dose deviation up to a
factor of 1.63 observed), and this effect was more pro-
nounced as the collimator size decreased [11].
CyberKnife planning has also been extended to the case
of moving targets [12, 13]. While the target may move dur-
ing treatment, critical structures in the vicinity may not move
with the same speed or direction. The relative motion of
organs with respect to one another requires highly accurate
planning. The temporal changes over the entire respiration
cycle are represented in a motion model (obtained from
C.E. Fasola et al.
either four-dimensional CT or by deforming an inhalation
image stack into an exhalation image stack), which is then
used for treatment planning. The linear programming
approach used by the CyberKnife can be extended to four-
dimensional inverse planning [14].
One of the major limitations of CyberKnife is the extended
delivery time for patients. Options for reducing the treatment
time are available in the planning system by reducing the
number of beams, nodes (positions of the robotic arm), and
monitor units while preserving the integrity of the treatment
plan [15]. In addition, the optimized path traversal feature
now allows the robotic arm to travel the shortest safe dis-
tance between nodes to deliver the treatment, thereby mini-
mizing the amount of motion required by the robot and
reducing treatment time significantly [16].
CyberKnife Treatment Delivery
The CyberKnife treatment delivery follows a step-and-shoot
manner. The robot travels along a set of predefined paths,
stopping at treatment nodes to deliver the dose. The design
advantage of the CyberKnife treatment delivery is its
automated near real-time image guidance. During treatment,
X-rays are frequently acquired and compared to the DRRs
obtained at setup to automatically compensate for patient
movement within a range of 10 mm. The robotic arm of the
CyberKnife is realigned before delivery of each beam to
account for translation and rotation of the target. If a signifi-
cant misalignment is present, radiation delivery is postponed
until the misalignment is corrected by movement of the treat-
ment couch [17]. While the system is capable of imaging
before every treatment beam, imaging every third to fifth
beam or every 20–60 s, depending on the compliance of the
patient, is generally sufficient. The accuracy of this system
design has been demonstrated to be submillimetric [18, 19]
and is comparable to frame-based systems [18–22].
The CyberKnife is capable of real-time tracking of targets
that move with respiratory motion with the Synchrony™ sys-
tem. Synchrony™ synchronizes internal motion of the target
by X-ray localization with the motion of the chest wall as
assessed by continuous infrared light emitting diodes placed
on the chest wall near the diaphragm that are detected by an
optical camera in the treatment room (Fig. 11.1). As the
patient breathes, the movement of the chest wall is correlated
with internal movement by a predictive model updated dur-
ing treatment (Fig. 11.5). The most recent 15 data points cap-
tured from the X-ray imagers are used for model prediction
updated in a first-in first-out manner. With the feedback from
Synchrony™, the radiation beams remain fixed on the target
while the robotic arm moves to account for tumor motion
with respiration. If the detected target position is significantly
different from the predicted position when the patient’s
breathing pattern changes, the treatment will be turned off
11 CyberKnife
Fig. 11.5 This schematic illustrates several aspects of dynamic respi-
ratory compensation with the Synchrony™ system. In this situation, the
movement of a lung tumor is determined in real time by correlating the
location of internal gold seeds (not visible) with external markers (IR
emitters). Tumor position is then fed back to the robot, which adjusts
accordingly for tumor motion
until the patient resumes a normal breathing pattern. A new
modeling procedure may be required if the patient moves
significantly or the breathing pattern changes significantly
(e.g., when the patient is awake vs. when the patient is sleep-
ing). The additional tracking with Synchrony™ typically
prolongs the treatment time by 20 %.
With the capability of image-guided motion tracking,
CyberKnife stereotactic radiosurgery represents a departure
from the previous notion of radiosurgery as solely an intracra-
nial treatment. Such refinements in technology have broad-
ened the clinical spectrum to include treatment to sites in the
spine, head and neck, lung, prostate, pancreas, and liver.
Image Guided Tracking System
Image-guided tracking of lesions is one of the key compo-
nents in the CyberKnife radiosurgery. Different image track-
ing algorithms are implemented for different anatomic sites,
which include Skull tracking, Fiducial tracking, XSight
Spine tracking, and XSight Lung tracking.
For intracranial lesions, the Skull tracking algorithm is
applied. It uses the bony anatomy of the skull as a reference
to continually track intracranial targets and correct for trans-
lational/rotational target shifts during radiation delivery.
A 2D–3D fast image registration algorithm [3] registers
the images acquired during treatment with the treatment
planning CT (through a library of pregenerated DRRs at
different rotation angles) using skull bony anatomy. Any
151
misalignment is corrected with frequent imaging during the
treatment. Treatment of cranial lesions with the CyberKnife
compares favorably to more conventional frame-based
intracranial radiosurgery in terms of dose conformality and
targeting accuracy [18].
Fiducial tracking with or without Synchrony™ is often
used in stereotactic body radiotherapy with CyberKnife.
Historically, fiducial tracking has been implemented to ade-
quately localize spinal targets. This tracking system involves
percutaneous implantation of radio-opaque fiducials under
fluoroscopic guidance, typically three to four 4 × 2 mm stain-
less steel screws placed in the vertebrae adjacent to the target
lesion. For other thoracic and abdominal lesions, at least
three small 0.8 × 4 mm gold seeds are placed in close prox-
imity to the lesion. The Fiducial tracking algorithm com-
pares the positions of the fiducials on X-rays acquired near
real time to their location on the DRRs and adjusts the treat-
ment beam accordingly [23]. If the target motion is correlated
with respiration, such as lung, liver and pancreas lesions, the
Synchrony™ motion tracking option is usually used during
delivery. If the target movement is caused by patient move-
ment or internal bowel movement, such as spine and pros-
tate, frequent imaging between beams is applied.
The clinically relevant accuracy of Fiducial tracking in
spinal lesions was investigated by Yu et al. [19]. In this study,
measurements were performed at three different CyberKnife
facilities using head and torso phantoms loaded with packs
of radiochromic film. The absolute displacement of the dose
contours from that defined during treatment planning was
reported to be submillimeter. The average offset was
0.3 ± 0.1 mm. The fiducial tracking error was below 0.3 mm
for radial translations smaller than 14 mm and less than
0.7 mm for rotations up to 4.5°.
For treatments that require Synchrony™, the tracking
accuracy largely depends on the accuracy of the correlation
model of the internal motion and chest wall motion. In end-
to-end tests with a phantom (with perfect linear correlation
between external motion and internal motion), the
CyberKnife is found to be able to follow the lesion with
submillimeter accuracy [24]. Perfect correlations do not
exist on real patients due to the irregular breathing and
hysteresis in tumor motion, so small residual errors remain
during treatment. The residual error is dependent on the
quality of the correlation model and is proportional to patient
and tumor motion. Pepin et al. studied the correlation and
prediction uncertainties based on 100 CyberKnife
Synchrony™ models for lung patients [25]. With 95 % mod-
eler point coverage, the uncertainty was 1.2 mm in the lateral
direction, 1.7 mm in the anterior–posterior direction, and
3.5 mm in the superior–inferior direction. Appropriate mar-
gin should be considered during PTV delineation to account
for this uncertainty.
Fiducial-free tracking is now available for spine radiosur-
gery, which increases patient convenience and reduces risks
152 C.E. Fasola et al.

Fig. 11.6 XSight Spine tracking

compares the (left) digital
reconstructed radiography (DRR)
with the (right) live image in a
region of interest (ROI) defined
by the user which includes the
maximum spine structures
located on or near the treatment
area. The DRR is synthesized
with the moving structures
excluded to increase the
robustness of the tracking method

Fig. 11.7 XSight Lung tracking

directly tracks the tumor volume
without implanted fiducials. The
displacement is determined with
maximum similarity measures
within the matching window

associated with fiducial placement. XSight Spine tracking
was initiated in 2004 and allows for tracking of spinal skel-
etal anatomy based on anatomic landmarks [26, 27]. Similar
to the skull-based algorithm, the XSight Spine tracking algo-
rithm aligns the live X-ray images with the DRRs generated
from the setup CT. DRRs are often synthesized with the
spine region only to remove moving structures and are
enhanced with imaging processing for more robust tracking.
Instead of using the whole image, the XSight Spine algo-
rithm only uses a region of interest defined by the user that
includes the spine bony structures near the treatment area
(Fig. 11.6). Because the spine is not a rigid body, the ROI is
divided into many small nodes (9 × 9 mesh), and the small
area near each node is treated as a rigid body. They are regis-
tered to the DRRs separately using maximum similarity
mapping. The detected displacement of each node constructs
a displacement vector field which is used to determine the
overall translations and rotations. This approach has been
shown to target spinal lesions with submillimeter accuracy
and compares favorably to previously published precision of
fiducial-based localization [4].
Similarly, XSight Lung Respiratory tracking system has
emerged as an option for fiducial-less tracking of lung lesions
[28]. The XSight Lung algorithm directory tracks the tumor
using the live images taken during the treatment (Fig. 11.7).
The GTV is contoured during the planning process to be used
as the tracking target, and a maximum similarity matching
technique is applied near the GTV region for tracking. This
tracking system only corrects for translational displacements,
and the rotations of the tumor are ignored. The patient using
XSight Lung is set up with XSight Spine tracking first to cor-
rect for any patient rotations. This system works best for
lesions with sufficient contrast from normal surrounding tis-
sue. Fu et al. found this approach can be used on peripheral,
radiodense tumors with diameters >15 mm [29]. The XSight
Lung tracking system uses Synchrony™ to correct the
11 CyberKnife
detected internal motion that is correlated with respiratory
chest wall movement [24].
In summary, the CyberKnife tracking systems in place
can track lesions in any direction throughout the body, thus
facilitating treatment of both intra-cranial and extracranial
sites. Submillimeter accuracy is achieved with CyberKnife
systems for Skull, Fiducial, and XSight Spine tracking meth-
ods [17]. For lesions that move with respiration, adequate
margin should be considered.
Clinical Indications
CyberKnife is capable of targeting most lesions treated with
the more conventional frame-based radiosurgery techniques.
With the advent of stereotactic body radiotherapy, the clini-
cal indications for use with the CyberKnife have been
expanded from intracranial to extracranial, including bone,
lung, pancreatic, hepatic, and prostate disease. Doses of radi-
ation vary depending on location. The main clinical goals of
stereotactic radiosurgery are to improve local control, allevi-
ate pain, or prevent tumor progression which could result in
symptoms. While a full review of each of these disease sites
is beyond the scope of this chapter and can be found in other
chapters of this textbook, what follows is a brief discussion
of each site specifically with respect to how CyberKnife has
been used and the reported clinical results.
Intracranial
Most conditions treated with standard frame-based radiosur-
gery are readily treatable with the frameless CyberKnife
using the same basic radiosurgical principles. However, the
combination of near real-time image guidance and robotic
treatment delivery can offer distinct advantages over conven-
tional frame-based radiosurgery under some clinical circum-
stances. Because of its robotic nature, the CyberKnife
enables an increase in both the range of beam trajectories
and, in some cases, the volume of space over which they are
distributed. Clinically speaking, this design provides greater
homogeneity, when desirable, and enhanced dose conformal-
ity for irregularly shaped targets. Even more importantly, fra-
meless stereotaxy allows for multi-fraction dosing schedules,
which may be used if late radiation damage is of concern.
The CyberKnife can be used to treat all the common intra-
cranial conditions currently treated with other radiosurgery
systems, such as intracranial tumors, arteriovenous malfor-
mations, and functional disorders such as trigeminal neural-
gia. However, the use of hypofractionation makes it feasible
to treat many larger tumors or lesions adherent to particu-
larly radiosensitive brain structures such as the anterior
visual pathways. Moreover, CyberKnife radiosurgical abla-
153
tion is readily extended to lesions that originate beneath or
extend through the skull base, such as tumors of the foramen
magnum and nasopharyngeal carcinoma.
Shimamoto et al. reported results of 94 patients with 136
brain metastases treated with doses of 24–27 Gy using
CyberKnife, showing 89 % local progression free survival
[30]. In a series from Stanford University, Chang et al.
treated 53 patients with 149 brain metastases with a median
dose of 19.6 Gy (range 14–30 Gy) with 91 % rate of local
control, defined as stabilization or decrease in lesion size.
Eight patients (5.4 %) had radiation brain necrosis [31].
Another series of 71 patients with 148 metastatic brain
lesions with mean volume of 6.6 cm3 treated with median
dose 20.7 Gy over 1–3 fractions showed local control rate of
83 % at 44 weeks of follow-up [32]. Hara et al. reported a
local control of 87 % in 62 patients with 145 renal cell or
melanoma metastases. The median prescribed dose was
20 Gy (range 14–24 Gy). Prior surgical resection did not
impact local control [33].
Without adjuvant irradiation, local control after surgical
resection of a brain metastasis is no greater than 40 % in
prospective trials, leading investigators to examine adjuvant
radiosurgery to the resection cavity [34, 35]. Using
CyberKnife, Choi et al. reported high local control rates and
acceptable toxicity in an updated series of 112 patients with
120 resection cavities treated with adjuvant stereotactic
radiosurgery with a median dose of 18.6 Gy (range
15–30 Gy). The average cavity volume was 8.5 cm3 with 12-
and 24-month cumulative local failure rates of 9.5 % and
11.6 %, respectively [36]. Stanford is now leading a prospec-
tive trial investigating dose escalation for large brain tumors
or large resection cavities of 2–5 cm in size [16].
Glioblastoma Multiforme
Investigators have reported on the use of CyberKnife for pri-
mary brain tumors such as glioblastoma multiforme (GBM).
Villavicencio et al. reported a series of 20 patients treated
with CyberKnife at the time of initial diagnosis of GBM and
26 patients treated at the time of disease recurrence or pro-
gression [37]. The group treated with CyberKnife at time of
recurrence or progression had a median survival rate of 21
months compared to 11.5 months in the group treated upfront
with stereotactic radiosurgery. Patients with more extensive
surgical resection had improved survival rates.
Conti et al. recently investigated a series of 23 patients
with unresected GBM treated with radiation alone using
CyberKnife stereotactic radiosurgery alone or combined
with temozolomide. Median survival was 12 months for the
group that received combination treatment compared to 7
months in the group that received stereotactic radiosurgery
alone. While surgery remains the standard of care for the
treatment of GBMs, the vast majority of failures (90 %)
occur within 2 cm of the original tumor [38]. CyberKnife
154
stereotactic radiosurgery is currently being investigated as
adjunct therapy following surgical resection in a prospective
trial at Stanford.
Perioptic Tumors
The use of hypofractionation enables treatment of lesions
near radiosensitive tissue such as the optic structures, which
are not well suited for single fraction treatment. High rates of
local control and visual preservation after hypofractionated
radiosurgery have been reported [39–41]. Adler et al. updated
a series of 49 patients with perioptic tumors within 2 mm of
the optic apparatus treated with CyberKnife radiosurgery
with excellent local control rates. Lesions included menin-
giomas, pituitary adenomas, craniopharyngiomas, and one
case of mixed germ cell tumor, most of which had been pre-
viously treated with surgical resections and/or conventional
radiation therapy. These lesions were treated with a mean
cumulative marginal dose of 20.3 Gy in 2–5 fractions. They
reported local control >95 % and visual preservation rate of
94 % at 49 months of follow-up. There was one case of
radiation-induced optic nerve injury in a patient previously
treated with conventional radiation therapy and three courses
of perioptic radiosurgery [39].
Vestibular Schwannomas
Vestibular schwannomas are benign tumors that can cause
significant morbidity including impaired hearing and bal-
ance from dysfunction of the vestibulocochlear nerve [42].
While observation without initial treatment for these benign
lesions is a reasonable option in some cases, surgical resec-
tion and stereotactic radiosurgery (single or fractionated ses-
sions) are standard treatment approaches. Compared to
surgery, stereotactic radiosurgery offers similar rates of local
control between 95 and 98 % with fewer side effects and
complications and superior long-term hearing preservation
rates [43]. Hearing preservation rates largely depend on pre-
treatment hearing status. Andrews et al. presented a series of
125 patients with vestibular schwannomas treated with
Gamma Knife stereotactic radiosurgery (n = 69) or linac-
based fractionated stereotactic radiotherapy (n = 56). Local
control was >97 % for both groups, but functional hearing
preservation was 2.5-fold higher in patients who were treated
with the linac-based fractionated treatment compared to sin-
gle session radiosurgery [44]. A recent meta-analysis on ste-
reotactic radiosurgery discussed 37 studies of treatment of
vestibular schwannomas with overall local control of 91.1 %,
serviceable hearing preservation rate of 59.3 %, and post-
treatment facial nerve dysfunction of 7.1 %. Of note, most of
these studies focused on single fraction stereotactic radiosur-
gery in treatment of these lesions [42].
In support of fractionated treatment of vestibular schwan-
nomas, Chang et al. published a series of 61 patients treated
C.E. Fasola et al.
with CyberKnife stereotactic radiosurgery to 18–21 Gy in
three fractions with 98 % local control, 74 % serviceable
hearing preservation, and no reports of trigeminal nerve
injury at 3 years of follow-up [45]. More recently Stanford
updated their results of fractionated stereotactic radiosurgery
for 383 patients. The majority of patients received 18 Gy in
three fractions. At a median follow-up of 3.6 years, local
control was 99 %. Serviceable hearing was preserved in
76 % of patients (among 200 patients) with serviceable hear-
ing prior to treatment. There were no cases of treatment-
related facial nerve dysfunction, but 2 % of patients did
experience trigeminal nerve injury [46].
Trigeminal Neuralgia
Trigeminal neuralgia (TN) is characterized by chronic epi-
sodic facial pain which is often refractory to medications.
Frame-based radiosurgical rhizotomy, most commonly per-
formed with the Gamma Knife, has been shown to be effec-
tive in the management of TN. The standard Gamma Knife
rhizotomy was modified using the capacity of the CyberKnife
to deliver non-isocentric plans. Rapid onset of pain relief
after CyberKnife treatment was first reported in a small
series of patients by Romanelli et al. [47]. Lim et al. reported
a series of 29 patients with TN who had previously tried
medical therapy and/or surgical procedures with persistent
symptoms treated with CyberKnife stereotactic radiosurgery
to a dose ranging between 60 and 70 Gy to a 6–8 mm length
of the retrogasserian region of the trigeminal nerve. At 10
months of follow-up, 90 % of patients reported significant
pain relief with a median time of 7 days. With regards to
facial numbness, 14 % of patients reported worsening facial
numbness and 10 % reported new onset facial numbness fol-
lowing treatment [48]. Villavicencio et al. reported a multi-
center experience of treatment of TN with CyberKnife
involving 95 patients. In this series, 67 % of patients reported
significant pain relief at a median time of 14 days, but only
50 % of patients had pain relief at 2 years of follow-up. Up
to 47 % of patients experienced some degree of facial numb-
ness following treatment [49].
In targeting the segment of the retrogasserian cisternal
portion of the trigeminal sensory root, pain relief can often be
achieved, but with a high incidence of facial numbness as
shown in the above series. As a result, a gradual dose and
volume de-escalation approach was used by Adler et al. to
treat a 6 mm segment of the nerve with a dose prescription of
60 and 75 Gy maximum dose. Among 46 patients, 85 %
experienced complete resolution of pain at a mean of 5 weeks.
One of these patients had recurrence of symptoms at 7 months
and was treated with a repeat session with resolution of
symptoms. At a mean follow-up of 14 months, 96 % of
11 CyberKnife
patients reported >90 % improvement in symptoms and 15 %
reported significant facial numbness [50]. In an Italian series,
33 patients with TN were treated with CyberKnife to doses
between 55 and 75 Gy targeting a length of 4 mm of the ret-
rogasserian portion of the trigeminal nerve, and 94 % of
patients reported initial pain relief with a median time to pain
relief of 30 days. There were no documented cases of facial
numbness following treatment. However, 33 % of patients
experienced relapse of symptoms at a mean of 9 months [51].
Currently, a dose of 60 Gy with maximum dose limited to
75 Gy prescribed along 5 mm of the trigeminal nerve is used
at Stanford for TN. The target volume is kept 2–3 mm away
from the pons, and the brainstem maximum dose is limited to
<25 Gy and V12 < 0.2 cc in an effort to minimize the risk of
brainstem necrosis.
Spinal Indications
With the degrees of freedom in beam arrangements available
with the robotic arm, spinal radiosurgery has emerged as a
natural application for CyberKnife with encouraging results.
In the first reported use of image-guided robotics to perform
spinal radiosurgery, Ryu and colleagues demonstrated the
safety and short-term efficacy for a variety of neoplastic and
vascular lesions [52]. Similar to the principles of intracranial
radiosurgery, the goals remain controlling local disease to
prevent or palliate bony pain, vertebral fracture, and/or nerve
and spinal cord damage. In an updated study, Gerszten et al.
reported on 125 patients treated with single fraction spinal
radiosurgery to include 393 patients with 500 metastatic spi-
nal lesions [53, 54]. Lesions in the cervical spine were
tracked using skull-based landmarks while tracking for lower
spine lesions was based on implanted gold fiducials at the
vertebral bodies of interest. Of these patients, 69 % had
received prior radiation treatment. Patients received stereo-
tactic radiosurgery in a single fraction of 12.5–25 Gy. At a
median follow-up period of 21 months, local control was
88 % among all patients and 90 % in a group of patients
without prior radiation. At 53 months of follow-up, long-
term pain relief was reported in 86 % of patients, and there
were no cases of radiation myelopathy [55, 56].
In a report on the spinal CyberKnife experience at
Stanford, 74 patients with 102 spinal metastases were treated
with 16–25 Gy in 1–5 fractions with the majority of patients
having received prior radiation. At a mean follow-up of 9
months, 84 % of symptomatic patients experienced resolu-
tion or improvement of symptoms. There were three patients
who developed treatment-related spinal injury. Upon further
investigation, there were no factors seen in dosimetry that
could account for the cases of spinal cord injury [57].
Other institutions have also reported their data on spinal
radiosurgery with the CyberKnife. Wowra et al. published
155
the Munich experience of single fraction radiosurgery using
XSight Spine (fiducial-free tracking). They reported a series
of 102 patients with 134 malignant spinal tumors, of which
the majority were spinal metastases, treated 15–24 Gy in a
single fraction. In this cohort, 32 % of patients received prior
spinal radiation. At a median follow-up of 15 months, local
control was 98 %. In an update, they reported the results of
287 patients with 348 lesions showing a local control rate of
94 % at median follow-up of 9.6 months and only one patient
developed myelopathy [55]. Heron et al. published the com-
bined experience at University of Pittsburgh and Georgetown
University, which included 228 patients with 348 lesions
treated with CyberKnife spinal radiosurgery. Patients
received a mean dose of 16.3–24.5 Gy depending on frac-
tionation (1–5 sessions). Pain control was excellent among
all patients and superior among patients treated in a single
session (100 %) compared to patients treated in multiple ses-
sions (88 %). However, local control (96 % vs. 70 %), the
rate of retreatment (1 % vs. 13 %), and overall survival (63 %
vs. 46 %) at 2 years were all superior among patients treated
with multiple fractions compared to patients treated with a
single fraction [58].
These results demonstrate the safety and efficacy of using
CyberKnife radiosurgery for treatment of spinal lesions. The
local control and symptomatic relief rates are particularly
impressive given the high proportion of patients who had
been treated with prior radiation therapy.
Intrathoracic Tumors
Many patients with non-small cell lung cancer present with
underlying pulmonary disease precluding them from surgi-
cal resection. Historically, conventionally fractionated radio-
therapy has been the treatment of choice for early stage
medically inoperable patients, but outcomes have been poor
[59, 60]. SBRT was developed as a means to dose escalate
radiation to improve local control and survival. Extracranial
stereotactic radiosurgery was first described by Lax and
Blomgren showing very high rates of tumor control in the
lungs and abdomen [1, 2]. Since then, SBRT has emerged as
a standard treatment for early stage lung cancer with
extremely good outcomes reported in prospective and retro-
spective studies. While a full discussion of published data is
beyond the scope of this chapter, in general, local control has
been reported to exceed 90 % with survival rates exceeding
that of historical rates [61, 62].
The feasibility of CyberKnife radiosurgical ablation
for pulmonary lesions was first investigated in 23 patients
with biopsy-proven lung tumors (15 primary and eight meta-
static lesions) by Whyte and coworkers [35]. After CT-guided
percutaneous fiducial placement, each patient was treated
with 15 Gy in a single fraction. Although radiosurgery itself
156 C.E. Fasola et al.

Table 11.1 Select studies reporting results of CyberKnife for lung tumors
N Tumors Dose Local control 1-Year survival
Brown et al. [70] (2009) 31 P 60–67.5 Gy/3–5 93 % 94 %
Le et al. [69] (2006) 32 P+M 15–30 Gy/1 78 %(P)/58 %(M) 85 %(P)/56 %(M)
van der Voort et al. [68] (2009) 70 P 45–60 Gy/3a 96 %(60 Gy)/78 %(45 Gy) 83 %
van der Voort et al. [67] (2010) 38 P 45–60 Gy/3–6 100 % 65 %
b
Pennathur et al. [66] (2009) 100 P+R+M 20 Gy or 60 Gy/3 67% (P) 44 % (P 2-year)
b
55% (R) 41 % (R 2-year)
b
42% (M) 84 % (M 2-year)
c
Vahdat et al. [65] (2010) 20 P 42–60 Gy/3 95 % 90%
c
Unger et al. [64] (2010) 20 P+M 30–40 Gy/5 63 % 54 %
Chen et al. [63] (2012) 40 P 42–60 Gy/3 91 % (3-year) 75 % (3-year)
Bibault et al. [28] (2012) 51 P 36–60 Gy/3 92 % 86 %
P primary non-small cell lung cancer, M metastatic tumors, R recurrent non-small cell lung cancer
a
1 patient received 36 Gy/3
b
Estimated from Kaplan–Meier curve
c
Larger central hilar tumors

was well tolerated, several patients experienced complica-
tions as a result of the implantation of fiducials. After limited
postsurgical follow-up, radiographic progression was found
only in two patients; the follow-up period ranged from 1 to
26 months (mean, 7 months). Because several local failures
were subsequently observed, the radiosurgical dose for lung
cancer has been gradually escalated.
Since then, there have been dozens of additional reports
showing the efficacy of CyberKnife for lung SBRT, some of
which are summarized in Table 11.1 [28, 63–70]. It is
expected that CyberKnife will continue to play an integral
role in the treatment of early stage lung tumors and oligo-
metastatic pulmonary disease, and the body of literature on
its clinical outcomes will grow significantly.
Pancreatic Tumors
The outcomes of unresectable pancreas cancer using frac-
tionated radiotherapy is generally poor, with local recurrence
rates ranging from 20 to 60 % [71]. In an attempt to improve
on these results, SBRT has been used as a method of dose
escalation. CyberKnife SBRT was first reported by Koong
et al. in a phase I dose escalation trial [72]. Fifteen patients
were treated with 15, 20, or 25 Gy delivered as a single frac-
tion. No grade 3 or higher acute toxicity was observed, and
none of the 6 patients treated at 25 Gy in a single fraction
developed a local recurrence. Since then, the investigators
have expanded on their experience with single fraction
CyberKnife treatment, with a local control rate of 84 % at 1
year and an isolated local failure rate of 5 % at 1 year [73].
Although CyberKnife SBRT has proved highly effective in
achieving local control, survival continues to be largely
determined by the high rate of distant metastases, as the
median survival was 11.9 months, similar to that reported in
the literature. Important to note is that the risk of grade 2 or
higher gastrointestinal toxicity was 25 % at 1 year, highlight-
ing the importance of dose conformality and normal tissue
sparing.
Other investigators have also reported on CyberKnife
SBRT for pancreas tumors. Mahadevan et al. reported on 47
patients treated for locally advanced pancreas cancer, giving
treatment after two cycles of gemcitabine [74]. Because of
the risk of duodenal toxicity, the investigators used a risk-
adapted dose based on tumor proximity to the duodenum.
The dose ranged from 24 to 36 Gy in three fractions. Local
control was 85 % with a very encouraging median survival of
20 months. The rate of late grade 3 toxicity was 9 %. Studies
using CyberKnife for pancreatic tumors are shown in
Table 11.2 [73–81].
Overall, rates of local control are encouraging and appear
superior to those reported for conventionally fractionated
external beam radiation. The duodenum, bowel, and stomach
remain critical dose-limiting organs, and an improved under-
standing of tolerance of these structures to hypofractionation
is needed to further improve the therapeutic ratio. In addi-
tion, the high rate of distant metastases continues to be the
predominant mode of failure and death, and improvements in
systemic therapy may allow CyberKnife and SBRT to play a
potentially larger role in the treatment of this disease.
Liver Tumors
Liver SBRT continues to receive a great deal of interest, both
for metastases and for primary tumors. Given the large
organ size, focal SBRT can potentially ablate tumors with
a high rate of success and a low risk of organ damage.
While resection remains the standard of care, tumors may be
unresectable due to tumor location or medical comorbidities
11 CyberKnife 157

Table 11.2 Studies reporting results of CyberKnife for pancreatic tumors

Series N Dose Local control (%) Overall survival (months) Toxicity
Chang et al. [73] (2009) 77 25 Gy/1 fraction 84 11.7 25 % Gr 3
Mahadevan et al. [74] (2011) 47 24–36 Gy/3 fractions 85 20 9 % Gr 3
Polistina et al. [81] (2010) 23 30 Gy/3 fractions 82a 10.6 0 % Gr 2+
Rwigema et al.b [80] (2012) 24c 20–24 Gy/1 fractiond 66e 26.7 0 % Gr 3+
Schellenberg et al. [79] (2008) 16 25 Gy/1 fraction 81 11.4 12.5 % Gr 3
Seo et al.f [78] (2009) 30 14–17 Gy/1 fraction 70 14 3 % Gr 4
Didolkar et al. [77] (2010) 85 15–30 Gy/3 fractions 92 18.6 22.3 % Gr 3+
Goyal [76] (2012) 20 22–30 Gy/3 fractions 81 14.4 16 % Gr 3
Lominska et al. [75] (2012) 28g 20–30 Gy/3–5 fractions 86 5.9 7 % Gr 3
a
At 6 months among 11 of 23 patients alive
b
Treatment given adjuvantly for close or positive margin
c
18 of 24 patients treated with CyberKnife
d
1 patient received 30 Gy in three fractions
e
At 1 year
f
Treatment given as boost after 40 Gy in 20 fractions
g
Treatment given for reirradiation

thus requiring nonsurgical ablative techniques such as radio-
frequency ablation, cryoablation, chemoembolization, and
radioembolization. Several reports have been published on
SBRT showing encouraging local control rates [82–86]. As a
result, SBRT has become an additional tool available for the
treatment of unresectable liver tumors, and CyberKnife has
been successfully implemented for this clinical indication.
The Synchrony™ system allows for real-time respiratory
tracking to compensate for breathing motion.
Investigators at Stanford have reported on single fraction
SBRT for liver tumors using CyberKnife, successfully esca-
lating the dose from 18 to 30 Gy with 2 patients experiencing
grade 2 gastrointestinal toxicity among 26 patients [87]. The
cumulative local failure rate was 23 %. Lanciano et al.
reported on 48 patients treated with liver tumors, showing
that local control was dose dependent. Patients treated with a
biologically equivalent dose (BED) of >100 Gy had a 2-year
local control of 75 % vs. 38 % for patients treated with
<100 Gy BED [88]. Goyal et al. reported 82 % local control
in 17 patients treated for primary and metastatic liver tumors
[89]. Others have reported results using CyberKnife specifi-
cally for hepatocellular carcinoma, with or without combina-
tion treatment with transarterial chemoembolization, showing
favorable response rates [90], suggesting that SBRT could be
used as a bridge therapy for liver transplantation [91].
Much remains to be learned about the role of SBRT for
liver tumors including the optimal dose schedule, tolerance
of the liver and other abdominal organs using hypofraction-
ation, and how best to combine SBRT with systemic agents
and other ablative therapies. As our understanding of these
issues improves through continued clinical experience and
longer follow-up, the indications for SBRT will surely
expand. As advancements in systemic therapies are made as
well, particularly for chemosensitive malignancies such as
colorectal cancer, more patients will likely present with
oligometastatic disease that requires locally ablative thera-
pies. Thus, SBRT and CyberKnife are poised to play an
increasingly important role in the management of these
patients.
Future Directions
Although preliminary, the above results with abdominal and
thoracic tumors have been encouraging. Nevertheless, much
more evidence is needed to establish a definite role for
robotic radiosurgery in managing non-neurologic disorders.
To this end, multiple clinical trials are under way worldwide
that seek to discover if CyberKnife radiosurgery can sub-
stantially impact the overall clinical outcome for a broad
range of extracranial indications.
Fiducial targeting of lesions within the major body cavi-
ties is both robust and extremely accurate. However, the
implantation process can be technically demanding, adds to
the complexity of the overall radiosurgical procedure, and is
modestly invasive. In the case of lung treatment, pneumotho-
rax is not uncommon. Although the challenges are consider-
able, a technology for targeting intra-abdominal and thoracic
lesions without fiducials will be a clear improvement in
robotic radiosurgery. Recent research suggests that motion
compensation without implanted gold markers may be clini-
cally practical [39]. Such technology would considerably
simplify treatment protocols and enhance patient comfort
and safety.
Among the other stereotactic radiosurgery systems,
CyberKnife distinguishes itself with its automated image-
guided tracking system and noncoplanar and non-isocentric
delivery fashion. The 2D–3D image registration is fast, the
158
dose accumulated from imaging is low, and the images are
excellent for localizing bony structures. The tracking process
is highly automated, making the setup procedure quick and
easy. The noncoplanar and non-isocentric delivery method is
powerful in creating highly conformal plans without sacrific-
ing the uniformity of the resulting dose distribution.
However, when treating larger targets (e.g., >3 cm), the
CyberKnife delivery time still faces challenges. The delivery
efficiency of the CyberKnife system is limited by the small
sizes of the collimators and the step-and-shoot delivery man-
ner. While the patient setup time is very quick (less than
5 min), the delivery time for a 5–6 cm volume could be up to
45–60 min with the current G4 system. On the other hand,
with a gated volumetric modulated arc therapy for a similar
target, treatment can be delivered within 5 min once the
patient is set up. An MLC attached to the CyberKnife could
significantly reduce the treatment time. Further improve-
ments could be achieved with the implementation of contin-
uous delivery method similar to the arc delivery on traditional
linear accelerator systems.
Alternative image-guided localization approaches could
be important to improve targeting. The CyberKnife system
does not provide a volumetric imaging system, which, though
perhaps less critical for intracranial lesions, could be very
valuable for locating soft tissue structures in the thorax or
abdomen where appreciable deformation and movement
occurs (e.g., liver, pancreas, lung, and prostate). Localization
with non-ionizing methods, including optical, ultrasound,
and radiofrequency beacon systems could be interesting
areas to explore. Recently, XSight Spine tracking has been
made available for prone positioning to reduce the length of
the beam path to the target of posterior targets, allowing
improved dose distribution and reduced normal tissue
irradiation.
Conclusion
CyberKnife is a radiosurgical system well suited for stereo-
tactic radiotherapy. The introduction of image guidance and
robotic delivery has dramatically expanded the scope of this
field. With the strong interest in SBRT and extracranial
radiosurgery, indications for CyberKnife will continue to
grow. As inevitable improvements in neuroimaging and
computer technology emerge over the coming years, they
will serve as an impetus for further improvements in robotic
radiosurgical technology. There is much to be learned on the
role of SBRT for various disease sites, but with improve-
ments in technology and systemic therapy, the field of SBRT
will continue to expand. As our understanding of normal tis-
sue tolerance with hypofractionation develops, we will be
able to further optimize dose fractionation schedules to max-
imize the therapeutic ratio. The role of SBRT in combination
C.E. Fasola et al.
with systemic agents and other locally ablative therapies
needs to be further investigated and likely represents the next
generation of studies. The CyberKnife is anticipated to play
an important role in this effort.
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11 CyberKnife
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 GammaPod
Yildirim D. Mutaf, Cedric Yu, Steven J. Feigenberg,
and William F. Regine
Background
Breast cancer is the most common malignancy among women
in the USA, with more than 200,000 new cases per year [1].
Awareness and regular screening have resulted in more
patients being diagnosed with early stage disease, for which
breast conservation therapy (BCT) is a standard treatment
option. Compared with mastectomy, BCT provides similar
outcomes with superior cosmesis and reduced psychological
and emotional trauma [2, 3]. However, local treatments (sur-
gery and radiotherapy [RT]) have not taken advantage of sig-
nificant advances in imaging. BCT, as it is practiced today,
has two key shortcomings: (1) local therapy lasts for at least
11 weeks, is expensive, and significantly affects quality of
life and (2) lack of precise image guidance results in poor
accuracy, which can negatively impact cure and cosmesis.
Breast-conserving surgery consists of lumpectomy, in
which the tumor plus a cuff of normal breast is resected.
Because most diagnosed cancers are clinically occult, sur-
geons rely on image guidance for tumor localization. Using
mammographic guidance, a needle is placed by the radiolo-
gist into or through the tumor to guide the surgeon “blindly”
to the tumor. Because of the poor geometric link between
imaging and surgery, the lumpectomy specimen is many
times larger than the index lesion (Fig. 12.1). The large vol-
ume loss is the primary reason for poor cosmetic outcomes.
Compounding this poor geometric link, >20 % of patients
have inadequate margins and require re-excision or mastec-
tomy to obtain optimal local control [4, 5]. Magnetic reso-
nance (MR) imaging defines the breast disease more accurately
than mammography, theoretically reducing the excess normal
breast removed at surgery and the number of operations
Y.D. Mutaf, Ph.D. (*) • C. Yu, D.Sc. • S.J. Feigenberg, M.D.
W.F. Regine, M.D.
Department of Radiation Oncology, University of Maryland
School of Medicine, Baltimore, MD, USA
e-mail: ymutaf@umm.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_12, © Springer Science+Business Media New York 2015
12
required to achieve clear surgical margins. Unfortunately, MR
imaging has not been shown to improve outcomes and may
actually increase the rate of mastectomy [5–7]. This is likely
because of the poor accuracy between breast imaging
(performed prone) and surgery (performed supine).
Four to six weeks after surgical resection, if re-excision is
not needed, radiation therapy is administered. In the USA, a
standard course of radiation encompasses the whole breast
and requires an additional 5–7 weeks, with treatment deliv-
ered daily, Monday–Friday. The overall duration of local
therapy/BCT (i.e., lumpectomy + radiation therapy) is a min-
imum of 11 week. As many as 35 % of elderly patients who
live a long distance from a treatment facility decide against
RT after BC surgery—decisions that contribute directly to
decreases in overall survival [8].
Hypofractionated Whole Breast Irradiation
and Accelerated Partial Breast Irradiation
In order to reduce treatment costs and increase utility of
radiotherapy, hypofractionated whole breast irradiation
(HWBI) and accelerated partial breast irradiation (APBI)
were developed. HWBI decreases the duration of whole
breast radiation therapy to 3–4 weeks. However, patients are
still faced with quality-of-life difficulties associated with
multiple repeat visits over a long time period. APBI is radi-
cally different in that only the surgical bed, rather than the
whole breast, is targeted for irradiation. Treating smaller vol-
umes allows safe delivery of higher doses of radiation per
treatment, obtaining the same biologic effectiveness in only
1–5 days [9–13]. Early results of several large prospective
phase III trials comparing APBI with whole breast irradia-
tion demonstrated similar outcomes, supporting the hypoth-
esis that for select patients [9, 14, 15], whole breast irradiation
may not be necessary. In NSABP B-39, the largest phase III
trial comparing whole breast radiation and APBI, APBI
can be delivered using invasive approaches via various
brachytherapy applications or 3D conformal RT (3D-CRT).
163
164
Fig. 12.1 (a) Preoperative CT scan of 1 cm breast cancer. Lumpectomy
demonstrated a 1 × 0.7 × 0.5 cm invasive cancer with 7 × 7 × 2 cm lumpec-
tomy specimen with margin of 2 mm. (b) Postoperative CT scan of sur-
gical bed, which was 40 cm3, 100-fold greater than 0.4 cm3 shown in (a)
On this study, more than 70 % of patients randomized to
APBI are treated using 3D-CRT as compared with brachy-
therapy, even though 3D-CRT treats a volume approximately
5× larger than the brachytherapy techniques [16]. This larger
volume irradiated leads to a concern that 3D-CRT could
result in a higher rate of subcutaneous fibrosis [17] and unac-
ceptable cosmesis [18, 19], as volume is one of the most
important predictors of morbidity [20]. Yet many patients
choose to receive 3D-CRT instead of brachytherapy because
of the distinct advantage of being completely noninvasive.
Role of Technologic Advances in Delivery of RT
Over the last 30 years, advances in immobilization, computer-
based treatment planning and delivery, and image guidance
have revolutionized the ways in which small tumors are
treated with RT. Stereotactic radiosurgery (SRS) was intro-
duced in 1968 as a tool for noninvasive neurosurgery but
was not widely adopted until 3D imaging became available.
The pinpoint accuracy and high dose concentration achiev-
able with SRS allow safe delivery of “ablative” doses of
radiation. SRS has been a success story for patients with
Y.D. Mutaf et al.
brain metastases by improving local control, quality of life,
and survival [21]. Its success has hinged on minimizing the
volume of normal tissue receiving a “significant” dose of
radiation while maximizing dose to the tumor.
SRS outside the brain, called stereotactic body RT
(SBRT), has been more challenging [22]. Unlike intracranial
targets that do not move in reference to a rigid stereotactic
head frame, targets located outside the brain cannot be per-
fectly immobilized and the organ/tumor motion requires the
physician to add a margin to ensure appropriate dose cover-
age of the target volume. The planning target volume (PTV)
is defined by an additional margin to account for tumor
motion and setup uncertainties. This added margin increases
the volume of tissue irradiated, which theoretically increases
the risk of side effects [23]. Over the last 15 years, solutions
have allowed SBRT to treat tumors outside the brain [24, 25].
In fact, in lung cancer, the results [26, 27] have been so
impressive that investigators are currently challenging the
paradigm of surgery as the standard of care for patients with
small lung cancers [28].
SBRT of breast cancer has been addressed in only two
published reports [29, 30]. These studies have severe limita-
tions because of poor immobilization and lack of adequate
image guidance, allowing only subtherapeutic doses of radi-
ation and possible marginal misses because of set up uncer-
tainty. One of the major challenges of SBRT for breast cancer
is that the breast is pliable. These challenges have been
solved in the brain, thorax, and abdomen with commercially
available immobilization devices. In addition in the breast,
surrounding structures have placed limitations on beam
delivery. These technical obstacles have been solved through
an NIH-SBIR grant mechanism (4R44CA132254-02) at the
University of Maryland by Yu et al. [31] with the inception
of GammaPod™ technology, commercialized by the Xcision
Medical System, LLC (Xcision). A detailed description of
the GammaPod™ device and underlying technology will be
provided in subsequent sections.
The GammaPod™ device has several advantages over
current technologies capable of SBRT, including but not lim-
ited to (1) the vacuum assisted breast immobilization device
has improved accuracy and reproducibility. In addition, the
patient is treated in the prone position, similar to positioning
for stereotactic breast biopsy or MR imaging of the breast,
thus minimizing the effect of breathing motion. Subsequently,
the margin required for PTV can be decreased from 1.0 to
0.3 cm, potentially reducing the volume radiated by three-
fold [32]. (2) This device uses 36 noncoplanar Co-60 sources
that rotate during treatment to form 36 noncoplanar arcs,
producing a dose distribution similar to that of the
GammaKnife™ for intracranial targets [33]. (3) This system
allows differential dosing of target volumes [34] (dose paint-
ing; similar to that in intensity modulated RT techniques),
which cannot be accomplished with any invasive APBI
12 GammaPod
approaches. This allows higher doses to the gross tumor with
lower “subclinical doses” to ablate microscopic foci, which
can lie 1.0–1.5 cm beyond the index lesion [35, 36].
GammaPod™ offers the opportunity to deliver curative
doses of radiation using SBRT more precisely than current
surgical standards, thereby minimizing the amount of breast
tissue ablated and improving cosmesis. If this treatment is as
effective as it has proven for lung cancer, SBRT could lead to
a paradigm shift similar to that seen in lung cancer, with
completely noninvasive treatment of early breast cancer with
only a few high dose “ablative” treatments delivered over the
course of less than 1 week.
Role of Preoperative RT in Early Stage
Breast Cancer
In preparation for developing a clinical trial using SBRT
with ablative doses of RT, we investigated the role of preop-
erative 3D-CRT APBI as a method to reduce morbidity and
allow greater utility of APBI. We have demonstrated that
using a preoperative target volume dramatically decreases
the PTV by a mean average value of 56 % when compared
with the standard postoperative target [32]. In a subsequent
publication, we reported that preoperative 3D-CRT APBI
showed significant clinical advantages by decreasing dose to
all surrounding normal tissues and substantially increasing
(by 60 %) the number of patients eligible for APBI using
3D-CRT [37]. Based on these dosimetric advantages, we are
currently testing this hypothesis on a prospective trial at the
University of Maryland. This trial uses the same treatment
guidelines (i.e., clinical treatment volume and PTV expan-
sions) and dose fractionation (38.5 Gy delivered in ten equal
fractions over 5 days) as NSABP B-39, with the only differ-
ence being the sequence of surgery and RT. Based on early
data from the first 25 patients treated on study, a complete
pathologic response was achieved.
These pathologic findings have been quite exciting for
two reasons. First, only a low “adjuvant” dose of radiation
was administered, and, second and more important, a
response was actually seen. These tumors are slow growing
and can take a long time to respond. Prostate cancer, which
has similar growth patterns, takes years to show histologic
resolution of tumor following radiotherapy. Therefore, we
believe that small, early stage breast cancer, SBRT may
replace lumpectomy and postoperative RT. With the less
aggressive, slower growing tumors in the breast, it is likely
that SBRT will approach or surpass the efficacy of 90 %+
local control rates seen in SBRT for lung cancer. Although
clearly many studies will be necessary to prove this hypoth-
esis, in order for SBRT to be realized as a standalone treat-
ment, a noninvasive measure of success is key which will
require functional imaging such as MRI or PET. If successful
165
and implemented clinically in the future, select patients will
receive SBRT alone. The geometric accuracy will likely
improve cosmesis by causing minimal-to-no volume loss,
eliminate surgical scarring, improve quality of life issues
currently associated with prolonged treatment periods, and
enhance overall outcomes.
GammaPod™ Technology
The GammaPod™ device comprises three major components:
the gamma irradiation unit housing the Cobalt-60 radioactive
sources and collimation structure, a breast immobilization unit
to facilitate stereotactic localization and prone patient support
and a continuous trajectory patient positioning assembly.
Irradiation Device
The GammaPod™ irradiation unit comprises of two mechan-
ical structures: a source carrier and a collimation unit as
shown in Fig. 12.2.
The hemispherical housing structure contains the radionu-
clide source in the form of 36 Cobalt-60 pellets. These pellets
are positioned equidistantly, 38 cm from the isocenter (source
to focal distance, SFD). With an SFD of 38 cm, achieving an
initial dose rate greater than 5 Gy/min inside a large breast
requires an estimated total Cobalt-60 activity in the range of
4,000–5,000 Curies. The Cobalt-60 source is double-encap-
sulated with the inner capsule packed tightly with smaller
Cobalt-60 pellets. The source shell dimension is customized
to hold the required number of radioactive pellets. The cylin-
drically shaped inner capsule of the source shell measures
approximately 11 mm in height and 3.4 mm in diameter,
reflecting the true radiation source size of a single source.
Sources are aligned in six columns across the 2π surface
of the source carrier, with 60° longitudinal separation. Each
source column is arranged in a spiral order, such that a source
is positioned at every 10° longitudinally. The latitude of each
column is also designed such that all 36 sources span an
angular section between 18 and 53°, i.e., with 1° of latitudi-
nal separation. This arrangement ensures that each of the 36
sources occupies a unique longitude and latitude coordinate
when the source carrier is rotated.
Sources are collimated by the primary collimator, located
at the exiting end of the source shell. The secondary collima-
tor, with the same hemispherical shape, is nestled within the
primary collimator. Collimation is performed by pre-drilled
circular holes aligned with the sources. By altering the align-
ment of the source carrier and collimator, three different col-
limation modes can be chosen (two open, one blocked). The
GammaPod™ is designed to have two collimator opening
sizes, 1.5 and 2.5 cm, in order to increase the dose shaping
166 Y.D. Mutaf et al.

Fig. 12.2 An artist rendering (left) and 3D model drawing (right) of GammaPod™ depicting prone placement of a patient. (Courtesy of Xcision
Medical Systems.)

Fig. 12.3 A schematic drawing for the two-layered breast immobilization cup is shown on left panel with embedded stereotactic frame imaging
fiducial wire. A photo of the prototype breast cup is also shown on right. (Courtesy of Xcision Medical Systems.)

capabilities of the device. In contrast to radiosurgery of intra-
cranial lesions, in breast cancer larger collimator sizes are
selected due to the typical tumor sizes and the need to steril-
ize the tissues surrounding the tumor owing to its multicen-
tricity nature.
When the selected collimator opening is aligned with the
source positions, the source carrier and the collimator are
rotated together to create 36 noncoplanar conical arcs all
converging at the isocenter. In addition, the 36 source block-
ing positions on the primary collimator are made of tungsten
rods, effectively reducing the radiation to acceptable leakage
levels at the beginning and end phases of the fraction.
The GammaPod™ irradiation unit is encased in a hemi-
spherical shielding body made of cast iron. There are two
shielding doors on top of the irradiation unit which opens
during the irradiation and stays closed at other times.
The shielding body and doors are designed to bring leakage
radiation levels below those set by the regulatory bodies
when the device is not in use. The irradiation unit and shield-
ing doors are equipped with an uninterrupted power supply
(UPS) unit to ensure that treatments can be terminated safely
in the event of facility power failures. The source carrier and
the shielding doors can also be controlled manually using a
hand crank should the other safety measures fail.
Breast Immobilization Apparatus
The GammaPod™ system utilizes a two-layered breast cup
in order to immobilize the breast (Fig. 12.3). Several inner
cup sizes accommodate patients with varying breast sizes.
The outer layer is composed of a solid plastic material and
12 GammaPod
connected to a vacuum system working at a comfortable
level of negative air pressure. While the patient is in the
prone position, the treated breast is positioned inside the
inner cup of the breast cup. The inner cup is perforated so
that when a vacuum is applied to the space in between the
outer and inner cups, the breast volume fills the entire con-
tour of the inner cup and the coordinate frame is transferred
to the patient’s anatomy. The inner and outer cups are tightly
coupled with a silicone flange, which is attached to the
patient’s chest wall with a thin layer of silicone restricting
breast mobility with respect to the inner cup. In preliminary
studies [38], the GammaPod™ immobilization system was
shown to reduce the setup uncertainty to 0.2 ± 0.1 (2σ) cm,
and therefore the amount of margin necessary for PTV expan-
sion may conservatively be set at 0.3 cm for radiosurgery
applications.
The breast cup immobilization system also has the benefit
of gently pulling of the breast volume away from the patient’s
chest wall, therefore providing larger separation between the
targeted area and the ribs, lung and the heart in the case of
left breast treatments. The increased separation is an added
advantage to the similar geometric advantages caused by the
prone positioning of the patient’s breast especially for pen-
dulous breasts. To further increase comfort and immobiliza-
tion, a wide strap is affixed to the base of the cup, which
wraps around the chest of the patient.
The outer cup also incorporates a stereotactic localization
frame with the help of a spirally shaped CT and
MR-compatible fiducial as shown in Fig. 12.3. The frame
consists of a helical hollow plastic tube wrapped diagonally
around the outer cup. The plastic tube is filled with either
MRI contrast solution or copper wires, and is solidly secured
to the machined groove on the outer cup. Once the fiducials
have been identified a shared coordinate frame system
between the immobilization device and the patient’s anat-
omy is created.
Continuous Trajectory Patient Positioning
System
The couch and the patient positioning system are critical
components of GammaPod™ stereotactic radiotherapy
device. The couch top has built-in pegs that are machined to
fit perfectly with the breast immobilization device, therefore
creating a rigid registration system. Using this registration
protocol, the shared coordinates between the immobilization
device and the patient anatomy become a global coordinate
frame between the treatment unit and the patient’s anatomy.
Two couch systems exist for GammaPod™ treatments:
The imaging couch top and the treatment couch. In both sys-
tems, the couch-tops are brought to an upright position using
a pivoted motor assembly that enables patient docking. Both
couch-tops consist of two holes to accommodate the treated
167
left or right breast while the contralateral hole is covered
with a lid. Once docking is accomplished, the patient is low-
ered to the treatment or the imaging unit (CT or MR device)
via a cantilever action of the couch actuators. This automatic
patient positioning mechanism reduces the amount of motion
and effort required by the patient, which could otherwise
compromise breast immobilization.
The treatment couch unit is also equipped with three-
dimensional motor controls which move the patient in rela-
tion to the radiation isocenter of the GammaPod™. This 3D
motion trajectory also enables continuous shaping of the
dose distribution across the target volume. Therefore, instead
of packing multiple spherical and static dose distributions,
generally referred to as shots, which result in large dose het-
erogeneities, the GammaPod™ attains a more uniform dose
distribution. This dose shaping allows for the treatment of
different target volumes at different dose levels (such as pri-
mary gross tumor volume (GTV) versus the surrounding rind
of subclinical disease extent receiving higher and lower dose
levels, respectively).
The GammaPod™ treatment couch is also equipped with
redundant safety features to prevent any collision of the
device components with the patient. One of the safety fea-
tures employs metal ports mounted on the shielding door
which prevent the lowering of the treatment couch when the
shields are closed. The treatment couch also acts as a physi-
cal block, preventing the shielding doors from closing while
the patient is lowered into the treatment position. Knowing
the outer breast cup dimensions also allows for the imposi-
tion of trajectory limits for treatment plan optimization and
thus prevents inadvertent collisions with the inner surface of
the hemispherical collimator structure.
GammaPod™ Treatment Planning System
The GammaPod™ stereotactic device is distributed with a
dedicated treatment planning system, called Ceres. In its
current implementation, Ceres provides capabilities for mul-
timodality image import, stereotactic registration and local-
ization, manual contouring and automatic detection of the
breast/body surfaces, inverse optimization, dose calculation
and evaluation, treatment export and various quality assur-
ance (QA) utilities.
After the breast CT/MRI images are imported, breast cup
fiducials are identified in a single cross-sectional image,
which initiates automatic detection of the entire spiral.
Refinements to the detected fiducial geometry are performed
to match the known helical geometry of the stereotactic
frame. After the registration of the stereotactic coordinate
frame of reference to the patient image set, the software
detects the actual breast contour within the breast cup and
creates the whole breast volume. At this point other organs
of interest, such as chest wall and ribs, lungs, and/or heart
168
volume, can be manually drawn. The target volume creation
starts with the delineation of the primary GTV and followed
by the generation of other concentric targets using margin
expansions from the GTV, e.g., CTV. During the margin
expansion process, the automatically generated contours are
restricted from expanding beyond the 0.5 cm distance to the
breast skin surface.
After contouring is completed, the input of prescription
and other dosimetric parameters, such as critical organ dose
constraints, are performed on the inverse optimization
engine, where the continuous trajectory of the radiation iso-
center within the breast is optimized for two available colli-
mator sizes, 1.5 and 2.5 cm. Multiple targets and different
dose levels can be accommodated in the treatment planning
system. The planner also has the option to use treatment time
as an optimization constraint. After optimization, the final
plan can be normalized (as a global scale) to achieve the
desired dose–volume levels.
In Ceres, the dose calculation algorithm utilizes previously
calculated dose kernels representing both the inner and outer
cup dimensions as well as multiple isocenter positions. Dose
kernels for each collimator and isocenter positions are
calculated using the Monte Carlo (MC) simulation. The
GammaPod™ Co-60 source and collimation structures
are modeled in detail using BEAMnrc code based on the
EGS4nrc [39] dedicated for radiation source simulation.
The outcome phase space data modeling the energy deposi-
tion profile is used as the input for final dose kernel generation
using the DOSXYZnrc code [40]. An interpolation between
these dose kernels is also performed to describe the resultant
dose distribution due to continuous beam trajectory.
In the current version of Ceres, tissue heterogeneities of
the patient are not taken into account and the whole breast
volume is regarded as having a uniform mass density of
0.935 g/cm3.
GammaPod™ Dosimetry
Single collimator static dose profiles used as primary dose
kernels in treatment planning systems for a medium-sized
cup is shown in Fig. 12.4 for 1.5 and 2.5 cm collimators in
coronal and longitudinal cuts. In a preclinical prototype unit,
two-dimensional dose kernels are compared to dosimetric
measurements as performed with radio chromic films (only
for 2.5 cm collimation). Prior to making comparisons, the
radiation isocenter of the GammaPod™ was verified with
respect to the mechanical isocenter of the combined couch
and phantom system. For isocenter verification, a small hole
was punched on the film sheets marking the mechanical iso-
center. As shown in Fig. 12.5, these holes, appearing as
peaks in the measured dose profiles, fall at the center of these
distributions, with the overlaid expected center of the pro-
Y.D. Mutaf et al.
files appearing as dips. The distances between the mechanical
and radiation isocenters of the distributions were measured
as 0.2, 0.1, and 0.4 mm in the x, y, and z dimensions, respec-
tively. This submillimeter level of isocenter localization
accuracy is deemed suitable for SRS units. Two-dimensional
isodose overlays also demonstrate the congruence of
expected dose distributions, as shown by the obtained dosi-
metric measurements with radiochromic film in Fig. 12.6.
Absolute Dosimetry
Absolute dosimetry measurements with the GammaPod™
unit can be performed with the vendor-supplied breast phan-
tom, which is made of ultra-high molecular weight polyeth-
ylene (UHMW-PE) material with a physical density of
0.935 g/cm3. Because of the noncompliant geometry of the
treatment unit and measurement phantom, the contemporary
AAPM TG-51 photon calibration standard cannot be used
for GammaPod™’s absolute dosimetry. Instead, the former
AAPM TG-21 photon beam calibration standard can be used
for dosimetric calibration.
In a preclinical prototype unit installed at University of
Maryland, the GammaPod™ device was loaded with 36
Co-60 sources with an average activity of 120 Ci each for a
total activity of 4,320 Ci. The absorbed dose in the polyeth-
ylene phantom at the isocenter was determined to be 5.61 Gy/
min for the static 2.5 cm collimator shot. Using the ratio of
the mass energy absorption coefficients, dose to water is
determined to be 5.45 Gy/min at depth in the polyethylene
phantom. This dose rate calibration was also cross checked
with OSLDs and determined to be 5.42 ± 0.09 (1σ) Gy/min,
demonstrating a very good agreement between the two inde-
pendent measurements. The absorbed dose in water at a
water-equivalent depth of 7.5 cm at isocenter was also deter-
mined using a scale factor, as described in TG-21, to correct
for attenuation differences in polyethylene versus water
using the ratio of linear attenuation coefficients (0.973).
Finally, given a total source activity of 4,320 Ci, the absorbed
dose rate in water was established as 5.31 Gy/min for the
2.5 cm collimator.
Treatment Plan Examples
GammaPod™ can treat breast targets having a wide range of
shapes and sizes. In fact, the GammaPod™ device is capable
of treating target volumes up to 8 cm in its largest dimension
although since complications will be related to the surface
receiving the same dose, the dose per fraction may be drasti-
cally different between small and large targets. GammaPod™
is therefore technically capable of target volumes in breast
that are common both in pre- and post-lumpectomy settings.
12 GammaPod 169

Fig. 12.4 Dose kernels used for a static 1.5 and 2.5 cm shots (E-size breast cup) calculated using Monte Carlo. Apex preferential beam direction
is apparent in the low dose isodose lines with a characteristic cross shape in the YZ plane

Post-operative Treatment Planning Example
The lumpectomy cavity (LC) of 4.1 cm3 on a patient’s left
breast is identified as the target volume in the post-op CT
images of a prone patient with the help of surgical clips. In
order to facilitate comparative analysis with conventional treat-
ment techniques (linac-based external beam, brachytherapy),
we followed the target delineation methodology commonly
prescribed in many accelerated partial breast protocols such as
NSABP B-39/RTOG 0413. Therefore, LC was expanded by
1.5 cm isotropic margins to include subclinical extension of the
disease and create a CTV (101.5 cm3). Next, a PTV contour was
generated using a 1.0 cm expansion to account for patient setup
uncertainties (256.4 cm3). In linac-based protocols, although
this PTV is used for beam aperture generation, it is trimmed
from the breast skin and chest wall by 0.5 cm to establish dosi-
metric goals and plan evaluation (PTV_EVAL). These volumes
are used to create three treatment plans for comparison: IMRT
and 3D-CRT plans for linac-based external beam radiotherapy
(shown in Fig. 12.7a, b) and a GammaPod™ plan (Fig. 12.7c).
170 Y.D. Mutaf et al.

Fig. 12.5 One-dimensional dose profiles for 2.5 cm shot in cardinal directions and congruence of mechanical and radiation isocenters demonstrated
with a matching dip and peak pair in each direction

Fig. 12.6 Two-dimensional dose profile for 2.5 cm shot in XY direction is shown as measured with radiochromic film (left), calculated dose
distribution (middle), and a 2D overlay of measured and calculated isodose lines (right)

Fig. 12.7 Linac-based 3D-CRT

(a) and IMRT (b) plans for a
postoperative APBI treatment.
PTV_Eval is denoted with a
green contour. GammaPod™
plans for 1.0 cm (c) and 0.3 cm
(d) setup margin expansions for
the creation of planning target
volumes. The case with 1.0 cm
setup margin (upper margin) is
identical to the linac-based
treatments in the way PTV
structures are generated. PTV_
Eval volume is denoted by green
contour with white dots
12 GammaPod 171

Fig. 12.7 (continued)

172
Fig. 12.8 Dose–volume histogram comparisons of linac-based 3D-CRT, IMRT, and GammaPod™ plans for PTV_Eval, ipsilateral normal breast
tissue, and lung and heart volumes corresponding to the postoperative scenario
Although the same volumes are used for both linac-based
and GammaPod™ plans for one-to-one comparisons, the
requirement of a 1.0 cm expansion for PTV is clearly an
overestimation for GammaPod™ treatments. This expansion
is prescribed mainly because of the setup uncertainties stem-
ming from APBI experience in supine setup linac-based
radiotherapy. The GammaPod™’s dedicated breast immobi-
lization device, stereotactic frame, vacuum suctioning of the
breast, prone setup, and same day imaging and treatment
characteristics are believed to reduce treatment setup uncer-
tainties to levels more common in stereotactic applications.
As mentioned earlier, the GammaPod™ immobilization
system has indeed been shown to reduce the setup uncer-
tainty to 0.2 ± 0.1 (2σ) cm, making it possible to reduce the
PTV expansion from 1.0 to 0.3 cm. In treatment plan com-
parisons, we therefore included two GammaPod™ plans,
one with 1.0 cm PTV expansion and another with 0.3 cm
(Fig. 12.7d), all other margins being equal. The volumes
of two PTV structures were 256.4 and 145.8 cm3, a PTV
reduction of 57 %.
As shown in Fig. 12.7, both linac-based treatment plans
yield larger irradiation of the ipsilateral breast volume to pre-
scription as well as lower level doses when compared to
GammaPod™ plans. The dose–volume histogram compari-
sons for ipsilateral normal breast volume and target volume
are also provided in Fig. 12.8. All plans demonstrate similar
target dose coverage as well as dose heterogeneity character-
Y.D. Mutaf et al.
istics, with GammaPod™ plans demonstrating a clear advan-
tage in sparing ipsilateral normal breast as compared to
linac-based treatment plans. Among the GammaPod™ plans,
the advantage of reducing the PTV margin from 1.0 to 0.3 cm
is apparent as the ipsilateral breast volume receiving 50 % of
the prescription dose drops by about 10 %. In terms of other
nearby critical organs, DVHs for heart and ipsilateral lung
are also displayed in Fig. 12.8. For the heart, all plans
resulted in low heart doses with the GammaPod™ 1 cm PTV
expansion plan slightly higher over the linac-based plans.
Although the comparison is statistically underpowered due
to single patient presentation, this could be expected from
the beam topology associated with covering the larger
PTV. On the other hand, GammaPod™ plans were effective
in obtaining better lung DVH values (none of the plans were
corrected for tissue heterogeneities).
Preoperative Treatment Planning Example
On the same CT scan, a hypothetical preoperative plan was
created. Although the anatomy depicted in the images are
post-lumpectomy, we created a GTV volume corresponding
to a hypothetical spherical lesion located at the center of the
cavity, with a volume matching the lesion volume reported in
other imaging studies (2.6 cm3). This volume was expanded
with only setup margins used to create the final PTV contours
12 GammaPod 173

Fig. 12.9 GammaPod™ plan

isodose dose distribution
(upper panel) and dose volume
histograms (lower panel) in the
preoperative target scenario
discussed in the text. GTV is
displayed with the yellow
contour and white dots depicting
the pre-operative lesion, while
PTV is denoted with the green
contour and white dots

(0.3 cm margin expansion). The intermediate CTV volume
and the treatment of subclinical disease extension will be
discussed below as a separate scenario. The isodose distribu-
tions from these plans and corresponding DVHs are demon-
strated in Fig. 12.9. For such small targets, the dose outside
the target volume falls to approximately 50 % of the target
dose in the first centimeter and further drops to 10–15 % in
the second centimeter of tissue.
Dose Painting with Pre-Op Target
and Subclinical Disease Extension
In the last scenario, we evaluated the previous pre-op GTV
target within a dose-painting strategy in conjunction with a
PTV expansion of 1.5 cm for the subclinical extension of the
disease. Therefore, two target volumes were created; a PTV_
high volume, receiving 100 % of the prescription dose, and a
PTV_low volume, receiving 50 % of the prescription dose
(half-dose is chosen for demonstration purposes only). The
PTV_high volume was the same volume as the previous pre-
op scenario where GTV was expanded only with the setup
margin (PTV_high = GTV + 0.3 cm). However, PTV_low
volume corresponds to the GTV expanded by 1.5 cm to cre-
ate a CTV which is subsequently expanded by 0.3 cm setup
margins (PTV_low = GTV + 1.8 cm). Therefore, the two
PTV volumes are concentric and the difference between the
two corresponds to the 1.5 cm CTV expansion. The isodose
distributions from these plans and corresponding DVHs are
demonstrated in Fig. 12.10. The DVH for PTV_low corre-
sponds only to the shell of 1.5 cm rind between the PTV_
high and PTV_low volumes.
174 Y.D. Mutaf et al.

Fig. 12.10 GammaPod™ plan

isodose dose distribution
(upper panel) and dose volume
histograms (lower panel) in the
dose painting scenario of high
and low dose levels discussed in
the text. GTV is displayed with
the yellow contour and white dots
depicting the pre-operative
lesion, while PTV_high is
denoted with the green contour
and white dots. The largest PTV
volume, PTV_low, is drawn with
the blue contour and white dots

angles surrounding the breast and can therefore shape the

Conclusions
The application of stereotactic principles to breast radio-
therapy has promising advantages over conventional linac-
based applications. In Figs. 12.7 through 12.10, the dose
distributions for treating the post- and preoperative target
volumes are demonstrated. The GammaPod™ is observed
to achieve good dose conformity. Additionally, linac-based
external radiotherapy techniques are usually limited by the
degree of freedom available for the selection of beam angles
and are therefore typically restricted to tangentially oriented
angles. This beam topology results in undesirable dose spill-
age outside the target volume and poor dose conformity.
With the utilization of a breast-dedicated source/collimator
design, the GammaPod™ utilizes a larger range of beam
dose with better conformity around the target volume. The
GammaPod™ device also generates sharper dose profiles
due to small collimator openings and a short axis-to-
collimation distance, all of which contribute to the apparent
dose conformity of GammaPod™ dosimetry.
In addition to the advantages gained by its beam geometry,
the GammaPod™ system also introduces a negative-pressure
breast immobilization cup with a built-in stereotactic frame,
as well as a highly dynamic patient positioning system. The
combined effect of these dedicated breast stereotactic tech-
nologies is to reduce setup uncertainties with respect to the
linac-based radiotherapy techniques. For a hypothetical clini-
cal target volume of 1.0 cm in radius, reducing the expansion
margin from 1.0 to 0.3 cm, as previously discussed, brings
about a volumetric reduction of nearly fourfold (34 vs. 9 cm3).
12 GammaPod
In summary, we present that in the application of stereo-
tactic concepts, GammaPod™ technology has the potential
to achieve specific benefits not available in conventional
breast radiotherapy techniques:
• A dose delivery system with rotating radiation sources
positioned circumferentially around the breast, providing
36 noncoplanar arcs, producing highly conformal dose
distributions.
• A dedicated breast immobilization device with a built-in
stereotactic frame to reduce localization uncertainty and
improve accuracy.
• The dynamic utilization and control of a patient position-
ing system during dose delivery that enables delivery of
uniform doses to the treated area. The same principle is
also utilized for differential dose painting for multiple tar-
gets with different levels of prescribed doses.
• Optimal beam geometry to match geometric shape and
orientation of a patient’s breast.
• Prone setup and irradiation geometry to maximize separa-
tion of the targeted breast area from critical structures
such as lungs, ribs, and heart.
• Automatic patient positioning system to transfer the
patient from the imaging room to the treatment room
without compromising the integrity of the stereotactic
coordinate frame.
• Simplified coordinate registration and treatment planning
with inverse planning optimization.
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 Stereotactic Body Radiation Therapy
Steven J. Feigenberg, Randi Cohen, Navesh K. Sharma,
Zain Husain, Shifeng Chen, and Laura A. Dawson
Introduction
Over the last 30 years, advances in immobilization, computer-
based treatment planning and delivery, and image guidance
have revolutionized the ways in which small tumors are
treated with radiation therapy (RT). Stereotactic radiosur-
gery (SRS) was introduced in 1968 as a tool for noninvasive
neurosurgery but was not widely adopted until three-
dimensional imaging became available. The pinpoint accu-
racy and high-dose concentration achievable with SRS have
allowed high “tumor ablative” treatment of target tissues.
SRS has been a success story for patients with brain metasta-
ses by improving local control, quality of life, and survival.
Its success has hinged on minimizing the volume of normal
tissue receiving a “significant” dose of radiation while maxi-
mizing dose to the tumor.
SRS outside the brain, called stereotactic body RT (SBRT)
or more recently stereotactic radioablation (SABR), has been
more challenging. Treatment planning of intracranial targets
involves delivery of a very conformal dose of radiation to the
radiographic target with no margin, because the brain does
not move in reference to the rigid stereotactic head frame.
When the target is located outside the brain, immobilization
is less accurate and organ/tumor motion requires the physi-
cian to add a margin to account for these differences to ensure
appropriate dose to the gross target volume (GTV). The plan-
ning target volume (PTV) is defined by an additional margin
S.J. Feigenberg, M.D. (*) • R. Cohen, M.D., M.S. • N.K. Sharma,
D.O., Ph.D. • S. Chen, Ph.D.
Department of Radiation Oncology, The University of Maryland
School of Medicine, Baltimore, MD, USA
e-mail: sfeigenberg@umm.edu
Z. Husain, M.D.
Department of Therapeutic Radiology, Yale University,
New Haven, CT, USA
L.A. Dawson, M.D., F.R.C.P.C.
Department of Radiation Oncology, Princess Margaret Cancer
Centre, University of Toronto, Toronto, ON, Canada
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_13, © Springer Science+Business Media New York 2015
13
to account for tumor motion and setup uncertainties. This
added margin increases the volume of tissue irradiated, which
theoretically increases the risk of side effects. Over the last 15
years, solutions have allowed SBRT/SABR to treat tumors
outside the brain.
SBRT refers to the use of a limited number of high-dose
fractions delivered conformally to targets with high accu-
racy, using biologic doses of radiation far higher than those
used in standard fractionation. Stereotactic refers to the use
of a reference system to aid in localizing the tumor. An exter-
nal reference system, such as a stereotactic head frame for
cranial SRS or internal fiducial markers including the tumor
itself, may be used for localization and guidance. For tumors
fixed to bony anatomy, such as base of skull cancers, image
guidance using bony anatomy may be appropriate; however,
often the position of the tumor is not highly correlated with
the bones or an external reference system, and imaging and
targeting of the tumor itself (i.e., image-guided radiation
therapy [IGRT]) may be required.
SBRT is becoming more popular, as evidenced by increas-
ing recognition at international meetings, a textbook devoted
to the topic [1], and an American Society for Therapeutic
Radiology and Oncology (ASTRO) consensus document on
SBRT [2]. The ASTRO consensus document defines SBRT
as high-precision radiotherapy delivered in three or more
fractions to very potent doses of highly conformal radiation
with steep dose gradients around the target. SBRT is “an
evolving technology,” and definitions may change with time.
The philosophies and techniques of SBRT can be applied to
longer fractionation regimens (when the target is intimately
associated with a critical serial functioning normal tissue, for
example) or shorter fractionations, including SRS.
Similar to cranial SRS, multiple static or dynamic beams
in a variety of beam arrangements, with or without segments
or intensity modulation, can be used to produce a dose distri-
bution in which isodose lines tightly conform to the target
volume. Although most reports on SBRT refer to megavolt-
age photon irradiation, protons are not excluded from the
SBRT definition. Inhomogeneity within the target volume is
177
178
permitted and hot spots have been encouraged within the
PTV to increase the chance of tumor ablation, although with
a larger rim of normal tissue found inside of the target vol-
ume in comparison to cranial SRS that complications may be
increased. Dose is generally prescribed to an isodose line
covering the PTV similar to cranial SRS, with a very steep
dose gradient outside the PTV.
SBRT is a noninvasive, outpatient intervention, generally
completed within 1 or 2 weeks, allowing for little to no
delays in systemic therapy. The short radiation treatment
time and high dose per fraction in SBRT have potential
radiobiological therapeutic advantages compared with con-
ventional fractionation, due to less tumor repopulation and
repair. In addition, there is growing evidence that SBRT/
SABR may have an impact on disease outside of the treated
volume decreasing regional and distant recurrences, the
“abscopal effect.” Furthermore, the shorter SBRT treatment
times are more convenient for patients and have resource uti-
lization advantages.
The rationale for SBRT is that there is a need for improved
local therapies for many primary cancers and also in the situ-
ation when there are “oligo” (i.e., isolated) metastases, spe-
cifically in sites where surgery has been shown previously to
be able to cure patients with “oligo” metastases (e.g.,
colorectal cancer (CRC), renal cell cancer, and sarcoma).
SBRT is less invasive than surgery, and once the safety of
SBRT has been established, SBRT has the potential to be
used in place of surgery in situations when surgery may be
associated with high risk. Even in incurable situations, SBRT
may be of significant advantage to patients with metastatic
disease on systemic therapy where only a few tumors are
increasing in size and the rest of their disease is stable.
Patients could be maintained on their current systemic ther-
apy, if they are tolerating, rather just changing to a new sys-
temic therapy of unknown efficacy and morbidity potentially
improving quality of life.
In this chapter, a historical perspective, rationale, techni-
cal details, and literature on SBRT/SABR outcomes and
complications will be reviewed. Specific applications of
SBRT will be reviewed in more detail where there is an
abundance of data including lung cancer and metastases,
liver metastases and hepatocellular carcinoma (HCC), spinal
malignancies and pancreatic cancer.
Historical Perspective
The first extracranial site to be investigated with SRS tech-
niques was the spine in 1993. A rigid skeletal fixation device
that immobilized the spine above and below the target was
used as a stereotactic reference frame to guide radiation [3].
Around the same time, Blomgren and Lax [4, 5] from
Sweden began applying stereotactic techniques to body
targets such as lung and liver tumors. They developed a body
S.J. Feigenberg et al.
stereotactic reference frame to aid in guidance of radiation.
Blomgren et al. [5] reported their initial experience in 1995,
in which 31 patients with primarily solitary lung and liver
tumors were treated with one to four fractions. Reproducibility
of this approach, based on patients who had repeat CT scans
in the treatment position, was found to be within 5 (axial) to
8 (cranial–caudal) mm for 90 % of setups with diaphragm
motion reduced to 5–10 mm with abdominal pressure.
Experience in North America has been growing exponen-
tially following the pioneering work of Dr. Timmerman [6–9]
who systematically evaluated SBRT by a series of prospec-
tive clinical studies. Based on this experience, he led the
Radiation Oncology Therapy Group (RTOG) initiative with
a multi-institutional phase II trial of SBRT in lung cancer
which was published in 2010 in JAMA [10]. The results
were so impressive that the paradigm of surgery as the stan-
dard of care for small tumors is currently being challenged in
RTOG 10–14 [11]. Similar North American studies have
been reported for liver metastases, vertebral metastases,
adrenal metastases, pancreatic carcinomas, recurrent head
and neck cancers as well as for tumors of the retroperito-
neum and pelvis.
Radiobiology
Radiobiologic Models
The linear quadratic model may not be valid for very short
fractionation schemes. In the early development of this
model, one of the developers expressed that the model is not
intended for doses higher than 8–10 Gy. The linear quadratic
model may overpredict tumor cell kill and underpredict toxic-
ity at the increased dose per fraction. Fowler et al. [12–14]
predicted that local control should be excellent for non-small
cell lung cancer (NSCLC) with biological doses of the order
100 Gy in 2-Gy equivalent dose or higher (α/β = 10), although
based on the pioneering work at Michigan [15, 16] the local
control was only 70 % at this dose level. Although there
seems to be a threshold of superior local control at 100
Gy (α/β = 10) when higher doses per fraction are used.
Fractionation schemes with an estimated tumor control prob-
ability (TCP) of 95 % or greater include 45 to 60 Gy in three
fractions and 60 Gy in five fractions, although one must be
extremely careful to review how the dose was prescribed as
investigators prescribe dose very differently. German investi-
gators [17] prescribe dose to the 65 % isodose shell while the
Japanese routinely prescribe to the isocenter—which can lead
to very different doses seen by the PTV. Due to the inadequa-
cies in the linear quadratic model in predicting outcomes,
investigators [18] have developed the universal survival
curve. This combines the linear quadratic model and the
multi-target model which may be more accurate. Although as
the investigators correctly point out, “the complex biology
13 Stereotactic Body Radiation Therapy
that underlies cell ablation and loss of clonogenicity pre-
cludes an explanation by any simple mathematical model.”
Mechanism of Action
It is clear that the mechanism of cell kill is different between
a conventionally fractionated course of radiotherapy as
opposed to the “ablative” doses used with SBRT. The classic
model of radiobiology is defined by the depletion of tumor
stem cells and undifferentiated progenitor clonogens for
radiotherapy to be curative. With conventionally fractionated
radiotherapy where large volumes of normal tissue receive
the prescribed treatment dose, normal tissue stem cells are
better at repairing radiation damage than tumor clonogens.
The surrounding microenviroment was not thought to be an
active contributor to this effect until recently. As a possible
explanation, Fuks et al. [19] initially suggested that contrary
to conventional (1.8–3 Gy) fractionation, high-dose radiation
(>8–10 Gy per fraction) specifically impacts more robust
endothelial apoptosis and microvascular dysfunction, which
in turn leads to increased cell death. Furthermore, hypoxia
resulting from standard fractionated radiotherapy regimens
results in a burst of pro-angiogenic activity in the tumor
microenvironment, generating HIF-1α, VEGF, and other
vasculogenic factors which, in turn attenuate radiation-
induced apoptosis in endothelial cells.
Immune Response to Radiation
SBRT appears to impact disease outside the radiated volume.
This is best exemplified by a retrospective experience from
William Beaumont Hospital [20] which compared patients
who were treated with either a sublobar resection or SABR
during the same time period. SABR not only resulted in a
drastically lower local failure rate (5 % versus 24 %, p = 0.05),
but more unexpectedly had a lower regional lymph node fail-
ure rate (18 % versus 0 %, p < 0.05) even though patients
were more likely to be surgically staged to be node negative
in the resected cohort (71 % versus 20 %). Given that patients
treated using SABR have a very small (tumor plus margin)
volume of tissue irradiated, and few if any lymph nodes
included in the treatment field, this was a surprising finding.
One possible explanation of this phenomenon is the stimula-
tion of T-cell immunity by SABR, leading to the eradication
of occult regional micrometastases.
The immune system has long been known to play a criti-
cal role in tumor surveillance and control [21]. It is thought
that tumors develop by escaping immune detection, either by
downregulating surface recognition antigens or by releasing
immunomodulatory cytokines that dampen the immune
response, and are found in greater prevalence in immunosup-
pressed populations. Conversely, a robust immune response,
179
associated with cytotoxic immune cell populations, is associ-
ated with improved tumor control [22]. Radiotherapy, in its
classic delivery with standard fractionation, has traditionally
been viewed as an immunosuppressive modality [23].
However, the actual effects on the immune system are
extremely complex with conflicting reports on whether they
promote or interfere with tumor reduction.
One of the leading hypotheses for this “abscopal” effect
with SBRT is its relationship to CD8+ T-cell-mediated
immune response. The lower than expected regional failure
rate with SBRT may be due to radiation-induced systemic
stimulation of T-cell immune responses, leading to eradica-
tion of occult regional micrometastases. Support for this
theory derives primarily from experiments in animal models.
A recent study examined the effect of ablative doses of radia-
tion therapy in a mouse melanoma model [24]. In this study,
mice with B16 melanoma tumors received 20 Gy of radiation
in a single fraction. Examination of the tumor microenviron-
ment and lymphoid tissues 1–2 weeks posttreatment demon-
strated tumor regression and an increase of infiltrating T
cells. When the experiment was repeated with athymic nude
mice, which lack T cells, no statistically significant decrease
in tumor volume was observed, suggesting that the effects
were T-cell mediated. Taken together, these studies suggest
that ablative doses of radiation alter the tumor microenviron-
ment, causing T-cell infiltration resulting in vigorous prim-
ing and expansion of effector T cells. The experiment was
repeated in wild-type mice with B16 tumors, which had been
subjected to antibody-mediated CD8+ T-cell depletion. The
therapeutic benefit to the ablative radiation was diminished,
and survival in this CD8+ depleted group was decreased by
75 %. In a separate experiment using a transplantable mouse
4T1 mammary carcinoma model (which mimics metastatic
ability of breast cancer cells to lung, bone, liver, etc.), abla-
tive radiation therapy delivered to the primary tumor site led
to a complete elimination of lung metastasis. This observa-
tion strongly suggests the induction of a potent antitumor
immune response. Separate experiments utilizing CD8 deple-
tion strategies demonstrate a relative increase in number of
distant metastases, again suggesting that CD8+ T cells are
critical for mediating protection against tumors. Taken in
combination, these studies suggest that CD8+ T cells play a
critical role in radiation-induced antitumor immune responses
(both locally and distantly), following ablative dose therapy.
Clinically, similarly suggestive observations have been
reported in several tumor types. Mahmoud et al. [25, 26]
recently demonstrated the influence of density and distribu-
tion of the cytotoxic CD8+ T cells in breast cancer patients.
Using immunohistochemistry staining of tissue microarray
cores, they established that infiltration of CD8+ T cells into
the distant stroma correlated with improved overall survival.
In addition, the number of T regulatory cells, the ratio of
CD4+ to CD8+ T cells, and the presence of T lymphocytes in
the primary tumor correlated with grade, stage, and survival.
180
Fig. 13.1 Baseline CT of
isolated liver metastases and
follow-up imaging at 3 months
and 18 months revealing no
evidence of progressive disease
Furthermore, several groups have demonstrated that the
presence of tumor-associated lymphocytes in breast cancer is
an independent predictor of response to anthracycline/
taxane-based chemotherapy [27]. Paulson et al. [28] have
demonstrated that intratumoral CD8+ lymphocyte infiltration
was the most important predictor of outcomes in patients
with Merkel cell carcinoma. Interestingly, in this population,
patients with tumors that demonstrated a robust CD8+ lym-
phocyte infiltration were observed to have the largest
improvements in regional and distant control as compared to
local control. A recently published report [29] appears to
substantiate this combination of ipilimumab with SABR. In
this case study, a patient with progressive metastatic mela-
noma receiving maintenance ipilimumab therapy was treated
palliatively with SABR for a painful paraspinal mass. While
there was no initial response, a single additional dose of ipili-
mumab not only significantly decreased the size of the para-
spinal mass but also caused regression of additional sites of
metastatic disease which were of considerable distance from
the radiated paraspinal mass. Further analysis demonstrated
that RT had increased antibodies to NY-ESO-1, an antigen
associated with melanoma, by 30-fold. Since presence of
antibodies to NY-ESO-1 had been associated with a more
robust response to ipilimumab, this may explain why this
patient had such an excellent response to disease within and
outside the radiation portal. Furthermore, the RT regimen in
this patient also led to a subsequent spike in inducible co-
stimulator, a marker of activated CTLs, suggesting an addi-
tional mechanism for the observed tumor control.
Imaging Response to SBRT
With these promising early results, two cooperative groups
are evaluating SBRT as an alternative to surgery. However,
assessment of tumor response to SBRT in a time frame that
will allow those with failures the maximal curative benefit
from salvage surgery remains a challenge. Furthermore, in
S.J. Feigenberg et al.
the medically inoperable population, identifying the extent
of tumor response to initial SBRT is critical in determining
further treatment response, as is identifying dose–response
characteristics on current SBRT trials. Specifically, is there
an imaging technique that can be used as a biomarker or
early surrogate marker of outcome? Currently, computerized
tomography remains the imaging modality of choice to eval-
uate response following SBRT. However, with the very high-
dose fractions utilized in SBRT, a significant percentage of
patients treated by SBRT will develop fibrosis within and in
close proximity to the treatment field. Takeda et al. [30, 31]
described solid consolidations on CT scans are seen as late
changes in the center or the periphery of the PTV in upwards
of 73 % of patients. Radiographic findings, that occur as a
result of SBRT, are more dramatic in appearance as opposed
to what is seen clinically (see Fig. 13.1). These consolida-
tions can be quite complex making serial CT follow-up
rather difficult, thereby making it difficult to determine
whether these changes are consistent with recurrent carci-
noma or radiation changes.
In this regard, assessment of tumor response to therapy
using functional information could be very helpful in
the absence of good anatomical imaging such as
18-fluorodeoxyglucose-positron emission tomography
(FDG-PET) scanning modality. PET scans have had a
significant impact on the management of patients with
many cancers but it has been studied most extensively in
NSCLC. Their most important contribution has been in the
improvement in the preoperative evaluation of mediastinal
lymph nodes over computed tomography (CT) scans alone
with increased sensitivity and specificity [32–34] and in
staging improving patient selection for curative therapy.
FDG-PET has also been prognostic in the pretreatment
setting and following induction chemotherapy [35] or
definitive chemoradiotherapy to determine tumor response
as defined by FDG uptake for predicting outcomes [36, 37].
Following SBRT, PET findings have been mixed with only
a few small series reported.
13 Stereotactic Body Radiation Therapy
A small prospective series [38] from Fox Chase Cancer
Center which included ten medically inoperable patients
treated for NSCLC on a phase I dose escalation demon-
strated that a drop in the maximum standardized uptake val-
ues (SUV) comparing the pre-SBRT and the 3-month
post-SBRT PET scan appeared to be a predictor of local con-
trol. A larger retrospective experience [39] from the same
institution including 26 patients addressed using FDG-PET
response (comparing pre-SBRT versus 3-month post-SBRT)
as a surrogate of local failure in greater detail. All 26 PET
scans were reviewed and interpreted by a single physician
who was blinded to the clinical results. FDG-PET scans were
analyzed semi-quantitatively by comparing pre- and post-
treatment changes in SUV. This study demonstrated two
major findings: (1) A lower initial SUV value was the only
significant factor associated with an increased risk of local
failure (3.4 versus 5.7; p = 0.045) with 4 out of the 5 local
failures having a low pre-SBRT SUV (<4). (2) Decreases in
post-SBRT SUV of >55 % of its pre-SBRT value signifi-
cantly decreased the risk of local recurrence. Similar find-
ings were seen when this data was combined with data from
the University of Maryland [40] which demonstrated a crude
local failure rate of 54.5 % failure rate (6/11) for patients
with SUV <4, while only 11 % (4/36) of patients with SUV
≥4 failed locally. Hoopes et al. [41] have described with
nearly 50 % of patients at 1 year having SUVmax changes
>3.5 from their prospective study and 15 % in their retro-
spective experience (4 of 28 with a max SUV >2.5).
Presumably, though, all were lower than pretreatment. These
patients were too compromised to undergo further treatment
and were thus followed. They remained without recurrence
between 8 and 22 months post these PET scans. This illus-
trates that the use of a specific SUV value is not useful and
therefore trying to determine a specific cutoff SUV for a
population to predict recurrence is not appropriate. With
these inflammatory changes so prevalent, it is imperative for
the reading nuclear medicine physician and treating physi-
cian to review the images to define the solid and inflamma-
tory components and their corresponding SUV in relationship
to the distribution of the treatment to minimize the possibil-
ity of false-positive readings. It is therefore to our advantage
to have scans read by a single physician for consistency in
reporting.
Further refinement of this data is vital as quantification
with SUVmax oversimplifies the evaluation of tumor
response and sometimes results in inconclusive or inaccurate
diagnosis. Currently investigators are trying to extract more
detailed spatial–temporal PET/CT features [42] that compre-
hensively characterize the whole tumor’s intensities and dis-
tributions, spatial variations (texture), and shape properties
which may become better predictors of treatment response.
In addition, novel radiotracers are in development. The use
of fluorodeoxyglucose (FDG) as the radiotracer of choice for
181
PET scanning has been recently challenged. Investigators
have looked at L-s-methyl-11C methionine (MET)
PET. While MET has been shown to have decreased in
inflammatory lesions as compared to FDG, a small series
from Japan in the SBRT setting showed very little difference
between the two tracers [43]. 18F -3′-fluoro-3′-deoxy-L-
thymidine (FLT) [44], a nucleoside reverse transcriptase
inhibitor, has been suggested to be superior to that of FDG in
detecting cellular and proliferative responses to chemother-
apy; the role of FLT-PET as a surrogate of response follow-
ing stereotactic body radiotherapy (SBRT) for lung cancer
remains unexplored. Similar data is available for patients
with liver metastases and lung metastases.
Normal Tissue Response to SBRT
Normal tissues that function primarily as parallel normal tis-
sues are made up of predominately structurally defined func-
tional subunits (FSUs) (e.g., peripheral lung, liver, kidney).
Serial functioning normal tissues, characterized by a chain of
function, are composed of primarily undefined FSUs (e.g.,
gastrointestinal mucosa, trachea, spinal cord, bronchus).
Parallel organ toxicity is mostly related to volume irradiated
(e.g., mean dose, volume treated to a threshold dose such as
V20), whereas serial organ toxicity is mostly related to the
maximum dose delivered to that tissue. Although useful, this
distinction between serial and parallel functioning organs is
likely too simplistic, and most normal tissues likely have
both parallel and serial functionality. This has been demon-
strated in elegant rat model experiments of spinal cord toler-
ance to radiation therapy by van der Kogel et al. [45]. The rat
spinal cord tolerance to radiation was found to be dependent
on the volume irradiated and the spatial distribution of dose.
The gray matter of the cord was found to be most resistant,
whereas the lateral white matter was most sensitive.
As the volume of normal tissues irradiated to high doses
with SBRT is generally less than the volume of normal tissue
irradiated with conventional fractionation, for normal tissues
that are primarily parallel functioning, if the volume irradiated
is low enough, the risk of toxicity may be extremely low
despite delivery of very high doses to a small volume.
However, for serial organs that are in close proximity to
tumors, even a small volume irradiated to a high dose may
lead to irreversible toxicity. Thus, SBRT should be used cau-
tiously for tumors adjacent to serial functioning organs such as
the esophagus or spinal cord. An increase in the number of
fractions may improve the therapeutic ratio and should be con-
sidered in place of hypofractionated SBRT in this situation.
With a dramatic increase in the fraction size and total
dose with SBRT, the repair mechanisms may not be initiated
as they would at a lower dose per fraction, potentially lead-
ing to permanent damage to the normal tissue within the
182
high-dose volumes and/or unpredictable effects outside the
high-dose volume. Given the potential for normal tissue
injury and that the volume tolerance of normal tissues to
such high doses per fraction is unknown, most SBRT has
been applied to small tumors (<5 cm) in which the volume of
normal tissue around the tumor is small. SBRT is being
investigated for larger tumor volumes [46], and it is hopeful
that clinical data will eventually be obtained to provide guid-
ance to what the dose–volume toxicity relationship is for
organs irradiated with inhomogeneous doses from hypofrac-
tionated fractionation schemes.
As very steep dose gradients are used with SBRT with
rapid falloff of dose in surrounding normal tissues, not only
is there substantial variability of dose throughout normal
tissues, but also there is substantial variability in the dose
per fraction. Thus, when dose–volume characteristics of a
normal tissue associated with toxicity risk are investigated,
correction for the variability in dose per fraction should be
considered. Unfortunately, accurate knowledge of the α/β
ratio for normal tissues is lacking. Clinical trials of novel
fractionation regimens are required to confirm outcomes and
toxicities associated with the many different fractionation
schemes used in SBRT. Under each of the clinical sections,
additional data will be presented based on complications to
the bowel, chest wall, rib, liver, and brachial plexus.
Immobilization
Overview
Given the sensitivity of highly conformal SBRT plans to
setup uncertainty and organ motion, reduction of geometric
uncertainties and organ motion is important. The choice of
patient position and immobilization may impact setup error,
organ motion, as well as intrafraction motion secondary to
patient discomfort. For example, prostate motion due to
breathing is reduced in the supine position compared with
the prone position [47, 48]. The different immobilization
devices and strategies that have been used for SBRT are
described below.
Spinal Tumor Immobilization
Similar to intracranial SRS with a cranial halo secured to the
skull with transcutaneous pins, rigid fixation systems have
been used for paraspinal and spinal SBRT. Hamilton in 1995
immobilized the spine for SBRT with rigid skeletal fixation
above and below the involved segments. With this system,
excellent accuracy, with less than 2-mm offsets, was observed
[3]. However, such an approach is invasive, and avoidance of
invasive fixation systems is desirable to minimize risks.
S.J. Feigenberg et al.
Noninvasive stereotactic systems using a frame, with or
without implanted fiducial markers, have been used for para-
spinal tumor SBRT with accuracy within 2 mm [49]. Optical-
guided three-dimensional ultrasound has also been used for
spinal SBRT to ensure that the patient does not move during
radiation [50].
Body Tumor Immobilization
Nonrigid fixation has been performed for SBRT with
specialized body frames that have fiducial systems attached
to the frame and a device to control respiration using abdom-
inal compression [4]. Abdominal compression using such
frames has been found to reduce diaphragm caudal–cranial
motion to less than 5–10 mm in most patients. Reproducibility
of target positioning using these frames has been reported to
be better than conventional immobilization systems, with
positional deviations of lung cancer and liver cancer position
less than 10 mm in 98 % of patients [4, 51, 52].
An option to these specialized body frames that facilitates
guidance is to not use the frames for guidance, but to image
internal anatomic references, such as bones near the target or
the soft tissue tumor itself, to define the treatment coordi-
nates. Repositioning and repeat verification imaging are
required to ensure the patient was moved to the correct posi-
tion. A variety of immobilization devices can been used with
this strategy, as long as they keep the patient immobilized
and preferably are (relatively) comfortable to minimize
intrafraction patient motion.
Assessment of Breathing Motion
Organ motion due to physiologic functions during a radia-
tion treatment fraction can be substantial. For example, the
liver can move up to 5 cm in the caudal–cranial direction
during free breathing [53] causing motion of the upper
abdominal and lower thoracic cavity. As this motion can
result in alternations in target and normal organ volume defi-
nitions, PTV margins, and the entire dose distribution, inter-
ventions to reduce the impact of intrafraction organ motion
are required for many SBRT patients, to facilitate dose esca-
lation and to reduce the volume of normal tissue irradiated.
Strategies to compensate for breathing motion include the
use of abdominal pressure, voluntary shallow breathing, vol-
untary deep inspiration, voluntary breath holds at variable
phases of the respiratory cycle, active breathing control
(ABC), gated radiotherapy, and real-time tumor tracking.
Although voluntary breath holds may be beneficial for some
patients, there is potential for leaking air and patient error,
particularly for patients with lung disease where usually
less than 30 % of patients can even tolerate this approach.
13 Stereotactic Body Radiation Therapy
ABC refers to organ immobilization with breath holds that
are controlled, triggered, and monitored by a caregiver. In
approximately 60 % of patients with liver cancer, ABC was
used successfully, with excellent reproducibility of the liver
relative to the vertebral bodies within the time period of one
radiation fraction (intrafraction reproducibility, σ, of the
liver relative to the vertebral bodies: 1.5–2.5 mm) [54, 55].
However, with ABC, from day to day the position of the
immobilized liver varies relative to the bones (interfraction
reproducibility, σ 3.4–4.4 mm), providing rationale for daily
image guidance when ABC is used for liver SBRT although
treatment time needs to be kept reasonable as patients with
poor performance status have increased treatment uncertain-
ties and all patients have increased uncertainties with treat-
ment times >10 min due to fatigue, muscle relaxation, or
peristalsis.
Gated radiotherapy, with the beam triggered to be on only
during a predetermined phase of the respiratory cycle, usu-
ally refers to the use of an external surrogate for tumor posi-
tion (as opposed to direct tumor imaging) to gate the
radiation. This can be used to reduce the volume of normal
tissue irradiated. Changes in baseline organ position can
occur from day to day [56], and thus image guidance is
important to avoid geographic misses, especially in the set-
ting of SBRT. One concern regarding gated radiotherapy has
been brought to light by a French prospective phase III trial
presented at ASTRO 2012 [57]. This trial was testing the
benefit of gating in locally advanced lung cancer setting and
surprisingly demonstrated an increase in radiation pneumo-
nitis in patients treated with gating. The manuscript will
hopefully shed more light on other variables that led to this
paradoxical finding but more importantly should put caution
in inexperienced users of this technology.
Tumor tracking is another approach to reduce adverse
effects of organ motion. An elegant real-time tumor tracking
system consisting of fluoroscopic X-ray tubes in the treat-
ment room allowing visualization of radiopaque markers in
tumors was first described by Shirato et al. The linear accel-
erator is triggered to irradiate only when the marker is located
within the planned treatment region [58]. As an alternative to
turning the radiation beam off when the tumor moves outside
treatment region, multileaf collimators, the couch position,
or the entire accelerator on a robotic arm may move with the
tumor to ensure adequate tumor coverage at all times (e.g.,
CyberKnife image-guided radiosurgery system; Accuray,
Sunnyvale, CA). The latter system uses dual orthogonal fluo-
roscopy tubes to track radiopaque markers in or near the
tumor at a preset frequency.
There are advantages to gating, breath hold, and tracking in
exhalation phase of the respiratory breathing cycle versus
inhalation. These include the fact that exhalation tends to be
more reproducible and is longer than inhalation, so that treat-
ment during exhalation reduces duty time. However, in certain
183
situations, there may be rationale for breath hold, gating, or
tracking during inhalation. For example, for lung tumors and/
or tumors adjacent to the heart, inhalation will reduce the den-
sity of the lungs and/or may move critical structures away
from the target volume.
Other approaches to minimize respiratory and non-
respiratory organ motion include maintaining the same pre-
parative regimen prior to each treatment and ensuring
comfortable immobilization and short overall treatment time
to reduce patient movement due to discomfort and physiologic
change in organs such as stomach filling. Another general
intervention is patient feedback, either auditory or visual.
Ideally, feedback would be from direct tumor imaging; how-
ever, feedback from imaging of adjacent organs, spirometry,
nasal flow monitoring, external marker position, or optical
monitoring of body contour are often more practical options.
If indirect measures of organ position are used, confirmation
for an individual patient that the indirect measure is indeed
directly related to organ position is mandatory.
Treatment Planning
Overview
As dose gradients are steeper and doses are higher with
SBRT than with conventional radiation therapy, the conse-
quences of error in tumor delineation, errors introduced by
dosimetry, and geometric uncertainties may be more dele-
terious. Thus, all aspects of treatment planning that are
important in conformal radiation planning are even more
crucial in SBRT, especially for tumors in close proximity to
critical normal tissues, where a systematic error could lead
to permanent serious toxicity if the normal tissue planned
to be spared from radiation is irradiated to the high doses
planned for the tumor.
Imaging at Simulation
At the time of simulation, patient positioning and the imaging
modality (CT, MRI, PET/CT), resolution (e.g., CT thick-
ness), and phase of contrast (e.g., arterial IV contrast for HCC
or how to give IV contrast during a four-dimensional scan for
a tumor near a major vessel) must be chosen carefully. The
patient treatment position should be kept the same as scan-
ning position. Due to the relatively long treatment time, a
comfortable patient position is preferred to reduce the
intrafraction motion. Since more beams are used at SBRT
planning and they need to be separated maximally in space,
beam arrangement should be considered during patient simu-
lation. For example, for lung cancer patient, lifting both arms
allows beam arrangements in 360°. The report of AAPM Task
184
Group 101 [59] has recommendations about the CT thickness
and scanning length. In this report, 1–3-mm CT slice thick-
ness was recommended and a typical CT scan for planning
purpose should cover the tumor site plus 5–10 cm in both
superior and inferior directions. If non-coplanar beams are
used, 15 cm is recommended to be extended in both superior
and inferior directions. Motion must be considered at this
time, as breathing introduces artifacts in the tumor definition,
normal tissue definition, and resultant errors in TCP and nor-
mal tissue complication probability (NTCP). Furthermore, if
motion is not considered, there is potential for a systematic
error from the time of simulation to the time of treatment to
occur. Motion due to breathing is largest for tumors near the
diaphragm (i.e., the upper abdomen and the lower thorax).
One method to account for motion is to eliminate it, for exam-
ple, with a breath-hold scan. Diagnostic breath-hold scans are
often obtained in the inhale position, which may not corre-
spond with the treatment position (e.g., exhale breath hold).
An effort to conduct all imaging to be used for planning with
the patient in the same position, with the same phase of breath
hold, is required. If breath hold is not possible or if reproduc-
ibility of this breath hold cannot be documented, reduction of
breathing motion may help reduce the negative impact of
breathing motion. However, even with a small range of
breathing motion, errors in tumor and normal tissue volumes
may occur, resulting in a geographic miss or excessive toxic-
ity. An option to breath-hold imaging is to obtain a four-
dimensional imaging data set. From this, any position could
be used for planning and image guidance [56]. Planning on
the exhale data set with asymmetric PTV margins is an option
[60], as is planning using the mean tumor position. The phase
of the breathing cycle in which the patient is planned should
correspond with the phase of breathing cycle used for image
guidance and treatment.
Target Volumes
A decision has to be made regarding whether a margin is
required for microscopic disease risk or the clinical target
volume (CTV) margin. Although in many SBRT series, no
extra margin for CTV has purposely been added but due to
the less steep falloff in dose when treating the body as com-
pared to the brain, there is always a dose gradient from the
prescription dose to a “microscopic dose” [61]. In addition,
the additional margin added for motion and setup error likely
overlaps with the needed margin extension. This added mar-
gin may also be significantly different based on histology
where subclinical disease distant from the index lesion is
more prevalent such as in breast cancer. At Princess Margaret
Hospital in Toronto, for our present SBRT liver cancer stud-
ies, a 5-mm margin around the GTV within the liver is used
to define the CTV. The planned minimum dose to the CTV
PTV is 27 Gy in six fractions, while the dose to the GTV
S.J. Feigenberg et al.
may be as high as 60 Gy in six fractions at the periphery.
Careful radiologic–pathologic studies accounting for organ
deformation and shrinkage are required to determine whether
the use of a CTV margin is required or not.
Finally, appropriate PTV margins must be used to ensure
that the actual planned doses are delivered to the tumor. The
PTV margins must consider setup uncertainty and internal
organ motion. Individual institution setup uncertainty data
should be used if available. Individual patient internal organ
motion is preferable to using population-based respiratory
motion. Of note, the classic PTV margin papers on PTV mar-
gin determination, such as that published by Van Herk et al.
[62], do not apply to very tightly conformal plans delivered
in a few fractions, such as those used in most SBRT cases.
Thus, the margin recipes that are used for conventional radia-
tion planning may be inappropriate for SBRT plans.
Modeling has demonstrated that when PTV margins are too
small, higher doses must be delivered for the same TCP [63].
Planning
Often, many beams or dynamic conformal arcs are used to
develop a highly conformal SBRT dose distribution. In prin-
ciple, a great number of beams maximumly separated in
space lead to more conformal plan; however, the beam opti-
mization should consider target size and irregularities, OAR
avoidance, the length of beam path, the treatment delivery
time, and patient safety. The energy of 6–10 MV is preferred
due to the neutron contamination and the larger penumbra of
high-energy photon beam. Limited high-energy beam may
be allowed if the beam path is larger than 10 cm. Sometimes,
non-coplanar beams or arcs are used if required to reduce the
dose to normal tissues. For example, 8–12 beams may be
used for a typical lung SBRT plan. Non-coplanar beam setup
should be used carefully to avoid the patient, couch, and gan-
try collision. Although the more beams are preferred in
SBRT planning, the resultant longer treatment time has to be
considered in practice. One strategy to obtain highly steep
dose gradients at the edge of the PTV is to close the aperture
of the beams to the PTV or less, not leaving a gap for penum-
bra as usually done for conformal radiation therapy. When
enough beams are summed together, the PTV may be cov-
ered by a lower isodose such as 65 % that is often at the
steepest part of the dose gradient. Choosing such a low
prescription isodose line may have some theoretical disad-
vantages since a significant rind of normal tissue is in the
PTV. Investigators at Fox Chase Cancer Center and at the
University of Maryland use a 3-mm distance between
the beam aperture and the PTV [64]. The prescription iso-
dose line between 70 and 80 % is reasonable if the rind of nor-
mal tissue inside the PTV is small or can tolerate this high dose.
Resultant high doses/hot spots occur in the center of the
PTV, perhaps giving the highest dose to the center hypoxic
13 Stereotactic Body Radiation Therapy
volume (although the potential benefit of this is unproven).
Of note, the use of many beams for SBRT is not mandatory.
For a peripheral liver tumor, three to five beams may be used
to reduce the overall radiation path length through the liver.
The use of segments within the beams can adjust the dose
distribution to ensure that the hot spot is within the GTV
while reducing the overall integral dose.
As the adverse effects of dosimetric errors are most pro-
nounced with SBRT, appropriate methods to consider cor-
rections for heterogeneities should also be used (see next
section).
Typical prescription doses for SBRT range from 5 Gy in
ten fractions to 20 Gy in three fractions. One to five fractions
are most often used, with a dose per fraction usually greater
than 6 Gy. The common feature to most of the SBRT frac-
tionation schemes is that they are biologically potent.
Multiple-fraction regimens have some radiobiologic advan-
tages to single-fraction SBRT. Clinical data is not available
to provide guidance for the most appropriate fractionation
for each clinical scenario. However, when the PTV is in very
close proximity to normal tissues that function serially, it is
reasonable to consider prolonging fractionation to minimize
the risk of toxicity to the serial function normal tissue.
It is a challenge to relate the prescribed dose to TCP, as
inhomogeneous doses are generally used and various deliv-
ery and verification techniques are utilized. For a moving
target not treated with image guidance, the actual delivered
minimal dose to the tumor may be lower than the prescribed
dose. Furthermore, there is heterogeneity in patterns of pre-
scribing dose. One method to account for inhomogeneous
dose distributions is to use equivalent uniform dose (EUD) to
tumor for reporting [65]. Of course, accounting for individ-
ual patient motion in the dose distribution or eliminating
motion would help ensure that the reported doses better
reflect delivered doses as well. Unfortunately, it is not pos-
sible to account for motion in current commercially available
planning systems.
Plan Evaluations
All conventional 3D plan evaluation methods apply to SBRT
plan, but three criteria are specially considered: dose confor-
mality, dose gradient, and dose heterogeneity.
Since SBRT delivers high dose (often >5 Gy per fraction)
in a small number of fractions (≤5), high-dose conformality
is required to minimize the dose to the normal tissue. A fre-
quently used conformality index is defined as the ratio of
volume receiving prescription dose to the PTV. A perfect
plan should have conformality index equal to 1, i.e., PTV is
covered by 100 % of prescription dose and no normal tissue
receives the prescription dose or above. This is not realistic.
Usually the conformality index of 1.3 is achievable.
The index could be larger for smaller target or irregular tar-
get. In current or recently closed RTOG protocols of lung
SBRT [10], for the target with maximum dimension between
185
2 and 7 cm, the conformality index was required to be less
than 1.2, and the plan was considered as minor deviation
with index between 1.2 and 1.4 but there is no good data to
suggest complications are higher with a poor conformality
index. As with similar data with intracranial SRS, target vol-
ume and proximity to critical structures usually trump the
effect of conformality.
A sharp dose gradient out of PTV is desirable for SBRT
plans. The dose gradient can be evaluated by how much
%/mm or ratio of volume receiving 50 % of prescription
dose to the PTV that was used in RTOG protocols of lung
SBRT [10]. Usually a sharp dose-off isotropically is pre-
ferred although this can be limited to less degrees of freedom
with non-coplanar fields, but the dose gradient can be larger
in one direction if close to a critical structure.
The dose heterogeneity is probably not as important as
the above two parameters, although it needs attention. To
increase the plan conformality index and dose gradient usu-
ally increase the dose heterogeneity. The dose hot spot
should be within the PTV, and the best place is the center of
the PTV.
The dose constraints to critical organs are different with
what are used in the conventional therapy. So far the dose
tolerance is still immature and the dose to organ at risk
should be evaluated carefully according to the peer-reviewed
publications or protocols.
Treatment Planning System Considerations
Related to Heterogeneity Corrections
The dose calculation heterogeneity correction is desirable
for SBRT planning, especially for lung or spine SBRT. The
treatment planning system (TPS) should be carefully evalu-
ated to see if it is suitable for SBRT planning or specific site.
Pencil beam algorithms have been discouraged for tumor
sites surrounded by low-density tissue [59]. It has been
reported that there was significant dose difference in the tar-
get periphery between pencil beam algorithm and superposi-
tion convolution algorithm for the lung SBRT [59]. Although
the Monte Carlo simulation is the most accurate dose calcu-
lation algorithm, it may not be widely available for commer-
cial TPS and take more time for dose calculation. The
convolution superposition algorithm is more suitable consid-
ering the accuracy and calculation time is rather similar to
Monte Carlo-generated plans.
Early in the North American experience with lung cancer,
heterogeneity corrections were not used because tissue den-
sity correction dose algorithms were not widely available. In
the absence of heterogeneity corrections, tumors completely
surrounded by air experience a dose build-up effect due to
the loss of electronic equilibrium, such that the periphery of
a tumor is under-dosed, and a higher dose is required to
achieve optimal cell kill [66]. Tumors that lack this air–tissue
interface, such as tumors abutting the chest wall or central
tumors, may have artificially high doses (“hot spot”) delivered
186
to the PTV, due to dose being delivered through low-density
air using very long path lengths. Xiao et al. [67] applied het-
erogeneity corrections to the original treatment plans of 20
patients from RTOG 0236. They observed an increase in iso-
centric dose in all patients following the application of het-
erogeneity corrections. However, the mean volume of PTV
receiving 60 Gy decreased from 95 to 85 %, and dose to
95 % of the tumor decreased by an average of 4.7 Gy [67].
Based on these findings, the use of heterogeneity corrections
would be associated with larger hot spot doses but worsened
overall tumor coverage, potentially leading to increased
complications due to the high-dose areas and higher poten-
tial for failure due to underdosing parts of the tumor. This led
the investigators to conclude that the RTOG standard dose
should in fact be 18 Gy per fraction delivered to the 95 %
isodose, for a total dose of 54 Gy. Notably, these patients all
had peripherally located tumors.
Investigators at the University of Maryland repeated this
work on patients with peripherally and centrally located lung
tumors. This study shows that dose to the internal target vol-
ume (ITV) increases with the application of heterogeneity
corrections and the effect was even greater with centrally
located tumors and larger. In centrally located tumors, where
more lung parenchyma is located between tumor and body
surface, intervening tissue density is overestimated. When
this is corrected, dose to the tumor increases, an effect
observed in this study. This too is true of larger tumors, where
increased beam widths traverse more parenchyma prior to
reaching the PTV. Given the data above, the inclusion of cen-
tral tumors in this sample may in part explain why the appli-
cation of heterogeneity corrections led to an increase in D95
in this study, versus a drop in D95 as observed in the paper by
Xiao et al. [67], in which central tumors were excluded.
Without heterogeneity corrections applied to treatment
plans, a higher dose must be prescribed to achieve adequate
dose to the tumor, which also results in a higher dose to the sur-
rounding parenchyma. This increases the risk of adverse out-
comes, which may help to explain the increased complications
seen in the initial Indiana experience. Based on these results,
the use of heterogeneity corrections allows the prescription
of a lower total dose and dose per fraction, with a comparable
dose to the tumor. This less aggressive dose prescription may
allow safer yet equally efficacious treatment of NSCLCs.
Image Guidance
Overview
Image guidance at the time of treatment can improve setup
accuracy, reduce PTV margins, and irradiate the volume of
normal tissue, facilitating safe dose escalation.
Traditionally, surrogates for the target have been used in
guiding the placement of treatment fields. For example, skin
S.J. Feigenberg et al.
marks for patient position are routinely used for initial patient
setup in practice. For some clinical situations, the use of skin
marks to align the patient can be done with high precision.
However, in most body tumors, the internal structures cannot
be accurately localized with the use of skin marks. It has
been reported the random setup error is up to 6.6 mm for
pancreatic cancer patients receiving SBRT based only on
body marker. The use of bony anatomy with electronic portal
imaging is another standard practice in radiation therapy.
However, for many clinical situations, the bony anatomy is
not well correlated with the internal tumor position. Options
for locating internal anatomy include the use of implanted
radiopaque fiducial markers as surrogates for the target, tis-
sues adjacent to the tumor, or the tumor itself. Fiducial mark-
ers may also be used to measure organ motion and/or track/
gate the beam.
Many of the published reports of SBRT have been on
patients treated with conventional linear accelerators.
However, more specialized treatment units are now available
with the potential to allow soft tissue image guidance and
reduced PTV margins. Examples of such systems include a
lightweight and robotic linear accelerator (CyberKnife;
Accuray, Sunnyvale, CA) and modified linear accelerators to
allow image guidance including accelerators such as Novalis
(BrainLAB, Inc., Westchester, IL), Synergy (Elekta
Oncology, Stockholm, Sweden), TrueBeam and Trilogy
(Varian Medical Systems, Palo Alto, CA), Artiste (Siemens,
Concord, CA), and TomoTherapy (Madison, WI).
Image-Guidance Strategies (Pretreatment)
Imaging at the time of treatment can be used for localization
for guidance, verification, and also as a quality assurance
(QA) tool that is evaluated by the treating physician prior to
each treatment. Verification that the appropriate dose is actu-
ally delivered is also important for SBRT. Soft tissue imag-
ing at the time of treatment can allow a measurement of the
impact of geometric uncertainties (such as organ deforma-
tion) at the time of treatment. When image guidance and
repositioning are used, imaging after repositioning should be
used to ensure the positioning moves were made in the cor-
rect direction.
When repositioning moves are required due to changes in
internal organ position, replanning is not routinely con-
ducted. However, when substantial changes in organ position
and or tumor size or breathing pattern occur, the dose deliv-
ered may be altered due to changes in radiation path lengths
and position of organs with difference heterogeneities. The
magnitude of dosimetric differences due to such changes
should be studied to better define in which situations replan-
ning may be of benefit. In addition, when soft alignments are
utilized, the treating physician should also ensure the volume
visualized on the volumetric imaging is similar to the ITV
13 Stereotactic Body Radiation Therapy
generated on the 4D CT as differences may be related to
different breathing patterns from day to day and may not
improve alignments.
Two-Dimensional Image-Guidance Equipment
Orthogonal megavoltage (MV) portal films and more
recently images from electronic portal imaging devices
(EPIDs) have traditionally been used for image guidance and
may be appropriate for targets adherent to the bones. MV
images of large fields of view can be obtained with 2–8 mon-
itor units (MUs) per image. These images not only can guide
therapy but also can verify the shape and orientations of the
treatment fields. If radiopaque fiducial markers are inserted
in or near the tumor, the fiducial markers themselves may be
used for guidance. Other alternatives for guidance include
using surrogates that are in close proximity to the tumor, for
example, the diaphragm as a surrogate for liver tumors
[68, 69]. An example of an anterior–posterior (AP) MV
image for liver cancer guidance, in which the diaphragm is
used for cranial–caudal positioning.
Due to the low contrast of MV radiographs and the doses
delivered with repeat MV imaging, orthogonal kV radio-
graphs and kilovoltage (kV) fluoroscopy have also been used
for image guidance of tumors and/or fiducial markers, either
immediately prior to each radiation fraction [68, 69] or
throughout radiation delivery [58]; kV X-ray tubes may be
ceiling or wall mounted or attached to the linear accelerator.
With both MV and kV orthogonal imaging, alignment
tools registering the images to digitally reconstructed radio-
graphs (DRRs) can improve the accuracy and efficiency of
image matching to determine the offsets in position. Such
alignments tools include template matching tools based on
therapists’ visualization of anatomy and/or automated image
registration of the region of interest (e.g., mutual informa-
tion). Decision rules including tolerance levels for reposi-
tioning must be integrated with the overall system.
Three-Dimensional Volumetric Image
Guidance
Technological advances allowing volumetric imaging allow
image guidance immediately prior to treatment using the
tumor or a soft tissue organ in close proximity to the tumor
for guidance, rather than the bony anatomy. Advantages of
volumetric imaging systems include that adjacent normal
organs can also be visualized for more accurate avoidance of
critical structures. Some of these volumetric imaging tech-
niques can also measure tumor motion due to breathing.
Since the soft tissue can be visualized with three-
dimensional volumetric images, it is possible to set up the
patients based on the tumor target or organ at risk if which
187
has more priority during the treatment. The pitfall of this
strategy is that it may introduce the large setup uncertainty
for target which has respiratory-induced motion. Currently,
the CT scanner is fast enough to image the moving target on
one breathing phase. The CBCT is slow and the moving tar-
get is more similar to internal moving target (ITV) on CBCT
images. The in-room CT is actually a CT scanner and the
moving target similar to one breathing phase. If the patient is
aligned based on the target between planning CT and CBCT/
in-room CT, the perfect target match may introduce the
errors due to the difference in breathing phases between
planning CT and CBCT/in-room CT. The correct strategy is
to align the patient based on the bony structure and make
sure that the target acquired through CBCT/in-room CT is
within the PTV on the planning CT.
In-Room CT
The placement of a diagnostic CT scanner in the treatment
room with a known geometric relationship to the linear
accelerator is one approach for volumetric imaging imme-
diately prior to treatment with the patient in their immobi-
lization device. Uematsu et al. have used this approach to
treat liver and lung cancers with SBRT. Uematsu et al.
reported that with repeat CT for frameless head and neck
cancer radiotherapy, there was a geometric vector error
ranging from 0.1 to 0.9 mm [70]. Multiple manufacturers
have developed products of this type, including Siemens’
Primatrom, Mitsubishi’s accelerator in combination with a
General Electric CT scanner, and Varian’s ExaCT target-
ing system [71–73]. All systems place the CT scanner in
close proximity to the linear accelerator, allowing the
couch to be moved from the imaging position to the treat-
ment position. The CT scanner gantry is often translated
during acquisition to minimize couch motion. Accuracy
has been reported to be under 0.5 mm [72], and it has been
reported to be improved with fiducial markers from 0.7 to
0.4 mm [71].
Advantages of in-room CT include that state of the art,
diagnostic-quality CT can be used for optimal image qual-
ity and robustness. Disadvantages of this system are that
the imaging and treatment isocenters are not coincident.
Accuracy of motion from the CT scanner gantry, the
accelerator couch, and the coincidence of the CT and lin-
ear accelerator isocenters needs to be verified. Limiting
patient movement between imaging and treatment (e.g.,
couch retraction <1 mm) should improve setup accuracy;
however, organ motion between imaging and delivery
may occur.
KV Cone Beam CT
Jaffray et al. [74] first described the concept of cone beam CT
(CBCT) for image-guided radiation therapy in 1997. CBCT
refers to combined kV X-ray imaging and MV radiation deliv-
ery in one integrated gantry-mounted system. Advancements
188
Fig. 13.2 Planning CT and kV
cone beam CT from each lung
cancer SBRT fraction. GTV from
the planning CT scan is shown in
orange and PTV in green
in large-area flat panel detector technology facilitated
volumetric imaging to be acquired in a single rotation of the
linear accelerator gantry. Planar kV images projections are
obtained as the gantry rotates about the patient on the linear
accelerator table, over 30 s to 4 min. CBCT three-dimensional
volume reconstruction images may then be obtained for posi-
tion verification or for image guidance (see Fig. 13.2).
Geometric calibration methodologies for CBCT systems [75]
and quality assurance recommendations [74] have recently
been proposed.
Doses delivered to obtain CBCT scans typically range
from 0.5 to 2 cGy. Two vendors have developed kV CBCT
systems: Elekta Synergy and Varian Trilogy and TrueBeam.
In addition to providing volumetric imaging for verification
and guidance, these systems have the ability to be used for
real-time kV tracking; the latter application has not been
used clinically.
Similar to in-room CT, artifacts may occur with kV CBCT
reconstructions due to high Z structures such as surgical
clips, hip prostheses, and dental fillings. Methods to reduce
these artifacts have been developed.
S.J. Feigenberg et al.
MV Cone Beam CT
CT imaging using MV beams has also been explored for
more than 20 years [76, 77] and has also been made possible
with advances in portal imaging technology. Advantages of
MV cone beam CT are that the treatment MV beam is used
to obtain the imaging, requiring less modification to the lin-
ear accelerator; the electron density estimates for treatment
planning are accurate; and there is no high Z artifact that is
associated with kV imaging.
MV cone beam CT has been used to aid in lung cancer
SBRT, as described by Nakagawa et al. in 2000. MV CT-aided
lung SBRT was used for treatment of 22 lung tumors [78].
Pouliot et al. recently reported the feasibility of acquiring
low-exposure megavoltage CBCT. Phantom and pig cadaver
head and neck images were acquired using a linear accelera-
tor dose rate of 0.01–0.08 MU per image, for a set of 90–180
projections, acquired in 1–2° increments over 45–60 s. MV
cone beam CT scans were obtained with doses of approxi-
mately 5 cGy. Despite the low efficiency of this system, vis-
ibility of high-contrast structures, such as air and bone, was
reasonable [79].
13 Stereotactic Body Radiation Therapy
MV TomoTherapy
MV TomoTherapy combines tomographic scanning capabili-
ties, from a conventional CT detector, with a linear accelera-
tor mounted on a rotating gantry. Simpson described the
initial development of an MV CT scanner for radiation ther-
apy in 1982 [76]. More recently, the TomoTherapy treatment
platform has become available for image guidance and veri-
fication. The MV treatment beam is used to obtain imaging,
with a lower energy, 3.5 MV instead of 6 MV. Computer-
controlled multileaf collimators, also on the rotating gantry,
have two sets of leaves that open and close to modulate the
radiation beam while the couch advances the patient through
the gantry bore, for helical intensity-modulated radiation
therapy (IMRT).
Similar to MV cone beam CT, there are no high Z artifacts
with MV TomoTherapy.
Image-Guidance Strategies (During Treatment)
Real-Time Tumor Tracking
Real-time tumor tracking while the radiation beam is on is
another approach to reduce adverse effects of organ motion.
An elegant highly integrated tracking system consisting of
four ceiling-mounted fluoroscopic X-ray tubes and four
floor-mounted flat panel imagers in the treatment room
allowing visualization of radiopaque markers in tumors was
first described by Shirato et al. [58]. This system has a tem-
poral resolution of 30 frames per second and a precision of
1.5 mm. The linear accelerator is triggered to irradiate only
when the fiducial marker is located within a predefined vol-
ume. This system has been used for image-guided radiation
therapy of lung, liver, and paraspinal malignancies.
As an alternative to turning the radiation beam off when
the tumor moves outside the treatment region, multileaf col-
limators, the couch position, or the entire accelerator on a
robotic arm may move with the tumor to ensure adequate
tumor coverage (e.g., CyberKnife image-guided radiosurgery
system). The latter lightweight (330 lb) linear accelerator
mounted on a robotic arm uses 6 MV, 5- to 60-mm collima-
tors, and a dose rate of 300–400 MU per minute, combined
with dual orthogonal fluoroscopy tubes to track radiopaque
markers in or near the tumor at a preset frequency. When the
beam is on, infrared external surrogates are continuously
monitored, while the internal anatomy is monitored every
few seconds with kV imaging. The external surrogates are
used for determining the breathing model, and the model is
updated based on the X-ray data obtained every few seconds.
The robotic linear accelerator responds to motion by moving
to an appropriate position, within a range of ±10 mm x, y, z
and ±1° pitch and roll, ±3° yaw. This system was found to
have a 0.3-mm accuracy when tested in phantom studies.
189
Disadvantages of this system include the need for fiducial
markers, long potential delivery times (up to 90 min), lack of
suitability for large tumors with motion more than 10 mm,
and highly inhomogeneous dose distributions.
Another system (Novalis: BrainLAB, Heimstetten,
Germany) also acquires kV orthogonal images and matches
the images to DRRs obtained from the planning CT. The
imaging axes are not coincident with isocenter, and a transla-
tion of patient position is required between imaging and
treatment. Accuracy of this system has been reported to be
within 3 % and 3-mm distance to agreement.
Recently, wireless transponders and infrared cameras to
track tumors have also been proposed as an imageless local-
ization system (Calypso Medical Technologies, Seattle, WA).
SBRT Patient Safety
Since SBRT gives very high dose and uses much smaller
planning margin than conventional therapy, more caution
must be given to avoid catastrophic dose delivery. The patient
safety has got more and more attention in radiation therapy
society. Recently, the ASTRO SRS/SBRT white paper was
published to address SRS/SBRT quality and safety consider-
ations. This chapter presented the personnel requirement and
training for radiation oncologist, medical physicist, medical
dosimetrist, radiation therapist, and administrator; presented
the technology requirements of simulation, planning, and
localization; and addressed the SRS/SBRT system accep-
tance and commissioning.
The report of AAPM TG101 also has recommendations
for SBRT patient safety issue. It recommends that at least
one qualified medical physicist presents during first fraction
of SBRT treatment and the qualified medical physicist should
be available for the following fractions. It also recommends
that the radiation oncologist should approve the image guid-
ance before each fraction treatment. The therapist should be
well trained for the SBRT procedure.
Equipment Quality Assurance
The equipment of SBRT mainly include the linac system and
imaging system. The QA frequency is daily, monthly, and
annually. Usually the radiation therapist performs the daily
QA and the qualified physicist reviews and approves it, and
the qualified physicist performs the monthly and annual
QA. Apparently SBRT linac has tighter tolerance than the
linac only for conventional therapy. The report of AAPM
Task Group 142 [80] published recommendations for SRS/
SBRT linac QA. The main recommendations about accuracy
tolerance are summarized here. It recommends that the laser,
the couch movement indictor, collimator size indicator, col-
limator rotation isocenter, couch rotation isocenter, gantry
rotation isocenter, and coincidence of radiation and mechan-
ical isocenter have to be within 1 mm. The couch rotation
190
indictor has to be within 0.5°. The imaging system includes
kV/MV imaging and kV/MV cone beam CT. It recommends
that the imaging and treatment coordinate coincidence
should be within 1 mm. For cone beam CT, the geometric
distortion should be within 1 mm, and the contrast, spatial
resolution, HU constancy, uniformity, and noise should agree
with the baseline.
Clinical Outcomes
The next several sections will review the most common clini-
cal sites where SBRT/SABR is delivered most commonly
where pertinent issues related to patient selection, simula-
tion, treatment planning, and morbidity specific to that clini-
cal site. This data should be used with caution when
extrapolating to other locations (i.e., primary liver versus
metastatic liver since the background normal tissue is already
partially injured) but will be good starting point prior to
treating a unique site.
Stereotactic Ablative Radiotherapy for Lung
Tumors
Lung cancer is the second most common cancer diagnosis
and the most common cause of cancer death for both gen-
ders. In 2012, there was an estimated 226,160 new lung can-
cer diagnoses in the United States and 160,340 deaths [81].
Of the 15 % of patients diagnosed with early-stage lymph
node-negative NSCLC, the 5-year relative survival is only
52 %. The current standard of care for these patients is sur-
gery [82]. When a patient cannot tolerate or refuses surgery,
radiation therapy is an excellent alternative with current lit-
erature suggesting outcomes following SBRT/SABR similar
to surgery. For patients with severe comorbidities, it is
important to understand what the natural history of early-
stage disease is. Approximately 50 % of patients require
treatment for symptoms at 1 year and on average 50 % die of
lung cancer at 2 years without treatment [83].
Patient Selection
This approach is widely accepted as the current standard of
care for peripheral T1 or T2 tumors or certain T3 tumors
(i.e., invading the chest wall) which measure less than
5–7 cm without any nodal involvement. Central lesions may
have a higher complication rate in comparison to peripheral
tumors based on the initial phase II experience published out
of Indiana [8]. In their single institution experience, “exces-
sive toxicity” was reported for patients with tumors located
within 2 cm of the proximal respiratory tree where the rate of
grade 3 and above toxicity was significantly higher among
patients with central tumors. This increase in toxicity may be
S.J. Feigenberg et al.
related to dose and dose per fraction. Stephans et al. [84]
reported the experience at Cleveland Clinic, which clearly
illustrates the effects of the higher biologic effective dose
(BED) on morbidity. Their institutional practice of SBRT
initially used 10 Gy × 5 fractions and subsequently changed
to the RTOG standard (18–20 Gy × 3) when RTOG 0236’s
results were initially reported. The local control rates showed
no difference between the two schemas, although they did
experience a high rate of chest wall morbidity with the higher
BED regimen (18 % versus 4 %, p = 0.028). In addition, fol-
low-up from the initial Indiana experience treating central
tumors reported lower grade 3 and higher side effects when
>3 fractions were used as opposed to three fraction (26.3 %
versus 7.7 %) [85]. However, caution is still indicated.
Washington University [86] has completed a phase I study
demonstrating 60 Gy in five fractions is safe for treating cen-
tral tumors and is currently accruing to a phase II study.
Many retrospective series also suggest a five fraction is safe
in treating centrally located tumors [87]. In addition, a multi-
institutional phase I/II [88] RTOG study is currently nearing
completion using a similar fractionation schedule as the
Washington University. Led by Videtic et al. [88] from the
Cleveland Clinic, the RTOG has currently completed testing
two less aggressive schemas (12 Gy × 4 fractions and
34 Gy × 1 fraction) in a randomized phase II trial, specifically
looking at morbidity at 1 year as the primary end point as
local control is expected to be 90 % in both arms (RTOG
0813). The less aggressive regimen will then be compared to
the current RTOG standard which is a subsequent phase III
trial. There is no lower limit of lung function based on pul-
monary function tests that predicts poor outcomes [89]. One
clinical entity that may have a higher risk of pulmonary
injury is patients with interstitial pulmonary fibrosis. Onishi
et al. [90] described 24 patients who died of fatal pneumoni-
tis in the large multi-institutional experience. Seventeen of
the 24 patient had IPF with 1 of the patients with usual inter-
stitial pneumonia. The absolute risk of fatal pneumonitis for
this cohort of patients in Japan is not known, but from
Washington University described a 20 % risk of pneumonitis
in patients with IPF. So a diagnosis of IPF is not a contrain-
dication for SBRT but does appear to be at a higher risk of
pneumonitis.
Treatment Planning
During the CT simulation, 3-mm slice thickness or less is
preferred. IV contrast may be helpful for tumors close to the
brachial plexus or for central tumors adjacent to vasculature.
The gross tumor volume (GTV) is contoured on pulmonary
windows, although soft tissue windows are helpful for
tumors adjacent to the chest wall and central lesions.
Contouring all the spiculations on lung windows is contro-
versial and not uniformly performed. At the University of
Maryland, only the bulky component of the spiculation is
13 Stereotactic Body Radiation Therapy
contoured (2-mm thickness) based on unpublished literature
suggesting that it is uncommon that these radiographic find-
ings correlate with clinically significant disease and is cov-
ered with subclinical doses in the area of dose falloff [61].
There are institutional preferences regarding the use of a
margin for microscopic extension and creation of a CTV. In
RTOG 0236, it was specified that the GTV was equivalent to
the CTV. Assessment of respiratory motion and creation of
an ITV is preferred to limit the PTV margins similar to SRS
in the brain. The ITV can be assessed with a 4D CT scan or
with fluoroscopy to track the tumor or a fiducial implanted
into the tumor. A margin of 0.5 cm to create the PTV from
the ITV is common. If an ITV is not created, population-
based margins of 0.5 cm axially and 1.0 cm in the cranio-
caudal directions were used historically in the Indiana
experience and RTOG 0236. However, the use of
patient-specific tumor motion is preferred. This can be per-
formed by fusing maximum inspiration and expiration
breath-hold scans to a free breathing CT, obtain a “slow” CT
simulation, if 4D CT is not available. 4D CT has been dem-
onstrated to result in smaller PTV volumes than any of the
other described options [91]. If there is significant respira-
tory motion, some have advocated for managing this with
abdominal compression or breath-hold maneuvers. The ben-
efit of abdominal compression is likely to be greatest for
lower lobe tumors. However, abdominal compression may
increase tumor motion in some cases and should be consid-
ered on an individual basis and there are several studies
which demonstrate increased failure with the use of abdomi-
nal compression and gating [92]. At the University of
Maryland, a CTV margin of 3 mm is added based on the
unpublished work from Fox Chase Cancer Center which
evaluated 25 consecutive patients who underwent a lobec-
tomy or sublobar resection for a curative procedure for
tumors <3 cm in maximum dimension and also had a diag-
nostic CT scan for review. Based on a comparison of CT and
microscopic pathology review, the entire microscopic extent
of disease was covered when 3 mm was added to the maxi-
mum extent of the disease contoured on standard lung win-
dows without chasing the spiculations in 95 % of the cases.
An additional 3 mm was added for setup error based on
obtaining a daily CBCT prior to each treatment.
Interfraction setup variation is reduced with image-guided
radiotherapy (IGRT). This can be performed by matching fidu-
cial location, which is vital to technologies which do not use
volumetric IGRT, and/or creating a CBCT with the patient
immobilized. These pretreatment images are compared to the
simulation images and adjusted as appropriate. Fusion of the
CBCT with the simulation CT using bony anatomy is recom-
mended, as there is minimal change in the target centroid posi-
tion relative to the skeletal frame [93]. The differences in
patient position based on matching with bony anatomy versus
soft tissue can be off by upwards of 8 mm on average but this
191
is primary based on our medically inoperable patients who are
likely to have emphysema and poorly functioning diaphragms
[94]. Alignment using soft tissue can be performed if imaging
acquired on cone beam imaging is similar to that generated by
the 4D CT-based ITV. If the volumes do not match, then the
treating physician needs to consider that the patient’s breathing
pattern may be different from the day of the initial 4D CT. This
difference may not be reflected accurately on the CBCT and
alignment based on soft tissue may therefore be inaccurate
potentially leading to a geographic miss. In this situation, a
bony alignment is preferable and treatment can be delivered if
the volume is safely within the PTV on the CBCT. If it is out-
side the volume, a repeat 4D CT is preferred.
At the University of Maryland, consideration of the accu-
racy of cone beam imaging is considered to be 2 mm such
that a shift will be performed only if the shift is 3 mm or more
based on the work from Princess Margaret Hospital [95].
Fractionation
There are two predominant fractionation schedules used in
the United States: the Japanese approach (12 Gy × 4) [96]
and the original Indiana approach developed by Dr.
Timmerman (18–20 Gy × 3) [6, 8]. Outcomes and dose–
response will be discussed under clinical outcomes. In the
original Indiana series that led to RTOG 0236, dose is calcu-
lated without heterogeneity corrections. When these are
applied, the dose is on average 10 % lower for the subset of
patients treated on the study [22]. The prescription isodose
line covering the PTV is usually 60–90 % depending on the
block edge margin (2–3 mm, respectively) used on each
beam’s eye view. Typically a minimum of 7–9 non-coplanar,
non-opposing beams are required to obtain adequate dose
falloff to minimize risk of morbidity (see Fig. 13.3). Plans
are assessed by dose conformality similar to strategies uti-
lized in the brain where the primary goal is to devise the most
conformal plan to the PTV with the secondary goal to mini-
mize the volume receiving 50 % of the prescription dose.
The currently accruing RTOG protocols recommend that
95 % of the PTV be covered by the prescription isodose and
99 % of the PTV receives a minimum of 90 % of the pre-
scription dose. A prescription isodose to PTV volume (PITV)
ratio of 1.2 or less is recommended, except for tumors
smaller than 1.5 cm as this constraint is difficult to meet.
Additional RTOG recommendations are in place to limit tox-
icity to normal structures. This includes no more than 15 %
of the PTV volume of tissues outside the PTV receiving
more than 105 % of the prescription dose. The so-called
intermediate dose spillage is limited by imposing criteria on
the ratios of the 50 % prescription isodose volume to the
PTV volume and the maximal dose at 2 cm from the PTV,
which are dependent on PTV volume. This uniform dose
falloff may be important especially in the parenchyma of the
lung where subclinical disease may be present.
192
Fig. 13.3 SBRT dose distribution for lung cancer
Clinical Outcomes
SBRT/SABR has been most widely studied in primary and
metastatic lung cancer. A summary of clinical data is shown
in Tables 13.1 and 13.2 and some of the major studies are
discussed in greater detail below.
Initial reports from the Karolinska Institute and Japan,
who first reported the use of extracranial stereotactic radio-
therapy included patients with lung cancer and lung metasta-
ses. In 2004, Onishi et al. reported a large multi-institutional
experience from 13 institutions in Japan of nearly 250
patients that had a major impact on clinicians taking care of
lung cancer patients. Using a variety of techniques and frac-
tionation scheme, local control was found to be 86 % at 5
years when adequate dose was delivered as compared to
50 %. In addition, the side effect profile was remarkably low.
Onishi suggested that the dose–response was based on deliv-
ering a BED greater than 100 Gy [25, 97]. This fraction may
be inadequate for tumors >3 cm and for lung metastases
where investigators advocate 12 Gy × 5 or 18–20 Gy × 3
[98, 99]. A BED of greater than 100 was an important factor
for local control even for centrally treated lung tumors [100].
In a large pooled analysis from the Elekta consortium of over
S.J. Feigenberg et al.
500 patients, a BED of 105 or greater predicted was
confirmed to predict for an excellent local control with no
clear benefit from further dose escalation [99]. Regional
nodal failures and distant metastases are more common for
central tumors and tumors >3 cm.
The North American experience was pioneered by
Dr. Timmerman at Indiana University where a series of pro-
spective protocols were conducted which led to the develop-
ment of all of the RTOG SBRT trials. His initial phase I dose
escalation study included 37 medically inoperable patients
with Stage I NSCLCs (<7 cm). The dose was escalated from
24 Gy in three fractions in 2 Gy/fraction intervals to 60 Gy
and higher in three fractions. The maximum tolerated dose
was not reached and 87 % of patients had tumor response,
including 27 % with a complete response [6] and a dose–
response curve where a local control of >90 % was achieved
when 18 Gy or higher fraction was used. A phase II study
was conducted using 60 Gy in three fractions for T1 tumors
and 66 Gy in three fractions for T2. Local control at 2 years
was 95 % and overall survival was 54.7 % at 2 years. Toxicity
was significantly greater for those treated with central tumors
[8] and was subsequently excluded from RTOG 0236.
13 Stereotactic Body Radiation Therapy 193

Table 13.1 Selected results of primary non-small cell lung cancer treated with SABR
Median Regional Distant
Reference (year Patient population Total dose (no. follow-up Local control metastasis Overall
published) No. patients (all N0 M0) fractions) (months) control rate (%) rate (%) survival
Uematsu (2001) [23] 50 18 pts received 50–60 Gy (5–6) 36 94 % 96 14 66 % at 3
40–60 Gy prior to years
SABR
Wulf (2004) [30] 20 10 % T1 30–37.5 Gy (3) 11 95 % NR 25 32 % at 3
50 % T2 years
40 % T3
Nagata (2005) [19] 45 71 % T1 48 Gy (4) 30 98 % 93 20 At 3 years:
29 % T2 83 % for T1
and 72 %
for T2
Timmerman (2006) [20] 70 50 % T1 60 Gy (3) 17.5 95 % at 2 100 10 55 % at 2
50 % T2 years years
Yoon (2006) [34] 21 62 % T1 30–48 Gy (3–4) 13 86 % 100 5 51 % at 2
38 % T2 years
Onishi (2007) [24] [25] 257 Multi-institutional 18–75 Gy (1–22) 38 86 % 89 20 47 % at 5
review years
63 % T1
37 % T2
Hof (2007) [32] 42 40 % T1 19–30 Gy (1) 15 95 % at 1 95 31 65 % at 2
50 % T2 year; 68 % years
10 % T2 at 2 years
Fakiris (2009) [35] 70 49 % T1 60–66 Gy (3) 50 88 % at 3 91 13 43 % at 3
51 % T2 years years
Baumann (2009) [36] 57 70 % T1 45 Gy (3) 35 93 % 95 16 60 %
30 % T2
Timmerman (2010) [29] 55 80 % T1 60 Gy (3) 34 91 % 87 22 48 % at 3
20 % T2 years
Ricardi (2010) [37] 62 69 % T1 45 Gy (3) 28 88 % at 3 94 24 57 % at 3
31 % T2 years years
Bral (2011) [28] 40 65 % T1 Central: 45 Gy (3) 16 92 % 95 15 52 % at 2
35 % T2 Peripheral: 60 Gy (3) years
Staging is AJCC sixth edition
NR not reported

Timmerman et al. reported the multi-institutional phase II
experience including 55 medically inoperable, NSCLC
patients with T1 (80 %) and T2 (20 %) N0 M0 tumors less
than 5 cm treated to 60 Gy in three fractions. After a median
follow-up of 34 months, the tumor control rate was 97.6 %.
At 3 years, the involved lobe (local) control rate was 90.6 %,
the local regional control rate was 87.2 %, and the distant
metastasis rate was 22.1 %. Median survival was 4 years
[10]. This work has now led to subsequent studies at the
RTOG (0618 and 1014) which are now challenging surgery
as the standard of care for early-stage lung cancer.
Complications
Despite the majority of the patients on these studies being
medically inoperable with significant comorbidities, there
are relatively few grade 3–5 toxicities related to radiotherapy.
Normal tissue constraints used in RTOG 0618 and 0915 are
shown in Table 13.3, although these values are more conser-
vative than the constraints employed by the Japanese. Dose–
volume analyses confirming and disputing these values are
described below.
Pneumonitis is the dose-limiting complication after con-
ventional radiation therapy for lung cancer. It is a clinical
diagnosis of exclusion, consisting of cough, fever, pleuritic
pain, and dyspnea, with occasional respiratory failure and
general inflammation and can be extremely difficult to dif-
ferentiate between a COPD exacerbation, an atypical pneu-
monia, and a viral infection. Characteristic radiographic
findings are often present, typically in the distribution of the
radiation fields. A prolonged course of prednisone is the
typical treatment using 50–60 mg/day initially followed by a
slow taper. Based on the low incidence, arbitrary constraints
194 S.J. Feigenberg et al.

Table 13.2 Selected results of lung metastases treated with SABR

Reference (year No. patients Total dose (no. Median follow-up
published) (no. lesions) Patient population fractions) (months) Local control Overall survival
Wulf (2004) [30] 41 (51) Primary site: 30–37.5 Gy (3) 9 90 % 33 % at 2 years
45 % lung or 26 Gy (1)
10 % breast
8 % colorectal
8 % kidney
8 % sarcoma
Yoon (2006) [34] 53 (63) Primary site: 30–48 Gy (3–4) 14 82 % NR
26 % lung
23 % liver
19 % colorectal
8 % esophageal
Hof (2007) [38] 61 (71) Primary site: 12–30 Gy (1) 14 89 % at 1 year 65 % at 2 years
51 % lung
30 % other histologies
12 % colorectal
Milano (2008) [39] 121 (293) Primary site: Most 50 Gy (5) 41 67 % at 2 years 50 % at 2 years
32 % breast
26 % colorectal
Norihisa (2008) [40] 34 (43) Primary site: 48–60 Gy (4) 27 91 % (crude) 84 % at 2 years
44 % lung
26 % colorectal
Rusthoven (2009) [41] 38 (50) 1–3 lung mets, < 7 cm 48–60 Gy (3) 15 96 % at 2 years Median 19 months
Ricardi (2012) [42] 61; 74 % Primary site: 36–45 Gy (3–4) 20 89 % at 2 years 67 % at 2 years
single nodule 46 % lung 1 pt 26 Gy (1)
21 % colorectal
NR not reported

Table 13.3 SABR lung normal tissue maximal point dose constraints receive 11.6 Gy in four fractions and the maximum 1.0 L
for three and four fraction regimens based on RTOG 0618 and 0915, should receive 12.4 Gy. Barriger et al. [101] reported the
respectively
dose–volume analysis from the Indiana experience which
Three included 273 patients treated with SBRT. The overall grade 2
fractions Four fractions
(20 Gy × 3) (12 × 4 Gy)
and higher pneumonitis rate was seen in 9.4 % of their
Spinal cord 18 Gy (6 Gy 26 Gy (6.5 Gy
patients with the majority (7 %) graded as 2. The most
per fraction) per fraction) important predictor of grade 2 and higher pneumonitis was
Esophagus 27 Gy (9 Gy 30 Gy (7.5 Gy the mean lung dose (p = 0.02) and V20 (p = 0.03). When com-
per fraction) per fraction) paring the RTOG cut point in V20 of 10 %, the investigators
Brachial plexus 24 Gy (8 Gy 27.2 Gy (6.8 Gy found that 10 % did not predict an increase in side effects
per fraction) per fraction)
(p = 0.42), but when the median value of 4 % was used, this
Heart/pericardium 30 Gy (10 Gy 34 Gy (8.5 Gy
per fraction) per fraction)
increased the risk fourfold from 4 to 16 % (p = 0.03).
Trachea/ipsilateral 30 Gy (10 Gy 34.8 Gy (8.7 Gy Although their most recent update suggests a V20 cut point
bronchus per fraction) per fraction) of 6.5 % continues to have a very low risk of pneumonitis.
Skin 24 Gy (8 Gy 36 Gy (9 Gy per The majority of these patients were treated with a three-fraction
per fraction) fraction) approach. When using less aggressive schemas, no grade 3
or higher pulmonary events were reported by Nagata et al. in
treating patients with 48 Gy in four fractions [96]. Onishi
were developed. The RTOG used the percent of lung receiv- et al. reported a 5.4 % incidence of grade 2 and higher pneu-
ing 20-Gy total or more (V20) be less than 10 % in RTOG monitis with no grade 5 events [97, 102]. Other, potentially
0236 and 0618. RTOG 0915 which uses a less aggressive permanent pulmonary toxicities after SABR include bron-
regimen used absolute volumes as opposed to percentages of chial damage that can be associated with total obliteration
the total where more than 1.5 L of the lung volume should of the airway lumen and downstream atelectasis. Tracheal
13 Stereotactic Body Radiation Therapy
stricture and/or necrosis with subsequent lung collapse or
injury is another toxicity that is possible after highly potent
SABR to medial lung cancers is rare.
Chest wall pain and rib fracture have been reported in
7–15 % of SBRT/SABR patients. Taremi et al. created a
nomogram using age, female gender, and dose to 0.5 cc of
the ribs to estimate the risk of bone injury following
SABR. In this study, 0.5-cc ribs receiving 60 Gy was associ-
ated with a 50 % risk of fracture [95]. Dunlap et al. found
that the median interval to onset of severe chest wall pain
and/or fracture following lung SABR was 7 months and the
best correlate was the volume receiving 30 Gy. The authors
recommended limiting the chest wall volume receiving
30 Gy in 3–5 fractions to less than 30 cc, but they similarly
saw a high risk for the volume receiving >60 Gy suggesting
fractionation may play a critical role [103]. Stephans et al.
[104] reported the dose–volume analysis from Cleveland
Clinic for their patients who received 60 Gy in three frac-
tions without the use of heterogeneity corrections that the
most important predictors of chest wall pain in the volume of
chest all receiving 30 and 60 Gy should be kept below 25 and
3 cc, respectively. Welsh et al. [105] reported the MD
Anderson experience using a less aggressive schema (50 Gy
in four fractions) suggesting the volume receiving 30 Gy is
also the most important predictor of grade 2 and higher pain,
but the absolute volume cut point is higher (50–100 cc).
Brachial plexus and phrenic nerve injuries are extremely
rare. Indiana University experience described seven brachial
plexus injuries, of which four were grade 2, one grade 3, and
one grade 4. When the dose was greater than the median
dose (26 Gy over three fractions), the 2-year incidence of
brachial plexus injury was 46 % versus 8 % (p = 0.038) for
lower doses [85].
Stereotactic Radiotherapy for Metastatic
Tumors of the Spine
For information on stereotactic radiotherapy for metastatic
spinal tumors, please see Chap. 45.
SBRT/SABR for Liver Tumors
SABR can be used to treat tumors originating from the liver,
such as HCC and cholangiocarcinoma, as well as those that
have metastasized from a different organ. Liver tumors from
metastatic disease occur more frequently than primary liver
cancer, of which CRC is the most common [106]. In 2012,
there was an estimated 28,720 new cases of liver and intrahe-
patic biliary duct cancer in the United States with an esti-
mated 20,550 deaths. Although the 5-year relative survival
rate for patients with cancer of the liver and bile ducts has
195
tripled in the last several decades from 3 % in 1975–1977 to
15 % in 2001–2007 (p < 0.05), most patients will die of their
disease [81]. With approximately 748,300 new cases and
695,900 cancer deaths globally in 2008, primary liver tumors
were the second most frequent cause of cancer death in men
and the sixth in women [81]. The standard of care for HCC
is surgical resection. For patients with cirrhosis, resection
alone is problematic since the precipitating etiology is still
present and subsequently orthotopic liver transplant (OLT)
appears to have a superior outcome for select patients with
reported 10-year survival rates of >70 % as it resects the
tumor and corrects the underlying etiology [107, 108].
Unfortunately, only 30–40 % of HCC patients may be candi-
dates for OLT or surgical resection [109]. If untreated, median
survival from HCC is 6–12 months [110]. Similarly, select
patients with metastatic disease to the liver from CRC appear
to have better outcomes with complete surgical resection of
all liver disease. These patients have a 5-year survival of
30–40 % [111]. Unfortunately, only 10–20 % of patients are
resection candidates [112]. For individuals with unresected
CRC, liver metastases have median survivals of 10–17
months which can improve to 20 months with systemic ther-
apy [113–115]. For unresectable primary liver cancers, the
use of radiofrequency ablation (RFA), radioembolization
with yttrium-90 microspheres, cryotherapy, percutaneous
ethanol or acetic acid injection, laser-induced thermal ther-
apy, and high-intensity focused ultrasound have been studied
[110, 116, 117]. SABR offers a completely noninvasive
approach to treat primary and metastatic liver tumors not
amenable to resection.
Treatment Planning
Planning SABR for liver tumors is more difficult for several
reasons. IV contrast is vital for accurate tumor delineation
and timing of administration is vital. In addition, as these
tumors near the diaphragm and in nonsmokers commonly
motion tumor motion can be significant. Therefore, trying to
deliver contrast during a 4D CT can be extremely difficult to
get an accurate tumor delineation and an accurate estimate of
motion. As the liver has a dual blood supply, tumors can be
fed either from the portal system or from the hepatic artery
and depending on the tumor type tumor delineation can vary.
HCC is typically hypervascular and fed from the arterial sys-
tem and subsequently the arterial phase imaging with CT or
MRI is necessary for proper delineation as opposed to liver
metastases which are best visualized during the venous phase.
MRI or FDG-PET scans can be fused to the CT to improve
visualization of the tumor, which radiation oncologists define
as gross tumor volume (GTV) although accuracy of the
fusion is generally 1–2 mm. CT slice thicknesses of 2–4 mm
are recommended to balance lesion detection rate and image
noise [81]. On MRI, CRC liver metastases tend to be hypo-
vascular and HCC demonstrates tumor arterial enhancement
196
with “washout” and a delayed enhancing pseudocapsule,
restricted diffusion, and T2 hyperintensity [118]. A CTV is
created by adding margin to the GTV for microscopic tumor
extension. In a clinicopathologic correlative study in HCC
patients, CT and MRI correlated equally with resected tumor
specimens. The authors concluded that margins of 5 and
10 mm would have encompassed 93 % and 100 %, respec-
tively, of the cases [119]. For CRC metastases, microscopic
extension can be found 0.2–10 mm from the main tumor,
with 80 % within 3 mm and 90 % within 6 mm [120].
Liver motion is predominant in the superior–inferior (SI)
direction and can vary greatly among individuals and breath-
ing patterns. SI liver motion ranges from 0.5 to 3.7 cm [121–
123]. Average anterior–posterior (AP) and left–right (LR) liver
tumor motion has been reported to be 1.0 cm (range: 0.4–
2.2 cm) and 0.8 cm (range: 0.4–1.5 cm), respectively [124].
Liver tumor motion can be measured in several different ways
by using (1) cine MRI, (2) fluoroscopy, or preferably (3) 4D
CT scan. Fiducial placement is beneficial for several reasons
when treating below the diaphragm with the only drawback
being the rare, but real risk of tumor seeding along the inser-
tion track. Fiducials, if placed in or near the tumor, can act as
a surrogate for tumor location during the 4D CT scan or can be
checked by fluoroscopy. In addition, fiducials can significantly
improve image guidance. Even with volumetric IGRT, the lack
of contrast difference in the liver makes it nearly impossible to
visualize the tumor unless it is at the edge of the liver or near
the gall bladder. Finally, fiducial placement is the only way
tumor tracking could be performed adequately. By measuring
organ motion, an appropriate margin can be added to the CTV
to create an ITV. To reduce the size of the ITV margins,
abdominal compression has been utilized by some to reduce
diaphragmatic and liver motion. In a study by Heinzerling
et al., abdominal compression almost halved tumor motion
from 13.6 to 7.2 mm [125]. Notably, abdominal compression
can increase AP motion due to liver deformation [126, 127].
An alternative to abdominal compression, which may not be
tolerated by all patients, is tumor tracking or gating.
A PTV is created from the ITV to account for setup errors
between radiation treatments. Interfraction reproducibility is
improved by doing image-guided radiotherapy (IGRT) prior
to each treatment. This is performed by matching fiducial
location with kV imaging and/or creating a CBCT with the
patient immobilized. These pretreatment images are com-
pared to the simulation images and adjusted as appropriate,
reducing interfraction motion.
Clinical Outcomes and Patient Selection
Local control rates of SABR for liver tumors range from 65
to 100 % at 1 year. Table 13.4 summarizes recently published
articles for SABR of primary and metastatic liver tumors.
The small number of patients in these trials and variations in
eligibility criteria makes direct comparisons difficult.
Inclusion criteria ranged from only primary or metastatic
S.J. Feigenberg et al.
liver tumors to a combination of both. Two of these studies
incorporated patients treated with SABR to liver lesions and
other anatomic locations within the same report [128, 129].
Radiation dose may be based on estimates of toxicity risk
[24, 130]. Additionally, some of the HCC patients underwent
liver transplant after SABR [131, 132]. Child–Pugh (CP)
class B patients were sometimes permitted, while other stud-
ies restricted to only class A patients. None included patients
with CP class C. The fractionation schemes vary from a sin-
gle large fraction up to ten fractions.
The ideal patient for liver SBRT has no extrahepatic
disease with >700 cc of normal uninvolved liver, has ade-
quate liver function (CP B or better) and is located >1.5 cm
from a luminal gastrointestinal structure. The maximum
tumor size is less than 6 cm for a metastasis or less than
8 cm for a primary HCC. Vascular involvement is not a
contraindication. Absolute contraindications are patients
with extrahepatic disease, >8 % of the liver involved with
cancer, have a small liver (<500 cc), CP C, <0.5 cm from a
luminal gastrointestinal structure or a tumor that is greater
than 15 cm for a metastasis or greater than 20 cm for a
primary HCC [133, 134].
Wulf [135], Rule [136], and Chang [137] demonstrated
improvements in local control with dose escalation. A recent
pooled analysis by Chang et al. of 65 patients with 102 meta-
static CRC lesions treated to a median dose of 41.7 Gy in
six fractions demonstrated local control of 65 % at 1 year
and 55 % at 2 years. They estimated that doses of 46–52 Gy
in three fractions were needed to have 1-year local control
of more than 90 % [137]. In comparison to lung SBRT,
patients with metastatic disease to the liver appear to have
the highest control rates with the most aggressive regimens.
Rusthoven et al. [109] have demonstrated the best local
control using 60 delivered in three fractions where the local
control was 92 % at 2 years including 100 % for tumors less
than 3 cm. Wulf et al. demonstrated an improved response in
patients treated with “high dose” which was defined as
26 Gy in one fraction or 36 Gy in three fractions (n = 26)
versus “low dose” which was defined as 30 Gy in three frac-
tions or 27 Gy in four fractions (n = 25) [135]. In a similar
fashion Goodman et al. reported the single-fraction phase I
from Stanford where better local control was seen with
doses of 26 and 30 Gy as opposed to 18 and 22 Gy [138].
Rule et al. demonstrated greater than 90 % local control
when 50 or 60 Gy was delivered in five fractions as
opposed to lower doses based on their phase I experience
[136]. As for the patients with HCC, 90 % local control has
been more challenging due to the underlying liver disease
having a major impact on tolerance of dose escalation.
Lower doses have been associated with higher response
rates compared to metastases; finding the appropriate dose
for tumor control that will not precipitate liver toxicity is a
challenge for HCC, especially when underlying liver func-
tion is poor (e.g., Child–Pugh B or C).
 13
Table 13.4 Studies of SABR for liver lesions
Study (year No. pts Tumor size Dose (no. Median
published) (lesions) Pt population (range) fractions) follow-up (range) Local control OS Toxicity
Herfarth (2001) [33] 37 (60) Inc: Surgical intervention 1–3 lesions. Max 14–26 Gy (1) 5.7 months 71 % at 1 year 72 % at 1 year No statistically significant
56 mets, 4 not possible each lesion 6 cm (1–26.1) (actuarial) (actuarial) changes in liver enzymes
primary liver Median 10 cc
tumors (1–132 cc)
Schefter (2005) [34] 18 mets, 1–3 lesions, < 6 cm Median 36–60 Gy (3) NR NR NR No grade 3–5 toxicities
including 6 >700 mL normal aggregate GTV
CRC mets liver receive < 15 Gy 18 cc (3–98)
Choi (2006) [35] 20 HCC (20) Single lesion Mean 3.8 cm 50 Gy (5–10) 23 months 80 % 70 % at 1 year No grade 3–5 toxicities
CP Class A-B (2–6.5 cm) (3–55) 43 % at 2 years
Stereotactic Body Radiation Therapy

No extrahepatic
disease
Mendez Romero 25 (45) total HCC or metastatic Median 3.2 cm 30.0–37.5 Gy (3) if 12.9 months 94 % at 1 year 75 % One grade 5 liver–HCC,
(2006) [36] tumors, not eligible (0.5–7.2 cm) mets, HCC without (0.5–31) Child B
for other local cirrhosis, or HCC
treatment (RFA or <4 cm with
surgery) cirrhosis
15 (31) CRC 25 Gy/5 or 30 Gy/3 82 % at 2 years Two grade 3 liver—met
mets if HCC >4 cm and pts
8 (11) HCC cirrhosis For HCC, 75 % at 1 One grade 2 asthenia—
CP Class A-B and 2 years met pt
Wulf (2006) [37] 5 (5) primary Estimated life 14 cc primary Low-dose 15 months 92 % at 1 year 72 % at 1 year No grade 3 or higher
liver expectancy (max 516) group = 28–30 Gy (2–85) toxicities
>6 months (3–4)
39 (51) mets No more than 50 % 9 cc met (max High-dose 66 % at 2 years 32 % at 2 years
total functional liver 355) group = 12–12.5 Gy
receive > 5 Gy (3) or 26 Gy (1)
Not surgical
candidate
Extrahepatic disease
controlled or treated
Dawson (2006) [38] 79 total CP Class A; >800 cc Median 293 cc Median 36.6 (6) NR 74 % NR NR
33 HCC non-involved liver (2.9–3088 cc) Range: 24–57 Gy (95%CI = 61–83 %)
12 IHC
34 Mets
Hoyer (2006) [28] 65 total pts, of Inoperable CRC Max 6 cm 45 Gy (3) 4.3 years 86 % at 2 years 67 % at 1 year 1 death from liver failure
whom 44 mets, 1–6 lesions
treated to liver Included SBRT to 38 % at 2 years 1 colonic perforation; 2
non-liver sites duodenal ulcers
No chemo within 1 13 % at 5 years
month
(continued)
197
 198

Table 13.4 (continued)

Study (year Dose (no. Median follow-up
published) No. pts (lesions) Pt population Tumor size (range) fractions) (range) Local control OS Toxicity
Tse (2008) [29] 31 HCC CP Class A; Median = 173 cc Median 36 Gy (6) 17.6 months 65 % at 1 year Median = 13.4 months 7 pts (23 %) progressed to
unresectable; (9–1,913 mL) (10.8–39.2) Child–Pugh class B
extrahepatic disease
okay if bulk of
disease in liver
10 IHC More than 800 cc Range: 24–54 Gy [11.7 months (HCC),
uninvolved liver 15.0 month (IHC)]
Every other day 1 year OS = 48 %
Lee (2009) [30] 68 met pts, Unsuitable or Median = 75.2 cc Median 41.8 Gy 10.8 months 71 % at 1 year Median = 17.6 months 7 grade 3–4 acute
including 40 refractory to (1.2–3,090 mL) (6) toxicities
CRC standard treatment
Life expectancy > 3 Range: 27.7–60 Gy 63 % 1 year for CRC 1 grade 5 late toxicity
months (6) mets (malignant bowel
>800 mL uninvolved 47 % at 18 months obstruction); 1 grade 4
liver (all histologies) late toxicity (small bowel
CP Class A obstruction)
Rusthoven (2009) 47 (63) mets, 1–3 lesions Max 6 cm 36–60 Gy 16 months 95 % at 1 year Median 20.5 months 1 grade 3 toxicity (skin/
[39] including 15 Extrahepatic disease Median 2.7 cm (6–54) 92 % at 2 years 30 % at 2 years soft tissue)
CRC pts permitted if treatable (0.4–5.8)
Cardenes (2010) 17 HCC (25) 1–3 lesions Cumulative 36–48 Gy (3); later 24 months 100 % at 1 year 58 % at 1 year and 2 2 pts radiation-induced
[31] diameter 6 cm or 40 Gy (5) for CTP B (10–42 months) years liver disease (RILD)
CP Class A or B; not less; median 1–2 fractions per
resection candidates; vol = 34 cc week
no progressive or (8–95)
untreated gross
extrahepatic disease
Goodman (2010) 26 (40) total 1–5 lesions Max 5 cm 18–30 Gy (1) 17 months 77 % at 1 year Median 28.6 months No acute or late grade 3
[40] Inc: 6 CRC Life expectancy > 6 (2–55) 64.3 % at 1 year. or higher toxicities
mets, 5 IHC, 2 months 50.4 % at 2 years
recurrent CP Class A
HCC Unresectable or
pt-refused resection
Seo 2010 [41] 38 Inoperable; all <10 cm 33–57 Gy (3–4) 79 % 68 % Gr 3 skin (1)
received TACE prior 2 years LC = 66 % 2 years = 25 %
to SBRT <42 Gy versus 81 %
>42 Gy
S.J. Feigenberg et al.
 13

Andolino (2011) 60 HCC Liver-only disease Median 3.2 cm CTP A: median 27 months 90 % at 2 years 67 % at 2 years No grade 3 or higher
[32] 44 Gy (3) non-heme toxicities
36 CTP A CTP B: median Median TTP For transplant pts, OS 20 % progressed CTP
24 CTP B 40 Gy (5) 47.8 months 96 % at 2 years class within 3 months
Rule (2011) [42] 27 (36), 1–5 liver mets Median 2.5 cm Dose escalation 20 month (4–53) 56 % for 30 Gy, 50 % for 30 Gy, 67 % No grade 4–5 toxicities
almost half cohorts: 89 % for 50 Gy, for 50 Gy, and 56 %
CRC >700 mL liver Range: 30 Gy (3) 100 % for 60 Gy at for 60 Gy at 2 years 1 pt in 50 Gy cohort had
receiving <21 Gy 0.4–7.8 cm 50 Gy (5) 2 years grade 3 liver function
60 Gy (5) tests
Bae (2012) [27] 41 (50) CRC 1–4 lesions included Max 7 cm Median 48 Gy (3) 28 months 64 % at 3 years 60 % at 3 years 3 grade 3–4 toxicities (of
mets, of CRC mets to (6–65) whom only 1 treated with
whom 11 (15) non-liver sites SBRT to liver)
treated to liver Radical resection of Median 13 mL Range: 45–60 Gy 57 % at 5 years 38 % at 5 years
Stereotactic Body Radiation Therapy

primary, inoperable, sum of (3)

or not amenable to individual GTVs
another local (2–123)
treatment
199
200
Complications
The use of radiotherapy to the liver has been limited in the
past due to radiation-induced liver disease (RILD). The exact
mechanism is unknown although it postulated that endothe-
lial injury or activation of hepatic stellate cells yields fibrin
and collagen deposition, resulting in fibrous veno-occlusive
disease [139, 140]. Hepatitis B virus status is an independent
predictor of RILD development [141] and is therefore antici-
pated to be a greater factor in HCC patients than those with
metastatic disease to the liver.
Clinically, RILD usually develops 2 weeks to 4 months fol-
lowing radiation to the liver, although it has been reported as
late as 7 months after radiotherapy. The aspartate transami-
nase (AST) and alanine transaminase (ALT) levels are moder-
ately elevated with minimal or no increase in bilirubin, but
there is an increase of alkaline phophatase to 3–10 times the
upper limit of normal. In severe cases, anicteric ascites and
hepatomegaly develop. It is usually self-limited and is man-
aged conservatively with medical management, though
10–20 % of patients may die from liver failure, particularly in
patients with preexisting hepatic dysfunction such as cirrhosis
[142]. In 1991, Emami et al. estimated normal tissue toler-
ances to radiotherapy based on pooled patient data. The 5 %
(TD 5) and 50 % (TD 50) probability of liver failure within 5
years were estimated based on liver volume. In conventional
fractionation, the TD5 at 5 years for 1/3, 2/3, and whole liver
was estimated to be 50, 35, and 30 Gy, respectively. At 5 years,
the TD 50 for 1/3, 2/3, and whole liver was estimated to be 55,
45, and 40 Gy, respectively [143]. More recent studies using
different modeling systems have demonstrated that the radia-
tion tolerance of the liver was higher than previously thought.
A median dose of 60.75 Gy delivered in twice-daily fractions
of 1.5 Gy resulted in 12 %, 9 %, and 1 patient (<1 %) develop-
ing grade 3, 4, and 5 toxicities, respectively [144]. Using the
Lyman NTCP model, there was an estimated 4 % increased
risk of RILD per 1-Gy mean liver dose above 30 Gy [69]. As
demonstrated by Dawson et al., the risk of liver injury is
related to whether the patient had primary or metastatic liver
tumors. The TD 50 for whole liver irradiation was 45.8 Gy for
liver metastases versus 39.8 Gy for primary liver tumors [69].
Although this may not be relevant in the patients undergoing
extreme hypofractionated regimens as used in SBRT.
Several prospective protocols have been reported and in
general have been minimal for patients with metastatic disease
as opposed to those with primary disease related to the under-
lying liver dysfunction. Rusthoven et al. [109], which reported
the best outcomes, utilized a three-fraction approach. Patients
included in their study include patients with 1–3 metastases
with the largest tumor <6 cm. Their most important dosimetric
parameter was based on the surgical literature and required the
volume of normal liver receiving less than 15 Gy to be at least
700 cc. Following these parameters, no dose-limiting side
effects were seen. Rule et al. [136] used a similar parameter
S.J. Feigenberg et al.
keeping the volume of normal liver receiving less than from x
Gy to be at least 700 cc, increasing the dose from 15 to 21 Gy
based on delivering five fractions as opposed to three.
Similarly, Rule et al. did not observe dose-limiting toxicity.
Cardenes et al. [131] reported a multi-institutional phase I
experience for patients with primary HCC. They included
patients with 1–3 tumors with a cumulative tumor size of 6 cm
with Child–Pugh scores of A or B. The starting dose was 36 Gy
in three fractions with planned escalations of 2 Gy per fraction
increments. The dose was escalated to 48 Gy in three fractions
without a dose-limiting toxicity for patients with a Child–Pugh
score of A. Two with Child–Pugh score B developed grade 3
hepatic toxicity at 14 Gy per fraction and the protocol was
amended to a five-fraction approach to 40 Gy which has been
tolerable. Mendez Romero et al. [120] described an 18 % inci-
dence of RILD although the patient population was very small.
The largest experience reported is from Princess Margaret
Hospital which utilized a six-fraction schema and included the
largest tumors as well. In their series, no patient developed
RILD but they exclude patients with Child–Pugh score B. They
did have 5 of 31 patients develop worsening of their Child–
Pugh score although 3 of the patients had progressive HCC
and had Child–Pugh score A6.
Other potential toxicities include hematologic, fatigue,
and nausea that can occur shortly after radiation treatment.
The greatest potential late toxicity other than liver is that of
the luminal GI organs, which include ulceration, bleeding,
and obstruction [24, 129]. Using a maximum dose of 37 Gy
in three fractions and 42 Gy in five fractions with additional
criteria based on volume of the GI organ at risk, there were
no grade 3 or higher acute toxicities and approximately 11 %
of patients developed late grade 3 toxicities. One patient died
of complications from duodenal perforation 11 months fol-
lowing SABR. Normal tissue constraints used in a Princess
Margaret six-fraction phase I study are shown in Table 13.5.
Pancreatic Cancer: The Rationale for SBRT
Pancreatic ductal adenocarcinoma (PDAC) is the fourth
leading cause of cancer-related death in the United States.
Table 13.5 SBRT liver study normal tissue permitted tolerances, in
six fractions for HCC [38]
Liver Iso-NTCP model, based on effective liver volume
irradiated (for <10 % risk, suggest mean liver
dose <16 Gy)
Esophagus Maximum dose (to 0.5 cc) <30 Gy
Stomach Maximum dose (to 0.5 cc) <30 Gy
Duodenum Maximum dose (to 0.5 cc) <30 Gy
Large bowel Maximum dose (to 0.5 cc) <34 Gy
Kidney D67% <15 Gy
Spinal cord Maximum dose <25 Gy
13 Stereotactic Body Radiation Therapy
Due to the lack of an early detection method, only
15–20 % of patients can undergo curative resection at the
time of diagnosis [81]. Among resectable patients who
receive postoperative radiotherapy, the median OS is
approximately 20 months but these patients do not reflect
the 25 % of patients with resectable disease who have
radiographically occult metastases and do not undergo
resection [145, 146]. For patients with resectable PDAC
who receive neoadjuvant therapy and do not undergo lap-
aroscopy prior to therapy, a median OS of 12–23 months
could be expected [147, 148]. Unfortunately, even in the
initially resectable population and despite curative sur-
gery followed by adjuvant chemotherapy and/or chemora-
diation, the risk of local and distant recurrence remains
high at 37 % and 75 %, respectively, and tumor recurrence
typically within 12 months after surgery [145, 146]. This
suggests the presence of disseminated cancer cells at the
time of surgery. For this reason, the role of conventionally
fractionated radiation therapy in addition to systemic che-
motherapy alone has been questioned due to the predomi-
nance of distant failures. Recently, improved systemic
options have been developed which may again alter the
patterns of failure such that local therapy may become
more important again.
Early Experience in Pancreas
While the experience with SBRT for pancreatic malignan-
cies is less than other sites, the rationale for using SBRT in
PDAC is quite similar to that in early lung cancer. The ben-
efits of hypofractionated RT allow for greater tumor kill due
to radiobiologic superiority and allow for less interruption
with more effective systemic chemotherapy regimens. Since
hypofractionated courses of therapy can be delivered in 1–5
treatments, generally in less than 1 week. This can make it
easy to incorporate into systemic therapy optimizing local
control without interfering with distant disease control since
systemic therapy will not need to be altered as in more con-
ventionally fractionated radiotherapy. Given its location, sur-
rounded by extremely radiosensitive critical structures such
as the small bowel, stomach, and liver, SBRT for PDAC rep-
resents a unique challenge. The small bowel has been known
to be susceptible to radiation-induced necrosis, bleeding, and
stenosis with conventional fractionation doses above 50 Gy
and the additional biologically equivalent dose can pose a
significant threat to the integrity of these critical structures.
In addition, accounting for pancreatic motion often results in
large ITV margins that may result in large volumes of small
bowel being treated.
Compared to the available clinical data with SBRT for
malignancies of the lung and liver, only a few prospective
studies have been published for PDAC similar to litera-
ture a decade ago for lung cancer [129, 149–151]. Similar
to the early experience in lung cancer, a wide range of
201
doses and treatment delivery tools have been used with
common result, very encouraging local control. In the
absence of prospective studies, single institutional expe-
riences have played a major role in our understanding of
the role for SBRT in pancreatic cancer. These can be
divided into experiences in the palliative setting, where
most of the prevalent data exists, and those in the neoad-
juvant setting.
Experience with SBRT as a Definitive (Including
Palliative) Treatment
The initial reports with the use of SBRT in pancreatic cancer
came from Koong and colleagues [149]. In a single institu-
tion phase I dose escalation study from Stanford University,
15 patients with locally advanced pancreatic cancer and
ECOG performance status ≤2 were treated with a single
dose of 15 (3 patients), 20 (5 patients), or 25 Gy (7 patients)
to the primary tumor alone with no specific targeting of the
elective lymph nodes. Treatment planning was performed on
thin-cut, contrast-enhanced CT images, and radiation was
delivered using the CyberKnife® system (Accuray Inc.,
Sunnyvale, CA). All patients had three to five fiducial mark-
ers implanted in the tumor to facilitate image guidance dur-
ing SBRT. Patients were treated with orthogonal X-rays prior
to treatment to ensure appropriate positioning of the fiducial
markers, with the pancreas immobilized in voluntary breath
hold. The treatment time ranged from 3 to 6 h. The proximal
duodenum was not allowed to receive more than 50 % of the
prescribed dose though the prescription isodose line was
variable from 64 to 85 %. Of the 15 treated patients, only 2
had received any prior RT as part of their therapy. Despite
treating patients with essentially advanced unresectable
tumors, 84 % local control was seen at 1 year with no acute
grade 3 or higher toxicity despite use of a very large single
dose [148]. In fact, local control in the patients receiving
25 Gy was 100 % (6 patients with imaging follow-up) though
they all failed distantly. Median survival for the entire group
of patients was 11 months. The most frequently seen adverse
events were grade 2 nausea, diarrhea, and abdominal pain in
5 patients. The same group subsequently performed a dose
escalation study using SBRT as a planned boost following
conventionally fractionated RT (1.8 Gy/fraction) to the pri-
mary and regional lymph nodes with 5-fluorouracil [151].
Based on the safety demonstrated in their phase I results, a
single dose of 25 Gy was administered for the boost dose to
the tumor alone [152]. Overall, the regimen was well toler-
ated with grade 3 acute GI toxicity noted in 2 patients who
subsequently went on to develop symptomatic duodenal
ulceration. Median survival was 33 weeks and median
progression-free survival was 17.5 weeks. All but one of the 16
enrolled patients were controlled locally; however, distant dis-
ease manifested in all of them eventually. Additionally from
the same group, Chang et al. [153] published a retrospective
202
experience of 77 patients treated with 25 Gy to the 95 % iso-
dose line covering the PTV. In this rather heterogeneous
group of patients (73 % unresectable, 5 % medically inoper-
able, 3 % marginally resectable, and 19 % metastatic),
median survival from date of diagnosis was 11.4 months.
Once again, grade 3 or higher acute toxicities were low with
only one patient experiencing a gastric ulcer. Late toxicities
(≥grade 3) included gastric ulceration in 3, duodenal stric-
ture in 1, and biliary stricture in 2 patients, respectively. Only
one patient experienced a grade 4 toxicity consisting of small
bowel perforation. Murphy et al. [154] reported dosimetric
parameters that predicted grade 2 and higher duodenal toxic-
ity which was seen in 11 % and 29 % of their patients at 6
and 12 months, respectively. Based on their data from deliv-
ering SBRT in a single fraction, the absolute volumes of the
duodenum receiving 10, 15, 20, and 25 Gy were all signifi-
cant predictors of increased toxicity. The absolute volumes
for each parameter were 16, 9.1, 3.3, and 0.21 cc, respec-
tively. In addition, when the maximum dose was >23 Gy, the
grade 2–4 duodenal toxicity rate was 45 % compared to
12 % when the dose was <23 Gy.
A recent retrospective publication of the University of
Pittsburgh experience by Rwigema and coworkers [155] also
suggests a relatively safe profile of SBRT for unresectable
pancreas. In their 71 patient experience of patients treated on
either the CyberKnife or the Trilogy linear accelerator system
(Varian Medical, Palo Alto, CA), patients received a single
fraction of between 18 and 25 Gy. Prescription was to the
80 % isodose shell when using the CyberKnife and to the 89 %
isodose shell when using the linear accelerator-based system.
Median survival for the entire group was 10.3 months, and
local failure was seen in 35 % of the patients. Dosimetric cor-
relatives suggested that local control was improved with doses
above 24 Gy being administered. Toxicity was once again low
with only 4 % of patients reporting ≥ grade 3 GI toxicity.
Mahadevan and coworkers [151] adopted a slightly less
aggressive approach using three fractions of SBRT sand-
wiched between cycles 3 and 4 of gemcitabine also using the
CyberKnife® platform. Local control was 85 % in their 47
patients with late grade 3 and higher toxicities related to
radiotherapy seen in only 9 %. For disease abutting a large
area of the duodenal loop, the prescribed dose was 24 Gy in
three fractions while disease with minimal contact in this
region was treated to 30 Gy in three fractions. PDAC with no
involvement of the duodenal c-loop was treated to 12 Gy in
three fractions for a total of 36 Gy on this study. Median
progression-free survival for these patients was 15 months
and the median overall survival was 20 months. In addition,
the sandwich approach with the initial systemic treatment
allowed patients with early metastases to be excluded similar
to the recommendations from the GERCOR study [156] and
thereby assuring local treatment only in appropriate patients.
These and several other reports have demonstrated that
S.J. Feigenberg et al.
SBRT for pancreas is associated with excellent local control,
with toxicity that seems similar when delivered with accu-
rate precision and careful planning.
Contrasting with the high level of safety and efficacy
from these reports, a prospective phase II trial [129] was con-
ducted in Denmark for patients with biopsy-proven adeno-
carcinomas of the pancreas that were N0 and less than 6 cm
in maximum dimension. They prescribed 45 Gy over three
fractions with the dose prescribed to the ICRU reference
point such that 95 % of the prescribed dose was delivered to
the CTV and 67 % of the prescribed dose was delivered to
the PTV. The CTV was defined as the GTV plus the sur-
rounding edema, while the PTV was defined as the CTV plus
5 mm in the axial direction and 1 cm in the cranial–caudal
direction. Motion management was controlled by two differ-
ent methods using abdominal compression or a “slow” CT
simulation. IGRT was performed using portal imaging. Their
findings were concerning, with patients having one or more
grade 2 side effects in 64 % of the patients by 2 weeks.
Despite the use of prophylactic ondansetron and pantopra-
zole for 4 weeks, acute toxicity at 14 days after therapy was
pronounced, with worsening of nausea and pain that
resolved in 8 of 12 patients 3 months after SBRT. Progression
to grade 2 or higher toxicity occurs in 79 % of patients and
the overall performance status is significantly deteriorating.
In addition some of the patients were lost to follow-up or
deteriorated quickly with only 14 of the original 22 patients
making it to 2 months after treatment and 4 patients with 6
months of follow-up. In 5 patients there was evidence of
severe mucositis (2), ulceration (2), and ulcus-perforation of
the stomach (1). The actuarial local failure rate was substan-
tially higher than other experiences at 43 %. In addition,
median survival and 1-year survival were also lower at
5.7 months and 5 %, respectively. There were differences in
their treatment approach that may explain the dismal out-
comes. Treatment was administered using a linear accelera-
tor-based approach using abdominal compression and a
stereotactic body frame, and was targeted to the primary
tumor and surrounding edema. The CTV (created by expand-
ing the tumor plus edema by 1 cm in the sup-inf direction
and 5 mm axially) was targeted to receive >95 % of the
prescribed dose while the PTV (including the motion com-
ponent) received at least 67 %. Therefore, these volumes
were significantly larger with parts of the duodenum and
stomach (included in the PTV) receiving up to 67 % of the
prescribed dose. Abdominal compression may cause patient
discomfort making longer treatments less reproducible
which can increase the likelihood of marginal failures that
could increase local failures and increase dose to critical
surrounding normal tissues inadvertently increasing side
effects. Also of note, the prospective nature of this trial man-
dated strict posttreatment biopsy protocols and may also
account for the larger percentage of patients identified with
13 Stereotactic Body Radiation Therapy
local failure when contrasted with those assessed by
imaging-based RECIST criteria in other studies. Therefore,
this dosing scheme and planning methodology may not be
safely deliverable to the upper abdomen. Although, most
investigators believe lower dose SBRT is more reasonable
for palliation.
Experience in the Borderline Resectable Setting
with a Goal to Achieve Resectability
More recently, Schellenberg et al. [152] from Stanford
reported two studies, using 3 weekly doses of full dose
(1,000 mg/m2) of gemcitabine (days 1, 8, 15) followed 2
weeks later by a single dose of 25 Gy administration to the
primary pancreas tumor on day 29. The first 16 patients
underwent SBRT using the CyberKnife platform with the
dose prescribed to the 95 % isodose shell. Subsequently,
patients went on to receive one further cycle of gemcitabine.
While none of the patients made it to resectability, all 16
enrolled patients were able to complete treatment, and 13/16
exhibited local control with minimal acute toxicity. Median
and 1-year overall survival were 11.4 months and 50 %,
respectively. Despite the initial minimal acute toxicity pro-
file, late toxicities included five grade 2, one grade 3, and one
grade 4 duodenal complications. Correlation of the toxicity
profile with treatment isodose lines did not seem to suggest
correlation of duodenal toxicity with a particular minimal
level of dose received. The second phase 2 study used the
sandwich approach once again using 25 Gy delivered follow-
ing 3 weekly doses of gemcitabine. However, treatment on
this study was delivered using a linear accelerator and 4D CT
and PET scan were used to delineate the target, and fiducials
were used to provide fluoroscopic target acquisition. A
9-beam arrangement was optimized to deliver dose to the
95 % isodose line. Median survival was 11.8 months and the
local failure rate was 5 %. Late grade 2 toxicity was seen in
20 % of the patients and late grade 3 toxicity was only seen
in 1 (5 %) patient. Subsequently, gemcitabine was adminis-
tered till disease progression. Overall, this regimen did sup-
port the limited use of SBRT in patients treated with
gemcitabine and allowed for a sandwich approach which
may be important as a strategy to address early treatment
with systemic therapy prior to local treatment.
An Italian phase I study by Polistina and coworkers [150]
treated 23 patients with a 10 Gy × 3 fractionation scheme
sandwiched between systemic dosing cycles of gemcitabine.
A complete (imaging based) response was seen in 9 % of
patients, along with a partial response in 61 % of patients and
no progression in 13 % of patients. Median survival was
10.6 months and no reported ≥grade 2 acute or late toxicities
were seen with local progression being seen in only 17 % of
patients. Furthermore, selected patients getting gemcitabine
and SBRT were still able to proceed to surgical resection, an
important observation when considering SBRT as a compo-
nent of future neoadjuvant strategies.
203
Future Directions
Recently, systemic therapy for pancreatic cancer has
improved significantly. Similar to breast cancer and lung
cancer, improving systemic control may have a major impact
on increasing local failures due to the predominant presence
of residual disease subsequently improved local control will
become vital. The PRODIGE 4/ACCORD 11 study by
Conroy and coworkers [157, 158] demonstrated a significant
improvement in median survival in metastatic PDAC increas-
ing from 6.9 to 10.5 months with 5-fluorouracil, leucovorin,
oxaliplatin, and irinotecan or FOLFIRINOX. This regimen is
now being investigated in all settings of this disease.
Investigators are currently testing the combination of this
regimen with SBRT to the involved disease.
Treatment Planning Considerations
The proximity of the pancreas to extremely radiosensitive
critical structures such as the duodenum, liver, kidneys, and
stomach, in addition to its association with respiratory and
peristaltic motion, presents a unique challenge in choosing
appropriate modalities for immobilization and for motion
accounting. In addition, it is often difficult to delineate the
tumor based on CT imaging. In the absence of well-endorsed
guidelines, a commonsense approach combining the experi-
ences of the currently available literature in this field suggests
that the use of multiphasic thin (ideally 2.5 mm) CT slices in
addition to a four-dimensional CT scan should be used at a
minimum. In experienced centers, the use of fiducial markers
can be an invaluable tool in daily setup verification or motion
tracking in the case of treatment with the CyberKnife. In all
cases, the use of oral contrast to delineate the stomach and
small bowel should be considered. In addition, intravenous
contrast should be used as long as renal function permits.
Conclusion
SBRT is an exciting new field of radiation oncology that brings
together many of the technological advancements that have
occurred recently in radiation oncology. SBRT is not specific
to one planning system or delivery method but requires utili-
zation of high-quality imaging for target definition, immobili-
zation, high-precision planning, and delivery and image
guidance. Using these technological advancements, potent
radiobiological doses can be delivered in convenient fraction-
ation schemes, generally ranging from one to five fractions.
Preliminary data suggest that SBRT can be delivered
safely with a high likelihood of local control and an accept-
able safety profile for most sites. Clinical outcomes are
expected to be improved even further if SBRT can be
combined with other treatments such as surgery and chemo-
therapy, and future research efforts should include determin-
ing optimal combinations of SBRT with other therapeutic
modalities.
204
The high doses and highly conformal SBRT plans are
more prone to error introduced by geometric or dosimetry
uncertainties. Such errors could lead to permanent and seri-
ous late normal tissue toxicity, and thus caution is required
when SBRT is used clinically. Serious late toxicities have
been reported after SBRT, including radiation-induced liver
injury and gastrointestinal bleeding. As we gain increased
experience with SBRT, the partial volume tolerances to
hypofractionated heterogeneous radiation delivered to nor-
mal tissues should be able to be better defined. Optimal frac-
tionations, methods of guidance, and clinical applications of
SBRT are not well established, and clinical trials continue to
be required in this field, especially in North America.
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 Part IV
Treatment of Disease Types
 Metastatic Brain Tumors
Edward W. Jung, John H. Suh, Samuel T. Chao,
Michael A. Vogelbaum, and Gene H. Barnett
Introduction
Brain metastases are a significant cause of morbidity and
mortality that affect 20–30 % of cancer patients [1]. The
incidence in the USA has been estimated to be 170,000—
200,000 cases per year [2]. Brain metastases most commonly
originate from tumors of the lung, breast, kidney, and mela-
noma. In some cases, the primary site is unknown. Melanoma
and lung cancer often present with multiple lesions, whereas
single lesions are more common with breast, colon, and renal
cell cancers. Malignancies which can present with hemor-
rhagic lesions include melanoma, choriocarcinoma, testicu-
lar, thyroid, and renal cell cancers.
A single brain metastasis is defined as one lesion in the
brain with at least one other region of extracranial metastasis
or uncontrolled primary, while a solitary brain metastasis is
defined as one brain metastasis without any evidence of
extracranial metastasis. An estimated 30–40 % of patients
present with a solitary lesion [3]. Multiple metastases are
defined as more than one intracranial lesion.
Despite improvements in imaging, surgical technique, and
radiation therapy, the prognosis for patients with brain metas-
tases remains poor. Historically, patients who receive no
treatment have a median survival of only 1 month. Those who
are treated with steroids survive a median of 2 months, and
those who undergo whole-brain radiation therapy (WBRT)
survive a median of 4–7 months after treatment [4–7].
Consequently, the development of brain metastasis is a feared
E.W. Jung, M.D. • J.H. Suh, M.D. (*) • S.T. Chao, M.D.
Department of Radiation Oncology, Cleveland Clinic Foundation,
Cleveland, OH, USA
e-mail: suhj@ccf.org
M.A. Vogelbaum, M.D., Ph.D. • G.H. Barnett, M.D., M.B.A.
Department of Neurosurgery, Cleveland Clinic Foundation,
Cleveland, OH, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_14, © Springer Science+Business Media New York 2015
14
complication in cancer patients, yet long-term survival is pos-
sible [8]. As such, decisions regarding treatment options for
brain metastases present therapeutic dilemmas for both physi-
cians and patients. This chapter reviews prognostic factors,
surgical results, WBRT, rationale for stereotactic radiosur-
gery (SRS), surgery compared with SRS, results of SRS with
and without WBRT, SRS to the surgical resection cavity, use
of radiation sensitizers and protectors, complications of SRS,
and future directions in treatment of brain metastases.
Prognostic Factors
Identifying factors that predict outcomes after treatment of
brain metastasis allows physicians to convey prognosis to
patients and helps streamline treatment decisions and expecta-
tions. The most commonly used prognostic scale for patients
with brain metastasis has been the Radiation Therapy
Oncology Group (RTOG) recursive partitioning analysis
(RPA) [9]. This scale divides patients into three classes based
on 1,200 consecutive patients enrolled in three RTOG trials
from 1979 to 1993. The vast majority of these patients had
unresectable and/or multiple metastases and received standard
doses of WBRT. The most important factors for predicting sur-
vival include extracranial metastases, patient age, Karnofsky
performance status, and control of primary tumor (Table 14.1).
A limitation of the RPA system is that it provides only three
prognostic groups and has little power to discriminate between
patients since most fall into one category (Group II).
A study from Lagerwaald and colleagues reviewed 1,292
patients with brain metastases [10]. In this Dutch study, lung
cancer was the most common primary disease (56 %). Median
survival was 3.4 months, and the 1-year and 2-year survivals
were 12 % and 4 %, respectively. The most important factors
affecting survival were treatment modality, performance status,
extracranial disease burden, and response to steroid treatment.
More recently, a prognostic scoring system was developed
specifically for patients undergoing stereotactic radiosurgery,
known as the score index for radiosurgery (SIR). This system
211
212 E.W. Jung et al.

Table 14.1 RTOG RPA classes for brain metastases Table 14.3 GPA scores for brain metastases
Factors Median survival (months) Graded prognostic assessment
Class I Age <65 and 7.1 Characteristic 0 0.5 1.0 Grade MS (mo)
KPS ≥70 and Age >60 50–59 <50 3.5–4 11.0
Controlled primary tumor KPS <70 70–80 90–100 3 6.9
and no extracranial metastases. # CNS mets >3 2–3 1 1.5–2.5 3.8
All 4 criteria have to be met. Extracranial mets Present – Absent 0–1 2.6
Class II All others not meeting criteria 4.2
From: Sperduto CM, Watanabe Y, Mullan J, Hood T, Dyste G, Watts C,
for class I and class III
et al. A validation study of a new prognostic index for patients with
Class III KPS <70 2.3 brain metastases: the Graded Prognostic Assessment. J Neurosurg.
RTOG Radiation Therapy Oncology Group, RPA recursive partitioning 2008 Dec;109 Suppl:87–9
analysis, KPS Karnofsky performance status
From Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T,
et al. Recursive partitioning analysis (RPA) of prognostic factors in three extracranial metastases, and number of brain metastases. For
Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int
melanoma and renal cell carcinoma, the significant prognos-
J Radiat Oncol Biol Phys. 1997;37(4):745-51; used with permission
tic factors are KPS and the number of brain metastases. For
breast and GI cancers, the KPS is the only prognostic factor.
Median survival by diagnosis is summarized in Table 14.4.
Table 14.2 Score index for radiosurgery in brain metastases (SIR) Breast cancer patients have the best overall survival based
Score on DS-GPA. This prompted a follow-up study to better strat-
Variable 0 1 2 ify these patients by analyzing a larger cohort [14]. Significant
Age (years) ≥60 51–59 ≤50 prognostic factors are Karnofsky performance status (KPS),
KPS ≤50 60–70 80–100 HER2, ER/PR status, and the interaction between ER/PR
Systemic disease status Progressive Stable disease or NED and HER2. The median survival time is 13.8 months.
disease partial remission Survival by GPA scores are as follows: 3.4 months for GPA
Lesions (n) ≥3 2 1 0–1.0, 7.7 months for 1.5–2.0, 15.1 months for 2.5–3.0, and
Largest lesion volume (cm3) >13 5–13 <5 25.3 months for 3.5–4.0. ER/PR positivity is a favorable
From: Lorenzoni J, Devriendt D, Massager N, David P, Ruíz S, prognostic factor, increasing median survival from 6.4 to
Vanderlinden B, et al. Radiosurgery for treatment of brain metastases:
9.7 months for HER2 negative patients and from 17.9 to
estimation of patient eligibility using three stratification systems. Int J
Radiat Oncol Biol Phys. 2004 Sep;60(1):218–24 20.7 months for HER2 positive patients.
KPS Karnofsky performance status, NED no evidence of disease/com- The DS-GPA will continue to evolve as larger cohorts of
plete clinical remission other tumor types are analyzed and our understanding of
disease-specific brain metastases is refined. Given the dispa-
takes into account five factors: age, KPS score, systemic dis- rate findings among different tumor types, diagnosis-specific
ease status, number of lesions, and largest lesion volume GPA provides a more accurate depiction of expected out-
(Table 14.2) [11]. The 0–10 point SIR scale is comparable to comes in patients by tumor type. It should be used to convey
RPA class in predicting outcome but needs to be validated in prognosis to patients and guide development of future clini-
larger studies. cal trials for patients with brain metastases.
The new and current RTOG standard for measuring prog-
nosis is the graded prognostic assessment [12]. This index is
based on 1,960 patients with data extracted from five con- Management of Brain Metastases
secutive RTOG brain metastases trials. The GPA is based on
four criteria: age, KPS score, number of brain metastases, WBRT
and the presence/absence of extracranial metastases. Each of
the four criteria is given a score of 0, 0.5, or 1.0, with the best Brain metastases originally were treated with whole-brain
prognosis in patients with a GPA score of 4.0 (Table 14.3). radiation therapy alone, which was first reported in the 1950s
As our understanding of brain metastases has evolved, it [15, 16]. Response to WBRT is best among patients with
has become increasingly important to distinguish prognosis small cell lung cancer, lymphoma, and germ cell tumors.
based on the primary tumor histopathology. A multi-institu- The RTOG conducted numerous trials from 1971 to 1993 to
tional analysis of 4,259 patients with newly diagnosed brain investigate various fractionation schemes and doses of
metastases from 11 institutions was performed to develop WBRT, which are listed in Table 14.5 [18–24]. In addition,
diagnosis-specific graded prognostic assessment (DS-GPA) the RTOG has investigated the use of hyperfractionation,
[13]. The significant prognostic factors vary by the type of radiation sensitizers such as bromodeoxyuridine, and radia-
primary cancer. For non-small cell lung cancer and small cell tion modifiers such as thalidomide [26] and found no
lung cancer, the significant factors are KPS, age, presence of improvement in overall survival. Based on these studies,
14 Metastatic Brain Tumors 213

Table 14.4 Diagnosis Specific Graded Prognostic Assessment (DS-GPA)

Median survival stratified by diagnosis and diagnosis-specific GPA score for patients with newly diagnosed brain metastases
DS-GPA
Diagnosis Survival in months 0–1.0 1.5–2.5 3.0 3.5–4.0 p (log-rank)
Non small cell lung cancer 7.00 (6.53–7.50) 3.02 (2.63–3.84) 6.53 (5.90–7.10) 11.33 (9.43–13.10) 14.78 (11.79–18.80) <0.0001
Small cell lung cancer 4.90 (4.30–6.20) 2.79 (2.04–3.12) 5.30 (4.63–6.83) 9.63 (7.50–14.95) 17.05 (6.10–27.43) <0.0001
Melanoma 6.74 (5.90–7.57) 3.38 (2.73–4.27) 4.70 (4.17–5.42) 8.77 (6.83–10.77) 13.23 (9.40–15.64) <0.0001
Renal cell carcinoma 9.63 (7.66–10.91) 3.27 (2.17–5.10) 7.29 (3.73–10.91) 11.27 (8.83–14.80) 14.77 (9.72–19.79) <0.0001
Breast cancer 11.93 (9.69–12.85) 6.11 (3.88–8.28) 9.37 (7.92–11.24) 16.89 (13.96–19.90) 18.74 (11.31–29.37) <0.0001
Gastrointestinal cancer 5.36 (4.30–6.30) 3.13 (2.40–4.57) 4.40 (3.37–6.53) 6.87 (5.03–11.63) 13.54 (9.92–27.12) <0.0001
Total 7.23 (6.90–7.60) 3.43 (3.02–3.84) 6.40 (5.78–6.90) 11.56 (10.47–12.78) 14.77 (12.85–17.05) <0.0001
Adapted from: Sperduto PW et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain
metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010;77(3):655–61
Data in parentheses are 95 % confidence intervals

Table 14.5 Prospective Radiation Therapy Oncology Group (RTOG) brain metastases studies (1971–1993)
Protocol (Reference) Year No. of patients Total dose/No. of fractions Median survival
RTOG 6901 [18] 1971–1973 233 30 Gy/10 Fx/2 weeks 21 Weeks
217 30 Gy/15 Fx/3 weeks 18 Weeks
233 40 Gy/15 Fx/3 weeks 18 Weeks
227 40 Gy/20 Fx/4 weeks 16 Weeks
RTOG 7361 [19] 1973–1976 447 20 Gy/5 Fx/1 week 15 Weeks
228 30 Gy/10 Fx/2 weeks 15 Weeks
227 40 Gy/15 Fx/3 weeks 18 Weeks
RTOG 6901 [20] 1971–1973 26 10 Gy/1 Fx/1 day 15 Weeks
RTOG 7361 [20] 1973–1976 33 12 Gy/2 Fx/2 days 13 Weeks
Ultra-Rapid
RTOG 7606 [21] 1976–1979 130 30 Gy/10 Fx/2 weeks 18 Weeks
Favorable pts. 125 50 Gy/20 Fx/4 weeks 17 Weeks
RTOG 8528 [10] 1986–1989 30 48 Gy/1.6 Gy bid 4.8 Months
53 54.5 Gy/1.6 Gy bid 5.4 Months
44 64 Gy/1.6 Gy bid 7.2 Months
36 70.4 Gy/1.6 Gy bid 8.2 Months
RTOG 9104 [22] 1991–1995 213 30 Gy/10 Fx 4.5 Months
216 54.4 Gy/1.6 bid 4.5 Months
RTOG 7916 [23] 1979–1983 193 30 Gy/10 Fx/2 weeks 4.5 Months
200 5 Gy/6 Fx/3 weeks 4.1 Months
Misonidazole 196 30 Gy/10 Fx + Miso 3.1 Months
190 5 Gy/6 Fx + Miso 3.9 Months
RTOG 8905 [24] 1989–1993 36 37.5 Gy/15 Fx/3 weeks 6.1 Months
BrdU 34 37.5 Gy/15 + BrdU 4.3 Months
Adapted from Sneed PK, Larson DA, Wara WM. Neurosurg Clin N Am 1996;7:505–515
Fx fraction, bid twice daily, Miso misonidazole, BrdU bromodeoxyuridine

30 Gy in 10 fractions became a popular fractionation scheme Surgery and WBRT

for patients with brain metastases. Although neurologic
symptoms improve in the majority of patients receiving
WBRT, local control is low, resulting in neurologic death in
25–54 % of patients [27].
Given the low local control rates associated with WBRT
alone, surgical removal of tumors—particularly for single or
symptomatic lesions—was explored in hopes of improving
local control and survival. Surgery can provide immediate
and effective palliation of symptomatic mass effect. Another
major advantage of surgery is establishing or confirming the
214 E.W. Jung et al.

Table 14.6 Phase III trials of WBRT vs. surgery + WBRT

WBRT dose(cGy)/No. MS KPS >70 CNS Local
Author Year Surgery of fractions/No. of weeks N (weeks) (weeks) death (%) control
Patchell [28] 1990 Yes 3600/12/2.5 weeks 25 40 38 29 80 %
No 3600/12/2.5 weeks 23 15 8 52 48 %
Noordijk [30] 1994 Yes 4000/20/2 weeks 32 43 33 35 N/A
No 4000/20/2 weeks 31 26 15 33 N/A
Mintz [29] 1996 Yes 3000/10/2 weeks 41 22 N/Aa 14 N/A
No 3000/10/2 weeks 43 25 N/Aa 28 N/A
WBRT whole brain radiation therapy, N number of patients, MS median survival, N/A not applicable
N/Aa, the mean proportion of days that the patients had KPS >70 was not different

diagnosis, especially for patients without primary tumor
pathologic diagnosis. Although one would expect the
probability to be low with advances in MR brain imaging, a
small percentage of patients undergoing surgical resection of
a presumed single brain metastasis seen on imaging may not
actually have a brain metastasis, for which adjuvant WBRT
would not be warranted. This percentage was as high as
11 % in the past [28].
Three randomized trials comparing WBRT alone vs. sur-
gery followed by WBRT for patients with single metastasis
have been completed and are summarized in Table 14.6 [28–
30]. These trials were based on the premise that improved
local control of a single brain metastasis would result in
improved survival. Patchell et al. demonstrated that surgery
and WBRT improved survival (40 vs. 15 weeks, p < 0.01),
local control (80 % vs. 48 %, p < 0.02), and functional inde-
pendence (38 vs. 8 weeks, p < 0.005) compared with biopsy
and WBRT [28]. This is the sentinel study that established a
clear advantage to surgically resecting a single lesion before
administering whole brain radiation therapy. Another study
by Noordijk included 63 patients with CT-confirmed single
metastasis who were randomized to surgery and WBRT vs.
WBRT alone [30]. Surgery and WBRT improved survival
and functional independence over WBRT alone (10 vs. 6
months (p = 0.04) and 7.5 vs. 3.5 months (p = 0.06), respec-
tively). Patients with active systemic disease, however, did
not benefit from surgery. The third trial by Mintz did not
demonstrate a survival benefit for patients undergoing sur-
gery (6.3 vs. 5.6 months, p = 0.24) [29]. This was most likely
a result of two factors: (1) the study consisted of a large per-
centage of patients with active systemic disease and (2)
patients with lower baseline KPS were included.
Due to the improved outcomes with surgical resection of
brain metastases, a second study by Patchell randomized
patients to surgery alone vs. surgery with WBRT to deter-
mine if adjuvant radiation therapy is necessary in the man-
agement of single brain metastasis [31]. In this phase III trial,
95 patients with a single metastasis status post gross total
resection were randomized to WBRT or no further treatment.
The primary endpoint was tumor recurrence in the brain
with secondary endpoints of survival, cause of death, and
functional independence. The addition of WBRT to surgery
decreased the chance for neurologic death (14 % vs. 44 %,
p = 0.003), decreased local recurrence (10 % vs. 46 %,
p < 0.01), and decreased tumor recurrence anywhere in the
brain (18 % vs. 70 %, p < 0.001). The majority of patients
(61 %) received WBRT at time of recurrence resulting in a
large crossover of the observation arm to WBRT. Survival
was not different, although the study’s endpoint was local
control and was not powered to demonstrate a survival
advantage [32]. This second Patchell study established the
value of adjuvant radiation therapy in management of a sin-
gle brain metastasis.
The type of surgical resection may also influence local
recurrence of brain metastases. A retrospective review of 570
patients from MD Anderson Cancer Center treated with sur-
gical resection alone demonstrated that piecemeal resection
predicts for higher local recurrence compared with en bloc
resection, with a hazard ratio of 1.7 (p = 0.03) [33]. Size was
also predictive, with tumor volume exceeding 9.7 cm3 having
a hazard ratio of 1.7 (p = 0.02) compared with smaller tumors.
Histologic subtype did not predict for local recurrence in this
cohort of patients.
Stereotactic Radiosurgery
Stereotactic radiosurgery is a technique that delivers a large
dose of ionizing radiation in a single or few fractions using
highly focused narrow beams to small intracranial targets
while sparing surrounding brain tissue [34]. Interest devel-
oped in using SRS rather than surgery to improve local con-
trol. Brain metastases have features that make them ideal
targets for SRS. They are usually spheroid in shape, located
in the gray-white junction, and have a maximum diameter of
less than 4 cm. Perhaps more importantly, brain metastases
are noninfiltrative, as opposed to primary gliomas. These
characteristics allow for accurate target delineation, plan-
ning, and treatment delivery. A single large fraction of radia-
tion appears to have an equal effect in all tumor types, even
14 Metastatic Brain Tumors
among radioresistant tumors such as renal cell carcinoma
and melanoma [35–38]. Ever since Sturm’s initial report of
12 lesions treated on a modified linear accelerator, a number
of papers have corroborated the benefit of SRS in newly
diagnosed and recurrent brain metastases [39].
The use of SRS alone or as an adjunct to whole brain
radiation therapy is based on the premise that improved local
control will reduce morbidity, improve quality of life, and
prolong survival. Nieder et al. reviewed the CT scans of 332
patients with brain metastases to evaluate local control and
time to local progression based on dose [40]. A biologically
effective dose (BED) using the linear quadratic model with
an alpha/beta of ten was derived for each patient. Partial
response rates significantly improved for patients with higher
BED suggesting that larger doses were needed to improve
local control.
Brain tolerance to radiation therapy is related to total
dose, dose per fraction, elapsed time of radiation delivery,
volume of normal brain irradiated, and the time interval from
prior radiation therapy [41]. From a radiobiological stand-
point, brain metastases are considered category IV targets,
which are targets with early-responding tissue surrounded by
late-responding normal tissue [42]. Since the tumor cells are
within the target, one would expect a high therapeutic index
for these targets given the steep dose gradient associated
with SRS. Unlike surgery, SRS also has the potential to ster-
ilize surrounding cells outside the high dose region.
Surgery vs. SRS
Based on the results of surgical resection for a single metas-
tasis, investigators explored the use of SRS for brain metas-
tases. This interest was based on potential advantages of
SRS, including outpatient delivery, no general anesthesia use
leading to shorter recovery time, minimal risk for bleeding or
infection, and lower cost. In addition, SRS is not limited by
location, number of lesions, comorbidity, or coagulopathy.
For these various reasons, SRS has become a viable alterna-
tive to surgery given the potential cost savings and quality-
of-life benefits [43, 44].
A multi-institutional retrospective review from the
University of Wisconsin, University of Florida, and Joint
Center for Radiation Therapy included 122 patients with a
newly diagnosed, potentially resectable single brain metasta-
sis treated by SRS with WBRT [45]. The local control rate
was 86 %. The median survival was 56 weeks with 25 % of
deaths related to brain tumor progression. Based on results
of this retrospective review, the investigators concluded that
SRS could be delivered in place of surgery.
Another study from M.D. Anderson Cancer Center com-
pared 13 patients treated with SRS and 62 patients treated by
surgery [46]. These patients were retrospectively matched for
215
important prognostic factors. The median survival was
7.5 month for the SRS group and 16.4 months for the surgery
group. The local recurrence for SRS was 21 % vs. 8 % for
surgery. They concluded surgery should be the preferred
treatment for surgically accessible lesions. However, careful
analysis of the SRS dosing strategy in this study indicates
that relatively low tumor margin doses were used, well below
the doses used in RTOG studies. A study from the Mayo
Clinic compared outcomes of radiosurgery vs. surgery and
found no difference in 1-year survival between the groups
[47]. This retrospective review included patients with tumors
who would have allowed for either type of treatment.
A retrospective study from Muacevic compared sur-
gery + WBRT vs. Gamma Knife radiosurgery (GKRS) alone
for patients with a single tumor ≤3.5 cm in diameter [48].
The 1-year survival rates (53 % vs. 43 %, p = 0.19), 1-year
local control rates (75 % vs. 83 %, p = 0.49), and 1-year neu-
rologic death rates (37 % vs. 39 %, p = 0.8) for the sur-
gery + WBRT group and SRS group, respectively, were not
statistically different.
Since all of the previously described studies are retro-
spective, patient selection bias was probably a key contribu-
tor to the mixed results and controversy regarding the benefits
of surgery vs. SRS. The Joint Center for Radiation Therapy
attempted to enroll patients onto a phase III trial comparing
surgery to SRS in the 1990s. After 3 years, only six patients
were enrolled due to patient or physician preference [49].
A prospective randomized trial from Germany compared
GKRS alone vs. surgery + WBRT for patients with a single
metastasis [50]. The study was closed early due to poor
accrual, with 33 patients in the surgery + WBRT arm and 31
patients in the GKRS alone arm. Overall survival, neurologic
death, and local recurrence were equivalent. Patients treated
with GKRS developed more distant recurrences (p = 0.04);
however, this difference was lost after adjusting for salvage
GKRS. GKRS patients had shorter hospital stay, less steroid
treatment, and lower CNS Grade 1 and 2 toxicities.
M.D. Anderson performed a prospective randomized trial
of surgery vs. radiosurgery for patients with a single brain
metastasis who are considered eligible for either treatment
[51]. Fifty-nine patients were entered into the randomized arm
(30 underwent surgery and 29 SRS), and 155 patients were
entered on the nonrandomized arm (89 chose surgery and 66
chose SRS). Although the results demonstrating increased
local recurrence with SRS alone have been presented in
abstract form, the statistical manipulations used in this study
are controversial and the results are yet to be published.
For patients with large resectable tumors or those without
histologic confirmation of a primary tumor, most clinicians
would agree that surgical resection should be considered
rather than radiosurgery. Surgical removal of the tumor is
more effective in alleviating mass effect, offers faster
improvement in neurologic function, and minimizes chronic
216
steroid therapy. Prolonged use of steroids can result in a
number of problems including diabetes, proximal muscle
weakness, peripheral edema, psychosis, susceptibility to
infections, and gastrointestinal perforation [52]. Conversely,
most would agree that small, deep lesions are best treated
with radiosurgery. To date, no randomized trial pitting radio-
surgery vs. surgery of comparable brain metastases has been
completed.
SRS for Recurrent Metastatic Disease
SRS for brain metastases was initially implemented in the
salvage setting. One of the first reports of SRS for brain
metastases consisted of patients with recurrent brain meta-
stases after WBRT or surgery. Loeffler et al. reported the
Joint Center for Radiation Therapy retrospective results of
18 patients with recurrent metastases after previous surgery,
WBRT, or both [53]. The majority of patients improved neu-
rologically after SRS with local control being achieved in all
patients. A follow-up report by Alexander et al. of patients
mostly with recurrent brain metastases reported tumor con-
trol rates of 85 % at 1 year and 65 % at 2 years, although the
control rates were lower for recurrent lesions [54]. Median
survival was 9 months after SRS in that study.
The University of Cincinnati reported the results of 84
patients with 1–6 lesions who developed recurrence after
WBRT [55]. Median survival was 43 weeks after
SRS. Median time to local failure was 35 weeks for all
lesions and 52 weeks for lesions treated with ≥18 Gy. A
study by Noël et al. of 54 consecutively treated patients
reported 1- and 2-year local control rates of 91.3 % and 84 %
and 1- and 2-year brain control rates of 65 % and 57 %,
respectively [56]. Cleveland Clinic published their experi-
ence of 111 patients who underwent initial WBRT followed
by SRS as salvage treatment [57]. The median overall sur-
vival from the initial diagnosis of brain metastasis was
17.7 months. Median survival after salvage SRS was
9.9 months. Median survival after salvage SRS was
12.3 months in patients who had their first recurrence
>6 months after WBRT vs. 6.8 months for those who devel-
oped disease recurrence ≤6 months after (p = 0.0061).
Primary site did not affect survival. Twenty-eight patients
(25 %) developed local recurrence after salvage SRS with a
median time of 5.2 months. A dose <22 Gy and lesion size
>2 cm were found to be predictive of local failure. In this
study, patients who recurred after WBRT and were treated
with salvage SRS were found to have good local control and
survival after SRS. WBRT provided good initial control, as
45 % of these patients failed >6 months after WBRT. Those
with a longer time to failure after WBRT had significantly
longer survival after SRS.
E.W. Jung et al.
Radiosurgery with WBRT
Based on the early results of SRS for recurrent brain metas-
tasis, SRS with whole brain radiation therapy was investi-
gated for newly diagnosed patients with the hypothesis that
the combination of WBRT with SRS would improve local
and regional control of brain metastases. A number of studies
have demonstrated high local control rates with the addition
of WBRT to SRS [54, 58–66]. These local control rates
ranged from 63 to 97 % with addition of WBRT vs. 42 to
87 % with SRS alone [36, 64, 66–68].
RTOG 9005 is an important phase I/II trial which deter-
mined the maximum tolerated radiosurgery dose for patients
with recurrent primary brain tumors or brain metastases
treated previously with fractionated radiation therapy [69]. In
this trial, 80 % of patients were treated on a linear accelerator
(LINAC) and 20 % were treated with Gamma Knife radiosur-
gery. The maximum tolerated doses were inversely corre-
lated with the maximum tumor diameter. The doses were
24 Gy for a tumor <20 mm in diameter, 18 Gy for 21–30 mm,
and 15 Gy for tumors 31–40 mm in diameter (Table 14.7). Of
note, investigators were reluctant to escalate the dose for
tumors <20 mm in diameter even though the maximum toler-
ated dose was not reached. The rates of radiation necrosis
were 5 %, 8 %, 9 %, and 11 % at 6, 12, 18, and 24 months
after SRS, respectively. Other factors that predicted for Grade
3–5 neurotoxicity were tumor dose and KPS. Table 14.8 lists
the RTOG CNS toxicity criteria used for RTOG 9005. The
study also reported on physics and quality control assess-
ments: MD/PD ratio, a measure of dose homogeneity, and
PIV/TV ratio, a measure of conformity of the treated volume
relative to target volume [70]. The results of RTOG 9005 are
the standard for determining dosing of SRS for brain metas-
Table 14.7 RTOG 9005 dosing guidelines for SRS
Size (mm) Dose to tumor periphery (Gy)
≤ 20 24
21–30 18
>30 15
Table 14.8 RTOG CNS toxicity criteria used for RTOG 9005 [76]
Grade 1 Mild neurologic symptoms; no medication required
Grade 2 Moderate neurologic symptoms; outpatient medication
required (e.g., steroids)
Grade 3 Severe neurologic symptoms; outpatient or inpatient
medication required
Grade 4 Life-threatening neurologic symptoms (e.g., uncontrolled
seizure, paralysis, coma); includes clinically and
radiographically suspected radiation necrosis and
histologically proven radiation necrosis at time of operation
Grade 5 Death
14 Metastatic Brain Tumors
tases based on size and have been incorporated into subse-
quent studies.
Shehata et al. evaluated the optimal SRS dose and influ-
ence of WBRT on tumor control among 160 patients with
468 recurrent and newly diagnosed metastases <2 cm in
diameter [66]. On multivariate analysis, the most important
factor for local tumor control was the addition of WBRT to
SRS (97 % vs. 87 % for SRS alone; p = 0.001). For patients
undergoing WBRT, doses >20 Gy resulted in higher Grade 3
and 4 neurotoxicity (5.9 % vs. 1.9 %) and did not result in
better local control. Thus, the authors recommended using
20 Gy for metastases <2 cm with combined WBRT.
The largest SRS dosing study is a single institution analy-
sis reported by Valery et al. on 377 patients with 760 lesions
treated with LINAC-based SRS. Seven patients had severe
complications including nine patients who developed radia-
tion necrosis. The median tumor volume was 4.9 cm3, and
median prescribed tumor dose was 15.6 Gy. The only factor
that influenced the risk for radiation necrosis was the confor-
mality index [71]. Age, KPS, homogeneity index, tumor vol-
ume, and delivered dose were not significant. This study
highlights the importance of achieving a highly conformal
plan for LINAC-based radiosurgery.
A multi-institutional retrospective study from ten institu-
tions analyzed outcomes for 502 patients with newly diag-
nosed brain metastases treated by SRS and WBRT. Patients
were stratified by RTOG RPA class [72]. For all RPA classes,
survival improved with the addition of SRS boost compared
with WBRT alone. Median survival for RTOG RPA class I,
II, and III were 16, 10, and 8 months for the SRS + WBRT
patients vs. 7.1, 4.2, and 2.3 months for the WBRT alone
patients, respectively. This study suggests a survival benefit
to the addition of SRS for all patients.
Three prospective trials compared the use of SRS + WBRT
vs. WBRT alone. The first trial from the University of
Pittsburgh enrolled 27 patients with two to four brain metas-
tases measuring <2.5 cm in maximum diameter [73]. The
study was stopped at an interim analysis at 60 % since a sig-
nificant difference in the 1-year local failure rate was noted
(8 % in the SRS + WBRT arm vs. 100 % in the WBRT arm).
The median time to local failure was 6 months for WBRT vs.
36 months for the SRS + WBRT arm. Median survival was
not significantly different for the SRS + WBRT vs. WBRT
arm (11 months vs. 7.5 months, respectively). The small
sample size, as well as possible selection and statistical bias,
may have affected the results.
Brown University enrolled 96 patients onto a 3-armed,
prospective randomized trial of Gamma Knife radiosurgery,
WBRT, or both [74]. Fifty-one patients underwent surgical
resection of large symptomatic lesions prior to randomiza-
tion, which was not evenly distributed among the treatment
arms. No difference in overall survival was noted among the
three study arms (7, 5, and 9 months for the SRS alone,
217
WBRT + SRS, and WBRT arms, respectively). The local
control rates were 87 %, 91 %, and 62 %, respectively. The
risk for developing new brain lesions was higher for the
patients who did not receive WBRT (43 % SRS alone vs.
19 % WBRT + SRS, vs. 23 % WBRT alone). However, the
study had major treatment bias given the unequal distribution
of patients undergoing surgical resection in the three arms.
The RTOG performed a large prospective trial (RTOG
9508) of 333 patients with 1–3 newly diagnosed brain metas-
tases on MRI, each <4 cm in diameter, randomized to WBRT
(3,750 cGy in 15 fractions) and SRS vs. WBRT alone [75].
Patients had a minimum KPS of 70 and were excluded if a
metastasis was located in the brainstem or within 1 cm from
the optic nerves or chiasm. Survival significantly improved
for patients with a single brain metastasis treated with
SRS + WBRT vs. WBRT (6.5 months vs. 4.9 months,
p = 0.04) despite the fact that 19 % of patients failed to
receive the intended treatment. On multivariate analysis,
RPA class (1 vs. 2) and tumor type (squamous or non-small
cell vs. other) had a statistically significant effect on survival.
Overall survival did not improve for the patients with 2–3
lesions although KPS at 6 months had stabilized or improved
with the addition of SRS + WBRT vs. WBRT alone (43 % vs.
27 %, respectively; p = 0.03). Steroid use was also lower in
the SRS + WBRT arm. Local control was improved at 1 year
(82 % vs. 71 %; p = 0.01). The risk of developing local recur-
rence was 43 % greater with WBRT alone (p = 0.0021). The
type of SRS unit did not influence results.
A retrospective study from Cleveland Clinic of 202
patients that met study entry criteria of RTOG 9005 analyzed
local control rates based on differences in prescription dose
[76]. With a median follow-up duration of 10.7 months, a
dose of 24 Gy to the tumor margin had significantly lower
local failure than 18 Gy or 15 Gy (hazard ratio 0.277,
p = 0.0005). The 18 and 15 Gy groups exhibited no statistical
difference in local control. The 1-year local control rates by
dose were 85 % for 24 Gy, 49 % for 18 Gy, and 45 % for
15 Gy. The improved control rates with 24 Gy suggests that
small tumors ≤2 cm are better controlled than larger tumors,
as one would expect.
Radiosurgery Alone
Despite evidence supporting the use of WBRT for patients
with single brain metastasis, SRS alone for treatment of
brain metastases has gained popularity and become a con-
tentious issue. The use of SRS alone has been mostly driven
by concerns regarding quality-of-life issues and the poten-
tial side effects of WBRT, especially cognitive effects for
long-term survivors [77, 78]. One of the early and com-
monly referenced papers regarding cognitive decline in
WBRT is by DeAngelis et al., which reported complications
218
in patients treated with fractionation schemes of
300–600 cGy/fraction to a total dose of 25–30 Gy [77]. Of
these 12 patients identified, all developed progressive
dementia, ataxia, and urinary incontinence, causing death in
seven patients. Although the incidence of WBRT-induced
dementia was 1.9–5.1 % overall, it is likely that this is an
underestimate of true incidence because only severely
affected patients were identified from chart review. Another
argument to treating with SRS alone is that some physicians
believe that patients can be effectively salvaged by repeat
SRS rather than WBRT [79].
It is important to note that patients undergoing SRS alone
may be at higher risk for morbidity associated with brain
tumor recurrence. A retrospective study from the University
of Kentucky reviewed 36 patients treated with SRS alone
with newly diagnosed brain metastases of which 22 patients
had a single lesion [80]. Seventeen of the 36 patients (44 %)
developed recurrent brain metastases, with 12 patients (71 %)
symptomatic and 10 (59 %) having neurologic deficits.
Several prospective trials have assessed whether patients
with brain metastases have neurocognitive deficits prior to
initiation of treatment. A recent prospective phase III trial
evaluated patients with brain metastasis with monthly neuro-
cognitive testing consisting of memory, fine motor speed,
executive function, and global neurocognitive testing [81].
Table 14.9 lists the neurocognitive tests that were performed
on this study. This trial demonstrated that 90.5 % of patients
had impairment of one or more neurocognitive tests at base-
line and 42.4 % of patients had impairment in four or more
tests. Another study from the RTOG demonstrated that tumor
progression resulted in a significant decline in the mini-
mental status exam (MMSE) after WBRT [82].
Chang et al. reported a prospective trial of neurocognitive
testing for patients with 1–3 newly diagnosed brain metasta-
ses to determine if neurocognitive function was spared with
SRS alone [83]. Eighteen of the 27 enrolled patients had
evaluable neurocognitive function data. At baseline, 66 % of
patients had some degree of impairment that was related to
total brain metastases volume. After SRS, acute and subacute
improvements in executive function and processing speed
Table 14.9 Neurocognitive testing used for phase III brain metastases
trial [62]
Test Neurocognitive domain
Hopkins Verbal Learning Test (recall) Memory
Hopkins Verbal Learning Test (recognition) Memory
Hopkins Verbal Learning Test (delay) Memory
Trailmaking A Executive
Trailmaking B Executive
Controlled oral word association Executive
Grooved pegboard dominant hand Fine motor
Grooved pegboard nondominant hand Fine motor
E.W. Jung et al.
occurred, but learning and memory skills declined. At 7–9
months after SRS, there was a suggestion of global decline
of neurocognitive function.
The RTOG reported on the feasibility of performing five
neurocognitive measures and administering a quality-of-life
instrument in patients with brain metastases [84]. The overall
compliance rate for administration and completion of these
measures and instruments was >95 % prior to treatment,
>84 % at the completion of WBRT, and >70 % at 1 month
after WBRT. Based on the encouraging results of this study
and others of similar design, future studies have more rou-
tinely incorporate baseline and follow-up neuropsychometric
testing as an inherent part of study design and patient out-
come evaluation. It is becoming increasingly evident that
neurologic/neurocognitive decline seen in cancer patients is
multifactorial and not exclusive to the effects of radiation
therapy alone. This has been demonstrated in recent publica-
tions implicating the potential significant impact of other
treatment modalities such as chemotherapy and/or surgery
on neurologic/neurocognitive function [85–88].
Large Institutional/Multi-Institutional
Results of SRS Alone
A UCSF retrospective study by Sneed et al. reported
outcomes of patients with one to four metastases treated by
SRS alone compared to WBRT plus SRS [68]. Physician
preference and referral patterns influenced the use of
upfront WBRT. The patients had similar median survivals
(11.1 months for SRS alone vs. 11.3 months for WBRT + SRS)
and local tumor control rates (71 vs. 79 %). The incidence
of distant brain metastasis, however, was significantly higher
in the SRS only group vs. WBRT + SRS (72 vs. 31 %).
Despite the higher rate of distant brain metastases, these
lesions were controlled with salvage therapies including
WBRT, partial brain radiotherapy, SRS, and surgery.
The authors concluded that survival was not compromised
by the omission of WBRT.
Another retrospective paper from Hasegawa et al.
reviewed 172 patients with brain metastases (3.5 cm or less
in diameter) managed by SRS alone [89]. One hundred
twenty-one patients had follow-up imaging with 80 % of
patients having solitary lesions. The median survival was 8
months, and the local tumor control rate was 87 %. At 2
years, the local control rate, distant brain control, and total
intracranial control rates were 75 %, 41 %, and 27 %, respec-
tively. Tumor volume significantly predicted for local con-
trol (p = 0.02) with tumor volumes of at least 4 cm3 having
local control rates of 49 % at 1 and 2 years. Based on these
results, the authors advocated withholding WBRT for select
patients with one or two tumors with good control of their
primary cancer, better KPS (90 or higher), and younger age
(<60 years old).
14 Metastatic Brain Tumors
One study prospectively evaluated the role of SRS alone
for patients with up to three brain metastases measuring
<3 cm in maximum diameter [90]. The study consisted of
101 patients with a total of 155 lesions. At 1 year, the local
control, distant brain freedom from progression, and overall
brain freedom from progression rates were 91 %, 53 %, and
51 %, respectively. The best predictor for improved overall
brain freedom from progression was the presence of a single
lesion and a greater than 2-year interval from primary diag-
nosis to diagnosis of brain metastases. The overall survivals
stratified by RTOG RPA class were 13.4, 9.3, and 1.5 months
for class I, II, and III, respectively (p < 0.0001). Median
survival was 7.6 months. These results suggested that SRS
alone can provide good local control but that distant failure
can be expected.
Another study from Pirzkall et al. reviewed an experience
of 236 patients with 311 brain metastases who underwent
SRS alone (158 patients) or SRS with WBRT (73 patients)
[67]. No difference was noted in terms of survival or local
control. The SRS with WBRT group had a trend toward bet-
ter survival compared with SRS alone (15.4 vs. 8.3 months;
p = 0.08) for the patients with no evidence of extracranial dis-
ease. The local control and distant brain control rates were
worse with SRS alone.
A multi-institutional retrospective review from ten insti-
tutions analyzed the results of 569 patients with newly diag-
nosed single or multiple brain metastases treated initially
with SRS alone vs. SRS and WBRT [91]. For all RPA classes,
survival was comparable between the two treatment groups
(RPA class I: 14 vs. 15 months, RPA class II: 8 vs. 7 months,
RPA class III: 5 vs. 6 months) suggesting that upfront WBRT
does not improve survival over SRS alone.
Phase II/III Trials of SRS With
or Without WBRT
The Eastern Cooperative Oncology Group (ECOG) phase II
trial of SRS alone for patients with renal cell carcinoma, sar-
coma, and melanoma (radioresistant tumors) with one to
three brain metastases was conducted with a primary end-
point of intracranial progression [92]. The purpose of this
trial was to evaluate the feasibility of SRS alone in manage-
ment of brain metastases before pursuing a phase III study.
This trial enrolled 36 patients; 31 were eligible by entry cri-
teria. The SRS dose was based on tumor size (24, 18, or
15 Gy). The median survival was 8.3 months with a median
follow-up of 32.7 months. The 3- and 6-month intracranial
failures with SRS alone were 25.8 % and 48.3 %, respectively.
Approximately 38 % of patients experienced death attribut-
able to neurologic cause. The authors concluded that
although survival was equivalent to published reports of
SRS + WBRT, the high rate of intracranial failures suggests a
judicial approach to omission of WBRT.
219
The Japanese Radiation Oncology Study Group (JROSG)
conducted a phase III study of SRS vs. SRS plus WBRT
(3,000 cGy/10 fractions) [93]. This trial randomized patients
with one to four brain metastases <3 cm in diameter to
SRS + WBRT (65 patients) or SRS alone (67 patients). The
primary endpoint of the study was overall survival with the
secondary points including brain recurrence, salvage brain
treatment, functional preservation, toxic effects of radiation,
and cause of death. At 12 months, WBRT decreased brain
tumor recurrence from 76.4 to 46.8 % (p < 0.001). Freedom
from new brain metastasis was also significantly better at 1
year for the WBRT and SRS group (63.7 %) compared with
the SRS alone group (41.5 %) (p = 0.003). Consequently, sal-
vage treatment was more frequently required in the SRS
alone group. No significant difference in overall survival,
toxic effects of radiation, death due to neurologic causes, or
differences in systemic or neurologic functional preserva-
tion were seen.
A prospective randomized trial for patients with 1–3
lesions comparing SRS plus WBRT vs. SRS alone with the
primary endpoint of neurocognitive function measured by
the Hopkins Verbal Learning Test-Revised (HVLT-R) was
conducted by Chang et al. at MD Anderson [94]. After
accrual of 58 patients, the trial was stopped early based on
the 96 % probability that the SRS + WBRT arm would show
a statistically significant decline in learning and memory
function (total recall) at 4 months. Congruous to the Japanese
study, there were more CNS recurrences in the group receiv-
ing SRS alone; 73 % of patients in the SRS + WBRT group
were free from CNS recurrence at 1 year, compared with
27 % of patients who received SRS alone (p = 0.0003). The
authors conclude that SRS with close follow-up is the pre-
ferred strategy. However, this study did not provide informa-
tion regarding long-term impact of WBRT or distant tumor
progression on neurocognitive function.
The EORTC completed a prospective phase III trial com-
paring the addition of WBRT to initial surgery or SRS for
patients with stable systemic disease and up to three brain
metastases [95]. The primary endpoint of this study was time
to WHO performance status >2. There were no differences in
overall survival or time to performance status deterioration
in either group. WBRT reduced the 2-year relapse rate at the
initial tumor site (surgery: 59 % vs. 27 %, p < 0.001; SRS:
31 % vs. 19 %, p = 0.04) and reduced new brain mets (sur-
gery: 42 % vs. 23 %, p = 0.008; SRS: 48 % vs. 33 %,
p = 0.023) in both groups. Furthermore, neurologic deaths
were higher in the arms not receiving WBRT (44 % vs. 28 %,
p < 0.002). As expected, salvage WBRT was more frequent in
the arms not receiving WBRT initially. An update to this trial
assessed health related quality-of-life (QOL) measures,
which was a secondary endpoint of the trial [96]. Patients in
the observation arm reported higher QOL compared with the
arm receiving WBRT. However, compliance was poor with
45 % of patients completing QOL assessment at 1 year.
220 E.W. Jung et al.

The North Central Cancer Treatment Group (NCCTG)
recently completed enrollment of a phase III trial (N0574)
comparing SRS vs. SRS followed by WBRT delivered within
14 days for patients with 1–3 brain metastases. The primary
endpoint is neurocognitive function.
SRS for More than Four Brain Metastases
With the success of SRS in treating patients with 1–4 brain
metastases and efforts to eliminate the effects of WBRT on
neurocognitive functioning, there has been increasing use of
SRS alone for patients with multiple (≥5) lesions.
Previously, there had been concern regarding the cumula-
tive dose to the whole brain when treating many lesions with
SRS. However, Yang et al. reported that 50 % of the brain
received less than 5 Gy when a maximum tumor dose of
40 Gy was used when treating 25 metastatic intracranial
tumors [97]. A more recent study by Yamamoto et al.
reviewed the median cumulative dose to the whole brain for
patients with at least ten lesions who were treated by GKRS
[98]. The median number of lesions treated with SRS was 17
(range: 10–43). The median volume for all tumors was
8.02 cm3 (range: 0.46–81.41). The median prescribed dose
was 20 Gy (range: 12–25 Gy). The median cumulative dose
to the whole brain was 4.71 Gy (range: 2.16–8.51 Gy). The
median brain volumes receiving >10 Gy, 15 Gy, and 20 Gy
were 64 cm3, 24 cm3, and 8 cm3, respectively.
With further assurance about the safety and efficacy of
SRS to multiple lesions, there have been more recent studies.
The local control and median survival of these studies are
summarized in Table 14.10 [99–106]. The North American
Gamma Knife Centers is currently proposing a trial of SRS
alone for patients with five or more metastases.
Since existing dose guidelines for SRS are based on 1–3
lesions, a physical model was developed to correlate the
peripheral isodose volume dependence on prescription dose
per target and increasing number of isocenters [107]. Simulated
and clinical multiple brain cases treated with the Gamma
Knife Perfexion were used to derive the model. The total num-
ber of targets ranged from 2 to 60. A significant increase in
volume was noted for the 12 Gy peripheral isodose volume,
which was strongly correlated with number of lesions but not
total target volumes. The 12 Gy target volume for multiple tar-
gets was increased by approximately 1 % per target when
15 Gy was used vs. 4 % per target increase when 20–24 Gy
was used. Based on these results, a reduction in dose of 1–2 Gy
is recommended when treating multiple lesions.
SRS for Brainstem Metastases
Metastases located in the brainstem portend a poor prognosis
and frequently present a challenge in clinical management.
Surgical resection is rarely a viable option due to high risk of
developing new or worsening neurological deficits. Patients
with brainstem metastases often present with focal neuro-
logic signs and symptoms due to anatomic location and local
mass effect, for which stereotactic radiosurgery would pro-
vide better symptomatic outcomes than whole-brain radia-
tion therapy (WBRT) alone. However, stereotactic
radiosurgery to the brainstem presents unique consider-
ations, mainly due to concerns of toxicity to critical struc-
tures and potential for brainstem necrosis. To date, there are
no prospective trials for brainstem metastasis SRS and no
established guidelines regarding dosing. However, there are
a number of retrospective single institution reviews in the
literature with favorable outcomes with limited toxicity
[108–119]. These results are summarized in Table 14.11.
Based on these studies, tumor margin dose ranges from
13 to 25 Gy, with Grade 3/4 toxicity of 0–11.5 %. Median
survival for patients with treated brainstem metastases is
4–12 months, with a local control of 76—100 %. These stud-
ies demonstrate that SRS for brainstem metastases is an
effective strategy for treatment.

Table 14.10 SRS for multiple brain metastases

Median
Number Median/mean Range (number of survival
Study Year of patients no. of brain mets brain metastases) Tumor type Local control (%) (months)
Suzuki [99] 2000 24 20 (mean) 10–47 All NR NR
Bhatnagar [100] 2006 205 5 (median) 4–18 All 71 % (1-year) 8
Kim [101] 2008 26 16.6 (mean) 10–37 All 79.5 (6 months) 7.85
Park [102] 2009 33 5.9 (median) 2–20 Lung NR 6.15
Yamamoto [103] 2009 456 6 (mean) 1–55 Non-lung NR 7
Nath [104] 2010 26 5 (median) 2–13 All 97 % (6-month) NR
Hunter [105] 2012 64 6 (median) 5 or more All NR 7.5
Grandhi [106] 2012 61 13.2 (median) 10–28 All 81 % 4
 14
Metastatic Brain Tumors

Table 14.11 Review of the literature: stereotactic radiosurgery for brainstem metastases
Median Median 1-year
tumor tumor Median Median actuarial
No. of No. of SRS Median volume margin follow-up survival overall Symptomatic Local Grade 3–4
Study Year patients lesions WBRT (%) modality age (cm3) dose (Gy) (months) (months) survival (%) improvement control (%) toxicity (%)
Koyfman et al. [108] 2010 43 43 34 (79.1) GK 59 0.37 15 5.3 5.8 32.5 n.a. 85 0
Lorenzoni et al. [110] 2009 25 27 17 (68) GK 53 0.6 20 10.5 11.1 37 n.a. 95 0
Kased et al. [111] 2008 42 44 24 (57) GK 55 0.26 16 6.9 9 31 1/10 (10 %) 77 9.5
Hussain et al. [112] 2007 22 25 3 (13.6) GK 60 0.9 16 8.5 8.5 32 2/22 (9 %) 100 5
Fuentes et al. [113] 2006 28 28 6 (21.4) GK 57.5a 2.1 19 11 12 37 16/24 (66 %) 92 0
Yen et al. [114] 2006 53 53 21 (39.6) GK 57.3a 2.8 18 9.8 11 42 21/35 (60 %) 86.5 0
Shuto et al. [115] 2003 25 31 9 (36) GK 54 2.1 13 5.2 4.9 50 n.a. 77.4 n.a.
Huang et al. [116] 1999 26 27 24 (92.3) GK 62 1.1 16 9.4 9 21.7 10/20 (50 %) 95 11.5
Hatiboglu et al. [117] 2011 60 60 9 (15) LINAC 61 1 15 5.3 4 n.a. 49/60 (82 %) b 76 3.3
Valery et al. [118] 2011 30 30 4 (13.3) LINAC 57 2.82 13.4 10.4 10 40 8/14 (57 %) 90 0
Kelly et al. [119] 2011 24 24 23 (96) LINAC 57 0.2 13 6.6 5.3 29 2/4 (50 %) 78.6 8.3
Lin et al. [109] 2012 45 48 21 (47) LINAC 60 0.4 14 n.a. 11.6 n.a. n.a. 88 % 4.7
GK Gamma Knife radiosurgery, LINAC linear accelerator-based radiosurgery, n.a. not available, SRS stereotactic radiosurgery, WBRT whole brain radiation therapy
a
Mean age
b
Stable or improved
221
222 E.W. Jung et al.

NCCTG N107C is an open phase III trial comparing SRS

Surgical Resection Cavity SRS
There has been a growing interest in delivering SRS to the
resection cavity after surgical resection of a brain metastasis.
This has been investigated due to the concern of cognitive
decline with WBRT. The rationale is that by delivering radia-
tion focally to the surgical resection cavity, one can take
advantage of the local control benefits of radiation, while
minimizing normal brain toxicity. As well, surgical resection
may have benefit compared to SRS alone, especially for
patients with large tumors that cause mass effect, or for
patients who present with acute focal neurologic signs or
symptoms, which would be resolved better with surgical
resection than SRS alone. There have been a number of sin-
gle institution studies looking at resection cavity SRS, with
results summarized in Table 14.12 [120–130].
The initial study reported in 2008 from the University of
Pittsburgh examined 40 patients who underwent tumor bed
Gamma Knife radiosurgery after initial resection, 32 of
which had a gross total resection [120]. Median survival was
13 months, with a local control rate of 73 %. GKRS was per-
formed at a median time of 4 weeks after tumor resection.
The median tumor margin dose was 16 Gy.
The largest and most recent study using LINAC-based
radiosurgery is from Stanford University, which retrospec-
tively examined 120 lesions in 112 patients [125]. A perti-
nent question to consider when treating a surgical resection
cavity with SRS is the appropriate margin to use after a gross
total resection. This study compared no margin vs. a 2 mm
margin around the resection cavity to determine if there are
differences in outcome. A total of 58 lesions were treated
with no margin vs. 62 lesions with a 2-mm margin. The study
found that 12-month local failure was reduced from 16 to
3 % with addition of a margin (p = 0.042). The median OS
was 17 months with a 1-year OS of 62 %.
to the surgical resection cavity vs. adjuvant WBRT in patients
with one to four brain metastases after surgical resection. The
primary endpoints of the study are overall survival and neu-
rocognitive progression at 6 months. Tumor bed control is
defined as the absence of new nodular enhancement of the
surgical bed. SRS treatment volume is defined as surgical
bed + 2 mm margin. Of note, unlike most SRS prescription
dose guidelines which are usually dictated by the maximum
tumor diameter, the prescription dose for SRS to the surgical
cavity is determined by the tumor volume, due to the frequent
irregular shape of the surgical cavities (Table 14.13). The
results of this trial should give us further insight into future
directions in treatment management of brain metastases.
SRS in Management of Large Brain
Metastases
Large brain metastases often cause neurologic symptoms
due to peritumoral edema and mass effect. Surgical resection
followed by WBRT has traditionally been the preferred man-
agement for large brain metastases. Traditionally, many cli-
nicians use an upper limit of 3 cm in diameter for consideration
of SRS for brain metastases. The role of SRS for larger
lesions is still an area of controversy and investigation.
A study from Pittsburgh examined the role of GKRS in
patients with brain metastases >3 cm in diameter [131].
A total of 70 patients without surgical resection were retro-
spectively reviewed, with 37 receiving GKRS alone, while
33 patients had prior WBRT. On the first follow-up MRI
after treatment, 41 % of tumors had >50 % volume reduc-
tion, 31 % had between 10 and 50 % reduction, and 28 % of
tumors were stable or larger. Tumor volume reduction was
associated with a single brain metastasis, no prior WBRT,
and tumor volume <16 cm3. Improved peritumoral edema

Table 14.12 SRS to the resection cavity

Local Age
Median control (median Follow up
Lead author Institution Year Patients (n) survival (~1 year) Modality Tumor margin dose or mean) (months)
Mathieu [120] Pittsburgh 2008 40 13 months 73 % GKRS 16 Gy 59.5 13
Quigley [121] Allegheny 2008 32 16.4 months 93.75 % LINAC 14 Gy to 80 % IDL 60 14
Iwai [122] Japan(Osaka) 2008 21 20 months 82 % GKRS 17 Gy 61 21.6
Soltys [129] Stanford 2008 76 15.1 months 79 % LINAC 18.6 Gy to 79 % IDL 58 8.1
Jagannathan [130] Virginia 2009 47 11.5 months 94 % GKRS 19 Gy 61 14
Do [123] UC Irvine 2009 30 51 % at 12 months 82 % LINAC 15 Gy to 80–90 % IDL 61.5 NR
Hwang [124] Tufts 2010 43 15 months 72 % GKRS 15–20 Gy 56.68 NR
Choi [125] Stanford 2012 112 17 months 90.5 % LINAC 20 Gy to 79 % IDL 61 11
Robbins [126] Henry Ford 2012 85 12.1 months 81.4 % LINAC 16 Gy to 90 % IDL 58 11.2
Hartford [127] Dartmouth 2012 47 53 % at 12 months 85.5 % LINAC 10 Gy to 80–95 % IDL 64 9.3
Ogiwara [128] Northwestern 2012 56 20.5 91.1 % GKRS 17.1 Gy 58.5 24
14 Metastatic Brain Tumors
Table 14.13 Dosing for surgical resection cavity stereotactic radiosurgery
3
Resection cavity size (cm ) Dose (Gy)
<4.2 20
≥4.2 to <8 18
≥8 to <14.4 17
≥14.4 to <20 15
≥20 to <30 14
≥30 to <5 cm max diameter 12
Adapted from NCCTG N107C; http://www.cancer.gov/clinicaltrials/
search/view?cdrid=701474&version=HealthProfessional
was associated with a single lesion, no prior WBRT and
breast cancer histology. Because of persistent symptoms,
10 % [7] of patients required craniotomy for salvage therapy.
The authors conclude that surgical resection is the preferred
treatment if possible for large lesions.
A more recent retrospective review from Stanford
University evaluated 97 patients with brain metastases >2 cm
who underwent surgical resection followed by cavity SRS
[132]. The rationale for the study was based on high rates of
local failure with single modality treatment of larger brain
metastases. The 12-month local failure rate was 9.3 % with
median time to local failure of 6 months. The 12-month inci-
dence of distant brain failure was 53 %, and median survival
time was 15.6 months. This study demonstrates that surgery
with resection cavity SRS can achieve good local control of
large brain metastases, while sparing or delaying WBRT.
Due to potentially worse toxicity with SRS for large
lesions, institutions have looked at fractionated SRS. A group
from Germany compared differences in efficacy and toxicity
when comparing single fraction SRS vs. fractionated stereo-
tactic radiotherapy for brain metastases [133]. The study ret-
rospectively examined 260 patients, with 138 patients
receiving single fraction SRS and 61 patients receiving frac-
tionated SRS. The fractionated SRS group included two
fractionation schemes: 5 Gy × 7 and 4 Gy × 10. They found
no difference in local control, progression-free survival, or
overall survival. Single fraction SRS was associated with
higher Grade 1–3 toxicity. Of note, fractionated treatment
was used for large lesions or lesions near critical structures,
but local control did not show a difference. A hypofraction-
ated treatment strategy may become a more prominent strat-
egy for larger brain metastases, but local control rates and
survival need to be validated prospectively in larger studies.
Complications Associated with SRS
Acute Complications
Acute side effects during the first week after SRS are uncom-
mon. Some of the complications include headache after frame
removal, infection of the pin sites, nausea and vomiting,
223
seizures, transient worsening of preexisting neurologic condi-
tions, and fatigue. The incidence of severe headaches after
frame removal is low [65]. Nausea/vomiting can be mini-
mized if the dose to the area postrema is kept below 375 cGy
[52]. The risk for seizures has been reported to range from 2
to 6 % [54, 55]. Seizure risk is higher with cortical lesions and
for patients with history of seizures. For these patients, anti-
convulsants should be considered, and steroid dose should be
increased.
Subacute complications occur within the first 6 months
after SRS. Alopecia has been reported in 5.6 % of patients
[54]. These patients had superficial tumors that resulted in a
dose of 4.4 Gy to the scalp. Neurological deterioration can
occur in some patients, which is usually treated with steroids.
A prospective study assessed the acute complications of
76 patients undergoing GKRS using CTCAE v.3.0, the Brief
Pain Questionnaire (Short Form), Brief Fatigue Inventory,
and the Tinnitus Handicap Inventory [134]. The majority of
patients (34 %) were treated for brain metastases, but also
included trigeminal neuralgia, schwannoma, meningioma,
arteriovenous malformation, and pituitary adenoma. There
was no significant difference in face swelling, headache, eye
pain, vomiting, seizures, or passing out at any intervals com-
pared to baseline. At 1 week, 24 % developed minimal scalp
numbness, which decreased to 2 % at 2 months. Pin site pain
was present in 13 %, which declined to 3 % at 1 month with
a median intensity level of 3 out of 10. Four percent of
patients developed pin-site infection at 1 week and none at 1
and 2 months. By 1 month, 10 % reported new local hair
loss. New or worsening fatigue was experienced by 23 %,
16 %, and 15 % of patients at 1 week, 1 month, and 2 months,
respectively, but 40 % reported fatigue at baseline. After
treatment, 1 %, 6 %, and 3 % developed new tinnitus at 1
week, 1 month, and 2 months, respectively, which was sig-
nificant when comparing baseline to non-baseline
(p = 0.0269). Thirty-two patients were employed prior to
SRS. Three (9 %) patients did not return to work. Twenty-
seven (84 %) patients returned to work a median of 4 days
after treatment. This prospective study demonstrates that
GKRS is well tolerated with few patients developing signifi-
cant acute effects. Many patients are able to return to work
shortly after GKRS.
Chronic Complications
Radiation necrosis is the most serious chronic complication
of SRS. In general, the risk of radiation necrosis increases
with higher doses, larger tumor volumes, and in patients
treated with prior radiation. The pathophysiology of radia-
tion necrosis is a coagulative process that predominantly
affects white matter. It is caused by small artery injury and
thrombotic occlusion. On pathology, these small arteries
224
Table 14.14 Dose constraints for single fraction brain SRS
Organ Endpoint
Brain Symptomatic necrosis
Brainstem Permanent cranial neuropathy or necrosis
Optic nerve/chiasm Optic neuropathy
Cochlea Sensory neural hearing loss
Adapted from QUANTEC
From Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, Eisbruch A, et al. Use of normal tissue complica-
tion probability models in the clinic. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S10–9; used with permission
demonstrate endothelial thickening, lymphocytic and macro-
phagic infiltrates, presence of cytokines, hyalinization, fibri-
noid deposition, thrombosis, and finally occlusion. The
primary mechanism of delayed injury in radiation associated
with necrosis is secondary to vascular endothelial injury or
direct damage to oligodendroglia. Depending on the tumor
location and rate of growth, radiation necrosis can present
with seizure, elevated intracranial pressure, obstructive
hydrocephalus, or herniation syndromes.
A number of MRI modalities can aid in diagnosis of brain
radionecrosis [135]. On MR spectroscopy, a lactate peak is
often manifested. On DWI, there can be increased signal due
to restricted diffusion in the region of necrosis. MR FLAIR
may elicit regions of edema surrounding the necrosis.
Dynamic susceptibility-weighted contrast enhanced (DSC)
perfusion MRI has also been used to delineate areas of
necrosis, which can be further characterized with pharmaco-
kinetic modeling [136]. However, definitive diagnosis of
radiation necrosis requires biopsy or surgical resection.
For single fraction radiosurgery, a clear correlation has
been demonstrated between the target size and the risk of
brain radionecrosis [137]. A study from Italy of 206 patients
treated with LINAC-based radiosurgery investigated factors
that predict for radionecrosis [138]. Median overall survival
and brain control were 14.1 months and 10 months, respec-
tively, with 1-year and 2-year local control rates of 92 % and
84 %, respectively. Severe neurological complications (RTOG
Grade 3 and 4) occurred in 5.8 % of patients. Brain radione-
crosis occurred in 24 % of treated lesions, of which 10 %
were symptomatic and 14 % asymptomatic. On multivariate
analysis, V10 through V16 Gy were independent risk factors
for radionecrosis, with V10 Gy and V12 Gy being the most
predictive (p = 0.0001). For V10 Gy >12.6 cm3 and V12 Gy
>10.9 cm3, the risk of radionecrosis was 47 %. The authors
suggest that since lesions with V12 Gy >8.5 cm3 confer a risk
of radionecrosis >10 %, hypofractionated SRS should be con-
sidered for eloquently located lesions. As well, larger lesions
would likely have larger volumes receiving high dose.
A number of QUANTEC (quantitative analysis of normal
tissue effects in the clinic) organ-specific papers published
in 2010 have reviewed late toxicity and radiation. These
E.W. Jung et al.
Dose (Gy) Rate (%)
V12 < 5–10 cm3 <20
Dmax <12.5 <5
Dmax <12 <10
Prescription dose ≤14 <25
recommendations are based on a review of available data in
the literature to summarize dose constraints for clinical use.
With regard to tolerance dose to the optic nerves and chiasm,
consistent agreement has been reached on the low risk of
radiation-induced optic neuropathy for a Dmax of ≤10 Gy, and
one major study indicated a low risk with a Dmax of ≤12 Gy
for single fraction radiosurgery [139]. With regard to brain-
stem toxicity in single fraction SRS, Dmax <12.5 Gy is associ-
ated with <5 % risk [140]. Higher doses of 15–20 Gy have
been reported with low incidence of complications, but this
may be an artifact of poor survival. With regard to overall
brain radionecrosis, toxicity increases rapidly once the vol-
ume of any part of the brain receiving >12 Gy is >5–10 cm3
[137]. A modified QUANTEC summary of pertinent dose
constraints for single fraction brain SRS is provided in
Table 14.14 [141].
The general strategy for treating radiation necrosis is to
decrease the edema and necrosis. Usually, high doses of ste-
roids are used to minimize neurological deterioration. If the
patient becomes symptomatic despite steroids, surgical
resection can be considered. Anticoagulation with coumadin
to prevent vessel thrombosis can also be used. In some cases,
hyperbaric oxygen has been used for patients who are poor
surgical candidates, have multiple areas of radiation necro-
sis, or have a surgically inaccessible lesion. In a retrospective
review of 40 patients, 90 % reported subjective improvement
and 80 % had objective neurologic improvement with hyper-
baric oxygen [142]. Steroids were discontinued or decreased
in two thirds of patients. A randomized trial is underway at
the University of Cincinnati comparing surgery with hyper-
baric oxygen.
More recently, Bevacizumab (Avastin) treatment is being
used in the management of radiation necrosis [143]. Since radi-
ation necrosis leads to hypoxia, elevated levels of VEGF have
been seen which may lead to further edema. Therefore, block-
ing VEGF from reaching capillary targets is a logical treatment
option for radionecrosis [144, 145]. Another potentially prom-
ising treatment option is the use of laser interstitial thermal
therapy [146]. Laser interstitial thermal therapy was originally
used for treatment for brain tumors in 1990. It delivers focal
laser energy selectively to coagulate tissue with interstitial
14 Metastatic Brain Tumors
hyperthermia and exhibits a sharp ablation boundary zone.
This technique may be particularly useful for areas of radione-
crosis that are refractory to medical management as previously
described and are not amenable to surgical resection.
Costs
SRS for patients with multiple brain metastases, especially
those with poor prognosis, will likely undergo further scru-
tiny as the costs of various treatments are evaluated for cost-
effectiveness. Although the costs of SRS vary based on the
type of technology used, number of lesions treated, and insti-
tutional costs, estimated Medicare costs for SRS are
$10,000–$27,000 per procedure as compared to $2,300–
$7,650 for WBRT [53]. Unfortunately, no universally
accepted threshold exists in the USA for determining whether
treatment provides good value for its cost. Traditionally, the
quality-adjusted life years (QALY) has been used. Since the
overuse of any technology can be a result of a number of fac-
tors including misaligned incentives under the fee-for-
service payment system and patient preference for
cutting-edge technology, it is important that neurosurgeons
and radiation oncologists demonstrate the value of radiosur-
gery for patients with multiple (>5) brain metastases.
Administering SRS with WBRT instead of SRS alone
may contribute to additional cost. A recent study by Lal et al.
compared SRS alone vs. SRS + WBRT for patients with three
or less brain metastases, using actual life years saved (LYS),
quality-adjusted life years, and incremental cost-effectiveness
ratio (ICER) [147]. Compared to SRS with whole brain radi-
ation therapy, SRS alone has a higher average cost ($74,000
vs. $119,000). However, SRS alone has a higher average
effectiveness of 1.64 LYS compared with combined SRS and
WBRT (0.60 LYS). The authors conclude that SRS alone
without WBRT is more cost-effective, even with salvage
treatment delivered down the line.
Chemotherapy and Radiosensitizers
Radiosensitizers are agents that can potentially increase the
lethal effects of radiation therapy when given concurrently
with radiation. Recent studies have examined the role of che-
motherapy and radiosensitizers with WBRT and/or SRS in
the hopes of improving survival.
A phase II study, PCYC-0224, evaluated the use of
motexafin gadolinium, a radiation sensitizer, given with
WBRT (37.5 Gy in 15 fractions) and SRS (15–21 Gy) for
patients with ≤6 brain metastases [148]. The primary end-
point was to evaluate toxicity in preparation for a phase III
study. A total of 65 patients were enrolled of which 45 (69 %)
225
were available for evaluation. New brain metastases were
detected in 11 patients (24.4 %) at the time of the SRS treat-
ment planning MRI. The median neurological progression-
free survival was 8 months and overall survival time was 9
months. The actuarial incidences of neurological progres-
sion at 6 months and 1 year were 17 and 20 %, respectively.
Grade 3 or higher neurotoxicity was seen in two patients, and
the authors conclude that motexafin gadolinium does not
increase toxicity and should be further studied.
A recent Phase I prospective study from Canada enrolled
26 previously irradiated patients with 1–4 progressive brain
metastases with a maximum diameter of 40 mm and KPS ≥60
[149]. Patients were enrolled to receive three different doses
of temozolomide (TMZ): 100, 150, and 200 mg/m2/day for
days 1–5. SRS was administered on day 5. SRS dose was pre-
scribed as per RTOG 9005 guidelines. The primary endpoint
was safety of increasing TMZ doses. Secondary endpoints
included local control and survival. The median number of
brain metastases was 1.5, with a median target diameter of
21 mm. The most common Grade 1–2 adverse events were
vomiting (23 %), nausea (23 %), edema (12 %), seizure (8 %),
psychosis (4 %), and thrombocytopenia (4 %). The frequency
of nausea and vomiting did not appear to be dose dependent.
Grade 3–4 toxicities were not observed. Median overall sur-
vival was 10.2 months. Crude local control was 87.5 %, with
a radiological response seen in eight of 24 evaluable patients
(33.3 %), and stable disease >6 months in 13 of 24 patients
(54.2 %). The authors conclude that TMZ can be given at
doses up to 200 mg/m2/day prior to SRS with good local con-
trol. Further randomized studies with greater patient numbers
will be needed to assess for the impact of addition of temo-
zolomide on local control and overall survival.
RTOG 0320 was a phase III trial which randomized
NSCLC patients with 1–3 brain metastases to 3 arms: (1)
SRS plus WBRT, (2) SRS plus WBRT with erlotinib, and (3)
SRS plus WBRT with temozolomide [150]. The rationale for
adding erlotinib or TMZ is its ability to cross the blood-brain
barrier. Of note, for patients randomized to receive chemo-
therapy, the treating physician could decide whether to give
erlotinib or TMZ. In the erlotinib and TMZ arms, chemo-
therapy was delivered with radiation therapy, and the investi-
gator could decide whether to give adjuvant chemotherapy.
This trial closed early secondary to poor accrual. The addi-
tion of neither erlotinib nor TMZ resulted in an improvement
in OS or time to CNS progression compared to the control
arm: WBRT + SRS alone. Interestingly, WBRT + SRS alone
resulted in an improved median survival time, which was not
attributable to excess toxicity in the chemo arms. The
WBRT + SRS arm had significantly less deterioration in per-
formance status at 6 months. Hence, there was no benefit to
the addition of chemotherapy and potentially a detriment to
clinical outcome.
226
Future Directions
Incorporation of newer imaging modalities such as MRS and
PET to aid in SRS planning and delivery of higher doses to
certain regions of the target may be the wave of the future
[151, 152]. Another area of interest is in the development of
improved hardware for SRS delivery. There have been recent
developments in a frameless, surface image-guided radiosur-
gery technique to treat brain metastases [153]. Originally, the
Gamma Knife uses a frame-based immobilization device, and
the early LINAC-based radiosurgery techniques also used a
frame-based system. However, patient discomfort and issues
with reproducibility in fractionated SRS are disadvantages
with the frame system. More recently, frameless systems have
been developed for LINAC-based radiosurgery, by providing
a custom fit mask and position monitoring with X-rays or
CT. However, these frameless systems subject the patient to
increased radiation exposure due to image guidance with radi-
ation. Further developments now allow for real-time monitor-
ing by externally attached infrared fiducials for intra-fraction
monitoring. When first developed, these fiducials were placed
on a bite block, but recent developments now allow for sur-
face image guidance using camera pods that capture facial
features for tracking. A recent study from UC San Diego of 44
consecutive patients demonstrates outcomes comparable to a
frame system, with a 6 and 12-month local control of 90 %
and 76 %, respectively. Distant brain failure rate was 46 %.
The Japan Clinical Oncology Group (JCOG) has a phase
III randomized control trial (NCT00280475) of postoperative
WBRT vs. salvage SRS for patients with 1–4 brain metastasis
from lung, breast, and colorectal cancers. The aim of this
study is to evaluate non-inferiority of salvage stereotactic
radiosurgery in the patients who received surgical resection
for brain metastases in comparison with postoperative whole
brain radiation therapy. The primary endpoint of this study is
overall survival. Secondary endpoints include performance
status preservation, mini-mental status (MMSE) preserva-
tion, and adverse events. This trial is still accruing patients.
As health care cost-effectiveness has become an increas-
ingly important issue in our health care system, there have
been more recent RTOG trials examining ways to reduce cog-
nitive decline with WBRT without SRS. RTOG 0614 is a trial
that assesses differences in cognitive decline in patients receiv-
ing WBRT with or without the administration of memantine,
an NMDA receptor antagonist used to treat Alzheimer’s dis-
ease [154]. With a median follow-up of 12.4 months, there
was no difference in OS or PFS. The primary endpoint was
difference in HVLT-R delayed recall. Memantine reduced
cognitive decline by 0.9 as measured by the HVLT-R delayed
recall at 24 weeks, but the results were not statistically signifi-
cant (p = 0.059). However, this study may have been under-
powered to detect a difference, as there were only 149
analyzable patients. Memantine reduced the relative risk of
cognitive decline by 17 % (p = 0.01) and delayed time to cog-
E.W. Jung et al.
nitive decline (p = 0.01). The addition of memantine reduced
decline in memory (p = 0.015), cognitive, executive, and global
function as well as processing speed (p < 0.01). The conclu-
sion is that memantine helps preserve cognitive function after
WBRT in patients with brain metastases.
Recognizing that hippocampus radiation damage may
induce cognitive decline in patients, a phase II study
(RTOG 0933) was opened to evaluate hippocampus sparing
WBRT delivered by an IMRT technique. The primary end-
point is neurocognitive decline measured by the HVLT-R
administered 4 months after WBRT. This trial completed
accrual with results suggesting preservation of memory
and QOL compared to historical series. (Gondi V et al.
ASTRO 2013).
Conclusions
Historically, whole brain radiation therapy has been the stan-
dard treatment for patients with brain metastases. Over the
past 20 years, stereotactic radiosurgery has developed an
increasingly important role in the management of brain
metastases. Although SRS has become an important thera-
peutic option, the appropriate utilization of SRS is contro-
versial. Studies have shown benefits of SRS as sole treatment,
as adjuvant therapy after surgery, as an adjunct to WBRT,
and as salvage treatment after WBRT. Retrospective studies
suggest that patients treated with SRS or surgery have com-
parable outcomes. RTOG 9508 provides level 1 evidence of
a survival benefit of SRS and WBRT compared with WBRT
alone for patients with a single lesion. For patients with more
than one lesion, the use of SRS and WBRT should be consid-
ered based on performance status, extent and activity of
extracranial disease, and steroid use. More recently, the
omission of WBRT has been advocated by concerns of the
potential risks of cognitive decline with WBRT and apparent
lack of survival benefit of additional WBRT. Surgical resec-
tion followed by SRS boost exhibits good local control for
single brain metastasis. The potential cognitive side effects
of WBRT must be balanced against the risk for increased
distant brain metastases and the cost of more frequent
follow-up scans when treating brain metastases with SRS
alone. A recent phase III trial has shown benefit in cognition
for patients undergoing WBRT who take memantine. Future
studies may find other drugs which could mitigate the side
effects of WBRT. Development and incorporation of radio-
sensitizers may help improve outcomes with radiation ther-
apy for brain metastases. As the prognosis improves for
cancer patients, the challenge of increasing progression-free
survival while limiting cognitive decline and other side
effects will continue to make the management of brain
metastases controversial. We encourage the participation of
patients with brain metastases in clinical trials to improve
outcomes and to help answer many important questions
about management of this very common disease.
14 Metastatic Brain Tumors
Case Presentation 14.1
History: This is a 73-year-old male with a history of renal
cell carcinoma status post right nephrectomy 10 years
ago. He presented with left-sided weakness. MRI was
obtained, which revealed a 1.7 cm right frontal lesion
(Fig. 14.1a, b). Staging work-up was negative.
He underwent Gamma Knife radiosurgery to the right
frontal lesion (Fig. 14.1c). A dose of 24 Gy was prescribed
Fig. 14.1 MRI of male with a history of renal cell carcinoma. See Case Presentation 14.1
Case Presentation 14.2
History: This is a 57-year-old female with history of a
T3N1M0, Stage III adenocarcinoma of the esophagus sta-
tus post radiation therapy (3,000 cGy/20 fx, 150 cGy/fx
bid) to the distal esophagus with concurrent chemother-
apy status post esophageal resection followed by an addi-
tional 3,000 cGy/20 fx, 150 cGy/fx bid to the tumor bed
with concurrent chemotherapy. She did well for 10 months
until she presented with a right-sided seizure. MRI
revealed a 2-cm left frontoparietal lesion (Fig. 14.2a, b).
She underwent whole brain radiation therapy
(3,750 cGy/15 fx using 250 cGy) followed by Gamma
227
to the 50 % local isodose line, which covered 100 % of the
target. The plan utilized 8 shots using an 8 mm helmet
without plugs. Tumor volume = 2.0 cm3. Maximum
dose = 4,800 cGy. Maximum diameter = 1.9 cm. MD/
PD = 2.00. PIV/TV = 1.70.
Three-month post Gamma Knife radiosurgery MRI
(Fig. 14.1d, e). The patient’s left-sided weakness
improved.
Knife radiosurgery within 1 week of completing WBRT
(Fig. 14.2c).
Treatment planning information, 1,800 cGy was pre-
scribed to the 50 % isodose line, which covered 100 % of
the target. The plan utilized 6 shots using an 18 mm hel-
met without plugs. Tumor volume = 5.3 cm3. Maximum
dose = 36 Gy. Maximum diameter = 2.5 cm. MD/PD =
2.00. PIV/TV = 1.64.
Three-month post Gamma Knife radiosurgery film
(Fig. 14.2d, e). She had excellent response to WBRT and
Gamma Knife radiosurgery.
228
Fig. 14.2 MRI of female with a history of adenocarcinoma of the esophagus. See Case Presentation 14.2
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 Metastatic Brain Tumors:
Viewpoint—Surgery
Raymond Sawaya, David M. Wildrick, and Fassil B. Mesfin
Introduction
Metastatic brain tumors continue to occur more frequently
than primary intracranial neoplasms and are a serious com-
plication of systemic cancer [1]. Their annual incidence
exceeds 100,000 [2, 3] and is on the rise as patients live lon-
ger from improved treatments for extracranial cancer [4, 5].
Thus, patients with brain metastases constitute a significant
fraction of the case load in the neurosurgery services at many
oncologic care centers.
Early in the 1900s, the results of surgical treatment of sin-
gle brain metastases were disappointing [6], with patients sel-
dom showing a median survival time of longer than 6 months [7].
Although this was longer than the 4–6-week survival time
typical of patients with untreated brain metastases, the surgi-
cal morbidity was high (15–50 %) [8], and whole-brain radia-
tion therapy (WBRT) alone was frequently favored for
management of patients with brain metastases. Since then,
the Radiation Therapy Oncology Group (RTOG) has demon-
strated that treatment of brain metastasis patients with WBRT
alone can extend their median survival time to 16 weeks [9–11].
In addition, two independent, prospective randomized studies
showed that surgery plus WBRT offered a survival advantage
superior to WBRT alone in such patients [12, 13].
After Leksell demonstrated the utility of focused beams
of high-energy X-rays in the ablation of intracranial tumors
[14, 15], the technique of stereotactic radiosurgery (SRS)
continued to evolve. During the 1990s, SRS was increasingly
used in the management of brain metastases, with some
investigators claiming that SRS alone produced results
R. Sawaya, M.D. • D.M. Wildrick, Ph.D. (*)
Department of Neurosurgery, The University of Texas
M.D. Anderson Cancer Center, Houston, TX, USA
e-mail: dwildric@mdanderson.org
F.B. Mesfin, M.D., Ph.D.
Department of Neurosurgery, SUNY Upstate Medical University,
Syracuse, NY, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_15, © Springer Science+Business Media New York 2015
15
similar to those obtained by combining SRS and WBRT, or
potentially, even equivalent to the outcome with surgical
resection [16–20]. With this in mind and because of the ease
of use of SRS and the perception that it costs less than con-
ventional surgery, some have even suggested that most meta-
static brain tumors should be managed exclusively with
SRS. This controversial notion has already led to treatment
of some series of brain metastasis patients with SRS alone
followed by observation [18, 19].
At The University of Texas M.D. Anderson Cancer Center
(“M.D. Anderson”), SRS is regarded as a specialized tool to
be used judiciously, as a given patient’s situation dictates,
rather than as a generalized treatment modality for brain
metastases. We continue to see surgical resection as playing
the central role in the management of patients with a limited
number of brain metastases [4, 21–24]. In this chapter, we
present our view of the relative roles of surgery and SRS in
terms of issues concerning patient selection, treatment out-
come, cost-effectiveness of the treatment, and the patients’
quality of life. These differences are summarized in
Table 15.1 [4, 13, 16, 23–27].
Patient Selection
When a patient presents with a brain metastasis and symp-
toms of mass effect, there is seldom a dispute that the lesion
should be removed surgically. Similarly, when a patient with
a brain metastasis presents in too poor a medical condition to
be a surgical candidate (or declines surgery), SRS represents
a logical treatment modality. Other patients with single brain
metastases can be sorted into three groups. The first group
has relatively large lesions (exceeding 3 cm in maximum
diameter) that can only be effectively removed by surgical
resection. Treatment of these tumors with SRS is not effec-
tive because the radiation dose must be reduced as the tumor
size increases, to prevent damage to surrounding brain tis-
sue. This relationship was clearly demonstrated by Mehta
et al. [25], who showed that with SRS, the rate of complete
233
234 R. Sawaya et al.

Table 15.1 Differences between surgery and stereotactic radiosurgery in the treatment of brain metastasis
Patient selection
Tissue diagnosis
Lesion size
Surgical candidate
Treatment outcome
Tumor status
Local control
Local recurrence rate
Median survival time
Complications
Presentation
Major neurological
Mortality (30-day)b
Cost-effectiveness
Quality of life
Relief from mass effect
Steroid use
Follow-up visits
Patient debilitation
a
Maximum diameter
b
Occurring within 30 days after the procedure
Surgical resection Stereotactic radiosurgery
Confirms the lesion is a tumor Cannot confirm the lesion is a tumor
Large, ≥1.5 cma; especially if there is mass effect Small, ≤2.0 cma; significant mass effect absent
Yes No (or patient declines surgery)
Removed (≥94 % on average) [4] Not removed
85 % for >40 months (up to 5 years) [23] 85 % at 12 months; 65 % at 24 months [25]
8 % [23] to 12 % [4] 30 % [26] to 47 % [27]
10 [13] to 16.4 [23] months 7.5 [23] to 14 [16] months
Usually immediate Frequently delayed; necrosis may necessitate surgical resection
7 % in eloquent brain; 6 % overall [4] 25 % in eloquent brain (RTOG grade 3) [24]
<2 % 1.8 %
Based on 3-day hospital stay Based on 1-day outpatient stay; includes no costs of
maintenance steroids, follow-up office visits, or follow-up MRI
Immediate Delayed
Tapered off over 2–4 weeks Can last for months; may cause dependence
Few Many
Not debilitated at home Debilitated at home

100
GTR Patients in the second group have very small lesions (less
than 10 mm in maximum diameter) that are not surgically
accessible and are located deep within the brain. In this situa-
80 tion, SRS provides an effective alternative to resection, superior
to WBRT, which was the only treatment previously available.
The third group of patients are those who have metastases
60
that are less than 3 cm in maximum diameter and are surgi-
Percent

cally accessible. Whether surgery or SRS is the best treat-

40 ment for these lesions is the subject of much current debate.
CR The 3-cm upper size limit referred to above is probably too
high for adequate SRS treatment. At M.D. Anderson, a rela-
20 tively recent study of 153 brain metastases from melanoma
treated with SRS [28] showed that the 1-year local control
rate of smaller tumors with a maximum diameter of no more
0 than 1.5 cm (volume = 2 cm3) was superior to that of larger
0 2 4 6 8 10 12 14 16 18 20
Tumor Size (cc)
lesions (75.2 % and 42.3 %, respectively; p < 0.05). Moreover,
another study at M.D. Anderson used SRS to treat brain
Fig. 15.1 Tumor size versus response to radiosurgery and surgery for metastases from different primary tumor types [26] and found
brain metastases. Comparison of a representative radiosurgery com- a 1-year actuarial local control rate of 86 % for lesions that
plete response (CR) curve [25] with a surgery gross-total resection
were 1 cm or less in maximum diameter (0.5 cm3) but only a
(GTR) curve (average percentage, 94 % from Table 15.2), showing that
CR rate with radiosurgery is tumor size dependent, whereas GTR rate 56 % local control rate for lesions larger than this (p = 0.0016).
with surgery is not (From Sawaya R. Surgical treatment of brain metas- Furthermore, an earlier study by a radiosurgery group in
tases. Clin Neurosurg 1999; 45:41–47. Used with permission) Pittsburgh [29] included only brain metastases that were no
larger than 2.5 cm in maximum diameter and found that treat-
response (CR; total disappearance of the magnetic resonance ment with SRS plus WBRT was superior to WBRT alone. It
[MR] image of the lesion after SRS) falls off dramatically is important to note that control rates similar to surgery for
with tumor volume such that if a tumor 2 cm3 in volume has lesions as large as 2 cm (volume ~5 cm3) can be achieved with
a 50 % CR rate, an 8–9-cm3 lesion shows about a 20 % CR the addition of fractionated WBRT [30]. Collectively, these
rate (Fig. 15.1). findings clearly indicate that for effective use of SRS alone
15 Metastatic Brain Tumors: Viewpoint—Surgery
(i.e., without the addition of WBRT), a cutoff point in brain
metastasis diameter that is lower than 3 cm is warranted.
Treatment Outcome: Survival
The controversy remains as to whether surgery or SRS is
more appropriate and effective to treat patients in the group
with single brain metastases that are surgically accessible
and range between 1 and 3 cm in maximum diameter.
Because no one has yet been able to complete a prospective
randomized study comparing treatment of such patients with
surgical resection and SRS, the question of which of the two
is more effective lacks a definitive answer.
In lieu of this, many retrospective studies have been per-
formed comparing surgical resection and SRS for brain
metastasis treatment. Among the more carefully constructed
studies of this type are those of Auchter et al. [16], Bindal
et al. [23], and Cho et al. [31].
Auchter and coworkers [16] performed a multi-
institutional retrospective outcome and prognostic factor
analysis of patients with single cerebral metastases who were
treated with SRS plus WBRT. From their database of 533
patients with brain metastases treated with SRS and WBRT,
they selected 122 patients who fulfilled the criteria for surgi-
cal resection established in the prospective randomized trial
of Patchell et al. [13], including having a single brain metas-
tasis that was surgically resectable (but no urgent need for
surgery), no prior radiotherapy or surgical treatment, inde-
pendent functional status (a Karnofsky Performance Scale
[KPS] score >70), and a non-radiosensitive tumor. They then
compared the outcome of these 122 patients with that of the
patients in the prospective randomized surgical series of
Patchell et al. [13] and Noordijk et al. [12]. The actuarial
median survival time after treatment with SRS plus WBRT
was 56 weeks compared with 40 weeks [13] and 43 weeks
[12], respectively, after surgery plus WBRT. The median
duration of functional independence was 44 weeks after SRS
and WBRT [16] compared with 38 weeks [13] and 33 weeks
[12], respectively, after surgery and WBRT. These results
indicated to Auchter et al. [16] that SRS plus WBRT pro-
duced outcomes for patients with single brain metastases that
were comparable with, if not better than, surgery plus WBRT.
Cho and coworkers [31] retrospectively reviewed a series
of 225 single brain metastases in patients treated with either
WBRT alone, SRS plus WBRT, or surgery and WBRT. There
was a similar distribution of prognostic factors such as age,
sex, KPS score, and metastasis location in these three groups
except for extracranial cancer, which was 14 % higher in the
group treated with SRS and WBRT. The actuarial median
survival times for patients treated with SRS and WBRT
(9.8 months) and surgery plus WBRT (10.5 months) were
nearly identical, but both were significantly better than for
those treated with WBRT alone (3.8 months). Other more
235
recent retrospective studies have also labeled resection and
SRS as equally effective in the treatment of small to moder-
ately sized brain metastases [32].
At M.D. Anderson, Bindal and coworkers [23] also retro-
spectively compared surgical resection and SRS treatment of
brain metastases. Thirty-one patients treated with SRS were
followed prospectively, and 62 patients treated with
conventional surgery were retrospectively matched to those in
the SRS group. Patients were matched according to primary
tumor histology, extent of systemic disease, preoperative KPS
score, time to brain metastasis, number of brain metastases,
and patient age and sex. WBRT treatment was similar in both
groups, and patient eligibility criteria for SRS were the same
as for surgery. Lesions treated by SRS were limited to those
<3 cm in maximum diameter, and 81 % of them were deemed
surgically resectable. There was a statistically significant sur-
vival advantage in the surgically treated group (16.4 months
median survival) relative to the group treated with SRS
(7.5 months median survival) (p = 0.0009 by multivariate anal-
ysis). In contrast to the conclusions of Auchter et al. [16] and
Cho et al. [31], Bindal’s group [23] concluded that surgery
was superior to SRS in clinically similar patients in terms of
survival, local recurrence, and morbidity. Thus, determination
of whether treatment of brain metastases with SRS is better
than, equivalent to, or worse than surgical resection must await
a phase III prospective trial comparing SRS with conventional
surgery for the treatment of single brain metastases.
Tumor Local Control and Recurrence
When brain metastases are removed surgically, local control
is produced by total removal of the tumor and elimination of
surrounding edema (Fig. 15.2). At M.D. Anderson, gross-
total resection (equivalent to complete response in radiosur-
gery) of metastatic tumors is achieved in 90–96 % of
instances, in both eloquent and noneloquent brain regions
(Table 15.2). With surgery, local control (absence of recur-
rent tumor growth after gross-total resection) typically per-
sists at an 85 % level at 1 year and remains there for an
interval ranging from 40 months to 5 years (Fig. 15.3).
Table 15.2 Gross-total resections performed for metastatic tumors in
different brain regions (gross-total resection is equivalent to a complete
response in radiosurgery)
Metastasis location
(tumor functional gradea) No. of patients GTR (%)
Noneloquent (I) 79 75 (95)
Near-eloquent (II) 61 55 (90)
Eloquent (III) 54 52 (96)
Total 194 Average, 94
GTR gross-total resection
a
Grade according to functional location
Source: Adapted from Sawaya R. Surgical treatment of brain metasta-
ses. Clin Neurosurg 1999; 45:41–47. Used with permission
236
Fig. 15.2 (a) Preoperative and (b) postoperative gadolinium contrast-
enhanced MR images of a brain metastasis in a patient with non-small
cell lung cancer. In each panel, the left and right images are T1- and
T2-weighted, respectively (From Sawaya R. Surgical treatment of brain
metastases. Clin Neurosurg 1999; 45:41–47. Used with permission)
Percent Free From Local Recurrence
100
MDACC Surgery
80
BRIGHAM Radiosurgery
60
40
MDACC Radiosurgery
20
0
0 10 20
Follow-up Time (months)
Fig. 15.3 Freedom from local recurrence (local control) of brain
metastases with radiosurgery and with surgery. Curve showing time
from radiosurgical treatment to local failure (BRIGHAM Radiosurgery)
in 42 patients treated at Brigham and Women’s hospital [25] superim-
posed on curves showing time from surgical resection (MDACC
Surgery) to local recurrence in 62 patients and time to local failure in 31
patients radiosurgically treated (MDACC Radiosurgery) at The
University of Texas M.D. Anderson Cancer Center [23] (From Sawaya
R. Surgical treatment of brain metastases. Clin Neurosurg 1999; 45:
41–47. Used with permission)
R. Sawaya et al.
In contrast, when brain metastases are treated with SRS,
it is common for the tumor to remain visible on computed
tomography (CT) or MR images. Local tumor control with
SRS is less stringently defined and, in addition to tumor
regression, includes lesions remaining unchanged in size as
well as those undergoing no more than a 25 % increase in
size/volume above the baseline measurement. This makes it
difficult and misleading to compare values published for
local control of brain metastases by surgical resection and
SRS. In some patients who have a brain metastasis that is
stable on MR images or increases in size by less than 25 %,
surgery may be required to relieve neurologic deficits result-
ing from mass effect and persistent edema (Fig. 15.4) [33].
After surgical resection of brain metastases at
M.D. Anderson, we have observed local tumor recurrence at
a rate ranging from about 8–12 % [4, 23], which is consistent
with the observations of others. In patients treated for brain
metastases with SRS, similar 1-year local control failure
rates (6–15 %) are often reported [16, 18, 19, 34–38]. These
numbers reported for SRS are flawed not only because of the
less stringent definition of local control with SRS but also
because tumor recurrence in brain metastasis patients is a
function of survival time, and many radiosurgical series of
these patients report such short survival intervals (8 months
on average) that failure of local tumor control cannot be reli-
ably determined. Treatment of brain metastasis patients with
SRS at Brigham and Women’s Hospital [25] gave an 85 %
local control rate at 1 year, but this dropped steadily to 65 %
after 2 years (Fig. 15.3). More recent series of brain metasta-
sis patients treated with SRS have presented overall recur-
rence values (30–47 %) [26, 27] that are much higher than
those typical of surgically treated patients. These numbers
may be more realistic, reflecting a trend toward increased
follow-up monitoring of patients, with more routine neuro-
imaging [28].
Complications
Complications arising from surgical resection of brain
metastases are usually evident immediately. Deleterious
effects of SRS treatment are frequently delayed and may be
missed in follow-up visits, leading to an underreporting of
30 40
complications. A study using SRS alone to treat brain metas-
tases showed a complication rate of only 8 % [19]; neverthe-
less, 70 % of the complications were acute and included
increases in seizures and worsening of preexisting neuro-
logic symptoms. Similarly, in a study of recurrence of brain
metastasis after SRS, Regine et al. [27] observed that recur-
rence was symptomatic in 71 % of patients and was associ-
ated with a neurologic deficit in 59 %.
With the advent of modern neurosurgical techniques,
especially intraoperative stereotaxy and ultrasonography,
few metastatic brain tumors are surgically inaccessible.
15 Metastatic Brain Tumors: Viewpoint—Surgery 237

Fig. 15.4 CT scan of a patient

with non-small cell lung cancer
who had a 3-cm brain metastasis
in the right anterior parietal lobe
(left) that was treated with
radiosurgery. Three months later,
the tumor shrank by 23 %, but
the edema and the patient’s
symptoms were unchanged
(right). The patient subsequently
underwent a craniotomy and total
resection of the mass. The results
of the surgery are shown in
Fig. 15.2 (From Sawaya
R. Surgical treatment of brain
metastases. Clin Neurosurg 1999;
45:41–47. Used with permission)

Table 15.3 Major neurologic complications of surgery for metastases
in different brain regions
Metastasis location No. patientsa No. complications (%)
Noneloquent 79 1 (1)
Near-eloquent 61 6 (10)
Eloquent 54 4 (7)
Average major neurologic (6)
deficit rate
a
Total = 194 patients
Source: Adapted from Sawaya R. Surgical treatment of brain metasta-
ses. Clin Neurosurg 1999; 45:41–47. Used with permission
In a study of 194 patients at M.D. Anderson [4], the 30-day
morbidity rate for any major neurologic deficit after brain
metastasis resection was 6 % (Table 15.3). Even for resec-
tions in eloquent brain regions, this value only rose to 7 %.
The common perception that SRS is safer to use than con-
ventional surgery to treat brain metastases within or near
eloquent brain areas may not be warranted. In a retrospective
study of neurologic complications in patients treated with
SRS for brain metastases at M.D. Anderson, we found that
such complications (including radiation necrosis, seizures,
and neurologic symptom development or worsening) were
highest for tumors in eloquent brain, reaching 25 % for com-
plications of RTOG grade 3 and above [24].
At M.D. Anderson, the current mortality rate for surgical
resection of brain metastases is less than 2 %. Although it
has been claimed that SRS poses little risk of permanent
neurologic morbidity in brain metastasis treatment, mortali-
ties have occurred. In the study by Bindal et al. [23], sponta-
neous intratumoral hemorrhage occurred in 3 of 31 patients
treated with SRS, causing the death of one. Kondziolka and
coworkers [29] compared brain metastasis treatment with
SRS plus WBRT versus WBRT alone and reported a 1.8 %
mortality rate within 4 weeks after SRS. Thus, it appears that
mortality rates for SRS and surgical resection of brain metas-
tases are similar.
Another potential source of complications when treating
brain metastases with SRS stems from its inability to provide
a tissue biopsy for pathologic diagnosis. Because 5–11 % of
patients with a prior history of cancer and a brain lesion that
appears consistent with a metastasis may actually have non-
metastatic disease (primary brain tumor, abscess, multiple
sclerosis plaque, or a hemorrhage) [13, 39], SRS treatment
of such lesions can lead to an adverse outcome. With surgical
resection of brain metastases, it is easy to histologically con-
firm that the lesion is metastatic cancer, and this situation
does not arise.
Cost-Effectiveness
SRS is frequently promoted as a lower-cost alternative to
conventional surgery in the management of brain metastases.
Two publications have emerged using retrospective analyses
to compare relative costs of SRS and surgery in an attempt to
bolster this position [40, 41]. Unfortunately, these cost anal-
yses have relied on surgical expenses and data on length of
hospital stay from publications on patient series that were
already more than a decade old, such as that of Patchell et al.
[13], and have not taken into account the drastic cost-cutting
measures adopted by most hospitals and surgeons around the
country during the past decade.
Moreover, these cost-comparison studies [40, 41] make
the assumption that SRS and surgery are “equiefficacious”
in the management of patients with cancer metastatic to the
brain. They also assign inferior median survival values to
studies employing surgical resection plus WBRT for brain
metastasis treatment relative to SRS, thereby inflating
the average cost of surgery. Because there have been no
238
A.Pre
% of Patients
0
28≤ 26 24 22 20 18 16 14 12 10 8 6 4 2 0 2 4
Time (Weeks)
Fig. 15.5 Graphs depicting the duration (in weeks) of steroid treatment
from the time of conventional resection of the index lesion (Time 0).
The duration of continuous treatment is shown both before (a) and after
(b) conventional resection. Note that surgical resection facilitated taper-
prospective randomized studies comparing SRS and surgery
with respect to patient outcomes, there is no accurate
statistical basis for the presumed “equiefficaciousness” or
the survival numbers put forth.
To accurately reflect the total costs of SRS and surgical
resection for brain metastases, the expenses involved in
patient follow-up must be included. Typically, with SRS, only
the 1-day cost of treatment is considered in cost-effectiveness
studies, with follow-up being ignored. At M.D. Anderson,
follow-up costs after surgery for brain metastases have been
severely reduced because most patients are now discharged
from the hospital after 3 days. Follow-up expenses after SRS
are more significant than for surgery because many routine
MR imaging studies and office visits are required to monitor
the delayed effects of the radiation. These delayed effects
require extended administration of medications such as dexa-
methasone, which becomes costly. In our study of patients
undergoing resection of brain metastases after failure of SRS
to control their lesions [33], after their SRS treatment and
prior to surgery, 40 % of 53 patients required continuous ste-
roid administration for 12 weeks, which is consistent with
steroid dependency and is not a trivial expense. After surgery,
more than 95 % of these patients were able to cease steroid
usage within 2–4 weeks (Fig. 15.5).
Quality of Life
For many decades, WBRT has been the treatment of choice
for patients with intracranial metastasis. A recursive parti-
tioning analysis (RPA) performed on patients enrolled for
WBRT in RTOG trials showed median survival times of
R. Sawaya et al.
100
B.Post
80
60
40
20
6 8 10 12 14 16 18 20 22 24 26 ≥28
ing off of steroid use within 2–4 weeks (From Vecil GG, Suki D,
Maldaun MV, et al. Resection of brain metastases previously treated
with stereotactic radiosurgery. J Neurosurg 2005; 102(2): 209–215.
Used with permission)
7.1 months, 4.2 months, and 2.3 months for RPA classes I, II,
and III, respectively [42]. RPA class I patients had a con-
trolled primary tumor, a KPS score ≥ 70, were <65 years old,
and lacked extracranial metastases, whereas those in RPA
class III had a KPS score < 70, and the intermediate RPA class
II consisted of all other patients. In RTOG trial 85-28, the
effect of higher doses of radiation was evaluated in patients
who had a single brain metastasis [43]. In this trial, patients
treated with a fractionated dose of 54.4 Gy or higher showed
improved survival and better neurologic function. When this
regimen (54.4 Gy) was compared with 30 Gy administered in
ten fractions, no benefit to overall survival was noted [44].
The neurotoxicity was similar in both trial arms. An
M.D. Anderson trial showed that patients treated with SRS
for metastatic brain tumors have a significantly reduced risk
of neurotoxicity relative to patients treated with WBRT [45].
Concerns about potential neurotoxicity with WBRT and
the development of SRS have led to the introduction of newer
approaches for the treatment of metastatic brain tumors.
Currently, SRS is emerging as an initial management or as an
adjuvant treatment modality for brain metastases. The effec-
tiveness of SRS is measured by local disease control without
the possible long-term neurotoxic or cognitive side effects of
WBRT [46]. SRS boost improves survival in selected patients
in whom the predominant problem is brain disease rather
than extracranial disease, and it is also used as a salvage
treatment for progressive intracranial disease after surgery or
WBRT. Furthermore, SRS compromises the blood supply to
the tumor by indirect vascular injury and subsequent sclero-
sis of blood vessels [47]. This, in fact, supports the notion of
local tumor control and possible tumor burden reductions
after SRS treatment of brain metastases.
15 Metastatic Brain Tumors: Viewpoint—Surgery
Surgical resection of a brain metastasis usually provides
immediate relief of neurologic symptoms produced by mass
effect of the tumor and the edema surrounding it. Thus, the
patient can be on his feet that much sooner, and few follow-
up visits are required. With SRS treatment of a brain metas-
tasis, radiation damage to the tumor frequently takes time to
develop, and the therapeutic effect with consequent resolu-
tion of neurologic symptoms may be delayed for days or
weeks. Multiple follow-up visits are required to monitor the
tumor’s response to SRS with MR imaging or CT. For symp-
tom relief, the patient must receive continuous steroid
administration that can last for months, while remaining
debilitated at home.
Conclusion
The debate continues as to whether surgical resection or SRS
is better in managing tumors metastatic to the brain. Settling
the issue of which modality affords patients the longer
median survival time awaits the outcome of a prospective
randomized trial comparing the two. Both methods have
clear benefits. Surgery has the advantages of immediate reso-
lution of mass effect, procurement of tissue for pathologic
diagnosis, and lack of the risk of radiation necrosis [48]. SRS
carries a decreased risk of hemorrhage and infection, has no
risk of tumor seeding, and is less invasive, potentially less
costly, and requires a shorter hospital stay than standard cra-
niotomy. Disadvantages of SRS include potential radiation
necrosis or exacerbation of peritumoral edema and a require-
ment for long-term steroid administration [49, 50].
In our experience at M.D. Anderson, we believe that the
size and location of the metastases along with the patient’s
clinical presentation can be used to recommend one modality
or the other. We almost always favor surgery in the case of
brain metastases larger than 3 cm in maximum diameter,
whereas deeply located lesions smaller than 1–1.5 cm in
maximum diameter are usually treated with SRS. If the
lesions lend themselves to treatment by either method, we let
the patient’s symptoms be the guide; lesions that produce
symptoms are more frequently treated surgically, and lesions
that do not can be treated with SRS. Of course, this approach
may be modified depending upon the patient’s systemic can-
cer status or medical condition. Patients who cannot tolerate
surgery, who have progressive systemic disease, or who are
expected to live for less than 3 months are treated with
SRS. The best management strategy for patients with brain
metastases should involve the complementary use of surgery,
SRS, and WBRT.
Acknowledgment We thank the Barbara Falik Research Fund for
helping make this work possible.
239
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 Metastatic Brain Tumors: Viewpoint:
Whole Brain Radiation Therapy
William F. Regine, Sarah F. Grabowski, and Roy A. Patchell
Introduction
Whole-brain radiation therapy (WBRT) is the mainstay of
treatment for most patients with intracerebral metastases. It
is useful for most newly diagnosed tumors and sometimes
also as salvage therapy for recurrent tumors.
Efficacy of WBRT
Given the general consensus that WBRT is an effective treat-
ment for brain metastases, it is surprising to note that there
have been limited randomized data comparing WBRT with
best supportive care or no treatment [1]. To our knowledge,
only one randomized trial (performed in the pre-computed
tomography era) has evaluated the addition of WBRT to sup-
portive care [2]. In this trial, 48 patients with presumed brain
metastases were randomized to steroids with or without
40 Gy WBRT. Although p-values were not given, the addition
of WBRT led to improved duration of remission as well as
median survival (14 vs. 10 weeks). Additional support for the
general efficacy of WBRT comes from comparing the out-
comes of patients after WBRT treatment with the natural his-
tory of untreated brain metastases. Data from large
retrospective studies [1, 3, 4] have shown that WBRT
increases the median survival time to 3–6 months and that
more than half of patients treated with WBRT die ultimately
W.F. Regine, M.D. (*) • S.F. Grabowski, M.D.
Department of Radiation Oncology, University
of Maryland Medical Center, 22 South Greene Street,
Baltimore, MD 21201, USA
e-mail: wregine@umm.edu; sgrabowski@umm.edu
R.A. Patchell
National Brain Tumor Center, Capital Institute
for Neurosciences, Capital Health Medical Center-Hopewell,
Two Capital Way, Suite 456, Pennington, NJ 08534, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_16, © Springer Science+Business Media New York 2015
16
of progressive systemic cancer and not as a direct result of
brain metastases. This contrasts with the natural history
of untreated patients, which is that patients live for a median
of 1–2 months and virtually all die as result of their brain
lesions [2, 5–7]. There is little doubt that WBRT does control
or improve symptoms, at least temporarily, in the majority of
patients with brain metastases. Responses to radiation can be
seen early in the treatment course, with 50 % of patients
experiencing an improvement in neurologic symptoms by the
second week of treatment [8]. Overall, the clinical and radio-
graphic response to brain radiation ranges from 50 to 75 %
[9]. Ultimately, the primary goals of the management of the
patient with brain metastases are to provide effective pallia-
tion, improve quality of life and, if at all possible, extend sur-
vival. To these ends, stereotactic radiosurgery (SRS) and
whole brain radiation therapy (WBRT) are effective treat-
ment modalities that often play a significant role in the man-
agement of brain metastases. Although sometimes thought to
be competing modalities, they are, in fact, quite complemen-
tary; SRS delivers ablative radiation doses with a high degree
of precision (typically in one fraction), whereas WBRT deliv-
ers lower amounts of radiation to the entire brain parenchyma
(typically over the course of weeks). The former is more
effective in treating clinically visible tumor deposits, whereas
the latter treats microscopic foci of disease and each has been
shown to improve outcomes in specific settings.
Unsettled Issues
Although there is general agreement on efficacy, no consen-
sus exists on the optimum WBRT dose and schedule for the
treatment of brain metastases. The best available data on the
effect of dose and schedule for the treatment of brain metas-
tases comes from several large-scale multi-institutional trials
conducted by the Radiation Therapy Oncology Group
(RTOG) [1, 8, 10–12]. These studies have shown no signifi-
cant difference in the frequency and duration of response for
total radiation doses ranging from 2,000 cGy over 1 week to
241
242
5,000 cGy over 4 weeks. Regimens of 1,000 cGy in a single
dose or 1,200 cGy in two doses were less effective and are no
longer in use. Typical radiation treatment schedules for brain
metastases consist of short courses (7–15 days) of WBRT
with relatively high doses per fraction (150–400 cGy per
day) and total doses in the range of 3,000–5,000 cGy. These
schedules minimize the duration of treatment while still
delivering adequate amounts of radiation to the tumor.
Attempts to Improve WBRT
Different fractionation and dosing schemes have been tried
in order to improve the effectiveness of WBRT with varying
results. Epstein et al. [13] reported a phase I/II dose-escalation
study of hyperfractionated radiotherapy using total doses of
48, 54.4, 64, and 70.4 Gy. No increased toxicity was identi-
fied and the three highest dose arms had a statistically signifi-
cant improvement in median survival over the lowest dose
arm. This study suggested a dose-dependent effect with the
use of hyperfractionated radiation in unresected, single brain
metastasis. Unfortunately, a large randomized RTOG trial,
studying both single and multiple brain metastases, failed to
show improvement in overall survival using a hyperfraction-
ated schedule of 54.5 Gy in 34 fractions compared with a
standard regimen of 30 Gy in 10 fractions [14].
Similarly, multiple randomized trials have failed to iden-
tify a benefit to the addition of radiosensitizers or chemo-
therapy to WBRT [9]. Investigators, nonetheless, continue to
search for drugs that will improve the therapeutic ratio
between normal brain tissue and tumor cells.
Complications of WBRT and the Concern
for Neurotoxicity
WBRT has complications. Almost all patients experience a
temporary loss of hair; although hair growth usually resumes
6–12 months after completing therapy. Also, in the short-
term, patients may have a transient worsening of neurologic
symptoms while receiving therapy. Many physicians believe
that maintaining patients on steroids during radiotherapy
will minimize radiation complications, although conclusive
proof of this has not been forthcoming. The long-term side
effects of radiotherapy are usually not a significant issue in
the treatment of patients with brain metastases because of the
relatively short survival time of these patients.
When discussing neurotoxicity, it is important to note that
nearly all patients with brain metastases present with neuro-
cognitive deficits prior to beginning WBRT [15]. Meyers
et al. reported the most extensive study evaluating neurocog-
nitive function for patients with brain metastases. This
detailed work examined neurocognitive function in patients
with brain metastases randomized to WBRT with or without
W.F. Regine et al.
the radiation sensitizer, Motexafin Gadolinium. 401 patients
were enrolled and each patient underwent a battery of eight
neurocognitive function tests at baseline and following treat-
ment. At baseline, 91 % of patients had a deficit, and 42 %
had deficits seen in four or more tests. Lesion volume was
predictive of initial neurocognitive deficit. This data is criti-
cal as most studies do not describe baseline neurocognitive
deficits. Not only does recurrence of intracranial disease
result in significant symptoms, it is also one of the most
important predictors of neurocognitive dysfunction. Meyers
et al. also noted a correlation between tumor progression and
worsening neurocognitive function [16]. Following treat-
ment, patients with tumor shrinkage at 2 months greater than
the population median had improved survival as well as a
longer time to neurocognitive dysfunction. Patients with a
partial response also had an improvement in execution func-
tion and visual motor scanning from baseline. In compari-
son, patients with progressive disease had a significant
worsening of neurocognitive symptoms.
One often quoted retrospective study by DeAngelis et al.
[17] suggests that as many as 11 % of long-term survivors
(>12 months) of brain metastases treated with WBRT develop
dementia. However, virtually all of the patients in that sam-
ple who developed dementia had been treated with atypically
large radiation fractionation schedules. The patients treated
with fraction sizes of 3.0 Gy or less per day did not develop
clinically apparent dementia. Thus, the actual frequency of
radiation-related dementia when using convention fraction-
ation schedules is not known, but is certainly less than 11 %.
In any event, the frequency of long-term neuropsychological
side effects of WBRT in adult brain metastases patients
appears to have been overestimated and seems to be within
the acceptable range when modern fractionation schemes are
employed. As such, the question is not whether WBRT alone
results in any neurotoxicity, but rather whether its overstated
risks are outweighed by the benefits of reduced intracranial
failure with associated neurocognitive dysfunction. In our
view it generally is. When discussing the pros and cons of
WBRT with patients, it is important that the physician main-
tains appropriate perspective regarding the toxicities associ-
ated with WBRT. For instance, recently, there has been
accumulating data suggesting that many systemic chemo-
therapies are associated with long-term neurotoxicities [18,
19]. That is not to say that all chemotherapy need be aban-
doned, but rather whenever prescribing treatment, one must
make sure that the benefits outweigh the risks.
WBRT With or Without SRS in the Treatment
of Brain Metastases
Because the majority of patients have multiple metastases,
the efficacy data for WBRT comes in a large part from treat-
ment of patients with multiple brain metastases. There is little
16 Metastatic Brain Tumors: Viewpoint: Whole Brain Radiation Therapy
doubt that WBRT is effective for multiple metastases, and it
is used routinely. The main controversy regarding the treat-
ment of multiple metastases involves the use of radiosurgery
(either with or without WBRT).
To date, there have been two randomized trials [20, 21]
assessing the efficacy of radiosurgery in the treatment of
multiple metastases. The first randomized trial was reported
by Kondziolka et al. [20]. In that study, 27 patients with mul-
tiple brain metastases were randomized to treatment with
WBRT alone or WBRT plus a radiosurgery boost. The study
was stopped early because the authors claimed to have found
a large difference in the recurrence rates in favor of radiosur-
gery. Unfortunately, the study used nonstandard end points
to measure recurrence. The investigators used any change in
measurement of the lesion rather than the more usual 25 %
increase in diameter. No attempt was made to control for ste-
roid use, radiation changes, or other factors that might pro-
duce small fluctuations in lesion size on magnetic resonance
imaging (MRI). Also, as a study with only 27 patients, it
lacked the statistical power to support any meaningful con-
clusion, regardless of p values. As a result, this study was
uninterpretable.
A second study was reported by Andrews et al. [21]. This
study (RTOG 9508) contained 333 evaluable patients with
one to three brain metastases who were randomized to treat-
ment with either WBRT (37.5 Gy) plus radiosurgery or
WBRT (37.5 Gy) alone. The primary end point was survival.
Overall, there was no significant difference in survival
between the two treatment groups (median, 6.5 months for
radiosurgery plus WBRT and 5.7 months for WBRT-alone,
p = 0.1356). There was no survival benefit from radiosurgery
in patients with multiple metastases (median, 5.8 months for
radiosurgery plus WBRT and 6.7 months for WBRT-alone,
p = 0.9776). (However, for patients with single metastases,
there was a significant survival advantage favoring radiosur-
gery, median 6.5 months vs. 4.9 months, p = 0.0393). Lower
posttreatment Karnofsky scores and steroid dependence
were more common in the WBRT-alone group. Multiple sub-
group analyses were performed, and a benefit for radiosur-
gery plus WBRT was found in several subgroups that
included patients with single and multiple metastases. These
subgroups were RPA class 1 patients, patients with metasta-
ses size equal to or larger than 2 cm, and lung cancer patients
with squamous cell histology. However, these subset analy-
ses were not prespecified, and the p values needed for signifi-
cance should have been adjusted for inflation of type I error.
When this was done, none of these subgroup analyses
showed a positive benefit for radiosurgery [22]. So, for mul-
tiple brain metastases, this was a completely negative trial
with regard to the major end points prevention of death due
to neurologic causes and overall survival.
Radiosurgery has been put to the test in the treatment
of multiple metastases and has not been established as
effective. Therefore, based on the best available evidence,
243
WBRT-alone is the treatment of choice for most patients
with multiple brain metastases (and the word “multiple” in
this context means more than one).
Adjuvant WBRT in Conjunction with Focal
Treatment of Brain Metastases
For the treatment of single brain metastases, randomized trials
have established the superiority of focal treatment (either con-
ventional surgery or radiosurgery) plus WBRT over treatment
with WBRT-alone. Therefore, good-prognosis patients with
single brain metastases should be treated with upfront surgery
or radiosurgery. However, with the establishment of the effi-
cacy of focal treatments for single brain metastases, a new
controversy has arisen as to whether adjuvant WBRT is really
necessary after a “complete resection” or “successful” treat-
ment with radiosurgery. Adjuvant WBRT is thought to be of
benefit because there may be residual disease in the tumor bed
or at distant microscopic sites in the brain. However, brain
metastases tend to be discrete masses that are theoretically
capable of being removed totally or destroyed, and so WBRT
may not be necessary after “successful” focal therapy.
There are several reasons for eliminating WBRT. First,
WBRT has adverse, long-term neuropsychological side
effects. Second, there are also the costs and time commit-
ment of the patient that must be considered. And finally,
there is the possibility that WBRT may simply not be needed
at all. It is theoretically possible to completely remove single
brain metastases by surgery, or to control them with radio-
surgery. Furthermore, neuroimaging has improved, and it
may now be possible to detect reliably additional metastases
that may be present and treat these with additional focal ther-
apy. If these last two statements are true, then there would be
little justification for adjuvant WBRT.
On the other hand, compelling reasons exist for giving
adjuvant WBRT. As a practical matter, it is likely impossible
to completely remove all metastases with conventional sur-
gery, and radiosurgery does not completely control multiple
tumors. In addition, neuroimaging may not have reached the
point yet where we can be absolutely certain that all metasta-
ses are being detected, and therefore some type of additional
treatment may be needed. Also, although WBRT does have
side effects, these side effects may not be as severe or as
common as was previously thought. Furthermore, most
patients with brain metastases have relatively limited overall
survival times, and so the really serious long-term side
effects are usually not an issue in their care.
Randomized trials [23–25] have addressed the question of
adjuvant WBRT in conjunction with focal treatment. A study
published in 1998 by Patchell et al. [23] examined the effect
of WBRT in conjunction with conventional surgery. In that
study, 95 patients who had single brain metastases that were
completely surgically resected were randomized to treatment
244
with postoperative WBRT (50.4 Gy) or to observation with
no further treatment of the brain metastasis (until recur-
rence). Recurrence of tumor anywhere in the brain was less
frequent in the radiotherapy group than in the observation
group (18 % vs. 70 %, p < 0.001). Postoperative radiotherapy
prevented brain recurrence at the site of the original metasta-
sis (10 % vs. 46 %, p < 0.001) and at other sites in the brain
(14 % vs. 37 %, p < 0.01). As a result, patients in the radio-
therapy group were less likely to die of neurologic causes
than patients in the observation group (6 of 43 who died
[14 %] vs. 17 of 39 [44 %]; p = 0.003). There was no signifi-
cant difference between the two groups in overall length of
survival or the length of time that patients remained func-
tionally independent.
The effect of WBRT in association with radiosurgery was
examined in a randomized trial conducted by the Japanese
Radiation Oncology Study Group and reported in abstract
form by Aoyama et al. [24]. In that study, 132 patients with
one to four brain metastases were randomized to treatment
WBRT plus radiosurgery or with radiosurgery-alone. The
WBRT total dose was 30 Gy. The radiosurgery dose was
18–25 Gy at the periphery of the lesion in the radiosurgery-
alone group and was reduced by 30 % in the WBRT plus
radiosurgery group. The median survival time was 7.5 months
in the WBRT plus radiosurgery group and 8.0 months in the
radiosurgery-alone group, p = 0.42. The 12-month brain
metastases recurrence rates were significantly (p < 0.001)
different (47 % in the WBRT plus radiosurgery group and
76 % in the radiosurgery-alone group). Death due to neuro-
logic causes and neurologic functioning were not signifi-
cantly different between the two groups.
Despite the fact that both of the randomized trials [23, 24]
showed clearly that WBRT prevented recurrences, these
studies have actually provoked controversy rather than set-
tling the issue. Results of these trials have been used as rea-
sons both to give and not to give adjuvant WBRT. The
justification for not giving WBRT holds that because no sur-
vival difference was found in either of the trials, WBRT
really adds nothing to the treatment. This argument fails on
several counts.
The Patchell study [23] used tumor recurrence as the pri-
mary end point and was not designed either to show a differ-
ence in survival or to rule one out. There was actually an
increase of 11 % in survival time in the WBRT group when
compared with the observation group. The relative risk of
improved survival with WBRT was 1.1. However, this was
not a statistically significant difference. Because there was a
statistically significant reduction in death due to neurologic
causes, ultimately adjuvant WBRT might have had some
positive impact on overall survival time. The estimated sam-
ple size required to detect a significant difference of 11 % in
overall survival with adequate power would have been 1,005
patients per group or 2010 patients total. For practical rea-
W.F. Regine et al.
sons, the study could not be designed to have this large of a
sample size and, therefore, was not designed to detect mod-
erate differences in survival, even one as large as 11 %.
There is an even stronger reason for discounting the
apparent lack of efficacy of postoperative WBRT with regard
to length of survival in the Patchell trial [23]. Recurrence of
tumor in the brain was the primary end point of that random-
ized trial, and this end point was the only truly direct mea-
sure of the effects of adjuvant WBRT. Up until recurrence of
tumor, the two treatment groups were distinct, and the
patients in each had received the treatment assigned by ran-
domization. However, at recurrence, no specific treatment
was mandated by the study design, and as a result, patients
received a variety of additional treatments. There was an
extremely large crossover of the observation group to WBRT.
Of the 32 patients in the observation group who developed
recurrent brain metastases, 28 patients got WBRT. Overall,
that means that 61 % (28 patients of 46 total) in the “no
WBRT” observation arm were, in fact, treated ultimately
with WBRT. For the purposes of length of survival and func-
tional independence, the study was virtually a comparison of
surgery plus immediate WBRT vs. surgery plus delayed
WBRT. This substantially diluted the effect of WBRT given
immediately postoperatively because WBRT probably
improved the length of survival and functional independence
in the observation group. Therefore, for all the reasons given
above, the Patchell study did not “prove” that WBRT had no
positive effect on survival.
The Aoyama trial [24] also failed to find any difference in
survival with the addition of WBRT. This study differed in
design from the Patchell study and was devised with survival
as the primary end point; it was originally powered to be able
to detect a 30 % or greater difference with 89 patients per
treatment arm. (Given that the Patchell study [23] and numer-
ous retrospective studies had failed to find a difference in
survival even close to 30 %, the Aoyama study [24] should
have been powered as an equivalence trial [if survival was
going to be used as the primary end point]). The study was
stopped after an interim analysis at 132 patients indicated
that the study was not going to show a statistically significant
difference in survival, even if all of the 178 patients origi-
nally projected to be in the trial had been randomized.
Therefore, any negative conclusion based on the original
power calculation, that is, that there was no more than a 30 %
difference in survival (or any other reasonable difference),
cannot be supported. This study also had an 11 % crossover
that further eroded the strength of any conclusions about sur-
vival. In addition, about half of the patients in both treatment
arms had multiple brain metastases. The study by Andrews
et al. [21] failed to establish the efficacy of radiosurgery in
the treatment of multiple metastases, and so the inclusion of
these patients is problematic and further reduces the number
of valid patients on which to base a conclusion about survival
16 Metastatic Brain Tumors: Viewpoint: Whole Brain Radiation Therapy
benefit. Thus, like the Patchell trial [23] before it, this
Aoyama study [24] was unable to show that there was no
difference in survival. Therefore, arguments based on the
supposed lack of efficacy of (immediate) postoperative
WBRT on survival are based on a misunderstanding of the
design and limits of the randomized trials.
In addition, the Aoyama study demonstrated that omitting
WBRT does not produce any difference in either gross neuro-
logic or neurocognitive functioning. From this information,
Aoyama et al. [24] and the Journal of the American Medical
Association (JAMA) editorial writer [26] concluded that the
addition of WBRT is not necessary and can be safely omitted
in the treatment of most patients with brain metastases.
However, even if one takes the data presented in the paper at
face value, it is possible to draw exactly the opposite conclu-
sion. As stated by the authors and the editorial writer, the
main reason for not giving WBRT is to avoid the long-term
neurotoxic effects of WBRT. Yet, this study found no differ-
ence in neurologic functioning, neurocognitive functioning,
gross radiation-induced side effects, or survival times between
the two groups. In fact, deterioration in neurologic function
attributable to progression of brain metastases was observed
in 59 % of patients in the WBRT group and 86 % in the SRS-
alone group (p = 0.05), indicating a significantly higher rate of
neurologic deterioration as a consequence of tumor progres-
sion in patients when WBRT is withheld. Interestingly, in
subsequent analysis among patients with normal MMSE at
baseline, WBRT resulted in an increased average duration
until deterioration (17 vs. 8 months, p = 0.05) [27]. Thus, at
very least, WBRT appears to significantly reduce the recur-
rence of brain metastases without demonstrable neurotoxic-
ity. Therefore, the trial by Aoyama et al. [24] seems to support
strongly the use of WBRT as upfront treatment in the man-
agement of most patients with brain metastases.
A more recent and widely publicized study evaluating the
role of WBRT following SRS for patients with`brain metas-
tases was reported by Chang et al. from MD Anderson (level
II evidence) [25]. Patients in this study were randomized to
15–24 Gy SRS with or without 30 Gy WBRT in 12 fractions.
The primary endpoint was a decline in Hopkins Verbal
Learning Treatment-Revised at 4 months. The trial closed
early after accrual of only 58 patients based on concern for
significantly worse neurocognitive outcomes secondary to
the addition of WBRT. WBRT patients were found to have a
52 % decline in HVLT-R at 4 months, whereas patients in the
SRS alone arm had only a 24 % decline. Once again, the
addition of WBRT resulted in decreased 1-year intracranial
recurrence (27 % vs. 73 %, p = 0.0003), including both
improved local (100 % vs. 67 %, p = 0.012) and elsewhere
(73 % vs. 45 %, p = 0.02) brain tumor control. Paradoxically,
and unprecedented in similar randomized trials, patients in
the WBRT arm had a significantly compromised median
survival (5.7 vs. 15.2 months, p = 0.003).
245
The trial, while commendable for its effort to prospectively
study neurocognitive function following WBRT, has several
shortcomings which make its findings difficult to generalize
[28]. For one, the study used patient stratification variables not
prognostic of the study’s primary neurocognitive endpoint. In
this study, patients were stratified by recursive partitioning
analysis class, number of brain metastases, and histology,
which are factors linked to survival rather than neurocognitive
function. The authors did not stratify by baseline neurocogni-
tive function, examination of which suggests at least a trend
toward increased neurocognitive dysfunction in the WBRT
group. Also important is the fact that the authors failed to
account/stratify for many medications commonly prescribed
to cancer patients—including opioids, sedatives, anticonvul-
sants, and steroids—that are known to cause neurocognitive
dysfunction. Second, the authors chose an endpoint with
questionable clinical relevance. The primary endpoint of their
study was an assessment of neurocognitive function using
only the HVLT-R at a single time point of 4 months; however,
given the complexity of cognitive function, a battery of tests
over time is required to accurately depict the neurocognitive
effects of RT [29]. In addition, this primary endpoint inadver-
tently biased the trial against WBRT as previous work had
already shown that RT has a transient effect on memory, as
measured by verbal learning tests. In serial neuropsychologi-
cal studies, Armstrong and colleagues [30] assessed patients
with low-grade glioma who received RT and found a transient
decline in verbal memory, with the nadir after RT correspond-
ing exactly to the 4-month time interval used by Chang and
colleagues [25]. Finally, as mentioned above, patients receiv-
ing WBRT inexplicably had a significantly shorter median
survival than patients who received SRS alone, on the order of
a threefold difference (5.7 vs. 15.2 months). This is particu-
larly perplexing given the improved CNS disease control with
WBRT (27 % vs. 73 % at 1 year). Moreover, three previous
randomized studies reported equivalent survival with the addi-
tion of WBRT to local therapy [23, 24, 31]. What specifically
led to such a survival difference is unclear, although close
inspection of the baseline patient characteristics suggests at
least a trend towards more favorable factors (RPA class I,
female gender, and lower median tumor volume) in the SRS
alone group. The authors suggest that the survival difference
might be due in part to more frequent surgical salvage in
patients who received SRS alone; however, the greater use of
surgical salvage is more likely to be the result of increased
CNS disease recurrence rather than a disproportionate ration-
ing of salvage treatments. Also, although patients receiving
WBRT had a higher proportion of systemic deaths, this is due
to a delay in neurological mortality, rather than an increased
systemic disease burden, a finding originally reported by
Patchell et al. [23]. Perhaps then the survival difference was
simply the result of statistical anomaly due to small patient
numbers. Regardless, this survival difference could in itself
246
explain the neurocognitive dysfunction found in patients
receiving WBRT. The primary endpoint of this study was an
assessment of neurocognitive function at 4 months (~1 month
prior to the median date of death of patients in the WBRT
group). Many studies suggest that patients with terminal can-
cer experience profound neurocognitive dysfunction [32, 33].
For example, Pereira and colleagues followed 348 cancer
patients with serial mini-mental state examinations (MMSE)
and found that patients who died had a trend toward decreased
scores, with 68 % of patients having abnormal MMSE scores
before death [32]. The decline in MMSE score was most pro-
found 1 month before death. As such, the higher neurocogni-
tive dysfunction noted in the WBRT group cannot be
confidently ascribed to radiation given the large survival dif-
ference noted between treatment groups, along with the tim-
ing of death in the WBRT group in relation to the single
4-month study endpoint (~1 month prior to median survival in
WBRT group).
The most forceful argument in favor of adjuvant WBRT
involves an examination of the effects of not giving
WBRT. Patients who do not receive adjuvant WBRT suffer
substantially more recurrent brain metastases than patients
who are treated with WBRT. As previously noted, the harm-
ful side effects of WBRT appear to have been overestimated
in the past and are probably in the acceptable range.
Unfortunately, the same cannot be said of the side effects of
recurrence of brain metastases.
Several studies [34, 35] have demonstrated that the recur-
rence of brain metastases has a negative effect on the neuro-
cognitive functioning of patients. A study by Regine et al.
[34] found that in 36 patients with brain metastases treated
with SRS alone, 47 % had recurrence of brain metastases and
71 % of the recurrences were symptomatic. Significantly,
59 % of the patients with recurrent tumors had associated
neurologic deficits and 17 % were unable to undergo salvage
brain therapy because of their overall poor general status
associated with brain tumor recurrence. These findings are
now substantiated by the level 1 evidence provided by the
Aoyama phase III trial [27] where deterioration in neurologic
function attributable to progression of brain metastases was
observed in 59 % of patients in the WBRT group vs. 86 % in
the SRS-alone group (p = 0.05); indicating a significantly
higher rate of neurologic deterioration as a consequence of
tumor progression in patients when WBRT is withheld [24].
Another study by Regine et al. [35] showed that, at 3 months
after treatment, patients treated for brain metastases with
WBRT had greater negative changes in their mini-mental sta-
tus examinations with uncontrolled brain tumors than they
did with controlled brain tumors (−6.3 points vs. −0.5 points,
p = 0.02). Also relevant (but perhaps somewhat farther afield)
was a study by Taylor et al. [36] showing that, in patients
with primary brain tumors at 12 months after treatment,
changes in mini-mental status examinations were worse in
W.F. Regine et al.
patients with uncontrolled tumors (−2.42 points) than in
patients with controlled tumors (+0.076 points) (p = 0.0046).
All of the patients in this study had received large total doses
of conventional radiation therapy.
These studies all strongly suggest that uncontrolled brain
tumors result in a substantial decrease in mental performance
and that this reduction far outweighs any decrement seen
with cranial radiation therapy. Therefore, the side effects of
recurrent tumors are worse than the side effects of preventive
treatment. This is an extremely strong argument for the use
of adjuvant WBRT in association with focal therapy.
WBRT for Recurrent Brain Metastases
Brain metastases often recur, and CNS progression may be
accompanied by systemic tumor progression and a decline in
functional status. In general, the same types of treatment
used for newly diagnosed brain metastases are also available
for recurrent tumors. However, the type of previous therapy
may limit the therapeutic options available at recurrence, and
the development of radioresistance is not uncommon.
If patients have not already had WBRT, they should be
treated with it on recurrence. However, often patients with
recurrences have already been treated with WBRT, and this
limits the amount of subsequent radiation that can be given
safely. The amount of additional radiation that can be offered
is usually in the range of 1,500–2,500 cGy, a total dose usu-
ally inadequate to control tumor growth.
Several retrospective studies [37–41] have attempted to
assess the efficacy of salvage WBRT. It is difficult to assess
efficacy from these reports. Rates of improvement ranged
from 27 to 70 %; however, the range of duration of response
was fairly uniform and was 2.5–3 months. The median sur-
vival ranged from 1.8 to 4.0 months. Relatively few long-
term complications were reported; however, because the
median survival is quite short, most patients did not live long
enough to develop the long-term complications of radiation.
The problem with the interpretation of these studies is that
they often used different end-point measurements for
improvement and had heterogeneous patient populations.
Some included patients with poor performance status and
extensive disease, while others selected out favorable sub-
groups for radiation. One recommendation based on a retro-
spective study [37] is to restrict reirradiation to patients who
showed an initial favorable response to radiotherapy, had a
longer disease-free interval, and who remain in good general
condition when the cerebral recurrence develops. However,
even in this favorable subgroup, only 42 % of patients
showed symptomatic improvement, and the median survival
after reirradiation was 5 months. Despite such relatively poor
results, additional radiotherapy is frequently one of the few
treatment options for patients with recurrent disease.
16 Metastatic Brain Tumors: Viewpoint: Whole Brain Radiation Therapy
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 Stereotactic Radiosurgery
and Radiotherapy in the Management
of High-Grade Gliomas
David Roberge and Luis Souhami
Introduction
Primary brain tumors are classified according to their pre-
dominant cell type. Glial neoplasms are the most common
primary intracranial malignancies and are classified as astro-
cytic tumors, oligodendroglial tumors, and ependymal tumors.
Astrocytomas are the most common variant of glioma and
most adult astrocytomas are high grade. Of these, glioblas-
toma multiforme (GBM or astrocytoma grade IV) represents
the most common subtype [1], making this the most common
malignant brain tumor in adults. Despite the best use of sur-
gery, radiation, and chemotherapy, long-term survival of
patients with GBM has been distinctly uncommon. In
unselected series, the 5-year-survival has been as low as 2 %
[2, 3]. Anaplastic astrocytoma (AA), or astrocytoma grade III,
represents less than 20 % of malignant gliomas and are asso-
ciated with a more favorable outcome [1, 4]. For the scope of
this chapter, only high-grade gliomas (HGG), which include
both grade III and IV astrocytomas, will be discussed.
High-grade gliomas are infiltrating tumors that can enlarge
rapidly, resulting in various signs and symptoms, such as
focal or generalized seizures, headache, visual disturbances,
speech disturbances, changes in mental status, and motor or
sensory deficits. Malignant glial cells are thought to evolve
from an accumulation of multiple genetic aberrations in nor-
mal precursor cells. In a stepwise fashion, this accumulation
of deleterious genetic alterations may result in transforma-
tion of a glial cell into a low-grade glioma and subsequently
into an aggressive phenotype associated with high-grade
tumors. Several molecular studies have generated multiple
D. Roberge, M.D. (*)
Department of Radiation Oncology, CHUM—Notre Dame,
1560 Sherbrooke E, Montreal, QC, Canada H2L 4M1
e-mail: david.roberge.chum@ssss.gouv.qc.ca
L. Souhami, M.D., F.A.S.T.R.O.
Division of Radiation Oncology, McGill University,
1650 Cedar Avenue, Montreal, QC, Canada H3G 1A4
e-mail: Luis.souhami@muhc.mcgill.ca
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_17, © Springer Science+Business Media New York 2015
17
markers linked with malignant gliomas including chromo-
somal deletion, addition, mutation, and gene amplification
that may have important clinical implications [5]. Both GBM
and AA can be of two types based on their clinical presenta-
tion. Primary high-grade astrocytomas occur de novo and are
associated with short duration of symptoms and worse prog-
nosis, while secondary high-grade gliomas often occur in
patients with a previous low-grade astrocytoma [6]. Unique
sub-populations, such as secondary frontal tumors with an
isocitrate dehydrogenase 1 (IDH1) mutation, make the case
for groups of tumors having distinct pathogenesis [7].
High-grade glioma is a local disease; distant spread is
uncommon and up to 90 % of initial recurrences are located
within 2 cm of the original enhancing lesion [8–11]. Overall,
the prognosis of HGG is related to tumor grade, performance
status, age, and treatment. Five other prognostic factors were
incorporated in a 1993 prognostic scheme based on recursive
partitioning analysis (RPA) of the individual patient data
from three Radiation Therapy Oncology Group (RTOG) tri-
als [4]. Using several prognostic variables, patients were
divided into six classes with median survivals ranging from
4.7 to 58.6 months. The RPA classification has been fre-
quently used in the comparison of treatment results and has
been updated to reflect improved outcomes following initial
combined treatment with temozolomide (Table 17.1).
Despite intermittent waves of enthusiasm regarding vari-
ous treatment modalities, the survival of patients with HGG
has only improved modestly from 1950 to 2000. In this chap-
ter, we describe and contextualize the use of stereotactic
radiosurgery (SRS) and fractionated stereotactic radiother-
apy (F-SRT) in the management of primary and recurrent
malignant gliomas.
Historical Perspective
The poor prognosis of HGG is known for many years.
In 1926, Bailey and Cushing, in reference to what they at
the time called “spongioblastoma multiforme,” made the
249
250
Table 17.1 RTOG recursive partitioning analysis classes [4]
Class Original RTOG definition
I Age <50, AA, normal mental status
II Age ≥50, KPS 70–100, AA, ≥3 months from first symptoms to treatment
III Age <50, AA, abnormal mental status or
Age <50, GBM, KPS 90–100
IV Age <50, GBM, KPS <90 or
Age ≥50, KPS 70–100, AA, ≥3 months from first symptoms to treatment or
Age >50, GBM, surgical resection, good neurologic function
V Age ≥50, KPS 70–100, GBM, either surgical resection and poor neurologic
function or biopsy only followed by ≥54.4 Gy EBRT or
Age ≥50, KPS <70, normal mental status
VI Age ≤50, KPS <70, abnormal mental status
Age ≥50, KPS 70–100, GBM, biopsy only, <54.4 Gy EBRT
following observation: “Operative procedures, howsoever
radical [block extirpations repeated on signs of recurrence;
saturation with X-rays or radium emanations after wide
decompression with or without surgical interference with the
tumor], have apparently done little more than to prolong life,
save vision, and alleviate headache for an average of a few
months. Whether deep Roentgenization ever does more than
hold the growth temporarily in check is problematical” [12].
By the time Elvidge, Penfield, and Cone published their
“McGill series” in 1937, the name “glioblastoma multi-
forme” had become widely accepted and neurosurgery was
still faced with the same “difficult human problem” posed by
these patients [13].
Thirteen years after the publication of Elvidge and col-
leagues, the following case history was published as part of a
paper reviewing 70 glioblastoma multiforme patients treated
at the Montefiore Hospital [14].
Case 17.1 represented the longest surviving patient in the
literature of the day [14]. Prognostic factors for the
Montefiore series were reviewed: “An analysis of factors in
survival revealed that operation had no significant effect on
longevity and irradiation a slight effect, if any. The longest
survivals occurred in patients with onset at 24–42 years of
age. However, age at onset was not a constant prognostic fac-
tor. The sex of the patient, the location of the neoplasm, or
the histologic appearance gave no indication as to longevity.
A significant lengthening of survival was found in those
patients whose initial symptom was a motor seizure.” If
patients dying within one week of surgery were excluded the
median overall survival was 13.1 months with postoperative
irradiation and 12 months without. It must, however, be
noted that for all cases of prolonged survival reported in this
paper, the patient had received irradiation.
As demonstrated by the previous series, irradiation had
been in common use long before randomized trials demon-
strating its efficacy. In 1947 Bush and Christensen wrote:
D. Roberge and L. Souhami
Median survival (months) Two-year survival (%)
RTOG EORTC/NCIC RTOG EORTC/NCIC
58.6 n/a 76 n/a
37.4 n/a 68 n/a
17.9 21.4 35 43.4
11.1 16.3 15 27.9
8.9 10.3 6 16.5
4.6 n/a 4 n/a
“While it is very difficult to judge of the effect of radiation in
these cases, it is our impression that this therapy is of definite
value. A half-hearted attempt of giving every other patient
Roentgen therapy was never carried through as we felt our-
selves unable to deprive the particular patient of what we felt
was the best chance” [15].
It was only in the early 1980s that both the Brain Tumor
Cooperative Group (BTCG) and the Scandinavian
Glioblastoma Study Group (SGSG) published results of ran-
domized trials of adjuvant irradiation [16, 17]. These trials
confirmed a large and significant increase in median survival
following the administration of postoperative irradiation, as
compared to surgery alone. In the Scandinavian trial, 45 Gy
of whole-brain irradiation increased the median survival
from 5.2 months to 10.8 months. In BTSG study 6901,
median survival increased from 3.2 to 8.1 months following
50–60 Gy of whole-brain radiotherapy.
Looking at the role of chemotherapy, a 1993 meta-analysis
by Fine et al. collated data from 16 randomized trials involv-
ing more than 3,000 patients [18]. Optimistic physicians saw
a large (52 %) difference in 2-year survival; pessimistic phy-
sicians saw a relatively small difference in median survival.
A subsequent meta-analysis from the Glioma Meta-analysis
Trialists group confirmed a 1.5-month increase in median
survival and failed to demonstrate any benefit of multi-drug
regimens over single agent nitrosourea compounds [19].
Adjuvant BCNU chemotherapy was considered standard of
care by most, although it was used variably in clinical prac-
tice. Subsequently, in a joint European Organization for
Research and Treatment of Cancer (EORTC) and National
Cancer Institute of Canada (NCIC) randomized trial [20],
concomitant and adjuvant temozolomide was shown to sig-
nificantly increase the survival of patients diagnosed with
glioblastoma multiforme. The median survival went from
12.1 to 14.6 months and the 2-year survival more than
doubled (26.5 % vs. 10.4 %). It is of interest to note that the
17 Stereotactic Radiosurgery and Radiotherapy in the Management of High-Grade Gliomas
control arm (radiotherapy alone) had the same median sur-
vival as reported in the 1949 series from the Montefiore
Hospital, highlighting how little progress had been made in
the previous 50 years.
Based on this EORTC/NCIC trial, the current standard of
care for GBM patients with a performance status of 0–1 (on
subgroup analysis, there was no benefit for patients with an
ECOG performance status of 2) is external beam radiother-
apy to 60 Gy and temozolomide. Although patients with AA
histology were not included in the trial, this regimen has
become for many a de facto standard as we await data from
current prospective studies.
Rationale for Stereotactic Radiosurgery
Infiltrating high-grade glial neoplasms would appear to be
poor candidates for the stereotactic application of single
fraction irradiation. These tumors are hypoxic, acute-
responding [21] and admixed with normal tissue [22, 23].
Despite these biological roadblocks, stereotactic radiation
has been pursued in the management of HGG. The use of
SRS (defined here as a radiotherapy technique characterized
by accurate delivery of high doses of radiation in a single
session to small intracranial targets in such a way that the
dose fall-off outside the target volume is very sharp) has
been based on the pattern of failure of this disease, the dose–
response data from external beam radiation, and early data
from interstitial brachytherapy trials [24, 25].
As mentioned previously, up to 90 % of patients recur
within 2 cm of the contrast-enhancing lesions—this despite
the fact that tumor cells can be found pathologically at
larger distances, often following the peri-tumoral edema.
Furthermore, multicentric or metastatic disease is rare [11].
Moreover, in an analysis of the Brain Tumor Study Group
data, a dose–response relationship has been shown for doses
of 50 to 60 Gy [26]. In this data set, the median survival
increases from 28 weeks at 50 Gy to 42 weeks at the 60 Gy
level. Significant improvement in median survival was also
observed in the randomized British trial comparing 45–60 Gy
[27]. All of these characteristics made SRS an attractive option
to be used as a focal boost in selected patients with HGG.
In the early 1990s, phase I/II data suggested that inter-
stitial brachytherapy improved local control and survival in
selected primary and recurrent HGG patients. At University
of California at San Francisco (UCSF), the median survival
of the first 18 patients treated with interstitial brachyther-
apy for recurrent GBM was 52 weeks with two patients sur-
viving more than 5 years [28]. In a subsequent NCOG
study [25], 107 patients with HGG were enrolled in a pro-
gram of brachytherapy added to external beam radiation
therapy (EBRT) and adjuvant PCV chemotherapy. In the 63
evaluable patients who were actually implanted, the median
251
survivals were 157 weeks and 88 weeks, respectively, for
patients with grade III astrocytoma and GBM. Brachytherapy
was associated with a high risk of radionecrosis and it was
felt that SRS might offer the focal dose escalation benefits
of implants with lessened toxicity. Unfortunately concerns
about selection bias [29], as a possible explanation for
these improved median survivals following brachytherapy,
appear to be have been confirmed by two subsequent nega-
tive phase III trials of brachytherapy by the BTSG [30] and
the Princess Margaret Hospital [31] groups. In these ran-
domized studies, the added use of a focal brachytherapy
boost did not lead to either a clinically or statistically sig-
nificant improvement in survival for patients harboring a
HGG. In the Toronto trial, the median survival was
13.2 months on the standard arm and 13.8 on the brachy-
therapy arm, while in the BTSG study it was 58.8 weeks on
the standard arm and 64.1 on the brachytherapy arm.
In 1985, Columbo et al. reported on the first patients
treated in Vinceza, Italy with a new technique for linear
accelerator-based radiosurgery using non-coplanar arcs [32].
Only 6/22 patients had adequate follow-up. Of these, one
patient was treated for a 3.5 cm grade III astrocytoma. Two
doses of 20 Gy were delivered during separate procedures.
This patient worsened within 2 months and underwent reop-
eration. Following this early experience, several institutional
reports have been published on the use of SRS boost in the
management of patients with HGG either at presentation or
time of recurrence. The non-invasive nature of SRS coupled
with the promising early results of interstitial brachytherapy
led to the inflated enthusiasm for the technique in patients
with HGG and a growing number of publications became
available over the years (Fig. 17.1). Many of these reports
were published before the results of the randomized trials of
brachytherapy and SRS were available.
Fig. 17.1 Publications on the radiosurgical treatment of HGG
252
Radiosurgery has predominantly been used in one of two
scenarios: in primary lesions as a supplement to wider volume
EBRT and in recurrent lesions as a single modality. Initially
F-SRT was explored to increase the therapeutic ratio in previ-
ously irradiated patients; it has since also been explored as a
boost in the treatment of newly diagnosed HGG patients.
With the advent of non-invasive immobilization devices and
sophisticated image-guidance, the use of F-SRT has become
more common—it has also become more difficult to distin-
guish from what is now “conventional” radiotherapy. We have
thus chosen to exclude from our review protracted treatment
schedules—even if labeled “stereotactic.”
Treatment Planning
Although each case must be approached on an individual
basis, the following general guidelines represent a reason-
able approach to the delivery of stereotactic therapy for HGG.
Stereotactic Radiosurgery
In the primary treatment of HGG, SRS is used as a boost to
EBRT. The goal of radiosurgery is to inflict precise damage
to tissue within the target volume, in this case proliferating
glial cells. Thus, only tumors with a limited diameter (at pre-
sentation or postoperatively) should be considered for
SRS. The RTOG considered a diameter of 40 mm the maxi-
mum diameter allowed for patient entry into the SRS trials.
As a larger area of potential microscopic disease is targeted
by the EBRT, the SRS target volume (PTV) is limited to the
tumor without margins. Individual programs have developed
expertise in PET or advanced MRI imaging. As long as the
technical and clinical limitations of these modalities are
understood, their use is reasonable—however, T1 contrast
MRI remains the standard modality for GTV definition.
Completely resected tumors are generally not considered for
SRS boosts but, in selected cases, reactive enhancement or a
rim of normal-appearing parenchyma can form the radiosur-
gery target [33].
The maximum clinically tolerated doses for the treatment
of HGG have been derived from the RTOG 90–05 phase I
study and are tumor size-dependent [34]. Single doses of 24,
18, and 15 Gy were found to be the maximum tolerated doses
for tumors diameters of ≤20 mm, 21–30, and 31–40, respec-
tively. These doses are usually prescribed to an isodose sur-
face between 50 and 90 %. Caution should be exercised
when treating brain stem lesions and lesions within 10 mm
of the optic chiasm, as these lesions were not included in the
RTOG study and the maximum tolerated radiosurgery dose
has not been clearly established for these structures.
For recurrent disease, similar principles apply. It is also a
general rule that only lesions smaller than 4 cm are considered
D. Roberge and L. Souhami
Table 17.2 Comparison of common parameters for stereotactic
irradiation modalities
Parameter SRS F-SRT
Tumor Size ≤40 mm ≤60 mm
Total Dose 15–24 Gy Variable (∼30 Gy in 5)
Fractions Single Multiple
Prescription isodose 50–80 % 70–90 %
Margins 0–2 mm 2–5 mm
SRS stereotactic radiosurgery, F-SRT fractionated stereotactic radiation
therapy
for SRS. In these cases the GTV is the enhancing lesion on the
T1 MRI. On a case-by-case basis, a CTV of a few millimeters
(~2–5 mm) can be added. For rigid immobilization systems
and systems with intra-fraction image-guidance, no additional
margin is added for the PTV.
Table 17.2 contrasts commonly used treatment parame-
ters for stereotactic irradiation in HGG.
Fractionated Stereotactic Radiation Therapy
For both primary and recurrent lesions, larger volumes can
be considered for F-SRT than SRS. Depending on the
planned dose of F-SRT and the use (concurrent or prior) of
EBRT, volumes of up to approximately 100 cm3 can be con-
sidered for treatment. Margins will depend on the volume to
be treated, proximity of critical structures, prior treatment,
and the image-guidance used. A reasonable approach for
recurrent disease would have the GTV equal to the enhanc-
ing lesion on a gadolinium-enhanced T1 MRI with a com-
bined CTV/PTV margin of 3 mm (mainly accounting for the
reproducibility of standard IGRT or a common three ply
thermoplastic mask-based immobilization system [35, 36]).
Table 17.3 [37–50] contains various published fractionation
schemes. Depending on the technique, dose would be pre-
scribed to the 50–90 % isodose surface after assessing the
plan for volume irradiated, subjective isodose distribution,
conformity, homogeneity, and dose to critical structures.
Linear Accelerator vs. Gamma Knife
HGG are large infiltrating tumors for which debates about
fractions of a millimeter are somewhat irrelevant. Because of
the necrotic and presumed radio-resistant core of high-grade
tumors, there might be a theoretical advantage to more inho-
mogeneous plans. As Gamma Knife (GK) treatments com-
monly use multiple isocenters and are prescribed to lower
isodose surfaces, they might offer a theoretical advantage
over more homogeneous single isocenter or dose painting
plans (if this were ever clinically verified, linear accelerator
(LINAC) centers could then choose to prescribe treatments
to lower isodose surfaces). This hypothesis was tested by
Table 17.3 Results of F-SRT for primary and recurrent high-grade gliomas
Author Glass [37]* Shepherd [38] Hudes [39] Lederman [40] Regine [41, 42] Baumert [43] Cho [44] Vordermark [45] Cardinale [46] Schwer [47] Fokas [48] Gutin [49] Fields [50]
Institution Temple Royal Marsden Thomas Jefferson Staten Island Kentucky Zurich Minnesota Würzburg RTOG Colorado Marburg MSKCC Colorado
Date of publication 1997 1997 1999 2000 2000 2003 2004 2005 2006 2008 2009 2009 2012
Number of patients 20 recurrent 33 recurrent 20 recurrent 88 recurrent 8 primary 17 primary 10 primary 19 recurrent 76 primary 15 recurrent 53 recurrent 25 recurrent 10 recurrent
1 recurrent
Histology GBM 13 AA 29 GBM 19 GBM GBM 6 GBM 15 GBM 10 GBM 14 GBM GBM 11 GBM GBM 20 GBM 7
AA 7 AO 3 AA 1 AA 2 AA 2 AA 5 AA 4 GR III 5 AA 3
LGG 1
Median age (range) 44.5 (6–73) 37 (19–55)a 52 (26–77) 56 (21–82) ≥18 51 (25–64.8_ 57 (17–80) 50 (11–74) 57.5 (25–83) 47 (23–65) 53 (22–71) 56 (30–80) 40 (22–72)
KPS – 80 (60–100)a 80 (60–100) 70 (50–90) ≥60 (5/12 WHO 70 (60–90) 90 (60–90) Zubrod 0–1 80 (60–90) 70 ≥ 70 60 (60–80)
0/1, 7 WHO 2)
Time from – 29a 3.1 (0.8–45.5) 6.5 n/a n/a n/a 19 (3–116) n/a 12 (3–57) – 14.5 (6–135) 14.5 (7–123)
Diagnosis (for From EBRT from EBRT
recurrent lesions)
Median fu (months) – – 8.5 >12 15a 25 (9–50) – – 22 7 8 6.6 4
Median tumor 14.3 24 (3–93)a 12.66 32.7 7.4 (1.5–27.2)a – 34 (4–70) 15 (4–70) – 41 (8.4–151) – 34 (2–62) 54 (6.7–123)
volume (range) (1.76–122) (1.5–150.3)
Median peripheral 42/7 (–) 35/7 30/10 24/4 14–28/2–4 19 27.5/11 30/6 50 Gy EBRT + 18–36/3 30/5 30/5 36/3
dose (range) (20/4–50/10) (21/7–35/10) (18/4–36/4) 7 (20–35/8–14) (20–30/2–6) 20–28/4 (20–60/5–30)
Median survival 12.7 AA 11 10.5 7 11 20 15.9 9.3 12.5 10 9 GBM 12.5 6
(months)
1-year survival (%) – – 20 17 56 77 67 – – – – GBM 54 –
Median prescription ≥70 90 (80–90) 89 (80–95) 90 (80–90) 50 prescribed 88 (75–90) 80 (70–90) 80–90 90 (80–93) prescribed 94 92 (90–97.6)
isodose (range) at isocenter at isocenter
EBRT All prior All prior All prior EBRT 99 % 59.4/33 60 60 (50.4–60) All prior EBRT 50 All prior EBRT All prior All prior All prior
EBRT? EBRT EBRT EBRT EBRT
Toxicity 15 % 45 % at 24 no GR III – 4/15 GR IVa 6 % necrosis 10 % – 20 % GR IV No symptomatic No > GR II 6 GR IV no 3 DLT
necrosis monthsa necrosis (mainly necrosis nocrosis
hematological)
*With cis-platinum
a
Of a larger group including other histologies
254
100
Linac
80
Gamma Knife
Survival Rate
60
40
20
0 patients with progressive disease or decreasing performance
0 6 12 18 24 30 36
Months
Fig. 17.2 Survival by SRS treatment delivery system in RTOG 93–05
(From Souhami L, Seiferheld W, Brachman D, et al. Randomized com-
parison of stereotactic radiosurgery followed by conventional radio-
therapy with carmustine to conventional radiotherapy with carmustine
for patients with glioblastoma multiforme: report of Radiation Therapy
Oncology Group 93–05 protocol. Int J Radiat Oncol Biol Phys 2004;
60:853–860. Used with permission from Elsevier.)
Larson and colleagues at UCSF in a Phase II trial [51]. In this
trial prescriptions were made to isodoses as low as 25 %. The
results, however, appear no different than would be expected
with conventional treatment (15 weeks median survival for
patients with recurrent grade IV tumors).
A review of the single-institution series will reveal a mix
of GK and LINAC-based treatments. The two largest series
are still from Pittsburgh [52] and Boston [53]—historically
prototypical gamma-knife and LINAC-based programs. Not
unexpectedly, there is no difference in result between these
two series—both reporting a median survival of 20 months
for the treatment of primary tumors. In the initial RTOG
Phase I trial of radiosurgery for recurrent tumors, there
appeared to be a large difference in results favoring GK in
the treatment of a mixed bag of primary brain tumors [54].
This was not born out in the much larger and more homoge-
neous experience of the RTOG 93–05 randomized trial [55].
In this trial, in a subgroup analysis, patients treated with
LINAC systems had a 14-month survival, not statistically
different from the 12.1-month survival of GK patients
(Fig. 17.2). If patients are to be treated with radiosurgery,
delivery system should not be an issue.
SRS in the Primary Management of High-
Grade Gliomas
The 1990s saw the publication of several small, retrospective
and prospective, series of patients treated with SRS boost in
the primary treatment of malignant glioma (Table 17.4)
D. Roberge and L. Souhami
[33, 52, 53, 56–66]. Ages ranged from 3 to 84 years and
Karnofsky performance status from 40 to 100. Overall the
median survival of patients treated with SRS was quite
encouraging, although some series reported no benefit in sur-
vival when comparing results to historical controls. However,
in a disease where more than 95 % of patients will ultimately
die of their disease, the median survival is dictated more by
patient-related than therapy-related factors [4]. By the very
nature of SRS, patients are selected for small tumors, more
complete resection (size determination being based on post-
operative imaging), and a good response to initial therapy
(when SRS is administered after EBRT ± chemotherapy,
status are likely to be excluded). Other potential sources of
bias include high patient motivation, more favorable tumor
biology, and aggressive treatment of recurrences. Taking these
selection factors into account, only one tenth to one quarter of
GBM patients will be eligible for radiosurgical boost [67].
The results of these radiosurgical series were viewed with
skepticism. In an attempt to reduce bias, authors sought out
retrospective control populations. One of the largest reviews
[68] attempted to retrospectively stratify 115 patients from
three institutions (Harvard, the University of Florida, and the
University of Wisconsin) according to the prognostic classes
of the RTOG recursive partitioning analysis of patients
enrolled on RTOG 74–01, 79–18, and 82–02 [69–71]. This
analysis concluded that there was a significant improvement
in both 2-year and median survival favoring SRS-treated
patients. Unfortunately, along with other flaws, the RTOG
classes are broad, do not include all known prognostic fac-
tors (most notably—tumor size), and convert important linear
variable into binary ones (age, mental status and KPS). Thus,
this approach, along with all retrospective comparisons, is
inherently flawed. Irish et al. [67] published an elegant anal-
ysis of 101 consecutive patients seen at the London Regional
Cancer Center. Of these 27 % were deemed eligible for
radiosurgery. The median survival of these patients was
23.4 months compared to 8.6 for the radiosurgery-ineligible
patients. This study highlights the significant effects of
patient selection. It also demonstrates that a patient group
can be selected that performs better than the most favorable
group of glioblastoma patients in the RTOG recursive parti-
tioning analyses—the RTOG class III patients (age > 50,
KPS ≥ 90) for whom the expected median survival was 18
months in the pre-temozolomide era. The bottom line is that
only randomization can control efficiently for all confound-
ing factors.
Having previously demonstrated the feasibility of a multi-
institutional radiosurgery trial [54] and encouraged by the
favorable survival of patients treated on phase I/II protocols,
the RTOG opened protocol 93–05 in 1994. This was a pro-
spective randomized trial evaluating upfront SRS followed
by EBRT with BCNU (Arm 1) vs. EBRT and BCNU (Arm 2).
Table 17.4 SRS in the primary management of high-grade gliomas
Kondziolka
Authors Selch [56] Masciopinto [57] Gannett [58] Buatti [59] [52] Shenouda [60] Shrieve [53] Nwokedi [61] Hsieh [62] Smith [33] Biswas [63] Villavicenci [64] Pouratian [65] Einstein [66]
Institution UCLA Wisconsin Arizona Florida UPMC McGill Harvard Maryland Northwestern Phoenix Rochester Multi- Virginia Case Western
center
Year 1993 1995 1995 1995 1997 1997 1999 2002 2005 2008 2009 2009 2009 2012
Number of patients 18 31 30 11 65 14 78 31 25 27 15 20 22 35
Histology 12 GBM GBM 17 GBM 6 GBM 45 GBM GBM GBM GBM GBM GBM GBM GBM GBM GBM
6 AA 10 AA 5 AA 20 AA
KPS (%) 100 % >70 57 % >70 97 % >70 all >90 Mean KPS 90 79 % >70 median 90 61 % >70 70 >60 >70 Median 82 Median 40 Median 90
(50–100)a (50–100) (60–100) (40–100) (60–100)
Median 20 (8–46) 16 (2–60) 24 (2–115) 14 (6–23) 6.5 (1–31)a < 34 10 25 23.6 34.6 13.2 5.8 (0.7–47) 13.4 (4.4–56) –
volume (cc) (1.5–85)
Median MPD 30 (15–35) 12 (10–20) 10 (0.5–18) 13 (10–15) 16 (12–25)a 20 12 (6–24) 17 12 12 10.4 20 (12–25) 5.6 (4–10) 15–24
(range)
Sequence Post-EBRT Pre-EBRT 12 Within 8 12–109 GBM median Pre-EBRT Post-EBRT, Within Post-EBRT Pre-EBRT Post-EBRT Alone or 91 % Pre-EBRT
weeks days 6.2 months median 4 weeks post-EBRT Post-EBRT
Post-EBRT 17 (median 4) post EBRT post diagnosis 14.2 weeks post-EBRT
AA median from diagnosis
3.9 months (range 1–42)
No EBRT 2 (typically post diagnosis
2–3 weeks)
Median survival 9 9.5 GBM 13 17 GBM 20 10 19.9 25 10 11.5 10.3 11.5 15.1 15.8
(months) AA 28 AA 56
2-year GBM 33 – GBM 8 – GBM 41 – 35.9 – – 22 % – – – –
survival (%) AA 100 AA 53 AA 88
Median 62 mean Mean 67 70 80 (70–90) 50 (40–90)a – 85 (60–100) 50 (45–65) 50 50 80 74.9 (66–89) 70 (50–80)a 50
prescription (40–80) (50–100)
isodose (%)
Median age 56 (35–79) 57.7 (20–78) 54 (5–74) 42.1 GBM 51 67.5 (45–78) 51 (12–84) 68 % >50 60.3 61 (19–79)a 57.8 61.3 (27–81) 58.6 (12–76) 62 (12–84)
(range) (15–77) (3–72) (33–81)a
AA 45
(3–73)a
EBRT 78 %, 0–66 Gy Median Median GBM all, 60 Gy 73/78 All, 24/31 > All, median All 60 Gy All 75 % EBRT 96 %, All 60 Gy
45–60 Gy 59.4 Gy 60 Gy mean 60 Gy 59 Gy 60 Gy 50–64 Gy (40–60 Gy) 45–66.6 Gy
(44–62) (54–60)
Chemo 15 % – 47 % None From 1990 None 68 % 100 % 48 % TMZ 75 % 27 % 46 % TMZ
Comments Accelerated Prospective + 1–5 fractions Prospective
EBRT gliadel and MRS-defined
TMZ
a
For larger group, including recurrent tumors
TMZ temozolomide, EBRT external beam radiation therapy
256
Fig. 17.3 Patient HL, a 73-year-old gentleman treated for glioblas-
toma multiforme on the radiosurgery arm of RTOG 93–05. Prior to
60 Gy of EBRT, the residual tumor in the left temporal lobe was boosted
Eligibility criteria required patients to be at least 18 years
of age, have a KPS of at least 60 %, and to have a histologi-
cally proved supratentorial, unifocal GBM. All lesions were
to be 4 cm or less in maximal diameter. Patients presenting
with tumors larger than 40 mm preoperatively were eligible
only if the postoperative imaging studies showed residual
tumors of ≤40 mm in maximal diameters.
In the investigational arm, radiosurgery was to be given
up front, within 5 weeks of surgery. External beam radiation
was the same in both arms: a volume encompassing the
tumor, surrounding edema (for the first 46 Gy) and a margin
was treated to a total of 60 Gy with daily fractions of 2 Gy.
BCNU was administered at a dose of 80 mg/m2 on days 1, 2,
and 3 of EBRT and then repeated every 8 weeks for a total of
6 cycles.
The first patient was treated in February 1994 and the
study was closed in June 2000 after the 203rd patient was
enrolled (thus meeting the accrual target of 200 patients).
Results were published in 2004 [55]. Figure 17.3 illustrates
the case of a patient treated on the experimental arm.
At a median follow-up of 61 months (Fig. 17.4), the
median survival for Arm 1 was 13.5 months (95 % CI: 11.0–
14.9) and it was 13.6 months (95 % CI: 11.3–15.2) for Arm
2 (p = 0.53). The 2-year actuarial survival rates were 21 % for
Arm 1 and 19 % for Arm 2. Disappointingly, patterns of fail-
ure were not influenced by the therapy with 90 % of patients
presenting with a component of local failure. There was also
no difference in the mini-mental or Spitzer [72] indices (a
validated quality of life index). Despite the exclusion from
analysis of seven patients having progressed prior to SRS, no
subgroup was identified as benefiting from SRS. An
intention-to-treat analysis including all randomized patients
produced nearly identical results.
D. Roberge and L. Souhami
using a three-isocenter plan using the McGill dynamic stereotactic
technique. 15 Gy was delivered to the 50 % isodose surface, as per pro-
tocol guidelines (a). The tumor failed locally 13 months later (b)
100
RT
80
SRS+RT
Survival Rate
60
40
20
0
0 6 12 18 24 30 36
Months
Fig. 17.4 Overall survival by treatment arm on RTOG 9305 (From
Souhami L, Seiferheld W, Brachman D, et al. Randomized comparison
of stereotactic radiosurgery followed by conventional radiotherapy with
carmustine to conventional radiotherapy with carmustine for patients
with glioblastoma multiforme: report of Radiation Therapy Oncology
Group 93–05 protocol. Int J Radiat Oncol Biol Phys 2004; 60:853–860.
Used with permission from Elsevier.)
Both acute and late RTOG grade 3 toxicities were more
frequent on Arm 1, although not significantly so. There were
no incidences of radiation-related grade 4 toxicity in either
arm. A total of seven patients did die of chemotherapy-
related toxicity.
Questions may arise about the timing of the radiosurgery
boost in the RTOG trial. Although both pre and post-EBRT
boosts have been used, a look at Table 17.4 will reveal that
post-EBRT boosts are more common in reported series. At
the time of the study design in 1993, the choice of an upfront
boost for the RTOG 93–05 trial was motivated primarily by
17 Stereotactic Radiosurgery and Radiotherapy in the Management of High-Grade Gliomas
Table 17.5 Timing of SRS in the primary management of high-grade gliomas
SRS before EBRT
Pros Increases number of eligible patients
All patients will receive protocol program
Decreases selection bias
Cons Patients not fully recovered from surgery
Radiosurgery potentially delivered to a larger target
Because of postoperative changes, imaging less satisfactory
SRS stereotactic radiosurgery, EBRT external beam radiation therapy
three factors: (1) to benefit from controlling potential-
accelerated tumor repopulation, (2) to avoid exclusion of any
patient entering the radiosurgical arm because of tumor pro-
gression during the EBRT, and (3) to avoid the bias inherent
in selecting patients after fractionated radiotherapy. Two
reports on the use of a focal boost post-EBRT published at
that time [67, 73] showed that a large proportion of patients
(10–47 %) developed tumor progression while undergoing
the EBRT. Even with the strategy of an up front SRS boost,
7 % of the patients in the SRS arm had to be excluded
because of tumor progression. Biologically early intensifica-
tion of the radiation seems favorable and there is no convinc-
ing evidence that a post-EBRT SRS boost is radiobiologically
advantageous over a pre-EBRT SRS boost.
Case series of post-EBRT boosts cannot report patient
outcomes on an intent to treat basis and have included
patients receiving radiosurgery up to a mean of 6.2 months
following their diagnosis [52]. The additional bias intro-
duced by including patients who still have small non-
progressing tumors and a good performance status several
months after their initial diagnosis is obvious. Of interest,
despite using a different temporal sequence of their boost
implants, in the two randomized trials of stereotactic brachy-
therapy boost [31, 74] both had similar results, failing to
demonstrate a survival benefit for this technique when given
either before or after the EBRT. A summary of the relative
merits of pre and post-EBRT SRS is presented in Table 17.5.
Although the Phase III data does not unequivocally disprove
any benefit to post-EBRT radiosurgical boosts, there is no
reason to believe that this approach is superior.
Thus, the best evidence currently available does not sup-
port an improvement in survival following the addition of a
SRS to a standard treatment regimen for GBM. There is
also no evidence of an improvement in quality of life or a
change in pattern of failure. There is, however, an increase
in both acute and late radiation-related toxicity. These are
essentially the conclusions of 2005 ASTRO evidence-based
guidelines–guidelines that can be interpreted narrowly as
stating that the benefit of SRS is only disproven for T1
MRI-guided pre-EBRT boosts in the pre-temozolomide era
257
SRS after EBRT
Better definition of tumor margins
Target may be smaller
SRS may be planned far ahead
Patients fully recovered from surgery
Target may enlarge
Tumor may grow beyond 4 cm
Performance status may deteriorate
Selection bias
vs. broadly concluding that SRS (or F-SRT) is unproven as
a beneficial treatment for any patient with a malignant
glioma [75].
SRS for Recurrent High-Grade Gliomas
Treatment of recurrent HGG is essentially palliative; cases of
patients surviving more than 5 years are anecdotal. Strategies
available [76] include reoperation, chemotherapy, EBRT
reirradiation, SRS, F-SRT, interstitial brachytherapy, and
supportive care. Each of these modalities has its own toxici-
ties and indications. Current published Phase III studies sup-
port an improvement in median survival from the use of
BCNU polymers [77] and an improvement in softer measures
of outcome from the use of oral temozolomide [76, 78, 79].
Survival outcomes from prospective randomized trials are
presented in Table 17.6 [80–83]. There are no phase III trials
of radiosurgery for recurrent tumors and only selected cases
are appropriate for salvage SRS. Figure 17.5 illustrates the
case of a patient treated at our institution with apparent clini-
cal benefit.
An early 1994 series from the University of California
San Diego included 15 patients with recurrent HGG [84].
Doses prescribed ranged from 12 to 15 Gy based on the tar-
get volume. Of the total group of 20 patients, seven suffered
intra-cranial pressure-related acute toxicity (fatal in one
patient) and one suffered from a late somnolence syndrome.
Outcome was not reported by tumor type.
Kondziolka et al. reported on the University of Pittsburgh
experience treating 42 patients with recurrent HGG [52].
Median survival from radiosurgery was unusually favorable,
30 months for GBM, 31 for AA. There were no cases of
acute toxicity and three patients experience late radiosurgery-
related morbidity. Overall 22/107 (21 %) of patients in this
series required craniotomy following SRS.
With the passage of time, little has changed in the scope
or results of series reporting SRS for recurrent HGG. More
recent reports do tend to be limited to GBM and include a
greater proportion of chemotherapy-treated patients. As an
258
Table 17.6 Survival outcomes from prospective randomized trials of
recurrent glioblastoma
Therapy Overall survival (months)
Lumustinea [80] 9.8
Bevacizumab [81] 9.2
Gliadel wafersa [82] 8.8
NovoTTF-100A [83] 6.6
a
Control arm
example, in a 2009 report, Villavicencio and colleagues
reported on 26 patients treated with salvage SRS [64]. In this
multi-institutional series, all patients had GBM and 96 %
received systemic chemotherapy. Survival from the time of
SRS was only 7 months. The longest surviving patient died
34 months after SRS.
Additional institutional series can be found in Table 17.7
[44, 51, 52, 56, 62–65, 84–88]. Common themes from these
series are:
• Despite median survivals of 7.5–30 months [52, 84], only
one patient is reported as surviving 5 years post-
radiosurgery (<0.5 %) [51].
• Toxicity is incompletely reported with up to 46 % of
patients experiencing treatment complications [84].
• Reported prognostic factors include histology, age, KPS,
and tumor volume [52, 85, 89].
The most credible investigation of the potential benefits
of salvage radiosurgery is a case–control study from the
M. D. Anderson Cancer Center [86]. In this report, 41
patients treated with salvage SRS were matched for KPS at
presentation, age, year of diagnosis, and size of recurrence
with 41 controls. Images of the control patients were
reviewed to confirm that the recurrences would have been
eligible for SRS. For the cases, the median survival from
SRS was 11 months vs. 10 months for the controls (calcu-
lated from the time of the imaging study showing the SRS-
treatable recurrence). Although the duration of survival was
similar in both groups (p = 0.45), the SRS-treated patients
had significantly fewer salvage craniotomies (mean: 0.9 vs.
1.4). The authors concluded that SRS was of benefit, in par-
ticular in avoiding a number of salvage craniotomies.
Fractionated Stereotactic Radiation Therapy
When introduced by Leksell more than 50 years ago [90],
stereotactic radiosurgery was intended as a means of creating
a “radiation injury.” The intent at that time was to destroy
brain tissue, not selectively inactivate tumor cells intertwined
with normal brain tissue. In an attempt to decrease complica-
tions through normal tissue repair and to potentially increase
efficacy by allowing reoxygenation and cell cycle reassort-
ment, several centers have treated small series of patients
with F-SRT. Often these series are of patients with recurrent,
D. Roberge and L. Souhami
previously irradiated, lesions where there was a concern for
toxicity. Beginning in 1987, patients were treated at our
institution with a regimen of 42 Gy given in fractions of 7 Gy
on alternating days over 2 weeks [91]. For these treatments,
rigid immobilization was performed with a halo type frame
[92]. Since this early experience, the general trend for F-SRT
has been towards smaller fractions using non-invasive
immobilization.
Authors from the Royal Marsden Hospital have reported
a series of 33 patients treated with F-SRT for recurrent pri-
mary brain tumors [38]. This was a dose escalation study
conducted from January 1989 to July 1994. All of these
patients had been previously irradiated. Doses ranged from 4
to 10 daily fractions of 5 Gy. The median survival of the 21
patients with recurrent HGG (11 AA, 10 GBM) was
9.6 months. A matched-pair analysis was performed using
patients treated for their recurrence with nitrosourea-based
chemotherapy. There was a small, statistically significant,
difference in median survival favoring the RT cohort. Late
toxicity (not graded) was seen in 36 % of the patients.
Between April 1991 and January 1998, 71 patients with
recurrent tumors (13 % anaplastic oligodendrogliomas, 87 %
high-grade astrocytomas, 15 % of these were dedifferenti-
ated low-grade tumors) were treated at the University of
Minnesota Hospital. A total of 46 of the patients in this retro-
spective review were treated with SRS and 25 with F-SRT
[89]. For the SRS cases, the median minimum peripheral
dose was 17 Gy. F-SRT was delivered to a median of 37.5 Gy
in 15 fractions. The median survival from stereotactic irra-
diation was 11 months for SRS and 12 for F-SRT (p = 0.3).
Acute complications were seen in 40 % of both groups. Late
complications (clinical/pathological necrosis or cranial nerve
palsy) were seen more commonly in the SRS group—30 %
vs. 8 % (p < 0.05). The authors concluded that as the F-SRT
group had worse prognostic factors, a similar median sur-
vival, and less late toxicity, it might represent a better treat-
ment option for recurrent high-grade gliomas.
Table 17.3 summarizes some of the larger published sin-
gle institution series of F-SRT for HGG. Fraction sizes range
from 2.5 to 7 Gy for what are mostly recurrent tumors.
Median survival for variable patient populations ranges from
7 to 20 months. Complication rates are incompletely reported
and range from none to 27 % grade 4 [38, 39].
Authors from Marburg, Germany, reported on 53 patients
with recurrent GBM treated at their institution with F-SRT
[48]. Between 1998 and 2008, a wide variety of regiments
were used to deliver a median total dose of 30 Gy (20–60 Gy)
in 2–5 Gy fractions. The reirradiation was well-tolerated
without acute or late grade 3 toxicity. After re-treatment, the
median survival was 9 months.
The same issues of bias that plagued the experience with
single fraction SRS apply to the experience utilizing
F-SRT. Treatment options for recurrent lesions are numerous.
17 Stereotactic Radiosurgery and Radiotherapy in the Management of High-Grade Gliomas
Fig. 17.5 Patient CB, a 55 year old, was treated for a left frontal GBM
on the radiotherapy only arm of the EORTC/NCIC protocol. His disease
progressed soon after the end of radiotherapy and he was given temo-
zolomide. The tumor progressed following the second cycle of temo-
zolomide. The patient was switched to BCNU chemotherapy and his
disease remained stable. Ten months post-EBRT, there was evidence of
further disease progression and he was treated with SRS (a). A dose of
If stereotactic radiation is used, the choice of fractionation
may represent a compromise between convenience and risk
of radionecrosis.
A more definitive answer may not soon come for
F-SRT. The EORTC and the Medical Research Council had
jointly initiated a randomized trial of F-SRT in the primary
management of high-grade gliomas. The patients eligible for
this study were those with ≤4 cm WHO grade III–IV glio-
mas, age <65 years with a good performance status. These
patients were to be randomized to partial brain radiation
(54–60 Gy) followed or not by F-SRT (4 × 5 Gy daily). This
study closed in December 2001 because of poor accrual.
Median survival for the 14 patients randomized the F-SRT
arm was a favorable 21.4 months, but outcomes were not
reported for the control patients [93].
The use of hypofractionated F-SRT in combination with
standard radiation therapy has been tested in Phase I/II trials,
in selected patients with primary GBM. Regine et al. [42]
treated 18 previously unirradiated patients with brain tumors
using a combination of conventional external beam radiation
therapy and a split-course F-SRT. Of these 18 patients, 11
were malignant gliomas. F-SRT dose schedule was based in
the residual tumor volume and varied from 7 Gy given 2–4
times. F-SRT was delivered pre and post-external beam radi-
ation therapy. Of 15 patients evaluated so far at a median
follow-up of 15 months, excessive toxicity was seen only in
the group with larger tumor volumes. Of interest, 38 % of the
patients requiring reoperation (3/8) were found to have only
necrosis without evidence of tumor cells.
259
15 Gy was prescribed to the 50 % isodose surface. He subsequently
developed what was felt to be an area of asymptomatic radionecrosis (b),
managed conservatively. He was well until the tumor progressed a sec-
ond time, 3 years following SRS (c). This second failure was at an edge
of the tumor bed outside the radiosurgery target volume (arrow) and
repeat SRS was performed. Five months later he was reoperated for fur-
ther progression and went on to live for 1 year following his second SRS
Motivated by the favorable survival (18–19 months) of
patients previously treated with the regimen of Cardinale and
colleagues [94], the RTOG conducted a Phase II trial (RTOG
BR-0023) testing a concurrent F-SRT scheme in patients with
primary supratentorial GBM [46]. This study was open from
March 2001 to June 2003 and was performed to assess the
feasibility, toxicity, and efficacy of this approach. On this
study, a relocatable immobilizer was used for the 4 weekly
fractions (5 Gy each for targets >40 mm, 7 Gy for smaller
targets) of F-SRT that were delivered using 3DCRT (GK and
cone-based SRS systems were not permitted) during weeks
3–6 of EBRT (50 Gy). Radiation was followed by 6 cycles of
BCNU (80 mg/m2 for 3 days every 8 weeks). A total of 76
patients were analyzed. Treatments were well tolerated with
only one acute grade 4 (lethargy) and one late grade 3 (necro-
sis) toxicity observed. Although patients with gross total resec-
tions did fare better than expected, the overall median survival
was 12.5 months and no difference was seen when the overall
results were compared to the RTOG historical database. Thus,
although feasible and well-tolerated, this dose-intense, accel-
erated regimen did not appear to improve survival. Although
the biological concept of F-SRT is interesting, attempting to
deliver a higher dose while shortening the overall treatment
time to limit accelerated repopulation, this prospective RTOG
trial suggests that a hypofractionated boost strategy may be of
limited value. In any case, with the merging of conventional
and stereotactic technologies, further attempts at dose escala-
tion are more likely to involve simultaneous-integrated boost
strategies than intercalated “stereotactic” treatment sessions.
Table 17.7 Results of SRS for recurrent high-grade gliomas
Author Selch [56] Chamberlain [84] Shrieve [85] Kondziolka [52] Cho [44] Larson [51] Larson [51] Mahajan [86] Hsieh [62] Patel [87] Pouratian [65] Biswas [63] Villavicencio [64] Cuneo [88]
Institution UCLA UCSD Harvard University of University UCSF UCSF M.D. Anderson Northwestern Henry Ford Virginia Rochester Multicenter Duke
Pittsburgh of Minnesota
Date of 1993 1994 1995 1997 1999 2002 2002 2005 2005 2008 2008 2009 2009 2012
publication
Number 17 13 86 42 46 26* 54 41 26 26 26 18 26 63
of patients
Histology 12 GBM 5 GBM 86 GBM (14 19 GBM 27 GBM GBM 14, GBM 39, GBM GBM GBM GBM GBM GBM GBM 49,
5 AA 8 AA transformed 23 AA 15 AA GRIII 12 GRIII 15 GRIII 14
from LGG)
4 AO
Time from Median 8 Median 15 Median 10.3 GBM mean Median 10 GBM median GBM median Median 11 Median 6.7 Median 12.5 Median 8 Median Median 13 19.6
diagnosis (4–96) (2.3–115) 18.9 (1–166) 12 (3–50), 7 (2–70), (3–49) 12.1 (4–44) (5–89)
(months) AA mean 19.8 GRIII median GRIII median
43 (7–175) 35 (2–145)
Median KPS 100 % >70 70 (50–100) 90 (70–100) Mean KPS 90 70 (40–90) 90 (70–100) 70 (40–90) 90 (70–100) Mean 70 80 (50–100) 80 (40–100) ≥ 70 84 (50–100) 90
(50–100)† 80 for GBM
Median tumor 28.6 36 (3–50.6) 10.1 6.5 (0.9–31)† 30 (3–125) GBM 8 GBM 9.1 4.7 (0.15–16.3) Mean 21.6 10.4 21 (0.3–110) 12.1 7 (0.4–48.5) 4.8
volume cc (6–121) (2.2–83) (1.6–29.7), (0.3–29.1), (0.3–60) (4.1–44.4)
(range) GRIII 2.7 GRIII 6
(0.4–13.4) (0.3–20.3)
Median 24.4 (mean) 12.5 (12–15.7) 13 (6–20) 15.5 (12–25)† 17 (9–40) GBM 15 GBM 16 – 12 18 (12–20) 6 (3–15) 12 20 (8–25) 15 (12
peripheral (12–17.5), (10–20), patients had
dose Gy GRIII 16.5 GRIII 17 F-SRT)
(range) (15–18) (15–18.5)
Median 10 GBM 15 10.2 GBM 30 11 (1–36) GBM 8.7 GBM 10.1 11 10 8.4 9.4 5.3 7 GBM 9
survival AA 7.5 AA 31 GRIII 15.6 GRIII 13.6
(months)
1-year – GBM 40 – 45 42 – 42 39 – – – – –
survival (%) AA 12.5
Median 64 80 80 (50–100) 50 (40–90)† 50 (40–90) 25–30 50 (45–55) – 50 90 70†† (50–80) 80 (40–90) 77.7 (65–88)
prescription
isodose
(range)
Median age 49 (27–79) 36 (17–62) 46 (9–77) GBM 51 48 (16–75) GBM 53 GBM 50 54 (17–69) Mean 58.2 53 (25–70) 60.7 (12–76) 57.8†† 56.4 (36–82) 47 (19–76)
(range) (3–72), (22–74), (21–77), (33–81)
AA 45 (3–73)† GRIII 44 GRIII 35
(24–62) (24–58)
Prior Chemo – 100 % 33 % – 57 % – – 90 % 73 % All had 10/26 100 % 96 % 100 % mean
subsequent 3.6 prior
chemo regimens
Reoperations 5/17 (46 % 19/86 3/22† 22 % – – 28/41 – 11/26 – 2/18 – –
complication
rate)
Survivors None None None 1 (74 months) None None None None None None None None None None
>5 years
* Patients treated on a protocol with marimastat
†
Including patients treated for a primary glioma
††
For a larger group of patients
17 Stereotactic Radiosurgery and Radiotherapy in the Management of High-Grade Gliomas
Treatment Toxicities
Significant acute complications—i.e., those occurring within
days to weeks of treatment—are unusual and generally self-
limited. Occasionally an exacerbation of existing symptoms
may occur, particularly in patients with moderate brain
edema and with larger lesions (3–4 cm). Most patients will
respond to increasing doses of corticosteroids.
Late complications attributable to SRS are usually defined
as necrosis within the treatment volume. In patients with
GBM, distinguishing radiation-induced necrosis from tumor
recurrence is often a very difficult problem and may lead to
an overestimation of the rate of treatment-induced complica-
tions. The rate of reoperation for ranges from 0 [58] to 54 %
[53]. However, viable cells are identified in the majority of
such reoperation specimens. Pure necrosis without residual
tumor cells is a rare event (Fig 17.6).
In the review involving three institutions and 115 patients
[68], late complications occurred in 16 % of the patients.
Radiation necrosis was diagnosed in the majority of the
patients (17/19) either by reoperation or by imaging evalua-
tion. Prolonged corticosteroid therapy was required in 47 %
of the patients. In the RTOG randomized trial (RTOG 93–05),
there were four cases (5 %) of grade III radiation toxicity in
the SRS arm and no cases in the standard arm. Of the 28
patients in the SRS arm undergoing subsequent salvage
Fig. 17.6 Patient EM is a 29-year-old patient at the time of diagnosis
of glioblastoma. From left to right, T1 contrast MRIs: after the initial
surgery (a), at the time of 18 Gy SRS salvage (b) (following 60 Gy
EBRT, TMZ and reoperation), showing symptomatic radiation necrosis
261
surgery, 7 (25 %) had only necrosis in the resection speci-
men, as compared to 3 out of 31 patients (9.6 %) in the
standard arm.
Clark et al. [95], from McGill University, have described
a single number parameter for use during F-SRT that may be
used to represent effective dosage to intracranial structures
that are irradiated with inhomogeneous dose distribution
having steep dose gradients. Evaluating biologically effec-
tive dose volume histograms, the authors obtained an inte-
gral biologically effective dose (IBED) for each case and
demonstrated a threshold value for late damage to the brain
stem consistent with similar thresholds that have been deter-
mined for external beam radiation therapy. Using α/β [alpha/
beta] ratio of 2.5 as representative of the dose–response of
brain stem tissue, they were able to establish a threshold
value in the region of 60 Gy2.5. Despite its apparent value,
IBED has not been integrated into practice and plan evalua-
tion typically continues to rely on maximum dose to normal
structures. Hopefully, following future ICRU recommenda-
tions for small field radiotherapy, dose to a small volume will
gradually supplant less reliable point dose reports.
When symptomatic radiation necrosis does occur, beva-
cizumab offers an alternative to surgery and steroids. Case
series have shown benefit but effects on oft intertwined
tumor and necrosis can be difficult to distinguish in HGG. A
small randomized trial that excluded glioblastoma patients
was able to show the benefits of a 12-week course of
(c) (potentiated by further chemotherapy) which required emergent cra-
niotomy (d) and resection. The patient is now without evidence of
active disease more than 2 years from diagnosis (e)
262
bevacizumab as all bevacizumab-treated patients had both
clinical and radiological response vs. none of the control
patients (p = 0.0013) [96].
Future Directions in Stereotactic Radiation
for Glial Neoplasms
New strategies in the application of stereotactic irradiation
for malignant gliomas include:
• Changes in imaging.
• Concurrent use of systemic chemotherapy.
• İntegration with bevacizumab.
There is persistent interest in functional imaging modali-
ties for HGG. This might be of interest in target definition,
especially for recurrent tumors treated with SRS where non-
enhancing tumor may be missed by gadolinium-enhanced
T1 MRI images. The group from UCSF has compared SRS-
treated volumes with metabolically active tumor volumes
defined by proton magnetic resonance imaging (1H-MRS)
[97]. A total of 26 patients were retrospectively divided into
high-risk or low-risk groups according to the amount of
overlap between the metabolic target and the SRS target.
The median survival was 15.7 months for patients in the
low-risk group and 10.4 months for those in the high-risk
group.
In a trial for newly diagnosed GBM patients, MRS was
used to target a post-resection, pre-EBRT radiosurgery boost
[66]. As a novel means of managing the large 10 × 10 × 15 mm
MRS voxels, an 8 mm Gamma Knife “shot” was used to tar-
get each suspicious voxel. Dose was selected as per RTOG
90–05. Radiosurgery was followed by 60 Gy of EBRT. As
the results of the EORTC/NCIC trial became available,
temozolomide was incorporated in the regimen. Survival for
temozolomide-treated patients was 20.8 months.
Combining new strategies in HGG stereotactic radiother-
apy, Neider et al have presented the results of a phase II study
looking at adding chemotherapy and molecular targeting to
F-SRT for recurrent HGG [98]. Forty-six patients were
treated with F-SRT (30 Gy in 6 fractions) to a target defined
using C11-methionine PET, CT, and MRI information. In 30
patients, F-SRT was sandwiched in a 6-month course of
temozolomide. Median survival was 11 months with temo-
zolomide, 6 months without. Toxicity was acceptable with
three reoperations for apparent radionecrosis, which, on
pathology, was combined with recurrent tumor.
Temozolomide is now in standard use for HGG, but there
have been a number of small trials combining SRS or F-SRT
with other alkylators (carmustine implants, cis-platinum)
[33, 41], other conventional chemotherapy agents (pacli-
taxel) [99] kinase inhibitors (gefitinib, vandetanib) [47, 50],
or dedicated radiation sensitizers (hyperbaric oxygen,
motexafin gadolinium) [100, 101].
D. Roberge and L. Souhami
Results of the Temple University and Staten Island look-
ing at chemotherapy (cis-platinum and Taxol) and F-SRS for
recurrent glioma have been reported [37, 99]. Retrospectively,
these results are similar to patients treated without chemo-
therapy and further use of these agents with SRS is unlikely.
A phase I trial (NCI-T99–0041) investigating the sensiti-
zation of SRS with Gadolinium Texaphyrin was reported at
AACR-NCI-EORTC conference with emphasis on the 8 T
MRI correlative studies [101]. In this trial GBM patients
with a KPS >60 and a tumor <40 mm were first treated with
conventional EBRT. Following EBRT an IV infusion of
Gadolinium Texaphyrin was given 3 h prior to a 10 Gy SRS
boost. In the first eight patients accrued, the median time to
progression was a disappointing 4.5 months.
The UCSF group has published its experience using an
MMPI inhibitor (Marimastat starting on the day of SRS and
continued until progression, death, or toxicity) in combina-
tion with SRS for recurrent HGG [51]. In this phase I trial,
patients’ outcomes were not clearly different than expected
for patients with recurrent HGG.
Investigators from Colorado have reported two Phase I
trials of kinase inhibitors and radiation for recurrent HGG
[47, 50]. In a trial with gefitinib, the drug dose was constant
(250 mg/day) and the F-SRT was escalated (from 18 Gy in 3
fractions to 36 Gy in 3 fractions). In the subsequent trial with
vandetanib, the F-SRT dose was constant (36 Gy in 3) and
the drug escalated. Drug and radiation toxicities were addi-
tive without a clear increase in radiation effects or median
survival (6 and 10.3 months).
Bevacizumab, a humanized monoclonal antibody to
VEGF, is unique in that it promises to both increase the
anti-tumor effect of radiation at the same time as may lower
the risk of symptomatic necrosis—particularly appealing in
re-irradiation. Bevacizumab already appears to improve
progression-free survival in primary (Roche press release, Aug
2012) and recurrent [81] glioblastoma and has pre-clinical and
clinical support for synergy with radiation. Early outcomes
from radiosurgery plus bevacizumab have been reported. A
retrospective analysis from the Duke group compared recur-
rent GBM patients having received SRS with (33 patients) or
without (16 patients) bevacizumab [88]. Although the cases
and control were not matched, the groups were similar and the
median survival of the patients who received bevacizumab was
significantly longer (11 vs. 4 months, p = 0.015). Bevacizumab
patients also had lower rates of radionecrosis (5 % vs. 19 %).
Based on this experience, Duke investigators conducted a
prospective study to evaluate SRS plus bevacizumab for
recurrent high-grade gliomas [102]. Fifteen patients (9
GBM, 6 grade III) were treated: SRS for lesions 0–2.9 cm,
F-SRT lesions measuring 3–5 cm. Patients received 10 mg/
kg of bevacizumab on the day of radiosurgery and again 14
days later. No grade 4 toxicity was seen and the median sur-
vival was 13 months.
17 Stereotactic Radiosurgery and Radiotherapy in the Management of High-Grade Gliomas
Gutin and colleagues at the Memorial Sloan-Kettering
Cancer Center also reported a prospective study of bevaci-
zumab and SRS for recurrent HGG [49]. Twenty-five patients
(20 GBM, 5 grade III) received bevacizumab 10 mg/kg every
14 days along with 30 Gy in 5 fractions of F-SRT. No radia-
tion necrosis was seen. For the GBM patients, the median
overall survival was 12.5 months.
Finally, Park and colleagues reported on 11 GBM patients
treated at recurrence with bevacizumab and SRS (median
16 Gy, range 13–18 Gy) [103]. These patients were compared
to SRS-treated 44 case-matched controls irradiated without
bevacizumab. Overall survival was improved in the bevaci-
zumab-treated patients (18 months vs. 12 months, p = 0.005)
and adverse radiation effects were less common (9 % vs.
46 %, p = 0.037).
The bottom line is that, despite past failures, as long as a
majority of HGG continue to fail locally, there will be inter-
est in dose intensification and local re-irradiation. As new
techniques to achieve this are tested [104], it will be impor-
tant to better report toxicity and remain wary of selection
bias to which small cohorts are prone.
Conclusion
The best level 1 evidence currently available does not support
an improvement in outcome from the use of SRS for primary
HGG. Despite the modest benefits achieved by escalating
EBRT dose to match normal tissue tolerance, it is unlikely
that variations in fractionation, total dose, or treatment deliv-
ery will lead to a significant change in the outcome for
patients with HGG. For a select group of patients with recur-
rent disease, SRS or F-SRT is a safe, reasonable but palliative
treatment. For recurrent HGG other treatment modalities
have been tested in phase III trials and only prospective inves-
tigation can define the exact role of stereotactic irradiation.
Case Study 17.1
“Case 1. S.S. Autopsy #9588.
In 1929, at the age of 37, this right-handed white
male had a convulsive seizure lasting a few minutes … .
In 1931, following an attack, he noticed loss of sen-
sation on the right side of the body and a right
hemiparesis.
In 1933, a partial motor aphasia developed. Dr. Paul
C Bucy operated on him in October, 1933. A firm area
measuring 2 cm. in diameter was found on the left side
in the gyrus just anterior to the precentral gyrus. An
attempt at complete removal was not made because of
the location. A small piece was taken for study. The tis-
sue was diagnosed by Dr. Percival Bailey as a malignant
263
glioma, probably a glioblastoma multiforme. Following
the operation, the patient as given a course of roentgen
therapy for a total of 6,068 r … .
In September, 1937, he was struck by an automo-
bile and was unconscious for 24 h. Sometimes thereaf-
ter his seizures returned. He gradually lost power on
the right side, and the aphasia became worse.
In October, 1939, he was seen by Dr. Leo Davidoff
… .An encephalogram was interpreted as showing
left-sided cerebral atrophy without evidence of
regrowth. Nothing further was done.
He entered Montefiore Hospital in August, 1939, at
the age of 49 … .There were now astereognosis in the
right hand, a partial motor aphasia, and some blurring of
the right disc margin … .During his stay in the hospital,
both focal motor and generalized seizures were noted.
Irradiation was not deemed advisable, and he was dis-
charged to be followed in the outpatient clinic. He had
difficulties in expressing himself. Because of this, he
insisted on being re-admitted in July 1941. At this time
it was felt that the paretic side was more spastic, and that
the motor aphasia now had a sensory component … .
He was given a course of roentgen-therapy amounting
to 3,000 r. with slight improvement. Thereafter he con-
tinued to have right-sided seizures until July, 1943,
when he rapidly became worse and died … .
Autopsy. A broncho-pneumonia was found to be
the immediate cause of death. The brain weighed
1,420 g … .There was a hemorrhagic tumor nodule,
measuring 3 × 2 cm., in the left 3rd frontal convolution
… .The tumor was a glioblastoma multiforme. There
were some spongioblastic portions, but there were, in
addition, extensive necrosis, pseudo-pallisading
around focal necrotic zones, thrombosis of vessels and
endothelial proliferation, perivascular lymphocytes,
numerous mitotic figures, and pleomorphism.”
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 Management of Glial Tumors:
Viewpoint—Surgery and Intra-
cavitary Radiopharmaceutical
Therapy
Kaisorn L. Chaichana, Linda Chen,
Salvador Manrique-Guzman, Lawrence Kleinberg,
and Alfredo Quinones-Hinojosa
Introduction
Gliomas are primary tumors of the central nervous system
that can be subdivided into low- and high-grade gliomas.
Patients with low-grade gliomas are considered to have a
better prognosis than patients harboring high-grade tumors
[1–13]. The median survival for patients with low-grade gli-
omas is between 5 and 10 years as compared to 1–3 years for
patients with high-grade tumors [1–13]. Regardless of tumor
grade, the overwhelming majority of patients will eventually
die from progressive and/or recurrent disease [1–13]. Despite
the poor prognosis for patients with gliomas, surgery has
been a mainstay of treatment [1–13]. An emerging adjunct to
surgical therapy is stereotactic brachytherapy (SBT) [14, 15].
This chapter will discuss the role that surgery and brachy-
therapy have for patients with gliomas.
Role of Surgery for Patients
with High-Grade Gliomas
High-grade gliomas include WHO grade III (anaplastic
astrocytomas) and IV (glioblastoma—GB). Patients with
high-grade gliomas are considered to have poor prognoses
[3–6, 12, 13, 16–19]. Patients with anaplastic tumors have a
median survival of approximately 3 years, while patients
with GB have a median survival of approximately 14 months
K.L. Chaichana, M.D. (*) • S. Manrique-Guzman, M.D.
Department of Neurosurgery, Johns Hopkins University School
of Medicine, Baltimore, MD, USA
e-mail: Kaisorn@jhmi.edu
L. Chen, M.D. • L. Kleinberg, M.D.
Department of Radiation Oncology, Johns Hopkins University
School of Medicine, Baltimore, MD, USA
A. Quinones-Hinojosa, M.D. (*)
Department of Neurosurgery and Oncology, Johns Hopkins
University School of Medicine, Baltimore, MD, USA
e-mail: Aquinon2@jhmi.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_18, © Springer Science+Business Media New York 2015
18
[2–6, 10, 11, 18–20]. High-grade gliomas are characterized
by their invasive and infiltrative nature, making curative
resection unlikely [20]. In fact, survival has changed little in
recent years despite advances in medical and surgical thera-
pies [21]. Walter Dandy in the 1920s performed hemispher-
ectomies for these lesions, and they would still recur on the
contralateral side [22]. Survival for these patients was still
less than 2 years [22]. As a result, the efficacy of surgery
alone for these lesions has been questioned and raises the
need to implement further treatment modalities to comple-
ment surgery.
In recent years, there have been an increased number of
studies supporting a role for extensive surgery in patients
with high-grade gliomas.
Lacroix et al. in 2001 analyzed 416 consecutive patients
with GBM [23]. They found that resections greater than
98 % were needed to significantly improve survival, where
survival increased from 8.8 to 13 months [23]. This study,
however, did not include adjuvant therapy into their survival
analysis [23]. Sanai et al. more recently studied 500 patients
with GB in 2011 and found that 78 % resection was needed
to confer a survival advantage [24]. Keles et al. in 2006 eval-
uated 102 patients with anaplastic astrocytomas [25]. They
found that the amount of residual tumor correlated with time
to progression and overall survival, where the most signifi-
cant threshold was 10 cm3 [25]. This study, however, did not
include patients with GB and did not account for extent of
resection, just residual disease [25]. Laws and colleagues
evaluated outcomes for 788 patients with malignant astrocy-
tomas from several institutions [26]. They found that patients
who underwent surgical resection had significantly longer
survival times than patients who underwent biopsy [26]. This
remained significant even after eliminating patients who
were considered poor surgical candidates [26]. This study,
however, did not evaluate the role of gross total, near total, or
subtotal resection [26].
We recently evaluated the role of extent of resection on
survival for 949 patients with malignant astrocytomas [12].
We found that there was a survival benefit for patients who
269
270
underwent both gross total and near total resection [12]. This
survival benefit was independent of age, degree of disability,
or subsequent treatment modalities for both WHO grade III
and IV gliomas [12]. The median survival for patients with
newly diagnosed GB who underwent gross total, near total,
and subtotal resection was 13, 11, and 8 months, respectively
[12]. Likewise, the median survival for patients with recur-
rent GB who underwent gross total, near total, and subtotal
resection was 11, 9, and 5 months, respectively [12].
Similarly, for patients with WHO grade III astrocytomas,
patients who underwent gross total resection had improved
survival as compared to patients with subtotal resection, even
after controlling for age, functional status, and revision
resection [12]. The median survival after primary resection
of WHO III astrocytomas for gross total, near total, and sub-
total resection was 58, 46, and 34 months, respectively [12].
These studies therefore suggest that achieving an increased
extent of resection may be associated with prolonging
survival for patients with malignant astrocytomas, but
randomized control studies do not exist.
Despite this growing body of evidence supporting
increased extent of resection for patients with high-grade
gliomas, not all studies support a positive correlation between
extent of resection and survival [27]. Levin et al. studied 90
patients with WHO grade III gliomas enrolled into a phase II
study for radiation and carboplatin [27]. They found that
extent of resection was not significantly associated with sur-
vival for this cohort [27]. Totrosa et al. also found no associa-
tion between survival and extent of resection for a similar
group of patients with anaplastic tumors [28]. Additionally,
Pope et al. evaluated 153 patients with high-grade gliomas
(43 with WHO grade III and 110 with WHO grade IV glio-
mas) [29]. They found no difference in survival between
patients who underwent surgery versus biopsy [29].
There have been five systematic reviews of the literature
to date evaluating the role of resection and survival [30–34].
Sanai and colleagues identified 28 studies on high-grade
gliomas with more than 75 patients [34]. They found of these
28 studies, 14 studies demonstrated an association between
extent of resection and survival and ten studies found no sta-
tistical association [34]. Grant et al. performed a Cochrane
review on biopsy versus resection for patients with high-
grade gliomas [30]. They excluded all 2,100 identified stud-
ies because they lacked statistical power, patient information,
and/or outcome data [30]. Hess [31] and Nazzaro [32] also
independently performed similar reviews and also concluded
that there was a lack of high-quality studies to conclude if
surgical resection provided a benefit for patients with high-
grade gliomas [31].
Although the survival benefit of extensive surgical resec-
tion is not demonstrated in all retrospective studies, the pre-
vailing consensus in numerous studies have demonstrated
K.L. Chaichana et al.
that gross total resection of gliomas improves overall survival
in comparison to subtotal resection and biopsy [2–6, 10, 11,
30–32]. In addition to the possible benefit of prolonging sur-
vival with safe, maximal surgical debulking, aggressive
resection provides a more representative sample for patho-
logical diagnosis and may also provide more improvement in
mass effect with subsequent symptomatic relief [26].
Maximal resection should therefore be pursued when safe to
do so for high-grade lesions (Table 18.1) [19].
Role of Surgery for Patients
with Low-Grade Gliomas
Patients with low-grade gliomas often have a better progno-
sis than patients harboring higher-grade tumors [3–10, 12,
18–21]. In fact, the median survival for patients with low-
grade gliomas is typically between 5 and 10 years [3–10, 12,
18–21]. Despite this more favorable prognosis, 50–75 % of
patients with low-grade gliomas eventually die from their
disease because of either tumor progression or degeneration
to a higher malignant grade [1, 7, 8]. The optimal treatment
for patients who harbor low-grade gliomas, however, remains
unclear because many patients are followed radiographically
and intervention is only pursued when clinical or radio-
graphic progression becomes evident [35]. Moreover, the
role of surgery in delaying recurrence and/or malignant
degeneration as well as prolonging survival remains contro-
versial [7, 35].
This lack of understanding of the effectiveness of surgery
for patients with low-grade gliomas is because there are no
randomized control trials or matched pair analyses. Keles
et al. performed a literature review of the role of surgery for
patients with low-grade gliomas and found 30 studies evalu-
ating the role of surgery for patients with low-grade gliomas
[1]. In this review, all but five studies were excluded because
they included patients with grade I gliomas, relied upon
intraoperative determination of extent of resection, and had
small sample sizes, among others [36–39]. These five studies
that met the inclusion criteria were also limited because
extent of resection was determined by intraoperative gross
visualization rather than neuro-imaging, and a distinction
between gross total and near total resection was not made
[36–39]. This review and others have found data supporting
a role of surgery in delaying recurrence and prolonging sur-
vival controversial [1, 40].
Despite this, there are an increasing number of studies
demonstrating a benefit for increasing extent of resection for
patients with low-grade gliomas [7]. Wisoff et al. evaluated
518 pediatric patients with low-grade glioma, and found that
extent of resection was significantly associated with
improved progression-free survival [41]. The 5-year survival
18 Management of Glial Tumors: Viewpoint—Surgery and Intra-cavitary Radiopharmaceutical Therapy 271

Table 18.1 Surgical management of glioma: summary and level of existing evidence supporting management
Tumor characteristics
and presentation
Large tumors, significant
neurologic deficit, and/or
medically intractable
seizures
Small tumors without mass
effect found on MRI,
transient neurologic
symptoms
Tumors located in motor,
sensory, or language
functional areas and/or
deep seated tumors
Low-grade glioma–surgical management
and considerations
Early surgical debulking with extensive resection
while minimizing neurologic dysfunction
Decompression of tumor provides
symptomatic relief and reduces tumor burden
Decreases risk for malignant transformation
(Level III evidence)
Consider watchful waiting and delayed
intervention
Monitor for radiologic progression
Monitor for clinical progression
of neurologic symptoms
Stereotactic biopsy only
Monitor for radiologic progression
Monitor for clinical progression
of neurologic symptoms
Consider resection
Intraoperative cortical mapping to identify
functionally critical areas (Level III evidence)
Consider resection in conjunction
with stereotactic brachytherapy
(Level III evidence)
High-grade glioma–surgical management
and considerations
Extensive resection which minimizes neurologic
dysfunction
Gross total resection improves patient overall survival
(Level III evidence)
Use of image guided resection to achieve more
extensive resection (Level I evidence)
Decompression of tumor provides symptomatic relief
and reduces tumor burden
Extensive resection which minimizes neurologic
dysfunction
Gross total resection improves patient overall survival
(Level III evidence)
Use of image-guided resection to achieve more
extensive resection (Level I evidence)
Decompression of tumor provides symptomatic relief
and reduces tumor burden
Extensive resection which minimizes neurologic
dysfunction
Gross total resection improves patient overall survival
(Level III evidence)
Intraoperative cortical mapping to identify functionally
critical areas (Level III evidence)
Use of image-guided resection to achieve more
extensive resection (Level I evidence)

rate was 99 % with gross total resection, 95 % with 1.5 cm3
residual disease, 94 % with 1.5–2.9 cm3 residual, and 87 %
with >3 cm3 residual [41]. The 5-year progression-free sur-
vival rate was 90 % with gross total resection and 45–65 %
with any volume (1.5–3 cm3) of residual disease [41]. More
recently, Smith et al. performed a retrospective volumetric
analysis of extent of hemispheric LGG resection in 216
patients and found that patients with at least 90 % resection
had 5- and 8-year survival rates of 97 % and 91 %, respec-
tively, while patients with less than 90 % resection had 5-
and 8-year survival rates of 76 % and 60 %, respectively
[42]. We recently evaluated 170 patients with low-grade gli-
omas and found that gross-total resection was associated
with increased overall survival as compared to patients who
underwent subtotal resection [11]. Five-year overall survival
after gross total, near total, and subtotal resection was 95 %,
80 %, 70 %, respectively, and 10-year survival was 76 %,
57 %, and 49 %, respectively [11]. Additionally, after gross
total, near total, and subtotal resection, median time to tumor
progression was 7.0, 4.0, and 3.5 years, respectively [11].
The median time to malignant degeneration after gross total,
near total, and subtotal resection was 12.5, 5.8, and 7 years,
respectively [11]. In a separate study, we found that gross
total resection was independently associated with delayed
malignant degeneration [7].
There is a growing body of evidence that surgery is an
effective treatment for patients with low-grade gliomas,
despite an absence of randomized control trials. For patients
who present with large tumors, significant neurological defi-
cits, and medically intractable seizures, immediate surgical
intervention is generally the preferred treatment option [7, 43].
Extensive resection without causing an iatrogenic deficit can
lead to improvements in overall survival, progression-free
survival, and malignant transformation-free survival [7–9, 44].
However, for incidentally discovered small tumors without
mass effect or symptoms, observation with surveillance
imaging is a viable option given the slow growth and natural
history of low-grade gliomas (Table 18.1) [45].
272
Intra-Cavitary Radiopharmaceutical Therapy
or Stereotactic Brachytherapy
The standard of care for patients with high-grade gliomas is
extensive resection, followed by radiation and temozolo-
mide chemotherapy [46]. Regardless of treatment, tumor
recurrence typically occurs close to the tumor margins [20].
At the tumor margin, there is an increased tumor cell density
[20]. Beyond the periphery, there is a sharp fall-off in cell
numbers as the distance from the resection cavity increases
[20]. Extensive surgical resection of gliomas can prolong
progression-free and overall survival by decreasing tumor
burden and possibly increasing adjuvant therapy efficacy as
it has with other types of solid tumors [47]. Moreover, the
use of adjuvant therapies have been developed to help
reduce the tumor burden at the tumor periphery. One of
these developments is SBT (Table 18.2).
It is generally considered beneficial to provide radiation
to the gliomatous areas around the surgical cavity, especially
for high-grade gliomas [14, 48, 49]. The techniques to deliver
this radiation include stereotactic radiation therapy and SBT
[14, 48, 49]. SBT involves the delivery of radiation by ste-
reotactically implanting radioactive sources near or within
tumors [14, 48, 49]. SBT can be applied peri- or postopera-
tively by either permanent isotope seeds or by temporary
catheters containing radioisotopes [14, 48, 49]. There are a
variety of different isotopes that can be administered for
radiation therapy including Iodine-125, Iodine-131, and
Iridium-192, among others [14, 48, 49]. The exposure times
of these seeds range from a few days to several months and
vary whether temporary implants or permanent seeds are
used [14, 48, 49]. In the central nervous system, the most
common radioactive source used for SBT are Iodine-125
seeds (125I) which emit low-energy radiation of 0.028–
0.035 meV and have a steep falloff dose that reduces periph-
eral normal tissue exposure [14, 15].
SBT has been used as adjuvant treatment following surgi-
cal resection for both primary and recurrent low- and high-
grade gliomas and has been used for tumors in eloquent
regions that are considered unresectable [14, 48, 49]. The
theoretical benefit of SBT is that it allows for precise surgical
implantation of radioisotopes within the tumor or tumor cav-
ity, thus providing local radiation to adjacent tissue while
Table 18.2 Summary of benefits and risks of stereotactic brachytherapy use in gliomas
Stereotactic brachytherapy benefits
Minimizes surgical intervention in functionally critical tissue
Avoids systemic toxicity of chemotherapy
Avoids neuro-cognitive effects in children who undergo EBRT
Retrospective series demonstrate both safety and efficacy
K.L. Chaichana et al.
sparing surrounding tissue [15]. Additionally, SBT avoids the
systemic side effects of chemotherapy and the potential neuro-
cognitive effects of external beam radiation therapy (EBRT)
[50]. However, while numerous retrospective studies have
demonstrated SBT to be safe and efficacious in gliomas [15,
51–56], three small single institution prospective randomized
trials failed to demonstrate a survival advantage [57–59].
Therefore, the efficacy of this treatment option requires further
investigation as well as potential advances in imaging and
implant technology before it will be widely used.
Procedure
SBT is based on the principle that radiation will induce
necrosis in a targeted tumor volume and that necrotic tissue
will then be removed by macrophages [60]. Stereotactic
computed tomography and magnetic resonance images
(MRI) are co-registered for treatment planning and dosime-
try calculations [61]. The typical cumulative, prescribed
dose ranges from 50–65 Gy over 3–5 days [14, 48, 49]. In
interstitial radiotherapy, 125I seeds are administered via ste-
reotactically implanted catheters intraoperatively [15, 62].
Dose rates vary and individual institutions vary over whether
a low dose, which allows build up of damage in tumor cells,
or a high dose rate, which decreases total treatment time, is
administered [14]. A potential barrier to the success of radio-
active seed brachytherapy may be the inhomogeneous distri-
bution of doses [14, 48, 49]. Tumor areas adjacent to seeds
receive a very high dose that may contribute to toxicity,
whereas the areas in between seeds may have cold spots and
the tumor is potentially under-dosed in these regions [63].
Recently, the advent of GliaSite brachytherapy allows for
administration of 125I on an outpatient basis [64–66]. With
GliaSite, an expandable balloon catheter can be implanted
intracranially near the tumor or within a resection cavity
thereby providing a conformal fit (Fig. 18.1) [64–66]. Liquid
125
I is then used as the source of radiation and the balloon is
inflated through an accessible subcutaneous port; this admin-
istration provides the opportunity for treatment to be admin-
istered after several weeks of postoperative recovery [66, 67].
As the liquid radioisotope distributes uniformly throughout
the balloon, there is a uniform delivery of radiation to the
region surrounding the balloon [64–66]. This minimizes the
Stereotactic brachytherapy risks
Prospective, randomized controlled trials have failed to demonstrate
a survival advantage
Invasive procedure when compared to external beam radiation therapy
Limited to tumors <5 cm in diameter and spherical in shape
Complications: Radiation-induced necrosis and neurological dysfunction
18 Management of Glial Tumors: Viewpoint—Surgery and Intra-cavitary Radiopharmaceutical Therapy
Fig. 18.1 GliaSite radiation therapy system device. (a) Schematic shows device components: balloon, subcutaneous tube, and infusion port.
(b) Intraoperative photograph of device implantation after tumor resection
potential for “hot” or “cold” radiation regions and also allows
for a predictable distribution of radiation dose, which
decreases with distance from the balloon surface [64–66].
Whereas stereotactic implantation of radiation seed catheters
can be placed in the midst of actual gross tumor, the GliaSite
technique is only useful when a surgical cavity has been cre-
ated by resection of all or most of the tumor [64–66]. There
also continues to be interest in developing targeted delivery
of radiation dose by using radioisotopes bound to molecules,
which preferentially bind to glioma cells [64–66]. In addi-
tion to 125I, I-131 labeled TM-601, a synthetic chlorotoxin,
has also been demonstrated to effectively deliver radiation
[68]. Efficacy has not been demonstrated, but this general
approach remains promising and continues to be a subject of
investigation.
Indications
Therapeutic management of gliomas includes some combina-
tion of stereotactic biopsy and radiologic monitoring, surgical
resection, and chemo-radiation therapy [3–5, 16]. Although
surgical resection is the gold standard, tumors located in elo-
quent or critical areas of the brain are not always amenable to
extensive debulking [49]. In children with inoperable low-
grade gliomas, SBT is a treatment option that avoids the
hematologic and otologic toxicity of chemotherapy and the
cognitive and neuropsychological deficits associated with
EBRT [50, 69]. In these children, retrospective studies have
found SBT to be safe and have an efficacy that is comparable
to conventional chemo-radiation with 5 and 10-year survival
rates of 97 % and 92 %, respectively [51, 52, 69]. Additionally,
in adults with low-grade gliomas, the combination of SBT
and microsurgery reduces the high complication rate of injury
to eloquent brain regions while effectively irradiating the
273
tumor in several retrospective studies [56, 70, 71]. For high-
grade gliomas, SBT has been utilized for both operated and
inoperable gliomas in combination with adjuvant therapies
and has been shown to be safely tolerated [55, 72]. Several
studies have retrospectively studied the safety and feasibility
of SBT in high-grade gliomas using GliaSite in combination
with resected brain tumors [66, 67].
Previous Studies
Previous studies (Table 18.3) have demonstrated the safety
and efficacy of brachytherapy for patients with gliomas.
Gutin et al. studied 63 patients who were administered
brachytherapy (125I) in addition to EBRT, procarbazine,
lomustine, and vincristine from 1982 to 1990. The median
survival for patients with anaplastic gliomas was 157 weeks
for those with implants and 165 weeks for those without
implants, while the median survival for patients with GB was
88 weeks for those with implants and 67 weeks for those
without implants [73]. Wen and colleagues treated 56
patients with GB from 1987 to 1993 [74]. The patients in this
study underwent surgery, limited field EBRT, and brachy-
therapy with 125I [74]. The median survival for patients
undergoing brachytherapy was 18 months compared with 11
months for a matched brachytherapy control group with sim-
ilar clinical and radiologic features [74]. Thirty six patients
(64 %), however, underwent reoperation for symptomatic
radiation necrosis [74]. Welsh et al. studied 20 patients from
eight institutions who underwent Gliasite brachytherapy
boost [66]. These patients underwent extensive debulking
followed by EBRT [66]. The average survival for this study
population was 11.4 months, which was 3 months longer
than historical controls [66]. Three patients (14 %) in this
series experienced central nervous system toxicity [66].
274 K.L. Chaichana et al.

Table 18.3 Summary of previous studies on the use of brachytherapy

Number Brachytherapy EBRT Median survival
Author Years of patients Glioma type type dose (cGy) (months) Complications
Gobitti et al.a 2006–2008 15 Recurrent WHO IV Gliasite 4,500 13 Radiation necrosis
(20 %), death (13 %)
Suchorska et al. 1982–2006 95 Recurrent WHO Iodine-125 20 3.3 % permanent
grade II morbidity
Chen et al.a 1999–2002 18 WHO IV Iodine-125 4,000 26.3 Radiation necrosis (61 %)
Welsh et al. 2000–2004 20 WHO IV Gliasite 5,000 11.4 Radiation necrosis (14 %)
Reardon et al. 1996–2003 43 Recurrent WHO Iodine-131 4,600 14.8 Radiation necrosis
III-IV (12 %), hematologic
toxicity (23 %)
Akabani et al. 1996–2003 18 WHO III-IV Iodine-131 4,800 18.2 Radiation necrosis (39 %)
Selker et al.b 1987–1994 133 WHO III-IV Iodine-125 6,000 15.7 Radiation necrosis
(15.3 %)
Koot et al. 1998–1995 66 WHO IV Iodine-125 (45), 5,000 16 Radiation necrosis (5 %),
Iridium-192 (21) Vascular ischemia (14 %)
Johannsen et al. 1992–1996 44 WHO III-IV Iridium-192 6,600 11.7
Laperriere et al.b 1986–1996 71 WHO III-IV Iodine-125 6,000 13.8 Worsened neurological
function (10 %)
Patchell et al. <1997 33 WHO III-IV Californium-252 5,400 10.9 Scalp necrosis (30 %)
Micheletti et al. <1996 24 WHO III-IV Iridium-192 2,500 8 Acute complication
Bernstein et al. 1986–1992 46 Recurrent WHO Iodine-125 10.6 Radiation necrosis (26 %)
III-IV
Wen et al. 1987–1993 56 WHO IV Iodine-125 18 Radiation necrosis (64 %)
Riva et al. <1994 24 Recurrent WHO IV Iodine-131 3,650 16
Gutin et al. 1982–1990 63 WHO III-IV Iodine-125 26
a
Study stopped because of complications related to brachytherapy application
b
Randomized control trial

In addition to these studies, there have been two random-
ized control studies to date on the use of brachytherapy for
patients with gliomas (Table 18.3) [58, 59]. Selker and col-
leagues randomized 270 patients with newly diagnosed
malignant gliomas to surgery, EBRT, and carmustine or sur-
gery, EBRT, carmustine, and interstitial radiotherapy boost
with 125I from 1987 to 1994 [59]. The median survival for
patients undergoing treatment with 125I was 68.1 weeks as
compared to 58.8 weeks [59]. The difference in survival was
not statistically significant [59]. Likewise, Laperriere et al.
randomized 140 patients from 1986 to 1996 to brachyther-
apy (125I) plus EBRT versus EBRT for patients with biopsy-
proven malignant astrocytomas [58]. The 71 patients
randomized to the implant arm had a median survival of
13.8 months as compared to 13.2 months for the 69 patients
with EBRT [58]. There was no significant difference in sur-
vival between the two treatment arms [58]. Thus, while SBT
remains a treatment option for both low- and high-grade
gliomas, the data is conflicting and inconclusive. This is true
when SBT is used in combination with standard surgical
resection and/or chemo-radiation.
Limitations and Complications
The risks and benefits of SBT are summarized in Table 18.2.
Patients who are more amenable to SBT include those with
tumors that are smaller <5 cm in diameter to minimize
damage to surrounding brain parenchyma [62]. Moreover,
patient selection is limited to those with spherical tumors, as
ovoid or complex polycyclic shapes create challenges in
obtaining uniform dose distributions [62, 70]. Complications
that are due to SBT radiation most commonly lead to blood-
brain barrier breakdown at high radiation doses and result in
radiation-induced necrosis [75]. Necrotizing radiation
changes can cause mass effect and lead to devastating side
effects including both transient and long-term neurological
dysfunction, increased use of steroids to reduce edema, and
formation of cysts that can exert mass effect [62, 70].
The GliaSite balloon brachytherapy is designed for sur-
gical cavities up to 3–4 cm in size [64–66]. A substantial
radiation dose can be delivered up to a cm or more beyond
the balloon surface such that minimal gross residual disease
can be encompassed [64–66]. However, the higher doses
18 Management of Glial Tumors: Viewpoint—Surgery and Intra-cavitary Radiopharmaceutical Therapy
required to deliver a sufficient amount of radiation at
increasing distances from the balloon surface may result in
more toxicity [64–66]. More study of this technique are
therefore required.
Conclusion
While there are no randomized control trials, there is a grow-
ing body of evidence supporting maximal resection without
causing an iatrogenic deficit for patients with high-grade
gliomas, as well as low-grade glioma patients with symp-
toms or enlarging tumors. SBT can be utilized as adjuvant
treatment for primary and recurrent low- and high-grade
gliomas in combination with surgical resection, chemother-
apy, and/or EBRT. The use of intracranial SBT can also be
helpful for patients with tumors located in functionally criti-
cal areas not amenable to surgical resection. However, to
date, randomized control trials have yet to show a survival
benefit for patients with SBT. Thus, while SBT can be uti-
lized in a select group of patients to minimize adverse side
effects of surgical and chemo-radiation treatment, more evi-
dence is needed to determine whether patient outcomes are
significantly improved with this therapy. The development
of new approaches or new radiopharmaceutical agents to
deliver intra-cavitary brachytherapy such as the GliaSite bal-
loon catheter which delivers a predictable homogeneous
dose distribution or the use of radiolabelled antibodies to tar-
get treatment at tumor cells has the potential to enhance the
therapeutic ratio of this approach.
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 Malignant Glioma: Viewpoint—
Chemotherapy
Roger Stupp, Krisztian Homicsko,
and J. Gregory Cairncross
Introduction
Despite optimal surgery and adjuvant radiotherapy, malig-
nant gliomas almost always recur [1]. One cause of failure is
explained by the diffusely infiltrating pattern of growth dis-
played by most gliomas, with malignant cells disseminated
far beyond the initial bulky tumor. Although most relapses
occur at or near the initial site of tumor, either along the
resection margin or at the edge of the radiation field, distant
recurrences or seeding of the cerebrospinal fluid (CSF)
occurs in long-surviving patients. Malignant gliomas are not
a localized disease but affect the whole brain and may dis-
play wide dissemination even at early stages. Thus, thera-
peutic strategies aiming only at bulky local disease are
doomed to fail. The successful treatments of the future will
need to eradicate microscopic disease in many sites within
the brain and do so without neurotoxic effects.
Obstacles to Drug Therapy of Brain Tumors
The Blood–Brain Barrier
The brain is considered a pharmacological sanctuary by vir-
tue of the blood–brain barrier. Many chemotherapeutics,
those that are large or hydrophilic, are unable to cross this
R. Stupp, M.D. (*)
Department of Oncology and Cancer Center,
University Hospital Zurich, Zurich, Switzerland
e-mail: roger.stupp@usz.ch
K. Homicsko, M.D., Ph.D.
Department of Oncology, Centre Hospitalier Universitaire Vaudois,
Lausanne, Vaud, Switzerland
J.G. Cairncross, M.D.
Southern Alberta Cancer Research Institute, University of Calgary,
Calgary, AB, Canada
L.S. Chin, W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_19, © Springer Science+Business Media New York 2015
19
protective barrier. In most malignant gliomas, the blood–brain
barrier is at least partially disrupted, evidenced by contrast
enhancement on computed tomography (CT) and magnetic
resonance imaging (MRI) studies. The blood–brain barrier
may not be an impediment to the identification of effective
drug therapies, because radiographic responses can be seen,
but it is a significant obstacle to achieve adequate tissue pen-
etration and to the development of curative drug therapies.
Infiltrating microscopic glioma hidden behind intact portions
of the blood–brain barrier escape the exposure to drugs that
do not cross the barrier and set the stage for tumor regrowth,
despite effective multimodality local therapies. Furthermore,
gliomas may induce aberrant capillary growth, which in turn
may limit the penetration of chemotherapeutics into the
tumor and adjacent brain. Other factors such as tumor size,
cell density, and increased intratumoral and intracerebral
pressure can inhibit blood flow and reduce drug delivery to
malignant gliomas.
Hence, a prerequisite for a highly efficacious antiglioma
drug, administered intravenously or by mouth, is the ability
to cross the blood–brain barrier. Barrier permeability can be
inferred from the chemical structure of the drug; however,
measurements of drug concentrations in brain and glioma
tissue are difficult. It is neither easy, nor ethical to perform
repeated brain biopsies to establish drug tissue levels, and
animal models of glioma are often too artificial to be helpful.
Measurements of drug levels in the CSF may be a valuable
surrogate for brain and glioma exposure, but false readings
may occur due to the effects of tumor edema or compartmen-
talization of CSF spaces that result from pressure effects or
circulating tumor cells that disrupt the flow of CSF [2].
The Complex Biology of Malignant Gliomas
The complexity of glioma biology is insufficiently reflected
by the conventional pathological classification as glioblas-
toma (World Health Organization grade IV), anaplastic
(grade III) astrocytoma, oligodendroglioma and mixed
279
280
oligoastrocytoma. Mutational analyses, gene expression and
methylation (profiling allowed identification of glioblastoma
subclasses proneural, neural, classical, mesenchymal), or
methylator phenotypes (CIMP) [3–5]. These molecular clas-
sifications explain, in part the observed prognostic differ-
ences and due to differences in the underlying genetic events
tumors from specific subtypes are likely to respond differ-
ently to biological therapies. Consequently development
of novel, targeted therapies needs to be tailored to specific
subtype and associated aberrations. In addition to this inter-
patient heterogeneity, the importance of intratumoral hetero-
geneity is increasingly recognized [6, 7]. Different regions of
the same tumor may harbor different genetic variations due
to clonal evolution within the tumor and hence while one
region of the tumor is sensitive to the therapy, other regions
can be resistant and hence response is limited and recurrence
is evident. An example of relevance in glioblastoma is the
constitutively activated variant of the epidermal growth fac-
tor receptor (EGFRviii) that is only expressed in a fraction of
tumor cells [8].
The tumor stem cell hypothesis and hierarchical structure
of tumors reflects also intratumoral heterogeneity [9]. These
tumor-initiating cells are capable of self-renewal and pro-
moting tumor regrowth (stemness). These cells are also
resistant to conventional therapy due to high expression of
multi-drug resistance proteins (MDRs, ABC transporters
also known as P-glycoproteins), and they are protected from
cytotoxic and ionizing radiation therapy in their frequent
dormant G0-cell cycle state [9]. In contrast to the initial
belief, stem-like cancer cells are generated in a dynamic pro-
cess also from more differentiated non-stem-like cells [10].
Thus combination treatment is required to target both stem-
ness and more differentiated tumor cells by conventional
therapy [11].
The tumor microenvironment is another source of hetero-
geneity. Cancer associated fibroblasts (CAFs) and tumor
endothelial cells are not only important in the development
of tumors but also in the maintenance and in response to
therapy [12]. While anti-angiogenic therapy is greatly lim-
ited by both tumor endothelial and cancer cell adaptation,
blockade of oncogenic signaling pathways in tumor cells by
tyrosine kinase inhibitors (TKIs) can be attenuated by the
expression of paracrine signaling proteins (like hepatocyte
growth factor, HGF) from the surrounding CAFs, that in turn
can activate pro-survival pathways (e.g., cMET) in tumor
cells [13].
Taken together, the understanding of the complexity of
tumor biology in tumor development and also in response to
therapy is crucial in our aim to overcome innate and adaptive
resistance mechanisms and to achieve more pronounced and
sustained responses [7].
R. Stupp et al.
Concomitant Medications
Many chemotherapy agents are metabolized by P450-
dependent hepatic enzymes. Antiepileptics and corticoste-
roids, commonly prescribed for patients with gliomas,
induce these hepatic enzymes, leading to rapid degradation
of certain classes of chemotherapeutics, undermining effec-
tive cancer treatment. The optimal concentrations of chemo-
therapeutics may be difficult to achieve when P450-inducing
drugs are co-administered. The pharmacokinetic profiles of
new drug therapies for malignant glioma must be assessed in
the presence of concomitant antiepileptic and steroid medi-
cations especially. Although the increased metabolism can
be overcome by increasing the doses of the chemotherapy
agents by several-fold, this approach will make drug ther-
apy prohibitively expensive and—more importantly—
potentially dangerous. Should the antiepileptic treatment be
discontinued inadvertently, a massive overdose of chemo-
therapy could ensue. To avoid such pitfalls, the use of
nonenzyme-inducing antiepileptics [e.g., valproic acid
(Depakene, Abbott, Chicago, IL), lamotrigine (Lamictal,
GlaxoSmithKline, Research Triangle Park, NC), gabapentin
(Neurontin, Pfizer, New York, NY), levetiracetam, (Keppra,
UCB, Brussels, Belgium), topiramate (Topamax, Ortho-
McNeil Neurologics, Titusville, NJ)] should be considered
[14–16]. In clinical practice, the enzyme-inducing effect of
dexamethasone and the enzyme-inhibiting action of the
anticonvulsant valproic acid are of lesser concern, and for
valproic acid circumstantial evidence suggests a possible
synergistic antitumor effect [17, 18].
How to Measure Antitumor Activity?
In oncology, new agents are initially tested for antitumor
activity in trials that assess whether the tumor type in ques-
tion shrinks noticeably after drug exposure. Shrinkage is
usually determined radiographically using CT or MRI and
described as a rate of response. By convention, a 20 %
response rate means that 20 % of the tumors tested were
smaller after drug exposure. The World Health Organization
(WHO) criteria specify measurement of perpendicular tumor
diameters, generating a baseline maximum surface area; a
reduction of the surface area by ≥50 % is considered a par-
tial response; disappearance of all tumor is defined as com-
plete response, and an increase by 25 % is considered tumor
progression. Regressions of <50 % or increases <25 % are
called stable disease. For neurooncology, these stringent
imaging criteria have been supplemented by an assessment
of the use of corticosteroids, which must be stable or decreasing
in dose in order to qualify for a response or progression to be
19 Malignant Glioma: Viewpoint—Chemotherapy 281

declared (the so-called Macdonald criteria) [19]. In recent
years in general oncology, unidimensional tumor measure-
ments have been proposed to simplify and speed up the pro-
cess of assessing response, however in neurooncology these
so-called RECIST criteria have not yet been adopted or vali-
dated [20]. With the increased use of anti-angiogenic agents
and their effect on normalizing the blood–brain barrier,
increased attention is to be given on the tumor extension on
T2 and FLAIR MRI images rather than solely assessing the
decrease in contrast uptake. An international working party
is addressing methodological issues surrounding response
evaluation with modern treatments. A first set of RANO-
criteria (Response Assessment in Neuro-Oncology) has been
published [21].
Because objective responses are uncommon in neuroon-
cology (i.e., most tumors are resistant to most drugs) and
may be difficult to measure, even when they occur, research
reports on the medical treatment of brain tumor frequently
interpret stable disease or minor response (less than 50 %) as
evidence of antitumor activity. This practice inflates response
rates and is of uncertain merit. With MRI having replaced
CT, the matter of response assessment has been further com-
plicated. Enhanced CT is a relatively simple imaging tool.
MRI, on the other hand, is a better and more complicated
machine with a wide assortment of T1, T2, fluid-attenuated
inversion recovery (FLAIR), diffusion, and other sequences:
Which ones should be used to assess the response of gliomas
to new drugs? For now, the WHO and Macdonald style
response criteria, currently usually applied to T1 sequences
on gadolinium-enhanced MRI, continue to be useful [22, 23],
when novel vasculature-modifying agents are employed, the
recommendations of the RANO consortium should be
considered.
Because many gliomas are difficult to measure using per-
pendicular diameters, and to acknowledge the possibility
that prolonged disease stabilization may indeed be a genuine
indicator of anti-glioma activity, the percentage of patients
who are progression-free at 6 months has been proposed as
an alternative measurement of drug efficacy in neurooncology
[24]. This endpoint, although never formally validated as a
surrogate of overall survival, has been widely adopted in
recent years in chemotherapy trials for recurrent malignant
glioma, and is often also used in the context of newly diag-
nosed disease, as well. Nevertheless, overall survival remains
the most important and reliable measurement of treatment
outcome and randomized trials the best way to test a new
drug for glioma [25].
Active Agents
Table 19.1 shows selected active cytotoxic agents.
Nitrosoureas
Nitrosoureas were the principal drugs for malignant glioma for
over 20 years. These lipophilic alkylating agents readily cross
the blood–brain barrier and have shown some activity in
patients with recurrent malignant glioma. Efficacy of lomustine
[CCNU] has recently been confirmed in prospective random-
ized trials where lomustine served as the control arm [26, 27].

Mechanism of action Toxicity

Carmustine (BCNU)
Lomustine (CCNU)
Nimustine (ACNU)
Fotemustine
Temozolomide
Irinotecan (investigational)
Bevacizumab
Table 19.1 Selected
active cytotoxic agents
Chlorethylating agent Myelosuppression
Nausea/vomiting
Pulmonary fibrosis
Chlorethylating agent Myelosuppression
Nausea/vomiting
(Pulmonary fibrosis)
Chlorethylating agent Myelosuppression
Nausea/vomiting
Thrombocytopenia
Chlorethylating agent Nausea/vomiting
Methylating agent Thrombocytopenia
Nausea/vomiting
Topoisomerase 1 inhibitor Diarrhea
Nausea/vomiting
Neutropenia
Anti-VEGF monoclonal antibody Hypersensitivity reactions
Hypertension, Proteinuria
Hemorrhage
282
Carmustine
Carmustine (BCNU) has been the most widely used chemo-
therapy for malignant glioma. In recent years, lomustine
(CCNU) or nimustine (ACNU; 1-[(4-amino-2-methyl-5-
pyrimidinyl)methyl]-1-(2-chloroethyl)-3-nitrosourea) have,
in part, replaced BCNU, to lessen pulmonary toxicity.
Fotemustine is a second-generation nitrosourea that has
single-agent activity against recurrent glioma [28]. In Japan
and Germany, nimustine (ACNU) is preferred, and fotemus-
tine is most popular in France and Italy [28–32]. Other tox-
icities include moderate and controllable nausea/vomiting,
and unpredictable and late myelosuppression (in particular in
patients who had previously received other chemotherapy).
Lomustine
Lomustine (CCNU) is an orally available nitrosourea and is
part of the PCV combination regimen. In recent years single
agent lomustine was used as the control arm in randomized
trials investigating novel agents. While those trials failed to
demonstrate superiority of the investigational drug, it con-
firmed in contemporary trials the efficacy of lomustine in
recurrent glioblastoma after first line chemoradiotherapy
[26, 27]. Response rates were low (4–9 %) with a PFS6 of
19–25 %, comparable to what had previously been reported
for temozolomide in this setting.
Procarbazine
Procarbazine is an alkylating agent that is given orally but
requires hepatic activation. In a randomized trial comparing
procarbazine vs. BCNU vs. BCNU and methylprednisolone
vs. methylprednisolone alone, the chemotherapy arms were
equivalent and slightly superior to methylprednisolone alone
[33]. Median survival was only 9–12 months from diagnosis.
In the setting of recurrent malignant glioma, response and
tumor control rates of 30 % have been reported [34, 35].
The PCV Regimen
In the 1970s, investigators from University of California San
Francisco (UCSF) developed the PCV regimen, a combination
of procarbazine, lomustine (CCNU), and vincristine.
In 1990, Levin et al. reported that adjuvant chemotherapy
with procarbazine, CCNU, and vincristine (PCV) yielded
better survival results than adjuvant BCNU for newly diag-
nosed malignant glioma. This assertion was based on a
reanalysis of a randomized trial conducted between 1977 and
1983 [36]. The survival difference favoring PCV was only
statistically significant for the subgroup of patients (n = 73)
with anaplastic astrocytomas (total patients randomized,
148) and good performance status, who had received at least
R. Stupp et al.
1 cycle of chemotherapy [36]. The superiority of PCV could
not be confirmed in a subsequent pooled analysis of 432
patients treated on Radiation Therapy Oncology Group
(RTOG) protocols [37]. The Medical Research Council (UK)
conducted a randomized trial of standard focal radiotherapy
(RT) vs. RT plus adjuvant PCV chemotherapy [38], finding
no difference in overall survival. Patients with grade 3 tumors
also did not benefit from PCV.
Temozolomide
Over the past decade, temozolomide (TMZ) has emerged as
an active agent against malignant glioma [39]. TMZ is an
oral alkylating agent, which is rapidly and completely
absorbed and spontaneously converts at physiological pH to
the active metabolite, MTIC. TMZ has linear pharmacoki-
netics with maximum plasma concentrations 30–90 min
after oral intake. Although recommended to be taken in a
fasting state (at least 1 h before and after intake), food will
only lead to a 10 % reduced area under the concentration
curve (AUC) and a delayed peak concentration [40]. TMZ
has an excellent penetration into all body tissues.
Pharmacokinetics of TMZ in the CSF have been reported.
The AUC in the CSF as a surrogate for brain tissue penetra-
tion corresponded with approximately 20 % of the area under
the curve (AUC) in plasma [41]. Similar to nitrosoureas,
TMZ is a DNA alkylating agent. Methylation of the O-6
position of guanine by TMZ is an especially important bio-
logical action, although not the most frequent adduct. If left
unrepaired, the guanine O-6 lesion triggers cytotoxic
responses and apoptosis.
Three pivotal phase II trials led to the approval of temo-
zolomide (Temodar; Temodal; Schering-Plough, Kenilworth,
NJ, now MSD/Merck & Co, Whitehouse Station, NJ). The
U.S. FDA granted provisional (accelerated) FDA approval
in 1999 for the treatment of recurrent anaplastic astrocy-
toma. In Europe, it was also approved for the treatment of
recurrent glioblastoma [42–44]. Although the objective
response rate in the glioblastoma trials was low (5 % and
7 %, respectively) and was only 35 % in the anaplastic
astrocytoma studies, each trial suggested an increase in the
fraction of patients being progression-free at 6 months
compared with a historical database [24]. This observation
encouraged further evaluation of TMZ as a therapy for both
recurrent and newly diagnosed malignant glioma. For recur-
rent glioma, a randomized phase III trial of TMZ vs. PCV in
previously irradiated, chemonaive patients has been con-
ducted by the British National Cancer Research Institute.
In a second randomization this trial also compared two
different TMZ administration schedules (standard 5-day
regimen vs. dose-dense 3 weeks out of 4). In this trial TMZ
efficacy was equivalent to PCV with less toxicity, however
19 Malignant Glioma: Viewpoint—Chemotherapy
dose intensification did not demonstrate an improved out-
come, numerically the standard regimen was slightly supe-
rior [45]. Similarly, a German randomized NOA-04 trial
also compared the standard to a dose-intensified TMZ regi-
men and could not show a benefit for the alternative dosing
schedule [46]. Intensification of the TMZ regimen failed to
demonstrate improved outcome in a large randomized trial
in newly diagnosed GBM patients (RTOG0525/Intergroup
trial, discussed below) [47].
The definitive role of TMZ in the initial treatment of
newly diagnosed glioblastoma was demonstrated in a ran-
domized phase III trial by the European Organisation for
Research and Treatment of Cancer (EORTC) and the NCI
Canada Clinical Trials Group [48, 49]. This landmark trial
established the role of early use of chemotherapy in the man-
agement of glioma, and led to definitive regulatory approval
of TMZ both in the United States, and worldwide. Further
details are discussed in the next main paragraph.
Temozolomide has also been extensively investigated in
recurrent anaplastic astrocytoma, mixed oligoastrocytoma
and oligodendroglioma. The response rate in these grade III
tumors was in the range of 20–40 %, with 50–70 % of
patients likely deriving some benefit [42, 50–53]
Bevacizumab and Anti-angiogenic Therapy
Unprecedented rapid disappearance of contrast enhance-
ment, reduction in peritumoral edema, and temporary clini-
cal improvement have been observed with the anti-VEGF
(vascular endothelial growth factor) monoclonal antibody,
bevacizumab and the VEGF receptor tyrosine kinase inhibi-
tor cediranib [54, 55]. The neutralizing antibody bevaci-
zumab will abrogate the vascular endothelial growth factor A
(VEGF)-mediated inflammation and restore the blood brain
barrier. This leads to less peritumoral edema and reduces
gadolinium-diffusion into the brain. Consequently, radio-
logical tumor extension appears to be lesser, and steroids
can be reduced or completely discontinued. This led to
enthusiastic large-scale use and investigation of anti-angio-
genic and vasculature-modifying agents in malignant glioma.
For cediranib, a randomized phase III trial compared single
agent cediranib vs. the combination of cediranib and lomus-
tine vs. lomustine alone. Although progression-free survival
favored the two experimental arms, no significant difference
in survival could by demonstrated with the addition of cedi-
ranib [27]. Actually, patients receiving lomustine fared best
with a median overall survival of 9.8 months (compared to
8.0 and 9.4 months in the cediranib alone or in combination
with lomustine arms, respectively, p = NS). In the United
States bevacizumab received regulatory approval for recur-
rent glioblastoma, based on two uncontrolled phase II trials
demonstrating a high radiological response rate, a decrease
283
in steroid requirements and median survival of around 9
months [54, 55]. The European Medicines Agency rejected
the application in the absence of controlled data [56].
Two independent phase III randomized trials have been
initiated by the RTOG (trial#0825) and by Roche (AvaGlio)
in newly diagnosed GBM patients. Bevacizumab is added to
standard chemoradiotherapy (TMZ/RT → TMZ, see below)
first line treatment. Both trials failed to demonstrate improve-
ment in overall survival, as expected radiological progression-
free survival was prolonged [57, 58]. Intuitively it appears
that prolongation in progression-free survival and a decrease
in steroid requirements would translate into improved
quality of life. However, the detailed analysis of net clinical
benefits in the Radiation Therapy Oncology Group (RTOG)-
sponsored study suggested the contrary, while quality of life
assessments in the Roche-sponsored AvaGlio study stopped
at the time of radiological tumor progression, and does not
allow for definitive conclusions. Furthermore, toxicity and
serious adverse events (hypertension, thromboembolic com-
plications, wound dehiscence and hemorrhage) were all
more prevalent in the bevacizumab-treated patients.
The integrin inhibitor cilengitide has also been investi-
gated in a large prospective phase III trial in newly diagnosed
patients. Despite promising results in non-comparative phase
II trials, no benefit could be demonstrated in the definitive
trial [59–61].
Miscellaneous Agents
Various other agents have been investigated and are occa-
sionally used in the treatment of recurrent glioma.
Randomized trials failed to demonstrate any relevant and
reproducible antitumor activity of the tyrosine kinase inhibi-
tors imatinib and erlotinib when used as single agents [51,
62]. Irinotecan is occasionally used as single agent [63, 64]
or in combination with bevacizumab [54], some activity has
been reported for cis- and carboplatin [65–67].
Primary Treatment of Glioblastoma
The value of radiotherapy in the treatment of malignant gli-
oma (both glioblastoma and anaplastic astrocytoma) was
established in randomized trials almost 30 years ago [68–
71]. Compared with supportive care or nitrosourea-based
chemotherapy alone, radiotherapy increased median survival
from 4 to 8 months. Subgroup analyses suggested that the
addition of chemotherapy to RT might further improve sur-
vival for patients with grade 3 and 4 tumors, but none of the
randomized trials demonstrated an unequivocal beneficial
role for nitrosourea-based chemotherapy. A meta-analysis
based on published studies, and in the year 2002 [72] and in
284 R. Stupp et al.

PcP prophylaxis
4 weeks
TMZ daily x 42d 5d 5d 5d x 6 cycles
4 weeks

1 6 10 14 18 22 week

RT; focal radiotherapy, 60 Gy over 6 weeks

RT 30 x 2 Gy to tumor volume + 2-3 cm margin

TMZ; temozolomdide (Temodal®, Temodar®)1

during RT: 75 mg/m2 daily (including weekend) for up to 49 days, on an empty stomach2,
PO 1-2 hours before RT, or in the a.m. on days without RT
adjuvant/maintenance: 200 mg/m2 (first cycle 150mg/m2) daily x 5 days, for 6 cycles

PcP; Pneumocystis jiroveci pneumonia prophylaxis

recommended during continuous TMZ chemoradiotherapy
pentamidine inhalations 1x/months 300 mg or trimethroprim/sulfametoxazole forte
3x/week
Alternative: monitoring absolute lymphocyte count, start prophylaxis only when lymphocytes
< 500/mm3, or CD4 < 200/mm3.
1 antiemeticprophylaxis: during chemoradiotherapy with low-dose TMZ usually simpe antiemetic sufficient, e.g.
metoclopramide or loperamide (5HT3 antagonist suggested for the first 2 days)
Adjuvant TMZ therapy: moderately emetogenic, primary prophylaxis with half-dose 5HT3 antagonist
recommended (e.g. ondansetron 4 mg, granisetron 1 mg)
2 empty stomach: fluids and light snack admissible

Fig. 19.1 Treatment scheme for newly diagnosed glioblastoma. From: Mino, Homicsko & Stupp: central nervous system In: M.A. Dicato (ed.),
Side effects of medical cancer therapy, Springer London 2013, doi:10.1007/978-0-85729-787-7_7; used with permission

the year 2002, an analysis of pooled individual data from
more than 3,000 patients in 12 randomized trials [73] found
a small but significant survival advantage, favoring chemo-
therapy in addition to surgery and RT at initial diagnosis. For
patients with both grade 3 and 4 tumors, a hazard ratio of
0.85 for chemotherapy equated to a 5 % improvement in
overall survival from 15 to 20 % at 2 years [73].
In a German multicenter trial with patient accrual from
1994 to 1999 BCNU was replaced by nimustine (ACNU),
another nitrosourea with less pulmonary toxicity [32].
Three hundred seventy-five patients were randomized to
radiotherapy and either ACNU/cytarabine or ACNU/teni-
poside; unfortunately there was no radiotherapy-alone
control arm. No difference in survival between the two
chemotherapy regimens could be shown; nevertheless the
survival outcomes were encouraging with a median sur-
vival of 16 months and a 2-year survival rate of 27 %
among 302 patients with glioblastoma. More than 90 % of
patients had undergone debulking surgery, and accrual
occurred over 6 years in 15 centers (average of three
patients per year per center). Thus, a strong selection bias
cannot be excluded.
In 2005, the EORTC and NCIC (National Cancer Institute
of Canada Clinical Trials Group) Intergroup trial demon-
strated beyond doubt that chemotherapy (i.e., TMZ during
RT and for 6 months afterward {TMZ/RT → TMZ})
improved overall survival in patients with glioblastoma [48].
In this phase III trial, 573 patients were randomized in less
than 18 months. Patients who received initial treatment with
RT alone (but may have received TMZ or other chemother-
apy at progression) had a median survival of 12 months com-
pared with 15 months for patients treated with TMZ/RT at
diagnosis. More importantly, the chances of survival at 2
years were only 11 % in the RT arm compared with 27 % for
those treated with TMZ/RT [49]. This trial established the
current standard of care for patients with glioblastoma and
serves as the benchmark to which newer strategies must be
compared (Fig. 19.1). These results compare favorably with
reported results among patients with small tumors eligible
for stereotactic radiosurgery. The good outcome in the
control arm also reflects the, albeit modest, activity of the
TMZ when administered as second-line therapy after tumor
progression.
Methylguanine Methyltransferase
Methylguanine methyltransferase (MGMT) gene promoter
methylation has been established as the single most impor-
tant predictive and prognostic marker in malignant glioma
19 Malignant Glioma: Viewpoint—Chemotherapy
Fig. 19.2 Survival according to MGMT status and treatment alloca-
tion (combined modality vs. RT alone). Left panel: survival of patients
with a methylated MGMT promoter if treated with TMZ/RT → TMZ
(blue) or initial RT only (red). Right panel: survival if MGMT unmeth-
[74, 75]. Patients whose tumors have a methylated MGMT
gene promoter, resulting in gene silencing, decreased
expression of MGMT, and less effective repair of DNA
damage caused by TMZ are benefitting most from the
addition of chemotherapy [76]. This predictive value has
been repeatedly confirmed in glioblastoma patients, while
in patients with anaplastic glioma, MGMT is a strong
favorable prognostic factor independent of treatment, but
loses in predictive strength [46]. In the pivotal EORTC/
NCIC trial glioblastoma patients with tumors in which the
MGMT gene promoter was unmethylated and thus presum-
ably fully expressed MGMT, no apparent benefit was
derived from the addition of TMZ during and after radio-
therapy [76]. Patients with an unmethylated tumor treated
with TMZ/RT had a median survival 13 months (2-year
survival rate of 14 %), compared to 12 months (2-year sur-
vival rate 2 %) when treated initially with RT alone (at
recurrence the great majority of patients received chemo-
therapy) [76]. In patients with an MGMT methylated
tumor, median survival was 22 months (2-year survival
46 %) when treated with TMZ/RT → TMZ, compared to 15
months (2-year survival: 23 %) if received RT alone at ini-
tial diagnosis (Fig. 19.2).
The RTOG0525/EORTC/NCCTG (North Central Cancer
Treatment Group) Intergroup trial aimed at overcoming the
MGMT-mediated resistance by dose intensification and
exhaustion of MGMT by continuous chemotherapy expo-
sure. Almost 1,200 patients were included and 833 patients
285
ylated according to randomized treatment allocation. Reprinted with
permission from Stupp R, Mason WP, van den Bent MJ et al.
Radiotherapy plus concomitant and adjuvant temozolomide for glio-
blastoma. N Engl J Med 2005; 352: 987–996; used with permission
were randomized after determination of and stratification
for MGMT status. The prognostic value of MGMT promoter
methylation status was confirmed with a median survival of
21.2 months for methylated tumors, compared to 14 months
for the unmethylated group [47]. However, neither treat-
ment intensification nor prolongation of the maintenance
chemotherapy for up to 12 cycles appeared to improve
outcome, overall median survival was 16 months from
registration (approx. 2–6 weeks after surgery). Ongoing
investigations are either stratifying patients according to
the MGMT status, or devising separate treatment strategies
for patients with and without MGMT promoter methylation
(see Elderly below).
Treatment of Anaplastic Glioma
Table 19.2 shows selected treatment options and potential
alternatives for anaplastic glioma.
Anaplastic Astrocytoma
Unlike glioblastoma, there are no randomized data providing
level I evidence on the role of chemotherapy in the initial
treatment of anaplastic astrocytoma. Some trials, however,
have suggested a benefit from adjuvant nitrosourea-based
therapy for patients with grade III tumors [70, 77].
286 R. Stupp et al.

Table 19.2 Selected treatment options and potential alternatives

Treatment Evidence level References Alternatives Evidence level References Remarks
Glioblastoma
TMZ/RT → TMZ × 6 for I [48] ACNU/RT → ACNU + VM26 III [21]
elderly patients
Methylated MGMT: TMZ II [90, 91] Hypofractionated RT II [88, 89] For elderly patients
Unmethylated MGMT: RT
Anaplastic astrocytoma RT I [68, 69, 71] BCNU/RT → BCNU II [33]
TMZ/RT → TMZ V [50] Analogy to GBM
Anaplastic grade III oligoastro/oligodendroglioma with LOH 1p/19a
RT → PCV x 6 II [83, 84] PCV × 4 before RT II [82, 85] Improved survival
RT → TMZ V Replace PCV by TMZ
or
TMZ → RT
TMZ/RT → TMZ V [50] Analogy to GBM
Recurrent glioma
TMZ II [42–45, 53] Procarbazine IV [46]
PCV IV [81]
Bevacizumab III [54–56] Irinotecan* IV [63, 64]

One of the few positive trials was reported by the
EORTC. Two hundred sixty-nine patients with malignant gli-
oma were randomized to focal RT vs. RT + dibromodulcitol
and BCNU [77]. The longer survival in the experimental arm
was mainly due to the subgroup of 29 (!) patients with non-
glioblastoma high-grade tumors. A confirmatory randomized
EORTC trial in grade III tumors failed to demonstrate a
statistically significant improvement in outcome [78]. A
randomized trial comparing adjuvant PCV with adjuvant PCV
plus difluoromethyl ornithine (DFMO), an ornithine decar-
boxylase inhibitor, has been reported [79]. Patients were ran-
domized at the end of RT. Those who had already progressed
or had declining performance status were not included in the
study. Patients with grade 3 gliomas experienced longer statis-
tically nonsignificant survival and time to progression in the
PCV + DFMO arm [79]. An identical trial in patients with glio-
blastoma was negative [79].
In one phase II trial, in patients with recurrent anaplastic
astrocytoma, TMZ has shown a high objective response rate of
35 %. A randomized trial (RTOG9813) comparing radiother-
apy plus adjuvant BCNU or CCNU vs. adjuvant TMZ in newly
diagnosed patients was closed early due to insufficient accrual.
The German NOA-04 trial compared two treatment strat-
egies: patients with anaplastic glioma were randomized to
either RT alone, and chemotherapy at recurrence vs. the
opposite sequence with a primary endpoint of time to the
second failure. The data suggest that it does not matter which
strategy is employed first. MGMT promoter methylation was
again a strong prognostic marker, however it was not predic-
tive for benefit from chemotherapy when analyzed by time to
first progression [46].
Anaplastic Oligoastrocytoma
and Oligodendroglioma
Since the year 2000 WHO criteria and greater awareness of
this subgroup, oligoastrocytoma and oligodendroglioma are
increasingly identified as separate and distinct tumor entities
[80]. While mixed oligoastrocytomas behave largely like
astrocytomas, pure oligodendrogliomas have a more favor-
able natural history. Specific molecular changes, in particular
the loss of genetic information on chromosomes 1p and 19q,
have been associated with high sensitivity to chemotherapy
and with particularly long survival [81]. Two randomized tri-
als investigated neoadjuvant (before RT) or adjuvant (after
completion of RT) PCV chemotherapy in patients with newly
diagnosed anaplastic oligoastrocytomas and oligodendroglio-
mas [82, 83]. Both trials confirmed a more favorable progno-
sis for patients with loss of heterozygosity (LOH) of 1p/19q.
While at initial analysis after a median follow-up of more
than 6 years, no benefit in overall survival was detected [82,
83], a subsequent analysis, performed in 2012 after a median
follow-up of 11 years, found a significant survival benefit for
patients with oligodendroglioma harboring a co-deletion of
chromosomes 1p and 19q [84, 85]. These findings are sup-
ported by the earlier observation of prolonged progression-
free survival in this genetically defined subset, suggesting
that prolongation of progression-free survival may be a mean-
ingful surrogate endpoint. These trials also emphasize that the
subgroup of patients with 1p/19q co-deletion represent a dis-
tinct pathologic entity and future revisions of the WHO clas-
sification may include molecular characterization as a
mandatory condition of pathological categorization.
19 Malignant Glioma: Viewpoint—Chemotherapy
How to Select Patients for Chemotherapy?
When considering patients with malignant glioma for a spe-
cific therapy, treatment-related, tumor-related, and patient-
related factors need to be considered. One of the most
important deterrents to chemotherapy is poor performance
status. Patients with poor neurologic function are unlikely to
improve substantially with chemotherapy. Similarly, patients
with poor general functioning are unlikely to tolerate chemo-
therapy sufficiently well to achieve a benefit, especially when
the response of malignant gliomas is often slow or protracted.
Tumor size and resectability are prognostic factors [86].
For large, deep tumors and tumors crossing the midline, only
biopsy with stereotactic guidance is suggested. Tumors in
these locations are often accompanied by rapidly progressive
neurologic symptoms, steroid dependence, and deteriorating
performance status. In all clinical trials, these types of
patients have very poor outcomes irrespective of treatment
with TMZ/RT or other treatment measures. In the EORTC/
NCIC trial, a trend for longer survival after TMZ/RT could
also be demonstrated among patients with a tumor biopsy
only (median survival 9.4 vs. 7.4 months, p = 0.09) (see sup-
plementary appendix to [48] at http://content.nejm.org/cgi/
content/full/352/10/987/DC1).
In our clinical practice, we aim at providing all care in the
outpatient clinic both with chemotherapy and radiotherapy.
For patients with severely impaired performance status, we
frequently recommend single-modality therapy or support-
ive care only. Nevertheless, French investigators reported on
a phase II trial including elderly patients (median age 77
years, range 70–87) with a Karnofsky performance status
below 70. Seventy patients were treated with single agent
TMZ (5/28 days). One third of the patients improved their
performance status to ≥70 % and regained some indepen-
dence and quality of life [87]. The median survival was
5.8 months, while subgroup analyses of patients with meth-
ylated or unmethylated MGMT showed median survivals of
7.2 and 4.4 months, respectively.
Treatment of the Elderly
Although the median age of glioblastoma patients in clinical
trials ranges from 52 to 57 years, the median age in daily
practice is 62–65 years. Glioblastoma is a disease of the
elderly. The age at diagnosis has been repeatedly shown to
be an important prognostic factor for survival. Based on poor
outcomes for patients over the age of 60 or 70 years, it had
been suggested that these patients should only be managed
with supportive care. However, contemporary randomized
trials have revisited this attitude. A French trial compared
287
radiotherapy (28 × 1.8 Gy, 50.4 Gy) with best supportive care
in 84 patients over the age of 70 years (median, 73 years,
range 70–85 years). Overall survival in patients receiving
radiotherapy was 6.8 months compared with 4 months with
best supportive care only (p = 0.002) [88]. Roa et al. reported
equivalent survival when treating glioblastoma patients over
the age of 60 years (mean 72 years) with either standard frac-
tionated radiotherapy (30 × 2 Gy, 60 Gy in 6 weeks) or with
hypofractionated radiotherapy (15 × 2.66 Gy, 40 Gy in 3
weeks) [89]. Median survival durations were 5.1 and
5.6 months, respectively (p = 0.57). In the EORTC/NCIC
TMZ/RT → TMZ trial, patients over the age of 50 years had
inferior overall survival, but the benefit afforded by TMZ/RT
was maintained across all age groups, including patients > 60
or 65 years (patients >70 years were not eligible for trial par-
ticipation) [49]. Therefore, combined treatment should not
be withheld based on age alone.
Two randomized trials compared exclusive radiotherapy
with chemotherapy alone [90, 91]. In the 3-arm Nordic trial
342 patients (median age of 70 years, range 60–88) were
randomly assigned to one of two RT (10 × 3.4 Gy or
30 × 2 Gy) schedules or standard dose TMZ monotherapy
[90]. The study showed that standard fractionated RT was
particularly poorly tolerated in patients older than 70 years,
and that single agent TMZ may be a valid alternative to
radiotherapy. Median overall survival was 6.0 months with
RT60 (30 × 2 Gy), 7.5 months with RT34 (10 × 3.4 Gy), and
8.3 months with TMZ (5/28 days) [90]. The German NOA-
08 trial compared standard fractionated RT (30 × 2 Gy) with
1 week on, 1 week off, dose-dense TMZ in 373 elderly
patients (median age 72 years, range 66–84) [91]. Overall
survival analysis favored RT (median 9.6 vs. 8.6 months,
p = 0.033), however exclusive radiotherapy appears to be det-
rimental for patients with a methylated MGMT. Taken
together elderly patients with methylated MGMT tumors are
best treated with TMZ chemotherapy, while unmethylated
fare better when treated with RT alone [91].
An ongoing trial coordinated by the NCIC in collabora-
tion with the EORTC is evaluating combined modality hypo-
fractionated TMZ/RT → TMZ vs. RT (15 × 3 Gy) alone in
patients over the age of 65 years but unfortunately, this trial
lacks a chemotherapy alone arm.
RPA Analysis
Grouping of the patients according to the RTOG recursive
partitioning analysis based on age, performance status, neu-
rologic function, treatment, and tumor grade allows for some
comparison between trials and variable distribution of prog-
nostic factors [92–94]. Table 19.3 shows recursive partition-
ing analysis of the EORTC/NCIC trial.
288
Table 19.3 Recursive Standard arm: radiotherapy
partitioning analysis of the
RPA class Median survival
EORTC/NCIC trial
3 14.8 (10.9–17.0)
4 13.3 (12.0–15.0)
5 9.1 (8.0–11.7)
RPA recursive partitioning analysis, TMZ/RT temozolomide and radiotherapy, N* upper confidence boundary
not reached
From: Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glio-
blastoma; recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial.
J Clin Oncol 2006; 24(16):2563–2569
Molecular Profiling
Molecular markers play an increasing role in understanding,
prognostication, prediction of response and treatment target
identification of glioma [95]. The chromosomal co-deletion
1p/19q is mediated by an unbalanced translocation, and is
characteristic for oligodendroglial tumors and associated
with benefit from chemotherapy [96]; EGFRviii mutation
and EGFR overexpression are associated with inferior prog-
nosis [8, 97–99], while IDH mutations, more commonly
observed in lower grade glioma, secondary glioblastoma and
younger patients, with a longer survival [100]. The role of
MGMT gene promoter methylation as a prognostic and pre-
dictive marker has been discussed above. Gene expression
signatures have allowed dividing tumors into distinct molec-
ular subclasses: proneural, neural, classical, and mesenchy-
mal [4, 101]. Lately, analyses of the tumor genome
methylation allow to further subdivide these subclasses [3].
The CpG island methylator phenotype (CIMP) correlates
largely with a subgroup of tumors of the proneural subclass,
enriched for IDH mutated tumors [3]. These few examples
illustrate the complexity of correlations and interactions of
genes, mutations, epigenetic modifications, and tumor pro-
files. Individual molecular tumor characteristics allow the
selection of an optimized treatment strategy in some
instances. Personalized cancer therapy is on the horizon, also
for glioma [3, 76, 101–103].
Chemotherapy Toxicity and Quality of Life
Systemic administration of chemotherapy is inherently asso-
ciated with the risk of nontarget organ toxicity. All cyto-
toxic agents currently used for the treatment of malignant
glioma may induce moderate or severe myelosuppression.
Carmustine may also cause severe interstitial pneumonitis in
20–30 % of patients [104–106]. A major limitation of the
PCV chemotherapy regimen is the cumulative hematotoxic-
ity, which frequently prohibits delivering the planned num-
ber of cycles and dose intensity.
R. Stupp et al.
Experimental arm: combined TMZ/RT
Two-year survival Median survival Two-year survival
19.6 (6.9–32.3) 21.4 (15.3–N*) 43.4 (28.0–58.9)
10.9 (5.8–16.0) 16.3 (14.1–18.3) 27.9 (20.5–35.3)
6.2 (1.1–11.2) 10.3 (8.6–12.4) 16.5 (8.8–24.2)
Although temozolomide is considered a particularly
well-tolerated chemotherapy, severe myelosuppression and
particularly thrombocytopenia, may occur in up to 5 % of
patients. Continuous low-dose TMZ (with or without
concomitant use of corticosteroids) will frequently induce
profound lymphocytopenia [107–109]. Counts of CD4 posi-
tive lymphocytes may fall well below 200/mm3, the thresh-
old recommended for Pneumocystis jiroveci (ex carinii)
prophylaxis in HIV-positive patients [110]. By extrapolation,
close monitoring of absolute lymphocyte and CD4 counts, or
prophylaxis with pentamidine inhalations or trimethoprim-
sulfamethoxazole is advised for those on continuous
low-dose TMZ.
Quality of life using the EORTC quality of life question-
naire QLQ-30 and a specific brain cancer module (BM-20)
has been evaluated in recent TMZ trials [111–113]. In a ran-
domized phase II trial, TMZ administration after first line
radiotherapy (±chemotherapy) was compared with procarba-
zine [43]. Quality of life was superior in several domains in
patients treated with TMZ compared with procarbazine
[111]. In the EORTC/NCIC trial, no detrimental effect on
quality of life was observed in the longer surviving TMZ/RT
patient group [113]. Except for a slight increase in fatigue
(6 % with RT vs. 9 % with TMZ/RT), there was no treatment
dependent difference in non-hematologic toxicities [48].
Chemotherapy or Stereotactic Radiosurgery
Stereotactic radiosurgery, despite promising reports on
selected patients in phase II trials and in retrospective series,
failed to demonstrate any prolongation of survival, qual-
ity of life, or local control and was the object in 2005 of a
systematic review by the American Society for Therapeutic
Radiology and Oncology (ASTRO) [114]. Apparent
improvements in survival in some non-controlled trials may
simply reflect patient selection [25]. To date two randomized
trials were started, but only one was completed. A stereotac-
tic boost of 15–24 Gy administered to tumors of ≤4 cm in
size before standard external beam radiotherapy showed no
19 Malignant Glioma: Viewpoint—Chemotherapy 289

Table 19.4 Advantages of chemotherapy and SRS

Chemotherapy SRS Remarks
Level of evidence I (glioblastoma) IV
Tumor size Any Tumors <3–4 cm Chemotherapy will treat microscopic
infiltrative disease, whereas SRS will only
eliminate visible tumor
Karnofsky performance status >60 % >80 % SRS requires anesthesia
Substitute for surgery No Yes If tissue previously available for histologic
diagnosis
Toxicity SRS risk of late radionecrosis
Systemic Manageable Absent
Local None Moderate
Drug interaction Possible None
Edema induction None Possible
Costs High Moderate
Treatment duration Long Short
Availability Large scale, anytime Limited, restrictive
Patient selection Minor, mainly Highly selected, applicable to only
performance status 10–25 % of high-grade glioma patients

improvement in any of the outcome parameters [115]. The
other randomized trial evaluating fractionated stereotactic
boost (5 × 4 Gy) administered after the end of external beam
radiotherapy was prematurely discontinued due to insuffi-
cient patient accrual [116].
Why increasing doses of radiation do not [117]?
Glioblastoma is an infiltrating tumor affecting the whole
brain, and the contrast enhancement and tumor extension
detected on MRI is “only the tip of the iceberg.” Stereotactic
radiosurgery can only be applied to tumors with a maximum
diameter of 3–4 cm, while malignant gliomas are large and
diffuse. Tumor cells outside of the field of irradiation can
serve as sanctuaries for tumor regrowth and maintenance,
this will inevitably lead to failure of all exclusively local treat-
ment approaches. Before the era of modern radiation therapy,
surgery was the sole treatment modality and heroic lobec-
tomies and hemispherectomies were performed in vain.
Even after extensive resections tumor recurred at distant
brain sites. The dogma of regional tumor recurrence popular-
ized by Hochberg and Pruitt [118] may need to be revisited.
As patients now live longer thanks to combined chemoradio-
therapy and other truly effective therapies, distant recurrences
are observed at increasing frequency. Table 19.4 shows the
advantages of chemotherapy and SRS.
Stereotactic radiosurgery not only requires equipment
and expertise, but also limited to a minority of patients with
malignant glioma (10–25 %) (reviewed in [119]). Only
patients with adequate performance status and with tumors
distant from vital structures are considered for radiosurgery.
In contrast, TMZ chemotherapy can be initiated in 90 % of
patients with malignant glioma without substantial toxicity.
Furthermore, level I evidence is available for the chemora-
diotherapy and adjuvant chemotherapy of newly diagnosed
glioblastoma [48, 49]. In this trial with 85 centers, many
smaller hospitals participated, confirming the applicability
of this treatment to everyday practice. The subsequent large
and pragmatic RTOG0525/EORTC/NCCTG Intergroup
study with more than 250 participating RT-departments (in
the majority North American hospitals) included 1,173
patients and confirmed the results of previous trials [47].
Stereotactic radiosurgery has the ability to deliver with
utmost precision high radiation doses, either as a single frac-
tion or as fractionated radiotherapy. However, in the case of
ill-defined targets, high precision is of limited value. In these
cases novel neuro-imaging techniques like tumor metabolic
evaluation with positron-emission tomography (PET) using
amino-acid tracer, or improved anatomical visualization
using diffusion tensor tractography can be useful.
The different treatment approaches of systemic and local
treatment are not necessarily mutually exclusive. The combi-
nation of stereotactic radiosurgery with TMZ in the frame of
the standard chemoradiotherapy is likely feasible and should
be properly studied in prospective randomized trials. The
repeated reports on feasibility of this approach in uncon-
trolled phase II studies, and frequently with inappropriate
historical comparators are misleading and a waste of the lim-
ited resources [120]. In vitro, temozolomide has been shown
to inhibit tumor cell migration. Similarly, the combination of
temozolomide and radiotherapy together with carmustine-
impregnated wafers (Gliadel; MCI Pharma, Baltimore, MD)
might improve local control while eradicating infiltrating
tumor cells [121].
In select patients with small and circumscribed recurrent
high-grade glioma, re-irradiation is increasingly used.
290
Median survival rates of 8–11 months have been reported,
but the absence of long-term survivors with grade IV tumors
indicate that this is not a curative strategy [122, 123].
Ongoing trials investigate the combination of stereotactic re-
irradiation with bevacizumab. The marked anti-inflammatory
effect of bevacizumab may allow larger RT-fields, better tol-
erance, and less toxicity [124].
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 Meningioma
Alessandra Gorgulho, Carlos A. Mattozo,
and Antonio A.F. De Salles
Introduction
Meningiomas are generally benign lesions that account for
15–20 % of primary brain tumors, affect predominately
middle-aged patients, and occur predominately in females
[1, 2]. The atypical and malignant meningiomas are charac-
terized by successive recurrences and an aggressive behav-
ior. Among all meningiomas, their incidence varies in the
literature ranging from 4.7 to 7.1 % and 1.0 to 3.7 % for
atypical and malignant, respectively [3–6]. There is absence
of female predominance in malignant meningiomas suggest-
ing that endocrinologic influences apparently correlated with
the genesis of benign meningiomas are not active in malig-
nant ones [4].
In general, meningiomas are usually well circumscribed,
globular, and slow-growing tumors that are thought to arise
from mesodermal arachnoid cells. These arachnoid cap cells,
localized on the apex of arachnoid granulations, are exposed
to the venous blood of the sinus and have a low rate of cell
division. The induction of cell division is thought to be an
early important step in the neoplastic transformation of these
cells. They are structurally similar to those of meningiomas,
and both tend to form whorls. However, this presumed origin
does not explain some unusual sites such as the ventricles or
within the cerebral parenchyma, where they probably arise
from perivascular arachnoidal cells [7].
A. Gorgulho, M.D., M.Sc. (*) • A.A.F. De Salles, M.D., Ph.D.
Department of Neurosurgery, University of California Los Angeles,
Los Angeles, CA, USA
Department of Neurosurgery, Hospital de Coração-Associação
do Sanatório Sírio, Sao Paulo, Brazil
e-mail: a_gorgulho@yahoo.com; agorgulho@mednet.ucla.edu
C.A. Mattozo, M.D.
Department of Surgery, Division of Neurosurgery, David Geffen
School of Medicine at UCLA, Los Angeles, CA, USA
Assistant Professor of Neurosurgery, Department of Neurosurgery,
Pontificia Universidade Catolica de Curitiba, Brazil
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_20, © Springer Science+Business Media New York 2015
20
Meningiomas are considered indolent tumors, but the nat-
ural history of any particular case is unpredictable. Although
three well-defined groups of meningiomas are currently used
(named grade I, benign; grade II, atypical; and grade III,
malignant), there were a great number of classifications
adopted in the literature, and, as a consequence, detailed cor-
relative clinicopathologic studies on this subject are difficult
to perform, and it is not possible to compare data from differ-
ent centers. The two reviews of the World Health Organization
(WHO) 2007 classifications provides histologic criteria of
meningiomas with reasonably good prognostic correlation
[8]. However there is a large body of the literature not based
on the WHO 2000 or 2006 WHO classifications. These clas-
sifications include increased mitotic count (2000) as the main
differentiation between atypical and anaplastic lesions. and
brain invasion as a criteria for atypia (2007).
Additionally, another characteristic of meningiomas is the
histologic dedifferentiation, increasing the grade as the suc-
cessive recurrences occur. This aspect is not often discussed
in the literature, and the existing series report an incidence of
4.4–18 % of cases [3, 5, 9, 10]. Ikeda et al. [11] demonstrated
that the major phenotypic changes in the progression of
meningiomas from the classic to the anaplastic type are the
loss of the meningioma’s architecture, a decreased expression
of epithelial membrane antigen (EMA), an increased expres-
sion of vimentin, and an expression of abnormal intermediate
filament proteins. Recently, al-Mefty et al. [12] published a
series of 11 (6 %) meningiomas with malignant progression
out of 175 recurrent lesions. Interestingly, they found a com-
plex karyotype present in the histologically lower-grade
tumor, contradicting the stepwise clonal evolution model.
Surgical Considerations
Microsurgery remains the best option for symptomatic intra-
cranial meningiomas if complete resection can be achieved
with low morbidity. Simpson [13] has proposed a system that
grades the extent of tumor removal and correlates with tumor
295
296
relapse. Grade 1 resection required gross total removal of all
visible tumor plus dural attachments and was associated with
9 % local recurrence. Gross total removal with dural cautery
constituted grade 2 resection and was associated with a 19 %
relapse. A partial resection was a grade 3 procedure with a
relapse rate of 40 %. Poorer control rates occurred after
grade 4 (decompression) or 5 (biopsy) procedures.
Since this system was proposed, many other reports have
confirmed that local relapse of meningiomas depends upon
the extent of first resection [14–16]. After gross total removal,
the local recurrence rate at 5 and 10 years approximate 10 %
and 20 %, respectively [16]. After less than gross complete
resection, relapse rates at 5, 10, and 15 years were recently
reported at 25 %, 70 %, and 90 %, respectively [16].
Jääskeläinen et al. [3] reported a recurrence rate 5 years after
complete resection of 3 % for benign, 38 % for atypical, and
78 % for anaplastic meningiomas.
Nevertheless, total excision including the dural site of ori-
gin is seldom possible, especially when important vascular
and/or neural structures are encased within the tumor or if
the tumor infiltrates adjacent anatomic structures [17–19].
The success rates associated with microsurgical excision of
benign skull base tumors has varied from 26 to 89 % [20–
25]. Although the mortality rate has decreased in recent
reports, a significant number of patients continue to experi-
ence adverse effects related to surgical procedures with rates
ranging from 15 to 26 % [24, 26–29].
Radiation Therapy
The benefit of conventional radiation therapy (XRT) to com-
plement subtotal resection of meningiomas is well estab-
lished [10, 20, 30]. External beam radiation therapy in doses
of 45–50 Gy reduces the progression rate after partial resec-
tion of meningiomas [30, 31]. A control rate of 72–98 % has
been reported, depending on the timing of XRT after surgery,
the extent of resection, the presence of cell atypia, the XRT
dose, the tumor location, and the XRT technique used [30–
34]. Glaholm et al. [32] reported 5-, 10-, and 15-year
relapse-free survival rates of 78 %, 67 %, and 56 %, respec-
tively, after postoperative radiotherapy.
Goldsmith et al. [33], in a retrospective review of 117
patients receiving conventional RT after subtotal resection,
reported a significant impact on progression-free survival
(PFS) after XRT related to total dose. The 10-year relapse-
free rate in those receiving ≤52 Gy was 65 % compared with
93 % for those receiving >52 Gy. For skull base meningio-
mas, a 5- and 10-year PFS rate of 92 % and 83 %, respec-
tively, has been reported after XRT [35].
Atypical and malignant meningiomas differ from their
benign counterparts in that they frequently recur after
complete excision and are more often fatal. Milosevic et al.
A. Gorgulho et al.
[36] studied the role of XRT for those lesions and found that
young age (<58 years), modern imaging and treatment
planning techniques, and a postoperative radiation dose of at
least 50 Gy contribute to improved outcome in patients with
atypical and malignant meningiomas. They also recom-
mended that all patients should receive radiation therapy
immediately after initial surgery. Dziuk et al. [37] stated that
adjuvant XRT, recurrence status, and extent of resection
were independent predictors of recurrence for malignant
meningiomas. They found that the 5-year disease-free sur-
vival after an initial total resection increased from 15 to 80 %
with radiation therapy. Recently, Ware et al. [38] published
their experience treating atypical and malignant meningio-
mas with resection followed by brachytherapy with perma-
nent low-dose 125I. The median freedom from progression of
the combined group of patients was 10.4 months.
Furthermore, this approach resulted in a high complication
rate. Their radiation necrosis rate was 27 %, with 13 % of
patients requiring additional surgery (Case Study 20.1).
The main criticism for XRT as a complement to surgical
resection has been a high long-term complication rate, which
has been reported to be from 17 to 38 % when patients were
followed longer than 5 years [39]. Nutting et al. [35] in their
skull base benign meningioma series reported that complica-
tions such as retinopathy, cataract, hypopituitarism, and
short-term memory deficit were likely to have been related to
irradiation, occurring in 13.4 % of the patients. The true inci-
dence of neuropsychologic side effects for patients who sur-
vive more than 6 months without tumor recurrence, as in the
case of meningiomas, has been significantly underestimated.
A study of 748 patients showed some degree of neuropsy-
chologic deficit in 29 %, and 12 % were classified as having
post-radiation dementia [40].
Stereotactic Radiation
Radiation therapy to large portions of the brain is necessary
only in selected meningiomas. Malignant meningiomas with
partial resection, as well as atypical meningiomas with risk
of dural spread, require more extensive radiation fields.
Well-demarcated benign lesions must be managed with focal
radiation, either stereotactic radiosurgery (SRS) or stereotac-
tic radiotherapy (SRT) depending on involvement of elo-
quent structures or volume of the lesion.
The application of SRS and SRT for treatment of menin-
giomas has been extensively studied at our institution. For
the radiosurgery procedures at UCLA, a Clinac 18 linear
accelerator (Varian, Inc., Palo Alto, CA) adapted to a Philips
SRS 200 was used from 1990 to 1996. A dedicated Varian
600 SR and X-Knife software (Radionics, Inc., Burlington,
MA) were introduced for the development of SRT, being
used from 1996 to 1998. The Novalis dedicated system with
20 Meningioma 297

Table 20.1 Tumor growth control after stereotactic radiation of benign Table 20.4 Tumor control rates for cavernous sinus meningiomas
meningiomas according to the UCLA grading system
Tumor size SRS (%) SRT (%) Total (%) Grade Meningioma radiologic aspect Tumor control (%)
Decreased 22 (34.9) 24 (33.3) 46 (34.1) I Confined to the cavernous sinus 90
No change 36 (57.1) 46 (63.8) 82 (60.7) II Involvement of the petroclival region 86
Increased 5 (7.9) 2 (2.7) 7 (5.2) without brain-stem compression
Total 63 (100) 72 (100) 135 (100) III Extension to and compression of the 86
Tumor control 58 (92) 70 (97.2) 128 (94.8) optic nerve, chiasm, or tract
IV Involvement of the petroclival region 42
with compression of the brain stem
Table 20.2 Clinical follow-up results V Extensive involvement of both 0
Neurologic findings SRS (%) SRT (%) Total (%) cavernous sinus
Improved 22 (35) 21 (32.3) 43 (33.5)
Unchanged 36 (57.1) 42 (64.6) 78 (60.9)
Worsened 5 (7.9) 2 (3.1) 7 (5.4) De Salles et al. [43] studied the role of SRS and SRT in
Number of cases 63 (100) 65 (100) 128 (100) the management of skull base meningiomas and proposed a
grade system (see the section “Patient Algorithm” later).
Table 20.3 Tumor growth control after stereotactic radiation of atypical They studied 40 patients (34 SRS; 6 SRT) treated during an
meningiomas 8-year period. Tumor control rates were 90 % for grade I,
Tumor size SRS (%) SRT (%) Total (%) 86 % for grade II, 86 % for grade III, 42 % for grade IV, and
Decreased 1 (6.2) 1 (20) 2 (9.5) no control for grade V (Table 20.4). The control rate corre-
No change 4 (25) 2 (40) 6 (28.5) lated well with the tumor grade (p < 0.036). Additionally, the
Increased 11 (68.7) 2 (40) 13 (62) complication rate was 7.5 % (three cases) occurring only in
Total 16 (100) 5 (100) 21 (100) SRS treatments. Since this report, grades III, IV, and V are
Tumor control 5 (31.2) 3 (60) 8 (38.1) treated with SRT at our institution.
The experience of treatment of cavernous sinus meningi-
omas with SRT was recently reviewed by Selch et al. [44].
miniature multileaf collimator capability has been used since They studied 45 patients treated with a median prescribed
1997 (BrainLAB, Munich, Germany). dose of 50.4 Gy delivered to a median tumor volume of
The whole UCLA meningioma series was published by 14.5 cm3. The 3-year progression-free survival rate was
Torres et al. [41] with a review of 161 patients who under- 97.4 % and the preexisting neurologic complaints improved
went SRS or SRT for treatment of 194 meningiomas in all in 20 % of patients. One patient had an ipsilateral cerebro-
locations. Clinical and radiologic follow-up were obtained in vascular accident 6 months after SRT, although this compli-
128 patients harboring 156 lesions. Stereotactic radiosurgery cation is not likely related to the procedure.
was used to treat 79 lesions, and SRT was used to treat 77
lesions. The overall mean follow-up period was 32.5 months.
The mean prescribed dose for the SRS group was 15.6 Gy, Stereotactic Radiosurgery
whereas for the SRT group, the dose was 48.4 Gy. For benign
tumors, the overall local control rate was 94.8 %. The control SRS has become a well-accepted modality for the treatment
rates for the SRS and SRT were 92 % and 97.2 %, respec- of a number of neurologic indications, ranging from primary
tively (Table 20.1). The overall rate of clinical improvement and metastatic malignancies to benign tumors, arteriovenous
was 33.5 %. Worsening of the clinical symptoms was malformations (AVMs), pain, and other neurologic condi-
observed in 7.9 % of patients who underwent SRS and in tions. Unlike conventional fractionated radiotherapy, SRS
3.1 % who underwent SRT (Table 20.2). The incidence of does not exploit differences in the repair capacities of normal
clinical complications in the SRS and SRT groups was 5 % and neoplastic cells after repeated exposure to sublethal
and 5.2 %, respectively. For the group of 21 atypical menin- doses of irradiation. SRS achieves a therapeutic ratio by vir-
giomas, the tumor growth control was 31.2 % and 60 % for tue of the steep dose gradient between the isocenter and sur-
the SRS and SRT groups, respectively (Table 20.3). rounding normal parenchyma, inevitably produced by the
The analysis of the long-term follow-up (mean, 72.5 convergence of multiple small radiotherapy beams. The bio-
months) group of 32 patients revealed tumor growth control logic effect is irreparable cellular damage and vascular
rate of 92.3 % and 100 % for the SRS- and SRT-treated occlusion within the high dose volume.
patients, respectively. Worsening of previous neurologic defi- Meningiomas have several characteristics that make them
cit was identified in two (7.9 %) patients treated with SRS. No excellent tumors for radiosurgery [45]. First, they usually
complications were found in the SRT patients [42]. grow slowly, which allows time for the effects of irradiation
298
Fig. 20.1 (a) MRI scan from Case 1 showing recurrence of an atypical
meningioma in left tentorium 45 months after initial resection. (b)
Treatment plan with shaped beans, 14 Gy, 90 % isodose line, volume
to materialize. Second, they are easily imaged with both
computed tomography (CT) and magnetic resonance imag-
ing (MRI), thereby facilitating accurate stereotactic targeting
and appropriate dose planning. Finally, a high dose with
rapid fall-off can be directed to the imaging-defined tumor
margin with confidence because meningiomas are usually
well demarcated and rarely invade surrounding brain tissues
(Fig. 20.1). The application of stereotactic radiation using all
available techniques, including linear accelerator (linac) [41,
43, 44, 46–48]. Gamma Knife [49–54], and proton beam
[55], has been reported in the literature.
The effectiveness of SRS and the risks of complication
depend on the size of the tumor. Lesions larger than 3 cm in
diameter must be treated with significantly lower doses of
radiation to avoid excessive risk of complications. Such small
radiation doses may make radiosurgery ineffective. Tumor
location also affects the treatment decision, depending on the
proximity to eloquent structures (especially the optic appara-
tus). Single-dose SRS is indicated for meningiomas smaller
than 3 cm or 20 cm3 in volume and with a minimal distance
from the optic apparatus of between 2 and 4 mm [54, 56, 57].
Furthermore, tumors causing significant brain-stem compres-
sion may not be suitable for single-dose radiosurgery because
a slight swelling during the course of tumor necrosis induced
by radiosurgery may not be tolerable. Many alternatives were
attempted in order to overcome such limitations, usually
resulting in treatment failure. This included two-staged proce-
dures [49, 58] or a decrease in the ideal peripheral dose [59].
A lack of homogeneity in the radiosurgery dose has been
a controversial issue in SRS treatment of brain tumors. Dose
A. Gorgulho et al.
1.07 cm3. Note that there is a side inversion in the brainlab treatment
plan software
homogeneity has been sacrificed to obtain conformal tumor
planning, thereby avoiding nearby normal structures.
However, those structures encased by the tumor, such as
cranial nerves, the carotid artery, or even the optic apparatus,
may be jeopardized with inhomogeneous radiation treat-
ment. Multiple isocenters restrict the prescription to low iso-
dose volumes with a very high gradient of dose between the
periphery and interior of the tumor. According to Nedzi et al.
[60], dose inhomogeneity ≥5 Gy was the most significant
factor associated with morbidity after SRS.
Within the past few years, however, the development of
miniature multileaf collimators has altered the way in which
radiosurgery is performed with linac systems. This technique
allows the beam to conform to the target closely and exclude
normal structures. In addition to high target conformity, the
“single isocenter shaped beam approach” results in a homo-
geneous dose within the target volume, as well as a highly
efficient planning and treatment process.
SRS has already proved to be effective in the treatment of
meningiomas. Kondziolka et al. [52] evaluated the long-
term outcome of 85 patients (90 % of them skull base
located) who underwent Gamma Knife radiosurgery. Tumor
control was obtained in 93 % of patients. Tumor resection
was necessary in five (5.8 %) patients because of delayed
tumor growth or persistent symptoms. New or worsened
neurologic deficits occurred in five (5.8 %) patients during
the follow-up.
Thirty-four percent to 71 % of meningiomas treated by
SRS are expected to decrease in size, and 37–57 % are
expected to stabilize [41, 51, 61, 62]. DiBiase et al. [63]
20 Meningioma
Fig. 20.2 (a) MRI scan at 33-month follow-up showing a new lesion in the floor of the left medial cranial fossa. (b) Treatment plan with shaped
beans, 18 Gy, 90 % isodose line, volume 0.65 cm3
studied the factors predicting local tumor control after
Gamma Knife radiosurgery in 162 patients harboring menin-
giomas. The median prescribed dose was 14 Gy to the 50 %
isodose line and the median tumor volume was 4.5 cm3. The
5-year disease-free survival was 86.2 %. The factors corre-
lated with a worse prognosis in their study were male
patients, conformity index less than 1.4, and tumor volume
greater than 10 cm3. However, patients who were treated
with less conformal plans that covered the dural tail had bet-
ter outcomes (Fig. 20.2).
Hakim et al. [46] published the results of 127 patients
with 155 meningiomas treated by SRS with linac, including
atypical and malignant meningiomas. The median marginal
dose was 15 Gy and the median volume was 4.1 cm3.
Freedom from progression was observed in 84.3 % of
patients at a median time of 23 months. The actuarial tumor
control for the patients with benign meningiomas was 89.3 %
at 5 years. Permanent complications were observed in 4.7 %
of patients.
SRS for patients with small- to medium-sized meningio-
mas was recently reported to provide tumor control equiva-
lent to Simpson grade 1 resection. Pollock et al. [64]
compared two groups of patients with lesions smaller than
35 mm. The 62 patients who underwent SRS with a mean
margin dose of 17.7 Gy had no statistically significant differ-
ence in the 3- and 7-year actuarial PFS when compared with
57 patients who underwent complete surgical resection,
including their dural attachments and bone abnormalities
(Simpson 1) with no radiation. Furthermore, SRS provided a
higher PFS rate compared with that in patients in whom
resections were Simpson grade 2 (p < 0.05) and grade 3–4
299
(p < 0.001). The complication rate was 10 % for SRS and
22 % for the surgical group (p = 0.06).
Patients treated by radiosurgery for meningioma must be
followed carefully. Flickinger et al. [65] studied a group of
219 meningiomas without pathologic verification. The actu-
arial rate of identifying a diagnosis other than meningioma
was 2.3 % at 5 and 10 years. Nakatomi et al. [66] reported
one patient treated by SRS for a supposed cavernous sinus
meningioma that required surgical resection 17 months after
because of recurrence. The postoperative diagnosis was pri-
mary cavernous sinus malignant lymphoma.
Kim et al. [67] recently analyzed the role of Gamma
Knife radiosurgery in 23 patients with 26 superficially
located meningiomas. The median tumor volume was
4.7 cm3, and the mean margin dose was 16 Gy at the 50 %
isodose line. The local control rate was 95 % with stable
MRI imaging in 65 % of the cases. Symptomatic and tran-
sient peritumoral high signal on T2-weighted magnetic reso-
nance (MR) images was observed in 43 % of patients. This
complication was associated with a high integral dose and a
large tumor volume. Moreover, tumor shrinkage was more
prominent in the patients with symptomatic high signal
(p = 0.03).
MRI showed peritumorous imaging changes in 24 % of
patients treated by SRS in the series published by Chang
et al. [61]. Their overall rate of symptomatic edema was
9.3 %. Furthermore, these imaging findings were related to
tumor dose in univariate analysis, and with tumor location in
the multivariate analysis. Radiation-induced imaging
changes were more often seen in convexity, parasagittal, and
falx meningiomas than in those of the skull base.
300 A. Gorgulho et al.

Table 20.5 Doses utilized in radiosurgery for intracranial meningiomas

Skull Base Meningiomas–SRS Peripheral
Author, Year Dose Variation (Gy) Technique
Meningiomas in the skull base account for the largest group Hakim, 1998 [46] 15 9–20 LINAC
of incompletely resected lesions usually due to cavernous Liscak, 1999 [59] 12 10–14 GK
sinus involvement, brain-stem adhesion, and infiltration of Kondziolka, 1999 [51] 16 9–25 GK
adjacent structures. Complete excision in these situations is Shafron, 1999 [47] 12.7 10–20 LINAC
unlikely without causing morbidity [68–70]. Stafford, 2001 [54] 16 12–36 LINAC
Villavicencio, 2001 [114] 15 12–18.5 LINAC
Meningiomas are the most frequent benign tumors treated
Friedman, 2005 [115] 16 10–20 LINAC
by radiosurgery, and the majority of them are located on the
Hasegawa, 2007 [116] 13 7.5–17 GK
skull base (Fig. 20.3). Liscak et al. [71] studied 176 patients
Pollock, 2012 [117] 16 N/A GK
with meningiomas located on the skull base. They obtained
N/A Not Available, LINAC Linear Accelerator, GK Gamma Knife
local control in 98 % of patients and a persistent morbidity
rate of 4.5 %. The rate of radiation-induced edema was 11 %.
Significantly lower edema occurrence was observed when the sinus treated by SRS. New cranial neuropathies were found
dosage to the tumor margin was lower than or equal to 14 Gy. in 19 % of patients. Additionally, all patients who developed
Chuang et al. [72] studied the linac-based SRS for 43 optic system neuropathy (6.4 %) received radiation doses
unresectable or partially resected meningiomas in the base of higher than 8 Gy to optic apparatus.
the skull. The 7-year local control in the SRS-alone group Leber et al. [75] correlated the doses delivered in the
and surgical excision with SRS group was 100 % and 84.4 %, treatment of cavernous sinus lesions by SRS with incidence
respectively (p = 0.21). of optic neuropathy. The actuarial rate was zero for patients
Using a mean margin dose of 13 Gy with a Gamma Knife who received a dose of less than 10 Gy, 26.7 % for patients
unit for treatment of 32 petroclival meningiomas, Roche receiving 10 to less than 15 Gy, and 77.8 % for those who
et al. [73] achieved local control in all patients. Although no received doses of 15 Gy or more (p < 0.0001).
new cranial deficit was observed, two patients developed Stafford et al. [76] reported 218 parasellar SRS proce-
hemiparesis due to pontine infarction. dures with 73 % of patients receiving more than 8 Gy to a
Spiegelmann et al. [48] studied 42 patients with menin- short segment of the optic apparatus. The overall incidence
giomas involving the cavernous sinus treated with linac. of radiation neuropathy was 1.9 %; the risk of neuropathy
A mean dose of 14 Gy was delivered to the tumor margin and was 1.1 % for patients receiving 12 Gy or less.
the median tumor volume was 8.2 cm3. Tumor control was Morbidity after SRS is strongly associated with tumor
observed in 97.5 % of the patients. Cranial nerve complica- volume and location [15, 77]. For these reasons, application
tions included new trigeminal neuropathy in 4.7 % and a new of SRS to cavernous sinus meningiomas has generally been
visual defect in 2.8 %. restricted to tumors <3 cm in greatest dimension and located
Despite the dosimetric advantages of SRS, permanent several millimeters from the optic apparatus [56, 77–79].
cranial nerve deficit is more common in the treatment of cav- These are the grade I and grade II of the UCLA classification
ernous sinus meningiomas. Tishler et al. [74] studied 62 [43]. Tumors grade III, IV, and V are candidates for SRT.
patients (42 with meningiomas) inside or near the cavernous See Table 20.5 for doses used in stereotactic radiosurgery
for intracranial meningiomas.

Stereotactic Radiotherapy

SRT is a treatment option that may be undertaken when the

Fig. 20.3 MRI scans 6 months after the second treatment by SRS
showing both lesions with decreased size
risk of SRS is unacceptably high; for instance, in cases in
which tumors involve the optic pathways, the brain stem, or
lesions with larger volume near eloquent structures.
This technique combines the physical dose localization
advantage of SRS with the radiobiologic benefits of dose
fractionation [80]. Unlike SRS, the treatment planning fidu-
cial system and patient immobilization device can be applied
noninvasively [81]. The accuracy of patient repositioning
during SRT has been documented [82–84]. A total fraction-
ated dose of ionizing radiation, known from conventional
20 Meningioma
radiation therapy experience to be effective for meningioma
yet tolerated by the central nervous system, can be delivered
by the SRT technique.
Lo et al. [85] studied a group of 18 patients treated by SRT
for meningiomas with a large volume or adjacent to eloquent
structures. The median dose was 54 Gy and the median vol-
ume was 8.8 cm3. The 3-year local control rate was 92.3 %;
one complication was reported (5.5 %). These findings were
not statistically significant, different when compared with
another group of 35 patients who underwent SRS with a
median dose of 14 Gy delivered to a median volume of 6.8 cm3.
The application of SRT was recently reviewed by Zabel
et al. [86] in 317 patients with benign and atypical meningio-
mas in all intracranial sites. The median total dose was
57.6 Gy delivered to a median volume of 33.6 cm3. The over-
all local control rate was 93.1 %. As expected, the local
tumor failure was significantly greater in patients with WHO
grade 2 meningiomas than in patients with WHO grade 1 or
unconfirmed histology (p < 0.002). Moreover, patients with a
tumor volume larger than 60 cm3 had a higher recurrence rate
(15.5 %) when compared with patients with tumor volumes
smaller than 60 cm3 (p < 0.001). They observed worsening of
preexisting symptoms and new clinical symptoms in 8.2 %
and 2.5 % of patients, respectively.
Skull Base Meningiomas–SRT
Skull base meningioma patients for whom microsurgery
and/or SRS are contraindicated seem to be the ideal applica-
tion of SRT (Fig. 20.4). Alheit et al. [82] studied a group of
24 patients (21 of them harboring skull base meningiomas)
treated by SRT with doses ranging from 50 to 55 Gy deliv-
ered to a median volume of 21 cm3. The progression-free
survival rate was 100 %, and two (8 %) patients experienced
Fig. 20.4 (a) MRI scan showing an incidental finding of a small falx
meningioma in a 77-year-old woman with high operative risk. The
lesion had a slight increase in size during 1 year of follow-up and was
treated with 14 Gy, 90 % isodose line. (b) Stable size of the tumor 40
months after treatment
301
Table 20.6 Doses utilized in stereotactic radiotherapy for intracranial
meningiomas
Author, year Dose/variation (Gy) Fractions (Gy)
Andrews, 2002 [93] 51 (50–54) 1.8
Selch, 2004 [44] 50.4 (N/A) 1.8
Henzel, 2006 [118] 56 (50.4–60) 1.8–2.0
Adler, 2006 [119] 20.3 (N/A) 2–5
Litré 2009 [120] 45 (N/A) 1.8
Combs, 2012 [121] N/A (25–68) 1.6–5
Gy Gray, N/A Not Available
early side effects, including one VII nerve palsy and one
Addisonian state.
Debus et al. [87] published a large series of 189 patients
treated by SRT for skull base meningiomas with a mean radia-
tion dose of 56.8 Gy. The median target volume was 52.5 cm3.
The tumor control rates for WHO grade 1 and WHO grade 2
tumors were 98.3 % and 77.7 %, respectively. Preexisting cra-
nial nerve symptoms resolved completely in 28 % of the
patients. Only 7 % of patients showed an impairment of pre-
existing neurologic symptoms, and 1.6 % experienced new
clinically significant deficits. These excellent results corrobo-
rate the UCLA experience with skull base meningiomas
treated with SRT [44]. See Table 20.6 for doses used in stereo-
tactic radiosurgery for intracranial meningiomas.
Intensity-Modulated Radiation Therapy
The intensity-modulated radiation therapy (IMRT) technique
modulates the intensity of the photon beam across the treat-
ment portal. It has shown the ability to conform the dose to
complex-shaped target volumes. Baumert et al. [88] made
comparisons between the treatment plans of SRT and IMRT
for skull base lesions. The conformity index and the sparing of
the organs at risk were better for the IMRT plan. The largest
improvement was observed for multifocal and irregular
tumors.
Pirzkall et al. published the results of IMRT treatment on
20 patients with benign skull base meningiomas. They used
a median minimum dose of 40 Gy delivered to a median vol-
ume of 108 cm3. In a median follow-up of 36 months, the
local tumor control rate was 100 %. The preexisting neuro-
logic symptoms improved in 60 % and worsened in 5 % of
patients. They also observed no radiation-induced peritu-
moral edema or new onset of neurologic deficits.
Interestingly, the application of intensity-modulated
stereotactic radiosurgery (IMSRS) for treatment of small
skull base lesions was compared with dynamic conformal
arc technique (DCA). Superior homogeneity and cover-
age for DCA was observed. The IMSRS also increased the
time for planning, dose delivery, and integral dose to the
brain [89].
302
The intensity-modulated stereotactic radiation therapies
(IMSRT or IMSRS) have limited application when treating
intracranial meningiomas; specific cases where the eyes or
the brain stem are surrounded by the lesion may benefit from
this technique (Case Study 20.2).
Special Applications of Stereotactic
Radiation
Optic Sheath
Optic nerve sheath meningiomas are uncommon, slow-
growing tumors that can be categorized as primary and sec-
ondary according to their origin. Although conservative
management can be considered, the most common treatment
is resection, which may lead to blindness due to damage to
the pial vascular supply of the optic nerve [90]. Radiation
therapy has been used in recent decades to treat these tumors
[91, 92].
SRT has been used as one alternative to avoid radiation-
induced optic neuropathy. Andrews et al. [93] treated 30
patients with 33 optic nerve sheath meningiomas with
SRT. Local tumor control was observed in all patients, and
they observed 92 % of preserved vision among the optic
nerves with vision before treatment. Improvement in visual
acuity and/or visual field occurred in 42 % of nerves. Visual
loss was observed in 2 (6.6 %) patients and 1 (3.3 %) devel-
oped optic neuritis responsive to steroids.
Becker et al. studied the role of SRT in 39 patients with
either primary or secondary optic nerve sheath meningiomas
using a median dose of 54 Gy. The tumor local control was
100 % after a median follow-up of 35 months. The rates of
visual field stabilization, improvement, and worsening were
70 %, 25 %, and 4 %, respectively. Additionally, new endocri-
nologic deficits after treatment were found in 14 % of patients
with primary tumors and in 8 % of patients with secondary
tumors. The visual improvement observed in patients treated
by SRT for optic sheath meningiomas was recently reported
to occur within 1–3 months after treatment in 81 % of patients
who experienced visual improvement [94]. Homogeneity of
the dose distribution becomes important when planning SRT
for these tumors, as frequently the optic nerve is surrounded
by the tumor. This is possible with shaped beams.
Atypical and Malignant Meningiomas
The role of conventional radiation therapy and brachyther-
apy in the management of atypical and malignant meningio-
mas is well established [33, 36–39]. Although many series
are focused on stereotactic radiation for treatment of menin-
giomas, relatively few published studies have defined its
A. Gorgulho et al.
Fig. 20.5 (a) MRI scan from a 74-year-old German woman with
an incidental found meningioma in the tip of the left temporal fossa.
She was followed with serial MRIs and growth was documented.
The patient refused surgery and accepted radiosurgery. (b) Treatment
plan showing inclusion of the dural tail within the prescription isodose
line (90 %, 14 Gy, shaped beam)
application in atypical and malignant histologic features
(Fig. 20.5). At our institution, SRS and SRT are used to sal-
vage recurrences after surgery and regional radiation.
Ojemann et al. [95], using a Gamma Knife unit, treated 22
patients with primary or recurrent malignant meningiomas.
The overall 5-year survival and progression-free survival
rates were 40 % and 26 %, respectively. Age (<50 years) and
tumor volume (<8 cm3) were significant predictors of better
prognosis. Complications were observed in 5 (23 %) patients
who developed radiation necrosis.
In the meningioma series published by Stafford et al. [54],
22 patients harboring either atypical (n = 13) or malignant
(n = 9) meningiomas were treated by Gamma Knife
SRS. They obtained 5-year survival rates of 76 % and 0 %
for atypical and malignant meningiomas, respectively. The
5-year local control rates were 68 % and 0 % for atypical and
malignant tumors, respectively. Univariate analyses of tumor
histologic features demonstrated no correlation between
complications arising after radiosurgery.
Harris et al. [96] studied the results of Gamma Knife
SRS for treatment of 18 atypical and 12 malignant menin-
giomas. The 5- and 10-year overall actuarial survival rates
for atypical meningiomas were 59 % (±13), and malignant
lesions had 5- and 10-year overall actuarial survival rates of
59 % (±16) and 0. These rates were not significantly differ-
ent from one another. Atypical meningiomas had a 5-year
PFS of 83 % (±7), and malignant tumors had a PFS of 72 %
(±10) (p = 0.018). They also found a significantly better
PFS for lesions treated without evidence of progression
before SRS.
The results published recently by Huffmann et al. [97]
using Gamma Knife SRS for treatment of atypical menin-
giomas is the first report where the WHO 2000 classifica-
tion criteria was clearly applied in a radiosurgery study.
They treated 15 patients with 21 lesions using a median
20 Meningioma
prescription dose of 16 Gy. The local tumor control and
marginal/distant tumor control were 95 % and 60 %, respec-
tively. The only patient with local relapse was treated with
a prescription dose of 15 Gy.
Zabel et al. [86] published a long-term follow-up to
meningiomas treated by SRT. A group of 26 patients harbor-
ing atypical lesions had 3-, 5-, and 10-year recurrence-free
survival rates of 96 %, 89 %, and 67 %, respectively. Atypical
histologic grade and tumor volume larger than 60 cm3 were
correlated with a significantly worse local control in com-
parison with benign meningiomas.
Combination of Surgery and Radiosurgery
The concern of some neurosurgeons about better functional
outcomes has led some groups to adopt more conservative
approaches for skull base meningiomas. Radiosurgery has
become more accepted and recently is being combined with
surgery. Aziz et al. [98] reviewed 38 patients who underwent
surgical resection for large sphenoid wing meningiomas that
invaded the cavernous sinus. They proposed that tumor por-
tions involving the medial compartment of cavernous sinus,
as well as portions that infiltrate the superior orbital fissure,
should be left for observation or stereotactic radiation.
Maruyama et al. [99] proposed a treatment strategy com-
bining nonradical surgery and radiosurgery for the manage-
ment of cavernous sinus meningiomas. Twenty-three patients
had partial or subtotal surgical resection with the main aim to
remove the tumor components extending outside the cavern-
ous sinus. This was performed when the tumor was attached
to or displacing the optic apparatus and the brainstem, in
patients with tumors larger than 3 cm in mean diameter, or in
tumors suspected of malignancy with the aim to obtain histo-
Fig. 20.6 (a) MRI scan showing a cavernous sinus and petro-clinoid
ligament meningioma in a 71-year-old woman with pain in V2 and V3
region. (b) Treatment plan with multiple isocenters, 16 Gy, 50 %
303
logic verification. The residual tumors underwent radiosur-
gery or fractionated radiotherapy depending on whether they
were larger or smaller than 3 cm. Another group of 17
patients underwent SRS-only, given the presence of tumors
smaller than 3 cm that were distant from optic apparatus. The
5-year actuarial local control rate was 94 %.
Recently, cytology of tumors located in the cavernous
sinus became possible [100]. Frameless stereotaxis allows
for needle biopsy of these tumors through the foramen ovale.
Biopsy of these tumors became part of the management of
tumors in the cavernous sinus requiring a differential diagnosis
(Case Study 20.3).
Recommendations
Patient Algorithm
Treatment decisions for meningiomas are best made by a
team of neurosurgeons and radiation oncologists representing
expertise in microsurgery, radiosurgery, and radiation ther-
apy. A combined approach to a tumor with microsurgery and
radiosurgery is promising. Decompression of critical
structures by microsurgery facilitates and increases the effec-
tiveness of radiosurgery. The literature suggests that conser-
vative resection followed by radiation therapy leads to better
preservation of neural function [24, 26, 101, 102].
When choosing a course of treatment, the patient’s age
and clinical status must also be considered. Radiosurgery
should be considered the primary option in elderly patients
in which the risks of surgery are too great or when the poten-
tial morbidity of surgery may be unacceptable (Fig. 20.6).
Because radiosurgery only requires local anesthesia, several
patients in their eighties and one in her nineties have
isodose line. (c) MRI scan showing stable image after 9 years of fol-
low-up. The patient is requiring only sporadic medication for facial
pain
304
Fig. 20.7 (a) MRI scans of a 52-year-old woman experiencing double
vision and lack of balance showing a large meningioma involving the
left cavernous sinus, left petroclival region extending into the prepon-
tine and premedullary cisterns. The patient refused surgery and was
successfully undergone radiosurgery for their meningiomas
at UCLA.
The clinical status of a patient should always be thoroughly
assessed prior to treatment. When choosing the best treatment,
it is important to note the onset, severity, and rate of progres-
sion of any symptoms. A patient who is asymptomatic may
choose to postpone any treatment until symptoms develop or
until imaging provides evidence of growth. A patient’s clinical
status may weigh heavily on the choice between radiosurgery
and microsurgery.
Patients with parasellar lesions with acute neurologic
deterioration and previous history of malignancy, immuno-
deficiency, or inflammatory disease could benefit from histo-
logic diagnosis before treatment. Since 2003, we have used
an image-guided frameless biopsy procedure via the fora-
men ovale, avoiding a major microsurgical procedure. This
procedure is well tolerated by the patient, with a short hospi-
tal stay [100].
The effectiveness of radiosurgery and the risks of compli-
cation depend upon the size of the tumor. Lesions larger than
3 cm in diameter must be treated with significantly lower
doses of radiation to avoid excessive risk of complications.
A. Gorgulho et al.
treated by SRT. (b) Treatment plan using shaped beams with 50.4 Gy in
28 fractions, 90 % isodose line, volume 39.22 cm3. (c) MRI scans
showing decrease in tumor size 43 months after treatment
Such small radiation doses may make radiosurgery ineffec-
tive; therefore surgical resection remains the best treatment
for large tumors. Patients who are not surgical candidates
who have tumors with large size and/or close to optic appa-
ratus or brainstem are given stereotactic radiotherapy instead
of SRS. Both modalities are used in different clinical sce-
narios in our department and should be available to comple-
ment each other, providing safer treatment options for
patients (Fig. 20.7).
Additionally, for cavernous sinus meningiomas, the deci-
sion between SRS or SRT is made with the help of our grad-
ing system [43]. Tumors confined to the cavernous sinus
(grade I) or involving the petroclival region without brain-
stem compression (grade II) are suitable for SRS. Lesions
with extension to the optic apparatus (grade III), involvement
of petroclival region with compression of the brain stem
(grade IV), or involvement of both cavernous sinus (grade V)
are recommended to receive SRT (Table 20.4). Surgical
efforts should be concentrated in turning a high-grade cav-
ernous sinus meningioma into a lower-grade tumor that may
be controlled by stereotactic radiation. Optic sheath menin-
giomas are also indicated for SRT unless the lesion has small
20 Meningioma
size in a patient without useful vision, when SRS or micro-
surgery may be used.
Procedure and Treatment Planning
At UCLA, the SRS procedure begins early in the morning
with the fixation of a stereotactic frame to the patient’s
skull. Routinely, a BRW (Radionics) or a BrainLAB stereo-
tactic frame is applied after administration of a local anes-
thetic. A stereotactic contrast-enhanced CT scan is obtained
and fused with a previously acquired 3-mm slice MR
image. Image fusion is performed using a mutual informa-
tion algorithm, which allows geometric alignment between
the two image sets. Thus, the CT scan is used for the preci-
sion of their anatomic localization, whereas high-resolution
MR images provide the anatomic details necessary for
treatment planning.
The same protocol is used for the SRT-treated patients;
however, the patients are immobilized with a custom-fitted
thermoplastic face mask (U-PLAST; BrainLAB) instead of a
regular frame [82]. Before each daily treatment, reproduc-
ibility of patient positioning is evaluated using the depth hel-
met method of Kooy et al. [83]. For both SRS and SRT
techniques, the three-dimensional treatment plans were
generated using a BrainLAB planning system (versions
3.5–4.03; BrainLAB).
The treatment plan is safely performed using the
“beam’s-eye-view” conformal technique (Fig. 20.8).
According to the tumor size and location, the radiation is
delivered using dynamic arcs or static shaped beams using a
dedicated 6-MV linear accelerator (Novalis; BrainLAB).
This equipment utilizes a micro-multileaf collimator,
obviating the need for multiple isocenters for dose
conformation.
Fig. 20.8 MRI scans 1 year after treatment showing the lesion stable in
size
305
Complication Avoidance
The dose is chosen based on tumor volume using an isoeffect
line generated from an integrated logistic formula. The for-
mula relates dose and volume to the incidence of complica-
tions after SRS for AVMs [103]. In general, the authors
attempted to remain below the 3 % isoeffect line for
prevention of permanent symptomatic brain injury. On a log-
log plot of dose versus volume, this line is straight with a
negative slope and has proved to be a reliable predictor of
SRS complications, as previously described by Kjelberg
et al. [104] Dose was also tailored to the surrounding anat-
omy and typically reduced for lesions near the brain stem or
cranial nerves; the optic chiasm was restricted to 8 Gy.
Using the beam’s-eye-view technique, the radiation arcs
or beams avoid the eyes and eloquent structures whenever
possible. Relative doses and sizes are designed to prevent
maximum dose to critical structures within or in close rela-
tionship to the tumor.
Future Directions
Decisions regarding conservative management versus
aggressive surgery and adjuvant therapy should rely on pre-
cise parameters. The use of dynamic contrast-enhanced per-
fusion MRI with T2-weighted sequences measuring the
endothelial permeability is useful in distinguishing atypical
meningiomas from typical meningiomas [105].
Although the new WHO classification recommends more
objective criteria [8], there is still lack of correlation between
grade and behavior in some cases. Recently, a new marker to
predict meningioma behavior has been used. The human
telomerase catalytic subunit (hTERT) expression has shown
significant correlation with recurrent meningiomas [106,
107]. Another promising tool is the use of DNA microarray
assay technology, which detects numerous genetic abnor-
malities, to differentiate meningioma subtypes [108].
Likewise, the surgery field has been taking advantage of
new technology in recent years. The advances in neuronavi-
gational computer technologies have allowed surgeons to
display three-dimensional reconstructions of the lesions in
relation to the vessels, nerves, and eloquent tracts [109]. The
diffusion-tensor imaging tractography has also been used in
treatment planning for radiosurgery [110]. There have been
significant advances in minimally invasive skull base sur-
gery. Standard approaches to difficult regions have been
developed to allow safer and more complete resection [111–
113]. As we better understand meningioma biology and
genetics, and master the surgical techniques, we can improve
patient outcomes and quality of life.
306 A. Gorgulho et al.

Case Study 20.1
A 47-year-old woman had a left frontotemporal atypical
meningioma that was resected on January 1998. On October
2001, she presented with headaches, and the MRI scan
revealed a small recurrence (Fig. 20.9a). She was treated by
SRS, 14 Gy delivered to 90 % isodose line, volume of
1.07 cm3 (Fig. 20.9b). The follow-up scan 33 months after
treatment showed a stable tentorial lesion (not shown) but a
new lesion (arrow) in the floor of the left medial cranial fossa
(Fig. 20.10a). The patient was retreated with 18 Gy delivered
to 90 % isodose line, volume of 0.65 cm3 (Fig. 20.10b). The
last follow-up MRI scan in January 2005 showed both
lesions decreasing in size (Fig. 20.11).

Fig. 20.9 Treatment plan with intensity-modulated stereotactic radiotherapy showing the sparing of eyes. The total dose of 59.4 Gy was
given with 33 fractions of 1.8 Gy delivered to 90 % isodose line for a volume of 24.83 cm3

Fig. 20.10 Coronal and sagittal MRI scans from Case 2 showing residual meningioma in frontal fossa and olfactory groove
20 Meningioma
Fig. 20.11 (a) MRI scan showing a left frontoparietal dural based
recurrent atypical meningioma. (b) Treatment plan with shaped
beans (with a left to right inversion), 47.6 Gy, 85 % isodose line in
28 fractions, volume 20.68 cm3. (c) MRI scan showing the tumor
Case Study 20.2
A 51-year-old woman had surgical removal of a frontal
fossa meningioma in January 2001 at an outside facility.
The patient was stable until early 2003 when she started
experiencing fatigue and headaches. The MRI scan
showed a residual tumor arising from the olfactory groove
and extending into the right cribriform plate and right eth-
moid. She underwent a craniofacial approach with incom-
plete tumor resection in August 2003. The pathology
Fig. 20.12 MRI scans from case 3 showing a cavernous sinus region tumor extending into the left cerebellopontine angle cistern and the
prepontine cistern. The images were suggestive of a meningioma
307
increasing in size after 20 months of follow-up. The pathology
report revealed malignant progression to WHO grade III
meningioma
report revealed meningioma with atypical features, and
the MRI scan showed residual lesion in frontal fossa
(Fig. 20.12). Given the aggressive behavior of this resid-
ual tumor and the vision preservation, the treatment
option was intensity-modulated stereotactic radiotherapy
(IMSRT). The patient was treated with 33 fractions of
1.8 Gy with a total radiation dose of 59.4 Gy delivered to
90 % isodose line, volume of 24.83 cm3 (Fig. 20.13). The
MRI scans 1 year after the treatment showed the lesion
stable in size (Fig. 20.14).
308 A. Gorgulho et al.

Fig. 20.13 (a) Screen shot of the navigation system showing the radiotherapy with a total dose of 45 Gy, 85 % isodose line. The volume
needle trajectory for the frameless foramen ovale biopsy. (b) Treatment treated was 17.0 cm3
plan with dynamic arcs. The tumor was treated with stereotactic

Fig. 20.14 MRI scans 6 months after treatment showing a remarkable tumor response to radiation. This behavior is compatible with the
diagnosis of a cavernous sinus lymphoma
20 Meningioma 309

Case Study 20.3
A 48-year-old man with diagnosis of AIDS had a 3-month
history of double vision and pain in the left periorbital
area as well as some decreased sensation in the left face.
The MRI scan showed an extraaxial mass in the cavern-
ous sinus region extending into the left cerebellopontine
angle cistern and the prepontine cistern. The radiology
report was suggestive of a meningioma (Fig. 20.15).
Given the patient’s history of HIV, the option was to per-
form a frameless cavernous sinus biopsy through the fora-
men ovale (Fig. 20.16). The pathology report revealed
that the tumor was likely of lymphocytic and histiocytic
origin. It was believed that the mass represented a lym-
phoma. The patient underwent stereotactic radiotherapy
with a total dose of 45 Gy in 25 fractions of 1.8 Gy deliv-
ered to the 85 % isodose line, volume of 17.0 cm3
(Fig. 20.16). The MRI scans 6 months after treatment
showed a remarkable decrease in size of the lesion. This
rapid response confirms the diagnosis of a cavernous
sinus lymphoma (Fig. 20.17).

Fig. 20.15 (a) MRI scan from a 71-year-old man with diagnosis of sylvian fissure lesion after 30 months. Only this lesion was treated
Parkinson disease showing multiples meningiomas. (b) The patient with 12 Gy, 85 % isodose line. (c) MRI scan showing the tumor
was followed and the MRI scan showed increase in size of the right slightly smaller in size 32 months after treatment

Intracranial
Meningioma

Symptomatic
Mass Effect Incidental Finding

Observation

No High Operative
Microsurgery Progression
Risk
Yes

Complete No
Stereotactic
Resection Radiation
Yes

• Not Eloquent • Eloquent

• Grades I - II • Grades III - V
• < 30 mm • > 30 mm

Observation SRS SRT

Fig. 20.16 Flowchart depicting selection criteria for stereotactic radiation of intracranial meningiomas used in our clinic
310
Fig. 20.17 The beam’s-eye-view image (above) as seen in the
treatment plan of a skull base meningioma (below) using the
shaped beam technique with micro-multileaf collimator structures
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 Meningioma: Viewpoint—Surgery
Lawrence S. Chin, David J. Padalino, Pulak Ray,
and John M. Caridi
Introduction
The first successful documented resection of this benign, slow
growing tumor was performed by Zanobi Pecchiolo (1801–
1866) at Siena University. In a vast surgical series published in
1847, 1,524 cases were described, one of which described a
large meningioma removed from the right sinciput through a
triangular flap. Then on December 15, 1887, William W. Keen
(1837–1932) was the first neurosurgeon to successfully resect
a meningioma in the United States. The patient proceeded to
survive for 30 years after without any clinical signs of recur-
rence [1]. Due to much debate over the etiology and pathogen-
esis of this tumor, it was not until 1922 in his text entitled
Meningiomas, Their Classification, Regional Behaviour, Life
History and Surgical End Results that Harvey Cushing charac-
terized the tumor as a meningioma, thus leaving room for the
histologic type to be clarified [2, 3]. It is now known that
meningiomas arise from transformed arachnoid cap cells
that form slow growing tumors that are attached to the overly-
ing dura [4]. While most are well circumscribed, approxi-
mately 10 % spread diffusely following and sometimes
invading the contours of the underlying bone. These are
termed meningioma en plaque and are much more difficult to
resect. Histologically, the WHO has separated meningiomas
L.S. Chin, M.D., F.A.C.S., F.A.A.N.S. (*) • D.J. Padalino, M.D.
Department of Neurosurgery, SUNY Upstate Medical University,
750 East Adams Street, Syracuse, NY 13210, USA
e-mail: chinL@upstate.edu; padalind@upstate.edu
P. Ray, M.D.
Department of Neurosurgery, Delaware Neurosurgical Group,
779 Christiana Road, Suite 202, Newark, DE 19713, USA
e-mail: pulak12@gmail.com
J.M. Caridi, M.D.
Department of Neurosurgery, Ichan School of Medicine at Mount
Sinai, One Gustav Levy Place, New York, NY 10029, USA
e-mail: John.caridi@mountsinai.org
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_21, © Springer Science+Business Media New York 2015
21
into three grades based on microscopic appearance [5]. WHO
grade I includes several variants, the most common being
the transitional, fibroblastic, and meningiothelial. Grade I
tumors generally follow a benign course and make up nearly
90 % of all meningiomas. Grade II tumors, which account
for 5–7 % of meningiomas, are associated with greater cel-
lular atypia and include the clear cell, chordoid, and atypical
variants (see Table 21.1). These tumors have a recurrence
rate 1.5–5 times greater than that of grade I varieties. Grade
III meningiomas (1–3 % of total meningiomas) include the
anaplastic, papillary, and rhabdoid variants. These tumors
have a high rate of invasion into surrounding tissues (including
brain), which leads to a higher incidence of recurrence and
may metastasize.
Comprising over 30 % of primary intracranial tumors, the
incidence of meningiomas in the population is 4.5 per
100,000 person-years with females outnumbering males by
2:1 according to some series, but up to even 6:1 in others [6].
The incidence has also been shown to increase with age.
Autopsy studies show that approximately 2.5 % of people
have an incidental meningioma [7]. Anecdotal evidence has
suggested several correlations with meningiomas. Cushing
believed that head trauma was affiliated with tumorogenesis,
but no definitive study has confirmed this despite multiple
attempts to find a correlation [3, 8, 9]. Although several stud-
ies have attempted to link viral infection to the development
of meningiomas, none have proved the causative effect [10].
There is also a link between breast cancer and meningioma
that has been observed in women, but not in men. A study by
Rao et al. showed that of 6,527 meningiomas and 153,599
breast cancers diagnosed in women and 2,327 meningiomas
and 1,668 breast cancers diagnosed in men found in five can-
cer registries between 1995 and 2003, the rate of breast can-
cer in women already diagnosed with meningioma was 80
times expected, and the rate of meningioma in women
already diagnosed with breast cancer was 58 times the
expected rate. No such association could be found in the
male patients [11].
315
316
Table 21.1 Meningioma classification by WHO grade
% of total
WHO grade Histological variants meningiomas
I—Benign Transitional, fibroblastic, >90 %
meningothelial,
psammomatous, angiomatous,
microcystic, secretory,
lymphoplasmacyte-rich,
metaplastic
II—Atypical Clear cell, chordoid, atypical 5–7 %
III—Malignant Anaplastic, papillary, rhabdoid 1–3 %
Apart from female gender, there are two other major
factors that do seem to lead to meningioma formation: radiation
and chromosome 22 mutation. The incidence of meningioma
has been found to be four times higher in patients who had
tinea capitis treated with local radiation compared to control
patients [12]. Another definitive correlation with meningio-
mas is deletions in the long arm of chromosome 22.
Numerous patients with meningiomas have been found to
have monosomy 22 and the gene thought responsible for
meningioma formation has been localized to the same region
as that of type 2 neurofibromatosis [13]. This may explain
the high correlation between NF2 and the development of
meningiomas.
The signs and symptoms associated with a meningioma
depend primarily on its site of origin. The most common pre-
sentation is a new onset seizure, occurring approximately
30 % of the time [14]. These seizures are most often general-
ized, but can be partial or complex partial. Headache, mental
status changes, hemiplegia, isolated cranial nerve deficits,
and signs of increased intracranial pressure may also be seen
in meningioma patients.
The radiographic diagnosis of meningioma is usually
made with CT or MRI. Unenhanced CT shows meningio-
mas to be slightly hyperdense compared to normal brain,
often with surrounding edema and variable mass effect;
adding intravenous contrast results in homogeneous
enhancement of the mass. MRI is the preferred method of
diagnosis because of its superior soft tissue resolution. The
tumor appears isointense to brain on an unenhanced
T1-weighted image (T1WI), but hyperintense with sur-
rounding white matter edema on a T2-weighted image
(T2WI). The addition of gadolinium contrast reveals a uni-
formly enhancing mass with a broad-based connection to
the surrounding dura. A dural tail is variably seen and rep-
resents growth of meningioma along the dura away from
the main tumor. The significance of this finding is that if
left untreated by either radiosurgery or surgery, since both
are focal treatment modalities, the chance for recurrence
L.S. Chin et al.
increases [15]. These tumors are nearly always extra-axial,
showing displacement of the cortex. Reactive sclerosis
(hyperostosis) of the overlying bone can also be seen in
some cases. Conventional catheter angiography, although
increasingly supplanted by MR angiography and CT angi-
ography, is often critical in the surgical planning because it
can determine the blood supply to the tumor, degree of vas-
cularity, patency of dural venous sinuses, and suitability for
endovascular embolization. Meningiomas are primarily fed
by branches from the external carotid artery, commonly the
middle meningeal or occipital artery, although large tumors
usually parasitize a significant blood supply from underly-
ing small pial arteries.
Surgical Decision-Making and Techniques
Numerous factors must be addressed when evaluating a
patient for surgery: age, location, size, symptoms, neurologi-
cal deficit, tumor growth rate, proximity to critical structures,
blood supply, venous drainage and sinus patency, previous
treatments, and most importantly, patient expectations. A
multidisciplinary approach with input from other disciplines
such as ENT, radiation oncology, and radiology, when appro-
priate, is important.
The distinguishing advantage of surgery over radiosur-
gery is the ability to achieve a gross total resection. The
incidence of tumor shrinkage following radiosurgery varies
between 20 and 40 %, and the actual amount of decrease is
fairly minor. Thus, overriding any other consideration is the
fact that some patients will insist on having even a small
benign tumor surgically removed. These patients should be
offered an opportunity for surgical resection provided that
the risks are acceptable. An optimal resection requires com-
plete removal of the meningioma with all of its dural and
bony attachments. In a classic paper by Simpson from 1957,
he describes the recurrence rates for meningiomas follow-
ing surgical resection [16]. A five tier grading system was
devised to describe the extent of tumor removal, with grade
I being the most complete and grade V being a simple
decompression. Simpson noted that the recurrence rate fol-
lowing grade I resection was 9 %, grade II was 19 %, and
grade III was 29 %. Later, a grade 0 was added to the
Simpson scale [17, 18]. This added a 2 cm margin of normal
appearing dura to a Simpson I resection. The recurrence rate
of a patient undergoing a grade 0 resection of a benign
meningioma is essentially zero. Clearly, the goal of surgery
is to perform a grade 0 or a grade 1 resection; unfortunately,
this may not be possible despite surgical expertise because
the most important variable that influences extent of resec-
tion is tumor location.
21 Meningioma: Viewpoint—Surgery
Convexity Region
Convexity meningiomas are found on the dura over the
hemispheres without extension into the dural sinuses or inva-
sion of the skull base. They represent approximately 15 % of
meningiomas and are the least likely to recur because they
are nearly always amenable to a grade 0 or 1 resection.
Intraoperative stereotactic guidance is helpful in localizing
the projection of the tumor on the scalp. A generous scalp
and craniotomy flap can then be tailored to allow for a 2 cm
margin around the tumor. Preoperative embolization is less
helpful than in other areas as the blood supply from dural
feeders is easily interrupted by incising the dura circumfer-
entially as the first step in tumor removal. Pial feeders are too
small to be embolized and are divided during the course of
tumor dissection off the brain. Large tumors may be adherent
to the pia causing unavoidable cortical injury in the process
of a complete removal. This superficial invasion does not
constitute a sign of malignancy, but neurological deficit is
possible and patients should be counseled appropriately.
Surgery should be considered anytime a patient wants a cure
of their convexity meningioma regardless of size and also
recommended strongly in patients with a tumor larger than
3 cm. Radiosurgery is reserved for asymptomatic, small
meningiomas, and the rare cases of recurrence following
resection (see Case 21.1).
Parasagittal Region
Parasagittal meningiomas account for 20–30 % of meningio-
mas and describe a location without intervening brain tissue
or dura between the tumor and the superior sagittal sinus (see
Case 21.2). Conventional angiography or (CT or) MR venog-
raphy is helpful in determining if the sinus is patent. When
there is invasion of a venous sinus, a complete resection
requires removal of the infiltrated sinus as well. This is ordi-
narily safe only with the anterior one-third segment of the
sagittal sinus. The scalp and bone flap will need to cross the
midline if the sagittal sinus is to be resected. Patients with
middle and posterior third sagittal sinus involvement and a
large tumor can benefit from a combined approach where the
bulk of the tumor is removed, which relieves mass effect on
the brain while leaving the residual tumor in the sinus to be
treated by radiosurgery. Preoperative embolization may be
useful in reducing blood loss during the debulking of large
tumors.
Each case should be reviewed individually, and not all
meningiomas need preoperative endovascular embolization.
Factors such as the size and location of the tumor as well as
317
the blood supply can influence the decision to embolize a tumor.
Typically, there is no need for preoperative embolization of
smaller size meningiomas at the convexity with dural feed-
ing arteries since there is no significant benefit with regard
to making the surgery safer for the patient or making the
resection technically easier. However, large skull base
meningiomas with deep feeding arteries that are large
enough to cannulate in order to inject embolic material such
as microspheres or liquid embolic agent may benefit from
embolization by reducing blood loss and causing tumor
necrosis, which will soften the tissue and lead to a techni-
cally easier removal of the devascularized tumor [19, 20].
Care must be taken to closely watch the patient after embo-
lization because post-embolization swelling with significant
mass effect on surrounding structures can occur. Some
authors have suggested performing the preoperative emboli-
zation within 24 h prior to the operation to allow for some
early necrosis and softening of the tumor tissue while mini-
mizing the duration of time that the patient could potentially
develop dangerous post-embolization edema. It is known
that tumor vessels can recanalize if left for greater than
24–48 h after embolization, but this is more likely with
some of the less durable liquid embolic agents that were
used in the past. Current technique with microspheres and
liquid embolic agents provide a much more durable occlu-
sion and recanalization is not as much of a concern. Some
have suggested waiting as long as a week in order to maximize
the devascularizing necrosis effects after the embolization
procedure [19, 20]. Embolization is usually not recommended
as a sole treatment.
Sphenoid Wing and Anterior Skull Base
Sphenoid wing meningiomas are divided into lateral and
medial depending on the site of origin. Lateral sphenoid
wing meningiomas may invade the sphenoid bone, but com-
plete resection is still possible provided the tumor is not big
and the dura of the temporal or frontal floor not extensively
invaded (see Case 21.3). Complete removal of a meningioma
originating from the medial sphenoid wing is a difficult task
for the surgeon because the tumor is likely involving the dura
around the optic nerve, superior orbital fissure, and cavern-
ous sinus (see Case 21.4).
Meningiomas from the anterior cranial floor (olfactory
groove, planum sphenoidale, tuberculum sella, and dia-
phragma sella) offer similar challenges because of the nearby
optic nerves, chiasm, and pituitary stalk (see Case 21.5). In
these tumors, a grade 2 resection (coagulation of the dural
attachment) is usually the best possible outcome. An overly
aggressive resection may injure cranial nerves II, III, IV, V,
318
and VI and/or the carotid artery and pituitary stalk. Identifying
and maintaining the arachnoid planes around the meningi-
oma and observing the lateral border of the cavernous sinus
can help protect neurovascular structures. Early interruption
of feeding arteries (e.g., anterior ethmoidal branches) at the
base of the meningioma diminishes tumor bleeding during
the debulking phase of the operation. Preoperative emboliza-
tion of these tumors can significantly reduce blood supply to
the tumor, but may have a relatively high risk of blindness
from embolization of collateral blood supply to the optic
nerve from external carotid branches. In general, the tech-
nique for meningioma removal involves dissection around
the periphery of the tumor with coagulation of feeding arter-
ies while avoiding significant brain retraction. Once this can
no longer be accomplished safely because of tumor bulk, the
meningioma is incised and internally debulked using coagu-
lation and ultrasonic aspirators. The capsule of the tumor can
then be infolded and dissected off the remaining brain and
neurovascular structures. The attachment of the tumor is
coagulated and, if possible, cut off the skull base.
The top priority when removing a meningioma from the
sellar/parasellar region is to decompress the optic nerves
and chiasm. Not only does this address the most serious
neurological deficit caused by the tumor, but any residual
tumor can be treated by radiosurgery. A separation of at
least 2–3 mm is needed to permit an adequate dose of radia-
tion to the tumor edge (12 Gy or higher) while keeping the
optic nerve dose to safe levels (<8 Gy). Since the cranial
nerves in the cavernous sinus are relatively insensitive to
radiation effects, there is little need to aggressively resect
tumor in this location. Visible residual tumor should be
treated aggressively with early radiosurgery because having
a maximum amount of separation between the tumor edge
and optic nerve or brainstem is critical in determining the
dose that can be safely delivered. A mistake is often made in
waiting to see if the residual tumor will start to grow.
Invariably it does and when finally recognized, the tumor
may be too close to the optic nerve to be treated by radiosur-
gery. At this point, the only options are fractionated radia-
tion therapy or repeat surgery.
Case Reports
Case 21..1
A 40-year-old man presented with seizures and mild left-sided
weakness. His MRI scan showed a right convexity meningi-
oma (Fig. 21.1a, b). He underwent a gross total resection
(Fig. 21.1c), but pathology indicated an atypical meningioma
(grade 2). He developed a recurrence 9 months later and
L.S. Chin et al.
Petroclival Region
This broad category includes meningiomas found in the
posterior cavernous sinus, tentorium, cerebellopontine angle
(CPA), and foramen magnum. Nearly all of these tumors,
particularly when large, will require a skull base approach.
A combination of transpetrosal, combined subtemporal and
transmastoid, retromastoid, and extreme lateral transcondy-
lar approaches may be needed and should be part of the
skull base neurosurgeon’s arsenal. In most situations, a skull
base specialist from ENT will be needed for their expertise
in the bony anatomy of the temporal bone. Preoperative
embolization is frequently helpful for larger tumors in this
region. Although radiographic gross total resections are
possible, it is rare to accomplish better than a grade II or III
resection (see Case 21.6). Thus, frequent MRI follow-up
(yearly intervals) even after a gross total resection is essen-
tial to catch an early recurrence. When residual tumor is
seen on postoperative imaging, it should be treated with
radiosurgery. When residual tumor is known to be left
behind but cannot be seen radiographically or if the histol-
ogy is grade II or III, fractionated radiation therapy should
be considered.
Conclusion
The ideal approach to a patient with a meningioma is to con-
sider both surgical and radiosurgical options. A multidisci-
plinary team often accomplishes this goal best although good
balanced opinions can be given in any clinical setting.
Surgery and radiosurgery should be thought of as comple-
mentary procedures rather than competing treatment modali-
ties. When relief of mass effect is needed because of tumor
size or patient’s symptoms, then craniotomy is the only
option. Radiosurgery can be used in smaller tumors and can
treat residual tumor, thus freeing the surgeon from having to
resect tumors from areas of the brain and skull that may
cause significant morbidity.
underwent gamma knife radiosurgery to a dose of 16 Gy @
50 % (Fig. 21.1d). In the first 6 months after radiosurgery he
developed transient radiation-induced swelling associated
with focal seizures and left arm weakness (Fig. 21.1e, f).
Approximately 1 year after treatment, the tumor has regressed
and the patient is neurologically normal (Fig. 21.1g).
(continued)
Case 21.1 (continued)
Fig. 21.1 MRI scans of a convexity atypical meningioma. (a, b)
Preoperative axial and coronal scans showing a convexity menin-
gioma with mass effect. (c) Postoperative axial scan showing com-
plete resection of tumor. (d) Gamma knife treatment MRI shows
Case 21.2
This 37-year-old woman presented with seizures and altered
mental status. A parasagittal meningioma occluding the sag-
ittal sinus was seen in the anterior 1/3 sinus (Fig. 21.2a, b). A
bifrontal craniotomy was performed and the tumor was
totally resected along with the sagittal sinus (Fig. 21.2c, d).
One year later, she has no recurrence of tumor.
Fig. 21.2 An anterior parasagittal meningioma involving the
sagittal sinus. (a, b) Coronal and sagittal MRI show a meningi-
oma arising from the sagittal sinus and anterior falx. (c, d)
Postoperative MRIs indicate complete tumor resection
recurrence of convexity tumor. (e, f) Three months after treatment
the tumor is unchanged in size, but there is an increase in surround-
ing edema as seen on flair images. (g) One year later the tumor has
regressed
Case 21.3
A 63-year-old woman was admitted with severe
headaches and confusion. MRI showed a large right
sphenoid wing meningioma (Fig. 21.3a). After preop-
erative embolization, a right pterional craniotomy was
performed with total excision of the tumor (Fig. 21.3b).
One-year follow-up shows no recurrence of tumor.
Fig. 21.3 A right lateral sphenoid wing meningioma. (a)
Preoperative axial MRI shows a large tumor compressing the right
frontal lobe. (b) Postoperative MRI shows a gross total resection
320
Case 21.4
This 47-year-old woman presented with headaches and
was found to have a right medial sphenoid wing menin-
gioma (Fig. 21.4a). A right pterional craniotomy was per-
formed to attempt a gross total resection. The entire tumor
Fig. 21.4 A large right medial sphenoid wing meningioma. (a)
Preoperative axial MRI shows a large tumor arising from the
medial sphenoid wing and cavernous sinus. (b) Only a small
Case 21.5
A 28-year-old woman presented with a bitemporal
hemianopsia and headaches. Preoperative MRI showed
a diaphragma sella meningioma (Fig. 21.5a). A right
pterional craniotomy with gross total resection of
tumor was performed (Fig. 21.5b). The optic nerves
were well decompressed and her vision returned to
normal. Three years later, she has no recurrence of
tumor and her vision remains normal.
L.S. Chin et al.
was removed except for the portion in the cavernous
sinus. This ensured adequate separation between the
tumor and the optic nerves, thus allowing the residual
tumor to be treated by gamma knife radiosurgery
(Fig. 21.4b). Follow-up 5 years later shows no change in
the small residual cavernous sinus mass (Fig. 21.4c).
amount of tumor is left in the cavernous sinus that is treated by
gamma knife radiosurgery. (c) Five years later, there is no change
in the residual tumor
Fig. 21.5 (a) Tuberculum sella meningioma causing a bitemporal
visual field cut. (a) sagittal MRI shows a meningioma arising from
the diaphragma sella with elevation of the optic chiasm. (b)
Postoperative MRI shows that the entire tumor has been removed
21 Meningioma: Viewpoint—Surgery
Case 21.6
This 39-year-old woman presented with severe headaches
and a large tumor based on the left petrous portion of the
temporal bone and tentorium (Fig. 21.6a–c). The tumor
appeared to involve the left mastoid aircells and had a
dural tail along the tentorium. After preoperative emboli-
zation, a radical excision was performed using a combined
Fig. 21.6 A very large petrous/tentorial meningioma. (a, b) Axial
and coronal MRI shows a meningioma infiltrating the mastoid and
compressing the left cerebellum and temporal lobe. (c) External
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 Meningioma—Viewpoint:
Fractionated Radiotherapy
Igor J. Barani, Arie Perry, and C. Leland Rogers
Introduction
Meningiomas are the most common intracranial neoplasm in
adults [1, 2]. The majority are benign, and collectively, they
form the most common group of intracranial neoplasms in
adults, comprising over 30 % of primary central nervous sys-
tem (CNS) tumors [2–5]. The reported incidence varies from
<[less than] 1 to>[greater than] 6 per 100,000 depending upon
the population and method of identification [3, 4, 6]. An
aggregate incidence of 2.6 per 100,000 has been calculated
from surgical series [7]. Extrapolating this to the population
of the United States, it can be expected that approximately
8,000 meningiomas will be diagnosed per year [7]. Many are
identified solely on the basis of imaging findings; in recent
studies, 35–62 % were diagnosed on the basis of imaging
alone [8, 9]. Using the University of Pittsburgh data, image-
diagnosed meningiomas may account for an additional 2,800
patients, bringing the total estimate to nearly 11,000 annually.
Even this sum is likely an underestimate. Meningiomas have
been identified in as many as 2.3 % of autopsies, many of
which are subclinical [10].
Except in the setting of neurofibromatosis type 2 (NF2),
meningiomas are rare in the pediatric population [11]. The
peak occurrence is during the sixth and seventh decades of
life, but the age range is broad, with a 5 % greater incidence
I.J. Barani, M.D.
Department of Radiation Oncology, University of California,
San Francisco, 505 Parnassus Avenue, Room L08, San Francisco,
CA, USA
A. Perry, M.D.
Department of Pathology and Neurological Surgery,
University of California, San Francisco, 505 Parnassus Ave.,
M551, San Francisco, CA, USA
C.L. Rogers, M.D. (*)
Department of Radiation Oncology, Virginia Commonwealth
University, 401 College St., Richmond, VA, USA
e-mail: Leland@GammaWest.com
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_22, © Springer Science+Business Media New York 2015
22
in all age brackets from the second to ninth decades [12, 13].
Age may have prognostic relevance. More aggressive
clinical and histologic features have been noted in children
and in young adults [14]. Jung et al. found that the growth
rate after subtotal resection (STR) was greater in patients
younger than 50 years of age (7.51 cm3 per year) than in
older patients (0.83 cm3 per year) [15].
Overall, meningiomas are more commonly diagnosed in
females, approximately 2:1 (female:male) [2, 16]. Yet, atypi-
cal and anaplastic meningiomas may occur more frequently
in men [17]. The reason for this gender distribution is unclear.
Progesterone and estrogen receptors have been identified in
greater than 70 and 30 % of meningiomas, respectively [17].
Increased estrogenicity is believed to be associated with an
increase in tumor-related symptoms during pregnancy or the
luteal phase of the menstrual cycle [18]. A heightened risk
has been described with obesity, and an increased relative
risk of breast cancer has been described in meningioma
patients, as has the converse [18]. These endocrinologic
associations are intriguing, but to date, no hormone-based
manipulations have been of therapeutic benefit [19, 20].
Meningiomas may present with focal neurologic symp-
toms depending on their intracranial location. Seizure is one
of the more common presenting signs, occurring in 26 % of
meningioma patients [21]. Many meningiomas of the skull
base present with lateralized cranial nerve deficits [22].
Raised intracranial pressure is uncommon at presentation,
but can occur secondary to obstructive hydrocephalus.
Therapy is therefore aimed at relieving neurologic symptoms
and providing long-term tumor control.
Meningiomas are neoplasms of the meningothelial cells of
the arachnoid layer and occur most frequently where these
cells are most numerous, namely within the arachnoid villi or
granulations that lie along the dural venous sinuses [23].
Furthermore, arachnoid cap cell clusters become more prom-
inent with age, corresponding to the age-related increase in
incidence of meningioma [25]. The most common locations
include the convexity (parasagittal dura, or attached to the
sagittal sinus), sphenoid ridge, and planum sphenoidale. Other
323
324
locations include the sylvian fissure, parasellar region, and
olfactory grooves. Meningiomas can also arise intraventricu-
larly from pia-arachnoid rests, and about 10 % occur infraten-
torially along the free edge of the tentorium, clivus, foramen
magnum, pretroclival ligament, and petrous ridge [24]. Less
frequently, optic nerve sheaths and spinal canal may be
involved.
Etiology
The etiology of meningiomas remains largely unknown.
Cushing and others invoked trauma as potentially caus-
ative, but this has not been substantiated in large epide-
miologic studies [26, 27]. Meningiomas occur with greater
frequency in patients with certain rare genetic conditions,
such as NF2, but this explains only a small minority of
cases [11, 14]. Ironically, despite its role as an effective
therapy for meningiomas, prior exposure to ionizing radia-
tion is also a risk factor for developing meningioma [7,
28–33]. Similarly, radiation-induced meningioma accounts
for only a very small fraction of cases. The vast majority
of meningiomas arise in the absence of any known predis-
posing factors and are often referred to as “sporadic.”
Radiation-Induced Meningioma
The data establishing radiation as the etiologic agent for
meningioma formation derives from experience with atomic
bomb survivors, and with cranial irradiation for tumors or
scalp irradiation for maladies such as tinea capitis [7, 28–33].
Based on an experience of tinea capitis in children who
immigrated to Israel in the aftermath of the World War II, a
sevenfold increase in neoplasms of the nervous system, diag-
nosed, on average, 18 years after treatment, with 19 menin-
giomas and 7 gliomas in nearly 11,000 subjects [29]. In a
separate study, Strojan and colleagues projected the risk of
developing meningioma after radiation therapy to be 0.53 %
at 5 years and 8.18 % at 25 years [32]. Indeed, radiation-
induced meningiomas remain the most common form of
radiation-induced neoplasm in literature [33]. In contrast, a
large retrospective cohort study comparing radiosurgery out-
comes with national cancer registries (approximately 5,000
patients with 30,000 patient-years of follow-up) did not
detect increased risk of malignancy [34]. This study supports
the safety of radiosurgery, and suggests a dose-volume effect
for radiation-induced meningioma. It may thus be expected
that modern irradiation techniques, aimed at high degrees of
conformality and at reducing high-dose as well as low-dose
volumes, would be beneficial.
I.J. Barani et al.
Classification
Although the majority of meningiomas are considered
benign (~80 %), it is well recognized that the biological
spectrum is wide and, for a substantial minority, the clinical
course difficult to predict. Even histopathologically benign
meningiomas can recur despite seemingly complete resec-
tion. It has been postulated that microscopic foci of tumor in
dural strips away from the main tumor mass may be respon-
sible [35]. This finds support in the fact that patients with
multiple meningiomas often display the identical NF2 muta-
tion in all tumors [36]. These studies suggest that even
benign meningiomas may spread peripherally through the
dura, possibly in a discontinuous fashion in some cases. If
microscopic nests are left behind, then recurrence is possible
despite a relatively indolent biology.
High-grade meningiomas (atypical and anaplastic) com-
prise roughly 25 % of cases and are considerably more
aggressive, being associated with increased morbidity and
mortality. Thus, in addition to the prognostic significance of
extent of resection, one of the most important factors to pre-
dict tumor behavior is histopathologic grading [37, 38].
Atypical meningioma (WHO grade II) has a 7–8-fold
increased risk of recurrence over benign tumors (WHO grade I)
and a slightly, but statistically significant increased risk of
mortality compared with age and sex matched controls.
Anaplastic meningiomas (WHO grade III) are fortunately
rare (1–3 %), but are associated with considerable risk of
death from disease, with the mean survival being less than 2
years in one study [39]. Therefore, following the diagnosis of
an atypical meningioma, more aggressive treatment may be
indicated [40]. This would similarly apply to anaplastic
meningiomas, although nearly all will eventually recur, and
often exhaust both surgical and radiation therapy options.
In the 2000 WHO classification scheme [41], the histo-
logical grading of meningiomas underwent substantial revi-
sion and standardization of criteria based on the
clinicopathological series from Mayo Clinic [37, 38]. This
has resulted in some upgrading of previously diagnosed
benign meningiomas to the atypical category [42]. To a lesser
extent, there has been a modest decrease in the number of
anaplastic or malignant meningiomas due to stricter diagnos-
tic requirements for these subtypes. In comparison, the most
recent WHO classification revision published in 2007 [43]
made minimal additional changes to meningioma grading,
the most significant being that brain-invasive meningiomas
are regarded as WHO grade II based on similar recurrence
and mortality to atypical meningiomas in general. However,
WHO chose not to make brain invasion itself another crite-
rion for the diagnosis of atypical meningioma, since benign-
appearing examples often do not share the same genetic
alterations seen in other high-grade meningiomas.
22 Meningioma—Viewpoint: Fractionated Radiotherapy
Histopathology
The current WHO classification lists 16 variants or subtypes,
falling into three grade designations (Table 22.1) [25, 44].
Four subtypes are higher grade by definition and include
clear cell (WHO grade II), chordoid (WHO grade II),
rhabdoid (WHO grade III), and papillary (WHO grade III)
meningiomas. However, the required fraction of such variant
histology in the tumor specimen to warrant a higher grade
designation has not been or standardized. Such determination
is at the discretion of the neuro-pathologist and often neces-
sitates secondary review in a specialty center.
With appropriate treatment, approximately 80 % of
benign (WHO grade I) or image-diagnosed meningiomas
remain progression-free at 10 years (Fig. 22.1). In contrast,
only about 35 % of atypical (WHO grade II) patients remain
disease-free at 10 years even with definitive therapy [37, 39, 43].
Anaplastic (WHO grade III) meningiomas have a mean over-
all survival of less than 2–3 years and often progress quickly
through serial treatments [39].
External Beam Radiation Therapy:
Benign Meningiomas
Benign Meningiomas
Although the majority of meningiomas are benign
(WHO grade I) and slow-growing, they may become large
enough over time to cause devastating neurologic deficits
Table 22.1 Grading criteria for meningiomas [43]
Benign meningioma (WHO grade I)
Any predominant histology other than clear cell, chordoid, papillary,
or rhabdoid
Lacks criteria of atypical, brain invasive, and anaplastic meningioma
Atypical meningioma (WHO grade II) (any of two major criteria)
Mitotic index ≥4 mitoses/10 high-powered fields (HPF)
At least three of the following five parameters:
• Sheeting architecture (two dimensional sheets with loss of whorls
and fascicles)
• Small cell formation (clusters of lymphocyte-like cells with high
N/C ratio)
• Hypercellularity
• Macronucleoli
• Spontaneous necrosis (e.g., not induced by embolization or
radiation)
Brain-invasive meningioma (WHO grade II)
Tongue-like protrustions of meningioma into adjacent brain
parenchyma
Meningioma containing islands of entrapped GFAP-positive
parenchyma
Anaplastic (malignant) meningioma (WHO grade III) (either of two
criteria)
Mitotic index ≥20 mitoses/10 HPF
Frank anaplasia (sarcoma-, carcinoma-, or melanoma-like histology)
325
and morbidity if left untreated. Therefore, therapeutic inter-
vention is often needed for most diagnosed tumors. In clini-
cal practice, surgery has been the treatment of choice for
most meningiomas. Resection enables histologic diagnosis,
relieves mass effect and associated symptoms, alleviates
tumor-induced seizures, and achieves high local control
rates. However, not all tumors can be completely resected
without considerable morbidity. The likelihood of safe and
complete resection depends, in part, upon site and surgical
accessibility, and is frequently precluded by involvement of
the cranial nerves, arteries, or by venous sinus invasion.
Gross total resection (GTR) is often not attempted in the cav-
ernous sinus, clivus, cerebello-pontine angle, sellar region,
or optic nerve sheath. This is significant since in his seminal
publication in 1957, Simpson correlated the extent of tumor
resection, associated dural attachments, and any hyperostotic
bone to local recurrence risk, and defined 5 grades of resec-
tion, so-called Simpson grades (Table 22.2) [45]. The surgi-
cal resection extent has been consistently identified as an
important prognostic feature [7, 12, 46, 47], and majority of
centers continue to use Simpson’s criteria.
More recently Sughrue et al. challenged the relevance of
Simpson’s classification in the modern era. With 373 WHO
grade I meningioma patients followed for a median of
3.7 years, they found no significant difference in 5-year
progression-free survival (PFS) following Simpson grade I–
IV resections, with respective 5-year PFS rates of 95, 85, 88,
and 81 % (p = ns) [48]. Similar findings were previously
reported by Condra et al. [46] and more recently by Oya
et al. [49]. Even though these studies did not identify a dif-
ference in local control after Simpson grade I–III resections,
they did generally reveal shorter PFS following Simpson
grade IV surgery [46, 49]. To directly address the predictive
value of resection extent, Hasseleid et al. [50] reviewed 391
patients with convexity meningiomas and were able to iden-
tify significant outcome differences between Simpson grade
I, grades II + III, and grade IV + V resections, continuing to
support the relevance and applicability of Simpson’s criteria.
Therefore, gross tumor resection (GTR, Simpson I–III)
remains the objective of meningioma surgery, and is achiev-
able in approximately one-half to two-thirds of patients [47,
51], depending on the tumor location [52]. For these situa-
tions, where complete and safe tumor removal is not possi-
ble, an effective strategy is STR followed by postoperative
radiation therapy or radiation therapy alone.
For benign meningioma, GTR is considered as definitive
treatment, but with extended follow-up, recurrences develop
in approximately 5–30 % of patients (Table 22.3 and
Fig. 22.1). For example, among 145 patients in whom GTR
was achieved, Mirimanoff et al. [51] reported 5-, 10-, and
15-year recurrence rates of 7 %, 20 %, and 32 % and second
operation rates of 6 %, 15 %, and 20 %, respectively. These
rates were confirmed by a large series from the Mayo Clinic
[12]. Condra et al. of the Unversity of florida, [46] reported
326
Fig. 22.1 Progression-free survival reported in 35 selected studies that
included fractionated external beam radiation therapy by year of publi-
cation. Please note that technological advances in imaging, treatment
planning and delivery primarily after the year 2000 resulted in superior
Table 22.2 Simpson grades of resection based on 265 patients
Resection grade Definition Recurrence (%)
1 GTR of tumor, dural attachments 9 patients with STR, Stafford et al. [12] found recurrences in
and abnormal bone
2 GTR of tumor, coagulation 19
of dural attachments
3 GTR of tumor without resection or 29
coagulation of dural attachments or
extradural extensions (e.g., invaded
or hyperostotic bone)
4 Partial resection of tumor 44
5 Simple decompression (biopsy) – with both poorer PFS and overall survival (OS). Despite
GTR gross total resection
From: Simpson D. The Recurrence of Intracranial Meningiomas After
Surgical Treatment. J Neurol Neurosurg Psychiatry. 1957;20:22–39;
used with permission
the importance of complete excision but found no associa-
tion between Simpson grade and local control or cause-spe-
cific survival, as long as GTR (Simpson grades 1, 2, and 3)
was achieved. For patients treated with surgery alone, GTR
resulted in 5-, 10-, and 15-year actuarial recurrence rates of
7 %, 20 %, and 24 %, respectively [46]. In a more recent
report by Soyuer et al., the respective 5-, 10-, and 15-year
rates were 23 % 39 %, and 60 %, the higher recurrence rates
(Table 22.3) likely reflecting the more routine use and
improved quality of neuroimaging [53].
I.J. Barani et al.
and more consistent outcomes in both cohorts of patients treated with
combined therapy (STR + RT) and RT alone. Advancements in surgical
techniques over the same time period did not yield similar improve-
ments in outcomes
Recurrence rates following STR alone are substantially
higher (Table 22.3 and Fig. 22.1). For example, among 116
39 % at 5 years and 61 % at 10 years. Condra et al. [46]
documented local recurrences in 47 %, 60 %, and 70 % of
patients with STR at 5, 10, and 15 years, respectively.
Overall, it is estimated that 40–50 % of patients with STR
develop local progression within 5 years, 60 % within 10
years, and at least 70 % within 15 years [46, 47]. In a recent
study, Jensen et al. [54] reported that STR was associated
these data, patients are frequently observed following
STR. For example, in a Mayo Clinic series of 581 patients,
116 (20 %) of whom has STR, only 10 (9 %) received adju-
vant radiation therapy [12].
For cases where GTR is not possible, radiation therapy
(RT), whether fractionated external beam radiation therapy
(EBRT) or stereotactic radiosurgery (SRS), is currently the
only accepted nonsurgical treatment option. Historically,
meningiomas were considered to be resistant to RT, and
authors of many older retrospective studies reported infre-
quent radiographic regression [55]. Additionally, concerns
about malignant degeneration were cited as a reason to
refrain from either definitive or postoperative RT [29, 56].
Consequently, many patients with inoperable or subtotally
resected meningiomas were observed. At present, malignant
22 Meningioma—Viewpoint: Fractionated Radiotherapy 327

Table 22.3 Selected studies of fractionated external beam radiation therapy for patients largely with WHO grade I or image-diagnosed (presumed
WHO grade I) meningiomas
Progression-free survival Clinical Tumor Late Time
GTR STR STR + RT improvement shrinkage toxicity point
Author Year N Technique (%) (%) RT (%) (%) (%) (%) (%) (years)
Adegbite et al. 1983 114 EBRT 74 34 82 10
Mirimanoff et al. 1985 225 EBRT 80 45 10
Barbaro et al. 1987 135 EBRT 96 40 68 0 Crude
Taylor et al. 1988 132 EBRT 77 18 82 10
Glaholm et al. 1990 117 EBRT 96 43 77 46 38 10
Miralbell et al. 1992 115 EBRT 48 88 16 8
Mahmood et al. 1994 254 EBRT 98 62 5
Goldsmith et al. 1994 117 EBRT 77 3.6 10
98a
Peele et al. 1996 86 EBRT 52 100 5 Crude
Condra et al. 1997 246 EBRT 80 40 87 24 10
Stafford et al. 1998 581 EBRT 75 39 10
Nutting et al. 1999 82 EBRT 83 14 10
Vendrely et al. 1999 156 EBRT 79 59 29 8
Pourel et al. 2001 26 EBRT 76 2.2 8
Dufour et al. 2001 31 EBRT 93 71 29 3.2 10
Jalali et al. 2002 41 FSRT 100 26.8 22 12.1 3
Uy et al. 2002 40 IMRT 93 23 5 5
Pirzkall et al. 2003 20 IMRT 100 60 25 0 3
Soyuer et al. 2004 92 EBRT 77 38 91 2.5 10
Selch et al. 2004 45 FSRT 97 20 18 0 3
Milker-Zabel et al. 2005 317 IMRT 89 42.9 23 0 10
Henzel et al. 2006 224 FSRT 97 43.4 46 0 3
Milker-Zabel et al. 2007 94 IMRT 94 39.8 20 4 4.4
Hamm et al. 2008 183 FSRT 93 23.2 2.7 3
Litre et al. 2009 100 FSRT 94 94 50–81 9 0 5
Korah et al. 2010 41 FSRT 94 3 5
Metellus et al. 2010 53 FSRT 94 94 58.5 30 1.9 10
Bria 2011 60 FSRT 95 60 1
96 3
Minniti 2011 52 FSRT 93 20 23 5.5 5
Mahadevan 2011 16 FSRT 100 19 4 2
Morimoto 2011 31 FSRT 87 1 5
Onodera 2011 27 FSRT 96.2 5.3
Ohba 2011 281 FSRT/SRS 88.3 63.7 92.3 5
96 99 5
Tanzler 2011 146 EBRT/ 93 99 6.8 10
FSRT/SRS
Paulsen 2012 109 FSRT 98 21 5 5
a
Goldsmith et al., 10-year PFS 98 % with treatment after 1980 when CT and MRI began to be used for treatment planning, versus 77 % before 1980
GTR gross tumor resection, STR subtotal tumor resection, RT radiotherapy, EBRT external beam radiation therapy, IMRT intensity-modulated
radiation therapy, FSRT fractionated stereotactic radiation therapy, SRS stereotactic radiosurgery (1–5 fractions)

degeneration has not been explicitly linked to RT [32, 51,
57]; rather, it is believed to be related to the natural history of
a subset of meningiomas [58, 59].
Most retrospective studies since the 1980s have demon-
strated that, for benign meningioma, postoperative RT after
STR improves local control (Table 22.3 and Fig. 22.1), and
perhaps even survival [46, 60]. Improvement in local control,
and frequently in tumor-related neurologic symptoms, was
observed despite the fact that only about one-fourth to one-
third of treated meningiomas exhibit tumor shrinkage
(Table 22.3).
Radiotherapy can also be used as a primary treatment for
meningiomas diagnosed radiographically or by biopsy.
In one of the earliest reports, Glaholm et al. [29, 56] reported
328
the outcome of 32 patients treated with primary RT without
resection at the Royal Marsden Hospital; 47 % disease-free
survival (DFS) was observed at 15 years. This was only mod-
estly lower than a corresponding 56 % DFS in patients
treated with STR + RT. More recent series demonstrate mark-
edly improved local control rates and PFSs, >93 % after
5–10 years of follow-up (Table 22.3) [61–64]. These out-
comes compare favorably to those observed after GTR for
benign meningiomas (Fig. 22.1) and, to a certain degree,
challenge the paradigm that surgery is the mainstay of
meningioma management.
The discrepant outcomes of older studies (before 2000)
versus more recent RT studies, whether in the postoperative
or primary setting, may be attributed to the technical advance-
ments in RT treatment planning and delivery techniques.
This trend is clearly illustrated in Fig. 22.1 for PFS, and in
Table 22.3 for RT-related late neurologic toxicity as well as
neurologic improvement. These observations are more
directly supported by the analysis of Goldsmith et al. [65] of
140 patients treated at the University of California, San
Francisco to a median dose of 54 Gy in the postoperative set-
ting where a PFS rate of 98 % was noted in those treated after
1980 (when computed tomography [CT] and/or magnetic
resonance imaging [MRI] was used for planning therapy)
compared to a rate of 77 % for patients treated before 1980
when advanced planning techniques were not available.
Newer treatment series also report the use of intensity-
modulated RT (IMRT) as well as fractionated stereotactic RT
(FSRT) (Table 22.3). IMRT techniques allow delivery of
dose via multiple convergent beams (Fig. 22.2), each of
which can be divided into zones of different intensities, so
that the integral dose can tightly conform to the shape of the
target. This can potentially minimize unnecessary irradiation
of the surrounding normal tissues, including the critical ante-
rior optic structures. FSRT is characterized by highly accu-
rate patient immobilization setup, use of a stereotactic
coordinate system, and sub-millimeter mechanical and beam
tolerances. All modern RT techniques rely on the use of
sophisticated imaging for treatment planning and verifica-
tion. It is believed, but not yet definitively proven, that these
newer treatment methods will continue to improve patient
outcomes and reduce RT-related toxicity.
It is worth noting that serious side effects of modern
methods of treatment planning and delivery are already quite
uncommon. For example, Debus et al. [66] reported on 189
patients treated with FSRT for large skull base meningiomas,
using median daily fractions of 1.8 Gy to a mean dose of
56.8 Gy. With a nearly 3-year median follow-up, the rate of
clinically significant neuro-toxicity (grade 3) was 2.2 %
(four patients), and 1.7 % (three patients) in the absence of a
preexisting neurologic deficit. The neurologic deficits
reported in the study included reduced vision, a new visual-
field loss, and trigeminal neuropathy. Goldsmith et al. [65]
I.J. Barani et al.
noted complications in 3.6 % of 140 patients treated with RT
after STR from 1967 to 1990. The observed RT-related tox-
icity in this study included retinopathy, optic neuropathy, and
cerebral necrosis. Further analysis of the data by Goldsmith
et al. [67] permitted construction of a model to predict that
optic nerve tolerance is 890 optic ret, equivalent to 54 Gy/30
fractions. This threshold dose is supported by only rare
observations of optic nerve injury with doses lower than
54 Gy, particularly with fractional doses ≤2.0 Gy [56, 68,
69]. Additionally, Uy et al. [70] noted no anterior optic path-
way injury with a median dose of 50.4 Gy and fractions of
1.7–2.0 Gy. Shrieve et al. [71] confirmed these findings as
well as the benefit of fractional doses at or lower than
approximately 2.1 Gy.
Other cranial neuropathies (non-optic) are uncommon
with modern treatment techniques but have been reported in
older series. For example, Selch et al. [72] found no
RT-related neuropathy in 45 patients treated for cavernous
sinus meningiomas to median dose of 50.4 Gy (1.8 Gy/frac-
tion). Similar findings were noted earlier by Urie et al. [73].
Brain or brainstem injury, including necrosis, is quite uncom-
mon in the modern era with conventional doses and tech-
niques. Similarly, edema is generally not observed following
fractionated RT, unlike single-session SRS treatment. For
this reason, fractionated RT may be preferred over SRS for
tumors in locations where edema is likely to develop and to
significant morbidity (e.g., parasagittal, cerebello-pontine
angle, and/or large meningiomas).
Optic Nerve Sheath Meningiomas
The management of optic nerve sheath meningiomas
(ONSMs) is almost exclusively nonsurgical. These rare
tumors comprise <2 % of all meningiomas and arise from the
meningeal lining of the optic nerves [74, 75]. They generally
grow very slowly within the subarachnoid space and the con-
fines of the optic canal, eventually compressing the optic
nerve itself and/or its vasculature. Patients usually present
with progressive vision loss, although some exhibit rapid loss
of vision. In a minority of patients, ONSMs are found inci-
dentally on imaging. Less common complaints include visual-
field defects, loss/alterations of color vision, and orbital pain.
Resection of ONSMs while keeping optic nerve in place
has been tried [76–80], but carries an unacceptably high
risk of visual complications and local recurrence. Resection
commonly impairs the blood supply and results in blindness,
even though the nerve is left grossly intact. For these rea-
sons, fractionated RT has become the centerpiece of ONSM
management. In one of the largest series published, Turbin
et al. [80] reported on 64 patients with ONSMs and found
that fractionated RT alone provided more favorable out-
comes than observation, surgery alone, or a combination of
22 Meningioma—Viewpoint: Fractionated Radiotherapy
Fig. 22.2 A representative intensity-modulated radiation therapy
(IMRT) plan for a right cavernous sinus meningioma (WHO grade I) in
a 52 years old patient with slight right temporal field deficit thought to be
related to disease encroachment on the right portion of the optic chiasm.
surgery + RT. Patients in the RT only group were the only ones
that did not demonstrate a statistically significant decline in
visual acuity after a mean follow-up of 11.5 years (range,
4.75–23 years); all other groups demonstrated a significant
decrement in visual acuity, including complete visual loss.
Irradiated patients received 40–55 Gy of fractionated RT
(1.8–2.0 Gy/fraction) over approximately 5 weeks. In a study
329
GTV is shaded red; a dose of 54 Gy/30 fractions was prescribed to the
95 % isodose line to minimize the risk of injury to the anterior optic
structures. Note: Maximal point dose for the plan (56.38 Gy) is located
within the tumor volume, and the maximum dose to the chiasm is <54 Gy
from Japan, Narayan et al. [81] evaluated 14 patients with
ONSMs who were treated with conformal, fractionated RT
to 50.4–56 Gy. After a median follow-up of 4.1 years, 86 %
of the treated patients had either improved or stable visual
acuity. These studies and six additional studies with simi-
lar results have established highly conformal, fractionated
RT as the first-choice treatment modality for patients with
330
ONSMs. In aggregate, the local control is excellent (95 %);
early visual improvement (<3 months from the completion
of RT) is attained in about half of the patients (54.7 %); and
complications of therapy are relatively uncommon [74, 82].
It is our policy to treat symptomatic ONSM patients with
highly conformal, fractionated RT to doses of 50.4–54 Gy
using daily fractions of 1.8 Gy; however, there is no uni-
form agreement as to whether patients with stable ONSMs
and stable vision should be approached with observation or
early RT. Patients with bilateral disease are generally treated
whereas those with unilateral tumors are observed provided
that they can be expected to comply with serial visual field
testing, and regular clinical and imaging follow-up.
Recurrent Meningiomas
Recurrent meningiomas after surgery and/or RT exhibit
markedly increased progression rates over newly diagnosed
tumors [46, 51, 68, 83], with mean interval to clinical recur-
rence of 4 years [51, 55]. Miralbell et al. [68] reported a
78 % PFS at 8 years in patients treated with surgery + RT for
recurrent tumors, compared to only 11 % with surgery alone.
Similarly, Taylor et al. [83] reported on 30 patients who
developed recurrent disease after their initial treatment; 15
underwent surgery alone, 10 surgery + RT, and 5 either
refused further treatment or were deemed inoperable. Local
control was 30 % at 10 years in patients who had surgery
alone at first recurrence, versus 89 % for patients who
received salvage radiation, with or without resection. The
Taylor et al. [83] study provides compelling support for the
use of salvage RT to doses of 54–59.4 Gy (1.8 Gy/fraction,
or similar regimens at 2 Gy/fraction) not only because of
superior local control, but also improved survival, at 10 years
89 % for surgery + RT compared to 43 % with surgery alone.
These data corroborate aggressive treatment for recurrent
meningiomas, even at first recurrence.
EBRT: Atypical (WHO Grade II) Meningiomas
Atypical, WHO grade II, meninigiomas account for approxi-
mately 20 % to 25 % of meningiomas [17]. In one recent
analysis, the rate of atypical meningioma rose to 35 % after
adoption of the modern WHO grading standards [84].
However, in the literature atypical meningiomas are a hetero-
geneous group, owing largely to the imprecise pathologic
classification criteria and varying classification schemes over
time. Given the recent changes in diagnostic criteria [43, 44],
the natural history of atypical meningiomas is now better
characterized. Systematic application of these criteria across
multiple centers will be critical toward achieving concordance
and defining subsequent management. The statistical associ-
I.J. Barani et al.
ations with RFS and OS were highly significant, with grade II
meningiomas having a nearly eightfold increased risk of sub-
sequent recurrence after GTR and a slightly increased mor-
tality rate.
Our ability to define impact of treatment on outcomes of
atypical meningioma patients is problematic since much of
the published literature consists of retrospective reports and
predates the new WHO classification criteria, which results
in relative under-reporting of atypical meningioma inci-
dence. There is general agreement, but not consensus, that
STR is insufficient treatment for WHO grade II meningio-
mas. For example, surveys of neurosurgeons in Germany
[85] and United Kingdom [86] indicated that 26 and 41 %,
respectively, do not recommend adjuvant radiotherapy after
STR of an atypical meningioma. These reports are corrobo-
rated by publications such that by Goyal et al. [87] who
reported 17 % 10-year local control rate for atypical menin-
giomas at a single institution, but despite this, was unable to
document a significant benefit associated with the use of
postoperative radiation therapy. Neurosurgeons often employ
a strategy of serial re-resection to manage tumor recurrence.
There is even less agreement regarding adjuvant treat-
ment following GTR. In Germany [85], 84 % of centers
(47 of 56) recommended surgery alone for initially diag-
nosed, gross-totally resected WHO grade II meningioma,
and in United Kingdom [86], 80 % of centers espoused such
a practice. Several retrospective reports [84, 87–90] have
supported this approach by suggesting that GTR alone is
sufficient and that adjuvant RT adds no utility. Jaaskelainen
et al. [58] reported a 38 % 5-year local recurrence after
GTR, and did not find a benefit to adjuvant RT. However, no
randomized trials have been completed to define an appro-
priate care pattern in this patient population, and many of
the cited studies are small, retrospectively analyzed, and
predate current WHO grading criteria. Additionally, many
of the RT doses used in these studies were too low to be
effective.
A modern study by Aghi et al. [40] in 108 patients with
atypical meningioma (per 2000/2007 WHO diagnostic crite-
ria) noted a 5-year local recurrence rate of 50 % following
Simpson grade I surgical resection alone, whereas there were
no recurrences in the small cohort (n = 8) receiving postop-
erative RT. Another recent report by Komotar et al. [91]
reviewed outcomes among 45 patients with a gross-totally
resected (Simpson grade I and II) atypical meningioma, con-
firmed by postoperative imaging, and found a 65 % actuarial
local recurrence rate at 6 years without, versus 20 % with
adjuvant RT. For patients with recurrent WHO grade II
meningioma, Mair et al. found that neither salvage surgical
resection extent nor salvage RT was predictive of outcome.
This is consistent with results from Aghi and colleagues [40]
where 10-year disease-specific survival after first recurrence
of 69 % even with salvage therapies. Furthermore, Kotomar
22 Meningioma—Viewpoint: Fractionated Radiotherapy
et al. [91] concluded that recurrences resulted in shortened
overall survival, and significant additional treatment burden.
Many investigators have recommended irradiation, irre-
spective of resection extent in this patient population [31,
46], but others, like Goyal et al. [86], argued that fractionated
RT has no significant impact on either local control and over-
all survival. Their retrospective analysis was based on a
cohort of 22 patients, 15 of whom underwent GTR (Simpson
grades 1–3), 4 STR, and 3 resection of unknown extent.
Eight patients received RT (2 after initial resection and 6 at
the time of recurrence). The median radiation dose was
54 Gy (range 35–59.4 Gy). After a median follow-up of
5.5 years, local control was 87 % at 5 and 10 years following
GTR, and RT had no significant impact on local control or
overall survival. This study highlights some of the difficul-
ties relevant to atypical tumors, including inconsistent use,
dosing, and timing of RT as well as wide variations in the
resection extent [31].
In the previously cited study by Aghi et al. [40] of 108
patients with atypical meningioma and Simpson grade 1
GTR, actuarial tumor recurrence rates were 7 % at 1 year,
41 % at 5 years, and 48 % at 10 years. Most recurrences
occurred within 5 years of surgical resection. Of the 108
patients, 8 received immediate, adjuvant RT to 59.4–61.2 Gy
(1.5–1.8 Gy/fraction) to the resection bed with a 1 cm margin,
and experienced no recurrences during the follow-up period.
This difference did not reach statistical significance (p = 0.1),
likely due to the small number of patients (n = 8) in the RT
cohort. The study also noted that 30 patients with recurrence
ultimately received EBRT or SRS, and 73 % underwent repeat
surgery, with a mean number of craniotomies of 2.7. Only one
meningioma transformed to WHO grade III tumor, but at 7
years, 33 % of patients died due to recurrent disease.
Similarly, Komotar’s study [91] of 45 patients with atypi-
cal meningioma (following Simpson grade I/II resection)
suggested a benefit to immediate adjuvant RT at a dose of
59.4 Gy to the tumor cavity plus 0.5–1.0 cm margin. In this
study, 32 patients had GTR alone and an additional 13 under-
went immediate adjuvant external beam RT after GTR
(GTR + EBRT). With GTR alone, 41 % (13 patients) recurred
at a median of 19 months whereas only 8 % (one patient)
recurred in the GTR + EBRT group at 52.5 months. This
translated into 6-year actuarial recurrence risks of 65 % ver-
sus 20 % (p = 0.085) with GTR and GTR + EBRT, respec-
tively. Other recent analyses similarly supported the use of
immediate EBRT in this setting [92].
These studies provide evidence for upfront postoperative
fractionated RT following GTR of an atypical meningioma.
However, the possibility remains that close clinical and
radiographic follow-up with delayed salvage RT as needed
may also be feasible. The key question in this patient subset
is whether early adjuvant or late salvage RT is more appro-
priate. Existing publications do not answer this question.
331
In contrast, other studies have reached different conclu-
sions regarding the role of adjuvant RT. Mair et al. [90] sug-
gested that EBRT was not appropriate following GTR, and
advised SRS rather than EBRT following STR. Despite these
differing conclusions, their report confirmed improved PFS
in patients who received adjuvant EBRT (STR + EBRT) com-
pared to STR alone cohort. Four-year PFS rates were 72 %
versus 13 % (p = 0.043), respectively. Stratification of resec-
tion extent was not done in this study, and the EBRT dose
was comparatively low (51.8 Gy in 28 fractions). Hardesty
et al. [93] reached a similar conclusion, reporting that adju-
vant RT (EBRT or SRS) following “aggressive microsurgical
resection” of an atypical meningioma did not significantly
impact recurrence risk. However, it is worth noting that no
patient with GTR + postoperative RT experienced recurrence,
with a median 52 month’s follow-up. The median EBRT dose
in this study was 54 Gy in 27–30 fractions.
Stessin et al. [94] performed an analysis of SEER data of
657 patients treated for “non-benign” meningioma between
1988 and 2007 (predating the updated WHO classification
system). Of these patients, 37 % (244 patients) received
adjuvant EBRT. When controlling for WHO grade (II versus
III), tumor size, resection extent, and diagnosis date, EBRT
did not appear to impart a statistically significant overall sur-
vival or DFS benefit. Paradoxically, overall survival was
lower in patients who received adjuvant EBRT compared to
those who were treated with surgery alone, perhaps reflect-
ing selection bias. This study did not consider details of RT,
including dose, target volume definition, and other treatment
parameters.
These apparent contradictions concerning adjuvant RT
following either GTR or STR of an atypical (WHO grade II)
meningioma suggest that RT technique and therapeutic
details may be important, including target volume definition,
dose/fractionation, and possibly, even mode of delivery. For
example, Park et al. [92] found that PFS was improved with
median RT dose of 61.2 Gy. Aghi et al. [40] noted no local
recurrences with doses of 59.4–61.2 Gy, and Komotar et al.
[91] had noticeably better outcomes with median EBRT dose
of 59.4 Gy. Hug et al. [31] found that local control for an
atypical meningioma was significantly enhanced by cumula-
tive doses of at least 60 Cobalt-Gray Equivalents (CGE),
using protons. Hoffmann et al. [95] identified 10 WHO grade
II patients and noted a postoperative recurrence rate of 50 %
and suggested a benefit to postoperative EBRT, especially
when radical surgery cannot be achieved, and recommended
a total dose of 60 Gy.
The recently completed RTOG 0539 study used a dose
of 54 Gy in 30 fractions for newly diagnosed atypical
meningioma following GTR; 60 Gy/30 fractions following
STR and/or for recurrent WHO grade II tumor of any extent.
Also recently completed was the EORTC 22042–26042 trial,
which employed 60 Gy following GTR, and added a 10 Gy
332
boost after STR. The results of these trials are expected to
generate high-quality evidence to help guide therapy in this
patient population.
Optimal dosing regimens, target volume definitions, and
choice among many different radiation modalities are in
need of further study. Data suggest that dose escalation may
be an important factor in non-benign meningiomas but such
escalation needs to be approached with caution since higher
rates of complication are possible [96].
EBRT: Anaplastic (WHO Grade III)
Meningiomas
These aggressive tumors are often diagnosed after surgical
resection. As with other meningiomas, surgical resection
extent correlates with recurrence rates [39, 87, 89, 97].
Outcomes following surgery alone are quite poor; 78 %
5-year recurrence rate has been reported following GTR for
patients with anaplastic meningioma [58]. In a study from
1998 by Dzuik et al. [97], 38 patients with “malignant
meningioma” were reported. Eleven of the patients had
hemangiopericytoma. With that caveat, adjuvant irradiation
following initial resection improved 5-year DFS to 80 %,
versus 15 % with surgery alone (p = 0.002). EBRT also
improved 2-year DFS for recurrent meningioma, but had
no impact upon 5-year DFS for this subgroup. For this rea-
son, most practitioners have recommended adjuvant RT
[48, 98, 99].
Sughrue et al. [100] recently evaluated the benefit of
resection extent for WHO grade III meningioma; all patients
were referred for postoperative RT. They found that aggres-
sive attempts to achieve GTR did not improve survival and
often resulted in compromised neurologic outcome. Instead,
they found that near-total resection (NTR), defined as >90 %
tumor debulking, resulted in improved survival when fol-
lowed by adjuvant RT. In this report, salvage surgery also
appeared beneficial; a median survival of 53 months with
salvage surgery was noted, as opposed to 25 months without
(p = 0.02). Salvage surgery was often followed by RT or even
I-125 brain brachytherapy [101]. This is in contrast to other
studies [102] suggesting that mode of salvage therapy for
WHO grade III meningiomas does not favorably impact sub-
sequent progression.
With only retrospective studies to guide treatment, the
true benefits of multi-modality therapy are not known. Many
published studies use varying definitions of anaplasia, surgi-
cal extent, RT parameters, and outcomes. In aggregate, most
studies [46, 53, 97, 102, 103] appear to report measurable
benefit to adjuvant EBRT ± SRS following surgery in ana-
plastic meningiomas.
Milosevic et al. [103] and Dziuk et al. [97] published
some of the earliest studies demonstrating benefit from
I.J. Barani et al.
multi-modality treatment (surgery + RT). These studies also
demonstrated that immediate, adjuvant EBRT offers a greater
benefit than EBRT at progression. Milosevic et al. [103]
found that patients treated to doses <50 Gy experienced infe-
rior cause-specific survival, as did those treated prior to 1975
(before routine use of CT-based planning). Dziuk et al. [97]
determined that EBRT improved 5-year PFS from 50 % to
80 %, and recommended a final dose of 60 Gy in the immedi-
ate post-op setting.
The issue of target volumes in the postoperative setting
for grade III meningiomas remains unresolved, particularly
when comparing SRS and EBRT treatments. With SRS,
Pollock et al. [99] reported tumor progression “away from
the original irradiated tumor” in 30 % of patients with atypi-
cal and anaplastic meningioma, occurring at a median of 15
months after SRS. Most reported recurrences were described
as “marginal,” that is, occurring “adjacent to the irradiated
tumor.” Mattozo et al. [104] evaluated recurrences more sys-
tematically after treatment with SRS and FSRT and found
that 77 % of recurrences were within the original surgical
resection cavity, and recommended that the entire surgical
cavity be targeted, with an SRS boost to the recurrent nodule
if desired, to reduce the risk of local relapse.
As mentioned above, the timing of RT in these patients
appears to be important. Most studies suggest limited benefit
from salvage RT (compared to immediate post-op RT).
Dziuk et al. [97] reported improved local control with the
addition of post-op RT after initial resection and found
2-year PFS improvement with salvage RT. However, there
was no benefit at 5 years in the salvage setting. Several inves-
tigators have demonstrated improvement in outcomes with
RT, but the magnitude of improvement has been highly vari-
able [31, 97–100, 102–107].
As with atypical meningiomas, higher RT doses appear to
improve local control for patients with anaplastic (WHO
grade III) histology. On review of WHO grade II/III patients,
Milosevic et al. [103] noted improved cause-specific survival
of 42 % with ≥50 Gy versus 0 % with <50 Gy. Similarly,
Goldsmith et al. [65] reported 5-year PFS of 63 % using
>53 Gy versus 17 % with ≤53, and Dziuk et al. [97] recom-
mended a dose of 60 Gy, even after GTR. Using either pro-
tons or combined protons and photons, DeVries et al. [108]
and Hug et al. [31] demonstrated increased local control and
survival with total doses exceeding 60 Gy. In a mixed group
of WHO grade II/III tumors, Hug et al. reported a 100 %
5-year local control for patients receiving ≥60 CGE versus
0 % for lower doses (p = 0.0006). This corresponded to
8-year local control of 33 % and 0 %, respectively. For the
WHO grade III subgroup, this translated into an overall sur-
vival difference at 5-years of 87 % for ≥60 CGE versus 15 %
for <60 CGE [31]. As mentioned in the atypical meningioma
section, dose escalation should be approached with caution
since significant toxicity can occur [96].
22 Meningioma—Viewpoint: Fractionated Radiotherapy
EBRT: Technical Factors
Technical improvements have favorably impacted the out-
come and side effect profile of patients treated for meningi-
oma with fractionated EBRT. Image-based techniques allow
treatments to be delivered with greater precision and confor-
mality [72, 109]. Local control improvements were substanti-
ated by Goldsmith et al. [65] and Milosevic et al. [103] during
analysis of their series that spanned the transition from CT- to
MRI-based planning. Goldsmith et al. [65, 110] found that
CT- and/or MRI-based target definition, along with appropri-
ate immobilization, resulted in 21 % improvement in PFS
(p = 0.002). This can be seen more broadly in published stud-
ies of meningioma treatments, as shown in Fig. 22.1, with
better clustering of reported treatment outcomes in the mod-
ern era (post 2000) in which MRI-based targeting and image-
guided delivery have been commonplace.
EBRT: Target Volumes and Dose
Target volumes are usually based on postoperative, contrast-
enhanced MRI. Preoperative imaging is sometimes helpful
in identifying disease extent when postoperative changes
complicate interpretation.
Image-diagnosed meningiomas can be treated with defin-
itive intent using fractionated EBRT to a dose of 54 Gy in
27–30 daily fractions. In these cases, the gross tumor volume
(GTV) is defined as the enhancing tumor mass on a
T1-weighted contrast-enhanced MR imaging. Clinical target
volume (CTV) is generally the same as GTV. Treatment
device-appropriate planning target volume (PTV) expansion
should be added to GTV to ensure precise treatment (e.g.,
GTV + 0.3 cm = PTV).
For gross-totally resected WHO grade I meningioma, adju-
vant RT is generally not indicated (pending results of the
RTOG 0539). However, the benefits of RT following initial
STR demand further clarification. At present either observa-
tion or early adjuvant RT can find support. Recurrent WHO
grade I meningioma tends to exhibit a more aggressive clinical
course and, irrespective of resection extent, should likely be
treated with EBRT to a dose of at least 54 Gy in 27–30 daily
fractions, or with SRS using a single dose or single-fraction
equivalent of approximately 14 Gy. In the recurrent setting,
the GTV is defined by the tumor bed and any gross residual/
persistent nodular enhancement. Neither cerebral edema nor
the dural tail [111, 112] need be specifically included in the
GTV. CTV represents a 1 cm expansion (anatomically con-
strained) beyond the GTV, and may be reduced around natural
barriers to growth such as uninvolved, non-hyperostotic skull.
The PTV consists of a geometric expansion beyond the CTV
to account for setup and treatment delivery uncertainties and is
333
device-specific, usually at least 3 mm. Gross-totally resected
WHO grade II meningiomas (Simpson grades I–III) may be
treated similar to recurrent grade I meningiomas, although a
modestly higher dose of approximately 60 (1.8–2.0 Gy) has
been proposed in some recent studies [31, 40, 91, 108].
In contrast, patients at high risk for local recurrence
require aggressive therapy. These patients include WHO
grade III meningioma of any resection extent, a recurrent
WHO grade II meningioma of any resection extent, or subto-
tally resected, newly diagnosed WHO grade II meningioma
(Simpson grade IV–V). In these patients, GTV is defined as
the tumor bed on postoperative, contrast-enhanced MR
imaging and includes any residual nodular enhancement.
Again, neither cerebral edema nor the dural tail should be
specifically included in the GTV. Two target volumes are
subsequently defined: CTV54Gy = GTV + 2 cm, and
CTV60Gy = GTV + 1 cm. Appropriate PTV expansions must
be added to CTV as above. Using IMRT, a concomitant boost
technique is possible, for instance—similar to the approach
used in the recent RTOG trial (RTOG-0539)—a PTV54Gy
may be treated to 54 Gy, while a larger PTV60Gy receives
60 Gy, both in 30 daily fractions. Some studies have reported
improved outcomes for atypical and malignant meningioma,
particularly following STR, using higher doses [108]. The
recently completed EORTC trial (22042–26042) employed
60 Gy, but added a 10 Gy boost for a final dose of 70 Gy in
35 fractions, following STR of either a WHO grade II or III
meningioma. As in any RT planning, care must be exercised
regarding location of doses beyond 60 Gy as this may cause
significant neurologic toxicity [96].
EBRT: Toxicity
EBRT side effects experienced by patients treated for menin-
giomas are few with approximately 5 % of patients experi-
encing more than transient neurologic morbidity. Early
publications identified no deleterious treatment-related side
effects [83, 113], but with longer follow-up injury to anterior
visual structures and select cranial nerves can develop. This
was apparent in a report by Debus et al. [66] of 189 patients
treated with FSRT using median daily fractions of 1.8 Gy to
a mean cumulative dose of 56.8 Gy. With a median follow up
of nearly 3 years, they identified clinically significant (grade
3) toxicity in 2.2 % [4] of patients, lower at 1.7 % [3] in the
absence of preexisting neurologic deficit. Reduced vision, a
visual-field cut, or trigeminal neuropathy was most common.
This represents substantial improvement over 38 % rate
reported by Al-Mefty et al. [114] using older RT techniques.
Similarly, Goldsmith et al. reported a 3.6 % (5 of 140) rate
of toxicity attributed to treatment in patients treated with
EBRT for subtotally resected meningioma. They noted reti-
nopathy in two, optic neuropathy in one, and cerebral necro-
334
sis in two patients [65]. In a separate publication, Goldsmith
et al. [67] constructed a model to predict optic nerve toler-
ance and recommended a maximum dose of 54 Gy in 30
fractions.
Non-visual pathway deficits can occur [66] but are
uncommon. Selch et al. found no treatment-related cranial
neuropathies of any kind in 45 cavernous sinus meningioma
patients treated with fraction sizes of 1.7 or 1.8 Gy per day
to a total dose of 50.4 Gy [72]. Urie et al. [73] concurred
that treatment-related neurologic deficits in this dose range
are rare.
Cerebral necrosis is also uncommon but has been
observed [68, 70, 114]. Many of the findings in the Al-Mefty
et al. [114] study in a series of 58 patients with a variety of
skull base, parasellar, or pineal region tumors who devel-
oped late brain parenchymal changes (29 %) ranging from 4
months to 23 years after treatment are likely related to anti-
quated treatment techniques. Modern series do not report
significant toxicity at doses <60 Gy delivered over 30 treat-
ment days provided that “hotspots” in excess of the prescrip-
tion dose are placed within tumor or other safe locations
(e.g., surgical cavity). In general, integral doses to the tem-
poral lobes and to large volumes of untargeted brain are
much lower with current conformal and image-guided tech-
niques. In particular, image-guided therapy allows radiation
oncologists to reduce treatment (PTV) margins by ensuring
precise daily setup.
Additionally, pituitary dysfunction [68, 69, 114, 115],
cerebrovascular events [56, 68, 72], second malignancy,
orbital fibrosis [116], edema [72], and other sporadic toxici-
ties have been reported. Toxicity rates (at various time points)
are summarized in Table 22.3 and range from 0 % to 8 % in
the modern era (after year 2000). It is worth noting that the
retrospective nature of most series often precludes reliable
accounting of treatment-related toxicity since reliable grad-
ing of these events is often not possible in retrospect.
EBRT: Cognitive Morbidity
Some retrospective studies have identified personality
changes [70] and memory loss [46, 68, 115, 116] as compli-
cations of EBRT. Steinvorth et al. [117] prospectively evalu-
ated cognitive outcomes in patients with skull base
meningiomas after FSRT. They used a comprehensive bat-
tery of neurocognitive tests before, after first fraction, at
completion, and 12 months after FSRT. They observed, after
the first fraction, a transient decline in memory and a relative
increase in attention. There was no cognitive deterioration
with additional follow-up. In another study of cognitive out-
comes in skull base tumors, Meyers et al. [118] evaluated 19
patients who received treatment to the paranasal sinuses to a
median radiation dose of 60 Gy in 30 daily fractions with a
comprehensive neurocognitive test battery at least 20 months
I.J. Barani et al.
and up to 20 years after primary treatment. Most patients
were treated using a three-field technique (one AP and two
lateral beams). Memory impairment was found in 80 % of
the patients, and one-third manifested difficulty with visual-
motor speed, frontal lobe executive functions, and fine motor
coordination. Cognitive outcomes appeared to correlate with
the total dose of radiation delivered but not with the volume
of the brain irradiated. The pattern of test findings was most
consistent with radiation injury to subcortical white matter.
These two apparently conflicting studies suggest that pre-
treatment cognitive deficits, the timing of evaluations, the
length of follow-up, and the choice of assessments are
important. To date, there are no robust prospective studies of
cognitive function in patients treated with EBRT for skull
base tumors. Given the relatively long survival of these
patients, it is expected that long-term sequelae of therapy
will manifest and will guide therapeutic choices in the future.
Conclusion
EBRT is highly effective in the management of meningiomas
and long-term data clearly indicate excellent tumor control
rates, with an acceptable incidence of complications. FSRT
techniques are capable of delivering highly localized irradia-
tion compared with conventional radiotherapy and have the
potential to reduce long-term radiation morbidity. EBRT and
SRS result in very similar local control rates, and either can
be recommended for many patients. EBRT is suitable for a
broader range of patients, whereas SRS achieves excellent
local control outcomes in a well-defined cohorts. SRS is usu-
ally limited by tumor diameter and volume restrictions to
ensure safe treatments. Common relative constraints (vary
by institution) on diameter have been 3.0–3.5 cm, with total
volumes of 7.5–15 cm3 [106, 119]. Pollock et al. [119] found
that SRS provides equivalent tumor control to a Simpson
grade I resection with small- to medium-sized meningiomas
of <3.5 cm in average diameter and <15 cm3. Kondziolka
et al. [106] reported excellent outcomes for tumors of
<3.0 cm in diameter or 7.5 cm3 volume. The primary reasons
for volume restriction, as suggested by Ramsey et al. [120],
is to reduce edema risk that is often associated with SRS
treatment of convexity or large meningioma, or those that
exhibit significant pretreatment edema. Edema risks are
markedly lower with EBRT, even for large tumors.
An additional constraint on SRS is the anterior visual
pathway which is exquisitely radiation sensitive. At many
radiosurgery centers, point doses to the optic nerves and chi-
asm are limited to 8 or 9 Gy, although some suggest that
small volume of the optic nerve can tolerate up to 12 Gy
[121]. Even at a higher tolerance limit, single-fraction SRS
would be excluded from treatment of ONSMs, as well as
some parasellar and orbital tumors. In aggregate, SRS can be
safely and effectively applied to smaller meningiomas at
22 Meningioma—Viewpoint: Fractionated Radiotherapy
adequate distance from the anterior visual pathways with
limited risk and side effects profiles.
EBRT does not suffer from these limitations when com-
monly accepted fractionation regimens are used. EBRT car-
ries only a small risk of edema or optic neuropathy.
Furthermore, FSRT allows highly conformal and precise
delivery, with excellent local control and expected improve-
ments in observed neurologic and cognitive toxicities.
Despite proven effectiveness of EBRT, there is a relatively
paucity of prospective, high-quality, randomized data neces-
sary to define optimal care pattern for patients with menin-
giomas. RTOG 0539 and EORTC 22042–26042 have
recently closed to accrual, and are a step in the right direction
as we expect these studies to help define standard-of-care for
these patients. There still remain many questions as well as
questions relating to optimal management, quality-of-life
and cognitive function. As these and other questions are
addressed, the management of patients with meningioma and
the role of EBRT to be more clearly defined.
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 Radiosurgery of Acoustic
Schwannomas
John C. Flickinger, Hideyuki Kano, and L. Dade Lunsford
Introduction
Acoustic schwannomas, also referred to as acoustic neuro-
mas or vestibular schwannomas, are benign tumors arising
from Schwann cells that ensheath the eighth cranial nerve.
Presenting symptoms can include hearing loss, tinnitis, pres-
sure sensation in the ear, imbalance, spells of dizziness (more
common than true vertigo), facial weakness or twitching,
and facial pain or paresthesias. They are usually relatively
homogeneously enhancing tumors, although they sometimes
can form cysts. They tend to arise within the internal audi-
tory canal and while they can slowly enlarge the canal, they
do not invade bone as meningiomas often do. Once they
extend outside the internal auditory canal, acoustic tumors
can expand more easily in the cerebellopontine angle where
they are not constrained by bone. Acoustic schwannomas
can be differentiated in CT and MR images from acoustic
region meningiomas by their lack of dural attachment and
invasion along the petrous bone at the porus acusticus [1].
Differentiation of acoustic schwannomas from meningio-
mas is not particularly critical for management of these
tumors by radiosurgery or radiotherapy since similar radia-
tion techniques are used for either tumor and tumor control
rates are high for either tumor.
Acoustic schwannomas can occur in a unilateral sponta-
neous form as part of Neurofibromatosis type 2 (NF-2),
where there is a high propensity to develop bilateral vestibu-
lar schwannomas. NF2 is an autosomal-dominant multiple
J.C. Flickinger, M.D. (*)
Department of Radiation Oncology, University of Pittsburgh,
Pittsburgh, PA USA
e-mail: flickingerjc@upmc.edu
H. Kano • L.D. Lunsford
Department of Neurological Surgery,
University of Pittsburgh School of Medicine,
200 Lothrop Street, Pittsburgh, PA 15213, USA
L.S. Chin, W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_23, © Springer Science+Business Media New York 2015
23
neoplasia syndrome resulting from mutations in the NF2
tumor suppressor gene on chromosome 22q. NF2 has a fre-
quency of one in 25,000 live births and nearly 100 % pene-
trance by age 60. Half of patients inherit a germline mutation
from an affected parent and the remainder acquire a de novo
mutation for neurofibromatosis type 2 [2].
While bilateral vestibular schwannoma development is
the hallmark of type-2 neurofibromatosis (NF2), these
patients can sometimes present with only a single acoustic
schwannoma at presentation, although usually at a younger
age than spontaneous unilateral acoustic schwannoma
patients. Usually NF2 patients will have one or more other
associated tumors. NF2 patients have a propensity to develop
other central nervous system tumors including non-acoustic
schwannomas, meningiomas, ependymomas, astrocytomas,
and neurofibromas. They may also develop peripheral neu-
ropathy, ophthalmological lesions (cataracts, epiretinal
membranes, and retinal hamartomas), and cutaneous lesions
(intracutaneous plaque-like lesions or more deep-seated sub-
cutaneous nodular tumors).
The cellular transformation of Schwann cells into schwan-
nomas is caused from a lack of the functional product of the
NF2 gene, which is the protein, schwannomin/merlin (S/M).
Lack of normal S/M protein in the schwannoma cell occurs
from a detectable direct genetic mutation in 50 % of sporadic
vestibular schwannomas, while in the other cases, epigenetic
factors or activation of protease cascade results in ineffective
S/M. The exact interactions of S/M with extracellular matrix,
membranous glycoprotein, and cytoskeleton appear to acti-
vate several pathways that could regulate the cell-cycle pro-
cess, apoptosis, and intercellular interaction [3].
Patient Assessment
Vestibular schwannomas most commonly arise in the ves-
tibular branch of that nerve. In spite of the site of their origin,
vertigo and/or balance problems are less likely to be the pre-
senting symptom than hearing loss or tinnitis because there
339
340
Table 23.1 Gardner-Robertson hearing (G-R) classification based on
the poorer of either pure tone average (PTA) or speech discrimination
score (SDS) class divisions [4]
G-R hearing class Criteria
Class I (good) PTA 0–30dB and/or SDS 70–100 %
Class II (serviceable/useful) PTA 31–50dB and/or SDS 50–69 %
Class III (non-serviceable) PTA 51–90dB and/or SDS 5–49 %
Class IV (poor) PTA 91dB-max and/or SDS 1–4 %
Class V (none/deaf) Untestable for PTA and/or SDS
are compensating overlapping control mechanisms that help
with balance. Acoustic schwannoma patients who deny any
balance problems can often be found to have vestibular
abnormalities with more extensive vestibular testing and
even simple tests like tandem gait testing in darkened rooms.
Hearing is usually graded with the Gardner-Robertson
Classification system [4] as shown in Table 23.1. Pure tone
average (PTA) is usually defined as the average of the dB lev-
els at which subjects identify pure tones at 500, 1,000, and
2,000 Hz, although some audiologists and otologists prefer to
include a fourth level of 3,000 Hz with the average to include
more of the high frequencies that help in speech discrimina-
tion. Speech recognition threshold (SRT) is defined as the
volume at which 50 % of the speech is correctly identified.
Speech discrimination score is the percentage of words recog-
nized at a particular volume. Speech discrimination testing is
done at an amplification above the PTA and SRT but can vary
slightly with the testing volume. Serviceable hearing is a term
used to classify Gardner-Robertson Class 1–2 hearing that is
useful in understanding speech. “Serviceable” is a better term
that “Useful” hearing since any residual hearing (even poor),
may often be useful to a patient. Extensive high frequency
hearing loss can leave a patient with 0 % speech discrimina-
tion but a testable pure tone average. Such hearing may still
be helpful in identifying and locating lower frequency (non-
speech) noises and thus have some use and can be incredibly
useful in patients with no hearing in the other ear.
Facial weakness occurs less commonly from tumor growth
or from iatrogenic (surgical or radiation) injury than hearing
loss in acoustic schwannoma patients even though the nerves
run side by side through the internal auditory canal. The
House-Brackmann classification for facial weakness [5]
(Table 23.2) was devised to grade postoperative facial weak-
ness following acoustic schwannoma surgery. Fortunately the
15–20 % rates of developing any facial neuropathy (tempo-
rary plus permanent) reported in early radiosurgery series
with higher doses of 16–18 Gy and less conformal treatment
plans have dropped to significantly less than 1 % in modern
series with lower doses of 12–13 Gy and better treatment
planning. Transient facial spasms or twitching without per-
sistent weakness may sometimes occur in acoustic schwan-
noma patients from facial nerve irritation. Chang et al. [6]
reported a series of six patients with hemifacial spasm from
cerebellopontine angle tumors (four meningiomas and two
J.C. Flickinger et al.
Table 23.2 House-Brackmann facial nerve grades [5]
Grade 1 Normal facial function in all regions
Grade 2 Mild dysfunction: light weakness not obvious at rest
Grade 3 Moderate weakness that is obvious at rest but not
disfiguring and with complete eyelid closure
Grade 4 Moderate to severe weakness: obvious disfiguring
weakness with incomplete eyelid closure
Grade 5 Severe weakness: barely perceptible muscle movement
with incomplete eyelid closure
Grade 6 Complete paralysis, no movement, loss of tone
Table 23.3 Koos acoustic schwannoma tumor size grading criteria
Koos Grade I Purely intracanalicular tumor limited to the internal
auditory canal only
Koos Grade II < 2 cm extracanalicular/CPA extension without
brainstem compression
Koos Grade III Extracanalicular/CPA extension >2 cm, with no
brainstem compression
Koos Grade IV Extracanalicular/CPA extension with any degree
of brainstem compression
acoustic schwannomas) managed by radiosurgery. Four of
6 obtained complete relief and one patient partial relief
of hemifacial spasm with accompanying tumor shrinkage.
The sixth patient with no relief had no tumor shrinkage.
New onset transient facial twitching has been observed in
rare cases following acoustic schwannoma radiosurgery but
seems to be a temporary response without any facial weak-
ness developing.
As acoustic schwannomas continue to grow, they may
compress the trigeminal nerve causing facial numbness,
pain, and/or paresthesias. Tumor growth may also lead to
brain stem compression and possibly obstructive hydroceph-
alus. The Koos classification (Table 23.3) is used to catego-
rize acoustic schwannoma tumors according to size.
Management Options
Management options for acoustic schwannoma include
observation, complete or partial resection, single fraction or
multiple fraction radiosurgery (with 2–5 fractions) and frac-
tionated radiotherapy (>5–30 fractions) with photons (X-rays
or Co-60 gamma rays) or with protons. Surgical intervention
is usually the preferred option for large acoustic tumors (par-
ticularly >4 cm) with no residual hearing in that ear and
problems such as obstructive hydrocephalus.
Kondziolka’s literature review of acoustic schwannoma
observation reported growth rates of 0–4 mm per year in
different series with average volume doubling times of
1.65–4.4 years [7].
When observation is chosen as the management strategy,
patients must stick to regular follow up audiometry and CT
or MR scans at the same imaging center with comparisons of
23 Radiosurgery of Acoustic Schwannomas
Fig. 23.1 Subtraction co-registration (fusion) T1-contrast enhanced MR images of a patient with bilateral acoustic tumors from NF-2 with 2009
images subtracted from 2011 images to highlight 2-year growth within the right sided tumor
the newest to the oldest scans. As with any slow-growing
tumor, slow but steady growth may sometimes be reported as
no interval growth for several successive scans when only the
two latest scans are compared by the radiologists, when com-
parison of the first to last scan identifies unmistakable growth.
High resolution imaging with fine cuts (1–2 mm cuts) and
software that allows volume calculation can be extremely
useful for early identification of limited tumor growth. One
technique for identifying tumor growth that can be useful at
the time of radiosurgery in NF2 patients with multiple tumors
(usually meningiomas and acoustic schwannomas) is image
co-registration (fusion) of old and new scans with subtrac-
tion of the old images from the new images to highlight
changes as shown in Fig. 23.1.
Higher growth rates have been reported for younger
patients and those with extracanalicular and cystic tumors.
Observation of small acoustic schwannomas in NF2 patients
with good hearing that appears to be stable may allow patients
to enjoy more time with good hearing and give patients with
tumors in their only hearing ear time to learn sign language
before their hearing is lost. Initial observation may also be the
best option for elderly patients with significant comorbidities
and small tumors. Initial observation also is a good strategy
for managing patients who want to delay treatment because
of anxiety about any potential side effects from radiosurgery.
A strategy of choosing to delay radiation treatment of an
acoustic schwannoma until significant growth and/or hearing
341
deterioration is documented exposes patients to the risks of
hearing loss during the follow-up intervals as well as poten-
tially higher hearing loss risk from irradiation of a larger
tumor while initial radiation treatment has only the risk of
hearing loss from treating the tumor at the time it is diag-
nosed. Kondziolka’s review of the medical literature on
observation versus radiation treatment provides a detailed
argument for early radiosurgical intervention [7].
Radiobiology of Tumor Control
and Complications
Prior to the advent of radiosurgery, vestibular schwannomas
were managed almost exclusively by observation or surgical
resection because of a belief that they were radio-resistant,
with the first article indicating effectiveness of radiotherapy
in controlling acoustic schwannomas (following incomplete
resection) published in 1987, following early reports of
successful control with gamma knife radiosurgery [8].
Since then, multiple radiosurgery and radiotherapy series
with long-term follow up demonstrated that vestibular
schwannomas have control rates equal or better than other
benign CNS tumors like WHO Grade-1 meningiomas and
nonfunctional pituitary adenomas using similar or lower
doses (in the range of 45–54 Gy at 1.8 Gy per fraction, 18–21
Gy in three fractions or 10–13 Gy in a single fraction).
342
Vernimmen and Slabbert calculated alpha-beta ratios of
2.4 and 1.8 Gy for control of acoustic schwannomas from
published literature using the Fraction Equivalent plot (FE)
and the Tucker methods, respectively [9]. Since the accepted
alpha-beta values for late reacting CNS injury (cranial
nerves, parenchymal brain injury or spinal cord) fall in the
range of 1–2.5 Gy, these findings would support limited, if
any, therapeutic gain from fractionation compared to single
fraction treatment. In contrast to this radiobiological analy-
sis, some centers report of better hearing preservation with
fractionated radiotherapy as opposed to single fraction radio-
surgery but all of these comparisons have difficulties. All
CNS tissue does not seem to be equally likely to manifest
clinically symptomatic radiation injury. Changes in function
of somatic sensory nerves (optic and auditory) are detected a
lower doses than somatic sensory nerves (trigeminal), while
motor nerves (Cranial nerve 7, as well as 3, 4, 6, etc.) appear
less likely to show radiation injury. Following radiation
treatment of acoustic schwannomas (by radiotherapy or
radiosurgery), hearing loss is the most frequent sequelae
(30–60 % in most series) explained by the anatomy of the
tumor and/or the sensitivity of the special sensory nerve,
while the rates of trigeminal neuropathy (usually 1–4 %)
exceed those of facial neuropathy (usually <1 %). The greater
risks of trigeminal versus facial nerve injuries are observed
even though a shorter segment of the trigeminal nerve is irra-
diated with generally lower doses than the facial nerve.
Analysis of the initial experience of acoustic schwannoma
radiosurgery at the University of Pittsburgh (including doses
of 12–20 Gy) correlated rates of trigeminal and facial injury
with dose and length of nerve irradiated [10].
Brainstem Tolerance
The parenchymal tissue in the brainstem tissue does not
seem to be inherently more sensitive to radiation injury than
other locations when assessed by the development of post-
radiosurgery T2 signal changes, yet those changes are much
more likely to result in neurological dysfunction than in
other sites [11].
Nakaya et al. reported the University of Pittsburgh radio-
surgery experience with 202 vestibular schwannomas and 44
meningiomas with brainstem compression after a median
marginal dose of 13 Gy [12]. Median tumor volumes were
3.9 cm3 (range, 0.8–39.0 mL) and 6.6 mL (range, 1.6–
25.1 mL) for acoustic schwannomas and meningiomas,
respectively. No clear brainstem injury (with brainstem
edema and/or enhancement) was identified with median
follow-ups 65 and 60 months for the vestibular schwanno-
mas and meningiomas, respectively. Although 13 Gy to the
edge of the brainstem seems reasonably safe from this report,
some contribution by radiation exposure to the nerve roots
J.C. Flickinger et al.
within the brainstem could not be ruled out to development
of the 3.5 % and 9.9 % rates of facial and trigeminal neu-
ropathies reported, respectively.
Adams et al. reported brainstem and cranial nerve injury
developing after LINAC radiosurgery to a dose of 12 Gy pre-
scribed to an 80 % isodose for treatment of an acoustic
schwannoma measuring 27 × 19 × 18 mm [13]. Four months
later she developed subjective right facial weakness and
reduced taste on the right side of the tongue (seventh cranial
nerve—CNVII) and by 8 months post-SRS, new right sided
facial numbness and tingling (fifth cranial nerve—CNV). An
MRI at 8 months showed reduction in tumor size to
20 × 16 × 14 mm with an adjacent area of enhancement (con-
sistent with parenchymal radiation injury) of the right lateral
pons/cerebellar peduncle which subsequently resolved. They
performed a γ-H2AX focus formation assay which revealed
impaired DNA damage kinetics in ex vivo-irradiated primary
tissues which suggest that the radiosurgery patient had an
inherent deficiency in double-stranded DNA breakage repair
mechanisms.
Hearing Preservation and Cochlear Tolerance
Hearing preservation rates after acoustic schwannoma radio-
surgery vary with prescription dose, length of follow up,
tumor size, pretreatment hearing, and cochlear dose. Kano
analyzed factors affecting hearing preservation in 77 acous-
tic schwannoma patients with Gardner-Robertson (GR)
Grade 1–2 hearing who underwent gamma knife radiosur-
gery at the University of Pittsburgh with doses of 12–13 Gy
between 2004 and 2007 [14]. He correlated hearing loss with
Grade 1 hearing (versus Grade 2), age <60 years, and mean
cochlear dose <4.2 Gy. 12/12 patients <60 years old with
cochlear doses <4.2 Gy retained serviceable (Grade 1–2)
hearing for 2 years or more. Although a single fraction
cochlear dose of 4.2 Gy seems rather low to expect a correla-
tion with hearing loss. Zuur et al. were able to identify mod-
est decreases in hearing within 101 head and neck cancer
patients undergoing 6–7 week courses of IMRT with median
cochlear doses of only 11.4 Gy [15]. Yomo correlated hear-
ing loss with a cochlear dose of 4 Gy or more in their series
of 154 acoustic schwannoma patients undergoing gamma
knife radiosurgery at Marseille [16]. Hasegawa et al. also
correlated hearing loss with cochlear dose [17]. Although
Kim et al., were unable to find a significant correlation
between hearing loss and cochlear dose in their series of 66
unilateral acoustic schwannoma patients undergoing radio-
surgery to a mean dose of 12 Gy, but did correlate hearing
loss with transient post-radiosurgery volume expansion of
≥20 % from baseline [18].
While most cases of radiation injury to cranial nerves 5
and 7 usually show up within 2 or 3 years after radiosurgery,
23 Radiosurgery of Acoustic Schwannomas
hearing decline following radiosurgery requires longer
follow up.
Yomo’s analysis of the Marseille SRS experience found
rates of hearing decline of 5.86 dB/year <2 years after SRS
to a mean dose of 12.1 Gy dropped to a mean of 1.86 dB/year
>2 years after SRS (p < 0.001) [16]. The 10-year Kaplan–
Meier rates for preserving the same Gardner-Robertson hear-
ing levels, serviceable hearing, and any testable hearing were
44.0 % ±11.7 %, 44.5 % ±10.5 %, and 85.3 % ±6.2 %,
respectively. Carlson reported the long-term hearing out-
come of acoustic schwannoma SRS with 12–13 Gy marginal
doses at Mayo Clinic for 44 subjects with a median audio-
metric follow-up of 9.3 years [19]. The Kaplan–Meier rates
of serviceable hearing preservation at 1, 3, 5, 7, and 10 years
following SRS were 80 %, 55 %, 48 %, 38 %, and 23 %,
respectively. Multivariate analysis correlated pretreatment
ipsilateral pure tone average (p < 0.001) and tumor size
(p = 0.009) with hearing loss. Roos reported the Royal
Adelaide Hospital low dose (12–14 Gy) linac SRS experi-
ence in 84 evaluable acoustic schwannoma patients. Their
Kaplan–Meier hearing preservation rate of 50 % at 5 years
declined to 23 % by 10 years. The estimated risk of hearing
loss after SRS for patients with initial PTA ≥ 20 dB was 5.0
(95 % CI 2.2–11.2) times than with PTA < 20 dB [20] Kano.
Trigeminal Neuropathy After Radiosurgery
Trigeminal nerve function can be preserved in the majority of
patients. Lunsford et al. [21] reported that patients with ves-
tibular schwannoma who received 18–20 Gy to the tumor
margin had a 73 % of preservation rate of trigeminal nerve
function. However, patients with vestibular schwannoma who
received 12–13 Gy to the tumor margin had a 3.1 % risk of
trigeminal neuropathy. Hasegawa et al. [22] reported that three
(1 %) of 287 vestibular schwannoma patients with a median
margin dose of ≤ 13 Gy developed facial numbness, including
two with transient and one with persistent facial numbness.
Facial Nerve Preservation
Facial nerve preservation rate varied between 91 and 100 %.
Lunsford et al. [21] reported that normal facial function was
preserved in 79 % of patients after 5 years in patients received
18–20 Gy to the tumor margin. But patients who received
12–13 Gy to the tumor margin had less than 1 % of facial
neuropathy. Hasegawa et al. [22] reported that three (1 %) of
287 vestibular schwannoma patients with a median margin
dose of ≤ 13 Gy developed facial palsy, including two with
transient and one with persistent palsy after a repeat
SRS. Regis reported transient facial palsy lower than 1 % in
1,000 patients [23].
343
Hydrocephalus After Radiosurgery
Hydrocephalus after radiosurgery reported 0–8 % of patients
[24]. Han et al. [25] reported the rate of symptomatic com-
municating hydrocephalus after radiosurgery was 5.6 %.
Factors associated with higher rate of hydrocephalus
included large tumor volume, female gender, and large vol-
ume of the lateral ventricle at the time of radiosurgery. Lee
et al. [26] reported that surgical intervention for hydrocepha-
lus after radiosurgery required 5 % of patients at a median of
15.5 months after radiosurgery.
Tumor Control
Long-term tumor control rates of acoustic schwannomas
with radiosurgery vary from 90 % to 98 % in different series.
Chopra reported long-term results with acoustic schwan-
noma radiosurgery to 12–13 Gy for 216 patients at Pittsburgh
with a Kaplan–Meier 98 % tumor control (freedom from
resection) at 10 years. Hasegawa reported on a series of 440
vestibular schwannoma (median tumor volume 2.8 cu cm)
patients, (including 93 or 21 % who had undergone prior
resection and 13 or 3 % NF-2 patients) with SRS to a median
marginal dose of 12.8 Gy with a median follow-up of
12.5 years. The 5- and ≥10-year Kaplan–Meier progression-
free survivals (PFS) were 93 % and 92 %. Their multivariate
analysis, correlated poorer progression-free survival with
brainstem compression with deviation of the fourth ventricle
(p < 0.0001), marginal dose ≤13 Gy (p = 0.01), prior treat-
ment (p = 0.02), and female sex (p = 0.02). The Kaplan–Meier
10-year tumor control rates were 94 % for tumors <10 cm3,
versus 77 % for tumors ≥10 cm3 (p < 0.0001). Among 363
patients with tumors <10 cm3, the actuarial 10-year Kaplan–
Meier tumor control was 96 % with >13 Gy (n = 123) versus
94 % with 12–13 Gy (n = 240), (p = 0.62).
Radiosurgery of Larger Acoustic Tumors
In addition to the 77 % tumor control reported by Hasegawa,
for SRS of acoustic tumors >10 cm3, other centers have
reported separate results for radiosurgery of larger vestibular
schwannomas. Milligan reported a 5-year Kaplan–Meier
tumor control rate of 82 % for 22 acoustic tumors >2.5 cm in
the CPA with SRS to 12–14 Gy at the Mayo Clinic. They also
found 5-year Kaplan–Meier rates of 15 % for facial weak-
ness and 23 % for hearing preservation [27] Kano reported
the Pittsburgh experience with 65 patients with acoustic
schwannomas 3–4 cm in diameter managed by radiosurgery.
Two patients (3 %) underwent resection within 6 months due
to progressive symptoms. Two years later, with 63 tumors
344
overall after the two post-SRS resections, 16 tumors (25 %)
had a volume reduction of more than 50 %, 22 (35 %) tumors
had a volume reduction of 10–50 %, 18 (29 %) were stable in
volume (volume change < 10 %), and seven (11 %) had larger
volumes (five of the 7 patients underwent resection and one
of the 7 underwent repeat SRS). Eighteen (82 %) of 22
patients with serviceable hearing before SRS still had ser-
viceable hearing after SRS more than 2 years later. Three
patients (5 %) developed symptomatic hydrocephalus and
underwent placement of a ventriculoperitoneal shunt. In four
patients (6 %) trigeminal sensory dysfunction developed,
and in one patient (2 %) mild facial weakness (House-
Brackmann Grade II) developed after SRS. In univariate
analysis, patients who had a previous resection (p = 0.010),
those with a tumor volume exceeding 10 mL (p = 0.05), and
those with Koos Grade 4 tumors (p = 0.02) had less likeli-
hood of tumor control after SRS. The 5–10 year Kaplan–
Meier tumor control rates were approximately 91 % and
74 % for tumors <10 cm3 and >10 cm3, respectively.
Another approach used with larger acoustic schwannomas
is to start with initial subtotal resection followed by radiosur-
gery to residual tumor. Van de Langenberg reported on 50 con-
secutive patients for large spontaneous acoustic schwannoma
Fig. 23.2 Radiosurgery plan for an intracanalicular acoustic schwannoma. The cochlea is labeled as “c,” the facial nerve as “7”
J.C. Flickinger et al.
(non-NF2) who underwent planned combined subtotal micro-
surgical removal followed by SRS [28]. Surgery was per-
formed through translabyrinthine (n = 25) or retrosigmoid
(n = 25) approaches. The median follow-up was 33.8 months.
They found clinical tumor control in 92 % of the cases and
radiological control in 90 %. One year post-radiosurgery,
facial nerve function was good (House-Brackmann Grade I or
II) in 94 % of the patients. One of the TWO patients who
underwent surgery to preserve hearing maintained serviceable
hearing after resection followed by GKS.
Radiation Treatment Planning Issues
Besides the usual concerns with producing highly conformal
radiation treatment plans for acoustic schwannomas several
specific treatment planning issues arise. Based on the analy-
ses for Pittsburgh and Marseille, the mean cochlear dose
should be kept below 4.2 Gy for single fraction radiosurgery.
Often the facial nerve is difficult to see on a treatment plan-
ning CT or MR scan particularly with larger acoustic
schwannomas. As shown in Fig. 23.2, where it can be seen
with a small intracanalicular acoustic schwannoma, the
23 Radiosurgery of Acoustic Schwannomas
Fig. 23.3 Treatment plan for an acoustic schwannoma using selective cochlear blocking
facial nerve (labeled as 7) runs superiorly and anteriorly in
the internal auditory canal. Care should be taken to avoid
high dose regions and generous treatment margins in this
region of the internal auditory canal. Since the auditory nerve
tends to run inferiorly and posteriorly in the internal auditory
canal (labeled as 8 in Fig. 23.2), it would be prudent to limit
radiation dose in that location to maximize chances of hear-
ing preservation. Figure 23.3 shows a treatment plan for a
larger tumor that uses blocking of beam channels that would
have contributed significantly to cochlear dose.
Salvage of Radiosurgery Failures
Tumors that show sustained growth after radiosurgery should
be managed with either complete surgical resection or radio-
surgery. Tumor control rates for repeat radiosurgery of
benign tumors seem relatively high considering that they
have failed prior radiation treatment and usually are retreated
to a lower dose. Kano reported the Pittsburgh experience
with repeat radiosurgery to a median dose of 11 Gy in six
patients (at a median of 63 months after a median initial dose
of 13 Gy) [28]. After a median follow up of 29 months (range
13–71) all tumors were controlled and no new neurological
sequelae were observed.
345
Yomo reported the Marseille experience with repeat
radiosurgery (median initial and retreatment doses of 12 Gy)
in eight acoustic schwannomas that progressed after initial
radiosurgery [29]. The minimum and median follow up after
repeat radiosurgery was 24 and 64 months. The median
interval between radiosurgery procedures was 46 months.
The median tumor volumes were 0.51 and 1.28 mL at the
initial and second SRS treatments, respectively. No tumor
progressed and 6/8 showed a significant decrease in tumor
volume. Serviceable hearing was preserved in only one of
the 3 patients with Gardner-Robinson I-II hearing at the time
of the second SRS. No other new neurological deficits were
observed after repeat SRS.
Hasegawa’s report included the management of 36 acous-
tic schwannoma patients who underwent further treatment
after initial radiosurgery [17]. Seven patients who underwent
resection did not have clear evidence of sustained tumor pro-
gression. Six underwent repeat radiosurgery but three of
them subsequently underwent tumor resection. Twenty five
patients (with mean tumor volumes of 10.7 cu cm) needed
surgery for ventricular peritoneal shunts to manage post-SRS
hydrocephalus. After their second intervention with surgery
or radiosurgery the 5- and 10-year Kaplan–Meier rates for
freedom from further intervention were 92 % and 91 %,
respectively.
346
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 Acoustic Neuroma: Viewpoint—Surgery
Gabriel Zada and Steven L. Giannotta
Introduction
Acoustic schwannomas are the most common neoplasms
arising in the cerebello-pontine angle. Treatment paradigms
for patients with acoustic schwannomas may be inherently
complex in nature, because of the multimodality treatment
options available and numerous clinical considerations,
including overall safety, hearing preservation, and facial
nerve function, among others. Over the past several decades,
the decision-making process for treating patients with acous-
tic neuromas has taken on even more complexity, given
trends toward improved radiosurgical treatment modalities
and earlier detection with advanced neuro-imaging. In expe-
rienced hands, surgical results provide rapid and reasonable
success rates to those seeking an excisional cure. On the
other hand, as longer-term follow-up has become available,
radiosurgical tumor control data, both fractionated and
unfractionated, have shown more impressive safety and
tumor control rates. In selected cases, simple observation
may also be a preferred strategy. Clearly, there is no best way
to treat all patients with acoustic schwannomas, and various
treatment strategies should be optimally used in a compli-
mentary fashion to achieve the best overall outcomes.
In the ideal situation, a simple comparison between effi-
cacy and safety data from several different therapeutic
options should be sufficient to make an informed decision.
However, aside from the various treatment options that exist,
additional factors beyond effectiveness often come into play,
G. Zada, M.D. (*)
Department of Neurosurgery, Keck School of Medicine,
University of Southern California, 1520 San Pablo Street,
Suite 3800, Los Angeles, CA 90033, USA
e-mail: gzada@usc.edu
S.L. Giannotta, M.D.
Department of Neurological Surgery, Keck School of Medicine
of USC, 1200 North State Street, Suite 3300,
Los Angeles, CA 90033, USA
e-mail: giannott@usc.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_24, © Springer Science+Business Media New York 2015
24
including patient preference, surgeon bias, cost, patient age,
and lifestyle issues. In our practice, the roles of providing
recommendations for neurosurgical treatment and/or stereo-
tactic radiosurgical treatment of acoustic neuromas depend
primarily on four major factors: (1) patient age (2) tumor
size (3) hearing levels, and (4) recurrence.
Conservative Management
As the availability of neuro-imaging studies increases, many
patients will have new tumors diagnosed in an incidental
fashion, without any subjective clinical symptoms. If tumors
are small, a logical strategy may be to simply follow with
surveillance imaging.
There are several studies, both short and long term, under-
scoring the fact that some tumors will change very little over
time [1–5]. Depending on the study, up to 85 % of follow-up
cases may show little or no growth of acoustic neuromas. In
addition, several authors have demonstrated decreased tumor
volume over time. Annual diameter growth rates have ranged
between 0.15 and 4 mm [6–9]. Some practitioners, however,
have witnessed alarming growth in rare cases, sometimes result-
ing in hydrocephalus and/or brainstem compression, highlight-
ing the unpredictability of a strategy that relies simply on
observation [5]. Cystic schwannomas, in particular, have been
reported to have faster growth rates and present with more con-
cerning signs related to brainstem compression [10].
Conservative management for young patients may therefore
be fraught with hazard. More often than not, their tumors will
grow, thus exposing them to greater risk associated with treat-
ment, or even eliminating the potential for treatment alterna-
tives. We have a large number of patients over the age of 70 who
are simply examined on a yearly basis and undergo imaging.
These patients infrequently require intervention, and radiosur-
gery is often employed if they do [11, 12]. Tumors that are too
large to be treated with radiosurgery in patients within this age
group are almost always offered operative therapy, unless there
are substantial comorbidities that preclude general anesthesia.
347
348
Surgical Management
The gold standard for treatment of any benign tumor is cura-
tive total removal. The concept of complete removal without
the need for lifelong surveillance is appealing to many
patients, making patient preference a major factor in the
selection of primary therapy. Thus, when deciding between
radiosurgical versus surgical alternatives, the realistic expec-
tation of a safe and total surgical obliteration is a powerful
incentive. Long-term follow-up data are available for selected
surgical series documenting the potential for long-term free-
dom from recurrence in experienced surgeons’ hands [9,
13–15]. In 379 surgical cases performed by the senior author,
no recurrences resulted when the nerve of origin of the tumor
was identified and sacrificed. Surgical treatment of acoustic
schwannomas is often the preferred intervention in patients
with larger tumors (>3 cm diameter), younger age, prior
radiosurgical treatment, those with a preference towards sur-
gical excision.
Prior to the advent of radiosurgery, it was the authors’
philosophy to offer microscopic total removal to all patients
with acoustic tumors. This strategy mandated, in many cases,
protracted dissection of a thinned out facial nerve at the
porus acousticus. Review of the senior author’s facial nerve
results shows 19 % of cases with long-term House Brackmann
scores of 3 or worse. Given the high rate of radiosurgical
control of small lesions, subtotal removal in certain narrow
circumstances may be a preferable alternative.
Over the past two decades, however, a new strategy has
been adopted in a majority of patients, in which the shift of
the operative strategy focuses on aggressive tumor debulking
with a major emphasis on maintaining facial nerve function.
Depending on the surgical approach utilized, it is not uncom-
mon to deliberately leave a residual amount of microscopic
tumor along selected functional anatomical regions, such as
the facial nerve, brainstem, or within the internal auditory
canal (during retrosigmoid approaches). This strategy is
most often employed in very large or vascular tumors.
Frequently, no evidence of residual tumor is identifiable on
postoperative MR imaging. If a visualized region of residual
tumor is identifiable on postoperative MRI, this can be sub-
sequently treated with radiosurgery, especially in cases
where documented tumor growth of the residual component
is observed [16, 17].
Long-term tumor control or cure is desirable to many
patients, but at what price? Among larger series, surgical
complication rates have become acceptably low. The most
common complication is CSF leaks, occurring in 2–25 % of
cases [9, 13–15, 18–20]. Major morbidity, including lower
cranial nerve palsy, ataxia, or long-tract dysfunction, is also
G. Zada and S.L. Giannotta
low, occurring 0–2 % of cases [9, 13–15, 18–20]. Mortality
from surgery is rare, occurring in 0.4–2 % of patients. The
two most important factors relating to safety and efficacy
associated with acoustic neuroma surgery are tumor size and
the surgeon’s experience.
Facial Nerve Preservation Outcomes
Of all potential negative factors, a majority of patients are
concerned about facial nerve function following surgery. In
fact, this is clearly how the most accomplished practitioners
of the surgical art keep score. It is important for the surgeon
advising a patient to be familiar with statistical outcomes
from recent surgical series and deem whether he or she can
offer similar results. Most reports define an “excellent” or
“good” outcome as a House-Brackmann facial nerve score of
1 or 2 [21].
A review of the senior author’s results in 379 acoustic
tumors of all sizes revealed a 79 % H-B 1 or two facial nerve
function rate. Depending on the size of the tumor, excellent
facial nerve functional results have been reported in up to
90 % of cases [9, 13–15, 22–30].
The Acoustic Neuroma Registry, started in the late 1980s,
catalogues the national results of various surgeons through
questionnaires and surveys. In a summary of 1,579 cases
recorded in this registry between 1989 and 1994, Wiegand
et al. found that in 92 % of cases surgeons felt the removal to
be total with 94 % preservation of the facial nerve continuity
[20]. Of these, 69 % had excellent facial nerve function after
follow-up at 1 year.
In order to attempt a more direct comparison between sur-
gery and radiosurgery, we sifted through the various publica-
tions to identify those who stratified facial nerve results
based on tumor size. Facial nerve outcomes after surgery for
tumors less than 3 cm were tabulated as single fraction radio-
surgery only addresses this subgroup of patients. As
expected, these facial nerve outcomes are laudable, with
favorable facial nerve outcomes in the 80–99 % range [13–
15, 25, 30, 31].
Another way to capture surgical results that can be com-
pared with radiosurgical data is to look at cases where the
surgeon attempted to preserve hearing. The majority of these
lesions would be in the size range for single fraction radio-
surgery. Shelton et al. reported that 89 % of their patients
experienced good facial function in a series of 106 cases,
performed through the middle fossa approach [32]. Other
groups have elevated their surgical techniques to where
facial nerve preservation and cochlear nerve preservation are
an expected outcome [33–38].
24 Acoustic Neuroma: Viewpoint—Surgery 349

Table 24.1 Approach selection.

Hearing Preservation Retrosigmoid Middle fossa Translabyrinthine
Size
The data on hearing is a bit difficult to interpret as patient <1 cm
outcomes are sometimes reported as simply at or near pre-op Lateral impact + +++ ++
levels. However, per the Gardner–Robertson scale a class I or Medial +++ +++ ++
<2.5 cm +++ 0 +++
II is considered as serviceable or better hearing [39]. In this
>2.5 cm ++ 0 +
scale pure-tone average of 0–30 db and speech discrimina-
Only-hearing ear +++ 0 +
tion of 70–100 % corresponds to class 1 hearing. Class 2 Hearing
hearing assumes 31–50 dB pure-tone average and 50–69 % >50/50 +++ +++ +
speech discrimination. The AAO-HNS Guidelines on the <50/50 + + +++
evaluation of hearing preservation also developed a system Recurrent + 0 +++
of classification with class A or B generally indicating useful
hearing [40]. Class A hearing includes <30 dB pure-tone
thresholds and >70 % speech discrimination. Class B
includes 30–50 dB pure-tone thresholds and >50 % speech
discrimination. Most reports use one of these two methods
for recording hearing outcomes.
The data with regard to hearing preservation among the
large series is somewhat variable. Good hearing can range
from 24 to 60 % depending on the series [9, 13–15, 18, 25,
26, 28, 30, 31, 36]. It is noteworthy that the Acoustic
Neuroma Registry data described by Wiegand et al. reports a
Fig. 24.1 (a) A 5 cm acoustic neuroma prior to resection. The patient
22 % hearing preservation rate [20]. presented with tinnitus, hearing loss, and signs of brainstem compres-
A cursory look at data from groups who report large series sion. (b) Postoperative image after a retrosigmoid craniotomy. All pre-
of middle fossa approaches would suggest that this strategy operative symptoms resolved
might be more effective in terms of hearing preservation.
Most accomplished groups report good hearing rates on the best approach for a given situation. Hearing preservation,
range of 50 % [32–35, 38, 41–43]. However, these series are facial nerve function, and incidence of total removal seem to
all biased towards the smallest of tumors. be practitioner or team related as opposed to approach
related. This suggests that technical expertise and strategic
operative decision-making can negate most disadvantages
Surgical Approaches related to the various approach strategies.
A retrospective review of our institution’s last 50 cases
Each of the three traditional approaches to the CP angle has of retrosigmoid resections was compared to the last 50
their own putative strategic advantages (Table 24.1). The translabyrinthine resections. Tumors were included that
translabyrinthine approach minimizes retraction, maximizes were 3 cm or less and results were categorized in terms of
exposure of the internal auditory canal, and facilitates defin- facial nerve outcome, incidence of total resection, and
ing the facial nerve within the canal. The retrosigmoid major complications. At discharge, 37 of the retrosigmoid
approach has the advantage of being stereotypical for most patients had an H-B score of 1 as compared to 28 of the
neurosurgeons while enabling the preservation of the hearing translabyrinthine patients. Combining H-B 1 and 2 scores
apparatus (Fig. 24.1). The middle fossa approach, while showed 82 % with the retrosigmoid cases and 70 % of the
admittedly for smaller tumors, also facilitates exposure of translabyrinthine. This did not reach statistical significance.
the lateral most extent of the internal auditory canal. There was one major neurological complication in the ret-
Proponents of each approach are able to post impressive rosigmoid group and none in the other group. Three cases
numbers in terms of safety and cure rates. Many studies have of subtotal removal resided in each group. Long-term fol-
looked at outcomes based on approach and no discernible low-up of these patients showed even less of a difference in
advantage has been documented for one approach over facial nerve function. This suggests that surgical technique
another [15, 33]. However, for purely intracanalicular tumors may be more important than approach strategies in terms of
several reports have shown that the middle fossa approach is outcome for acoustic tumors.
safer for hearing preservation than the retrosigmoid approach Ideally, each practitioner should have a working knowl-
[25, 35, 43]. A cursory review of the literature would suggest edge of all approaches. This can instill the wary patient with
no way to resolve controversies that may emerge as to the some confidence that decision-making is based on assess-
350 G. Zada and S.L. Giannotta

ment of the patient’s best interests. For those who are experi-
encing unacceptable results, altering approach strategy may
show modest benefits, but doing such will not make up for
deficiencies in surgical technique as it relates to the brain-
stem vascularity and cranial nerves.

Choice of Treatment Method (Radiosurgery

Versus Excision)

At our institution, the three traditional approaches for surgi-

cal excision of acoustic tumors are practiced. Further, addi-
tional technologies for radiosurgery (such as Gamma Knife,
Linac, Cyberknife, etc.) are offered. The surgical decision-
making is less predicated on available technologies or reli-
ance on a practiced single surgical approach, than it is on
patient age, tumor size, and need for hearing preservation
(Table 24.2).
Fig. 24.2 (a) A 2.5 cm acoustic neuroma in a patient who presented
with slight hearing loss. The fourth ventricle is distorted. This patient
elected to have radiosurgery. (b) Post gamma knife radiosurgical treat-
ment. Central necrosis is present as well as decreased pressure on pos-
terior fossa structures

that surgical excision is required following radiosurgery, it

Age and Tumor Size has been reported that tumor excision is much more chal-
lenging, and the resiliency of the facial nerve is compro-
For younger patients, emphasis is placed on surgical removal. mised, compared to nonirradiated patients [48].
A surveillance strategy in this group is likely to be futile, For large lesions greater than 3 cm, single fraction
since inevitably the lesion will cause further symptoms and radiosurgery has no role [49]. For these lesions, gross sur-
require treatment. Radiosurgery has a long follow-up period gical removal or in certain situations subtotal removal,
and the window of vulnerability for recurrence is potentially with follow-up radiosurgery or observation, is advisable.
wide. Reliable data on lifelong tumor control for patients in Subtotal removal for a patient with a single tumor and good
their 30s or 40s is lacking. For those in their 50s and 60s, hearing in the other ear should be an unusual event. A small
single fraction radiosurgery is an attractive alternative. residual may be left behind in an effort to avoid a major
Efficacy and safety statistics are available for this group and complication such as facial nerve sacrifice or brainstem
are highly acceptable (Fig. 24.2). Patients in older age groups injury. For younger patients with large tumors, surgical
rarely need any therapy unless their tumor is large enough to removal is the preferred strategy. The length of vulnerabil-
be threatening [11, 12]. Furthermore, radiosurgery is not ity for recurrence is too great for younger patients to rely
without its complications and failures, which develop in on subtotal removal. Some further therapeutic endeavor
approximately 3–34 % of cases in even the most experienced will ultimately be necessary, multiplying the potential for
centers [44, 45]. Serviceable hearing is lost in 30–43 % of complications.
patients following radiosurgery [46, 47]. Finally, in the event Large lesions in older patients can present some strategic
problems. This would seem like an ideal situation for hypo-
fractionated radiosurgery. However, with lesions greater than
Table 24-2. Treatment modality.
4 cm or somewhat smaller lesions with associated arachnoid
Radiosurgery Surgery Observe cysts usurping much of the available reserve in the posterior
Size fossa, radiosurgery with its attendant edema formation may
>2.5 cm + +++ 0
produce unacceptable risks 6–12 months posttreatment. Data
1.5 to 2.5 cm ++ ++ +
is sorely lacking for this modality in larger tumors. Until
<1.5 cm +++ ++ ++
Age
better long-term studies are available, older patients in good
<40 + +++ 0 health with large lesions should be offered the option of sur-
40 to 60 ++ ++ + gical removal. The decision for total versus subtotal removal
>60 +++ + +++ is made at the time of surgery and predicated on the likeli-
Hearing hood of complications. Radiosurgery as an adjunct can be
>50/50 +++ ++ ++ offered for any threatening residual. For large tumors in
<50/50 ++ ++ + older patients who are poor surgical risks, hypofractionated
Recurrent +++ + + radiosurgery is a logical option.
24 Acoustic Neuroma: Viewpoint—Surgery
Hearing Preservation
Hearing preservation in the context of surgical removal can
be expected in experienced hands to be successful 50 % of
the time with intracanalicular tumors and 30 % with larger
lesions that are generally under 3 cm. This presupposes good
functional hearing to begin with. Attempts to save hearing in
a marginal or poorly hearing ear will be unrewarding. That
ear will be a constant source of distraction to the patient as it
picks up unstructured background noise and reduces the
overall functionality of the hearing. Thus, compromises in
surgical strategy to preserve the function of a poorly hearing
ear should be vigorously resisted.
Single fraction radiosurgery is fast growing in popularity and
may become the treatment of choice in the absence of an expe-
rienced surgeon with a proven track record for the safe and
effective removal. For those lesions less than 3 cm, one can
expect at least 50 % hearing preservation or better assuming
accepted proven radiosurgical techniques are utilized. The
major drawback in prescribing it for all small acoustic tumors is
the lack of long-term efficacy data. For many patients, the need
for continued surveillance and the thought of the continued
presence of the lesion are negative satisfiers.
If an acoustic neuroma recurs and is deemed in need of
treatment, the first option should be radiosurgery. This
assumes the tumor regrowth has been detected before it has
grown too large for radiosurgery. In these cases a translaby-
rinthine surgical approach will offer the largest corridor
while minimize the need for retraction or dissection of previ-
ously scarred brain. A repeat retrosigmoid craniotomy may
prove difficult.
Choice of Surgical Approach
Our preference is to use the translabyrinthine approach for
all tumors where hearing preservation is unlikely (Table 24.1).
Thus, it is used in all large tumors and those with poor hear-
ing. Certainly those greater than 3 cm would be treated this
way and most with speech discrimination scores of less than
50 %. The only time we would favor a retro sigmoid approach
in a large tumor would be the case of a large lesion in an only
hearing ear where a subtotal removal is contemplated.
In tumors that protrude from the porus acousticus, the
retrosigmoid approach is preferred for hearing preserva-
tion (Fig. 24.3). In our most recent 80 cases using this
approach, functional hearing resulted in 30 %. We limit the
use of the middle fossa strategy for those small intracana-
licular lesions that are impacted in the lateral end of the
internal auditory canal.
Other factors come into play as patients try to make
informed decisions. Socioeconomic and educational status
351
Fig. 24.3 (a) Intraoperative view of acoustic neuroma during a left ret-
rosigmoid craniotomy. (b) After tumor removal, the nerves of the porus
acousticus are seen. Note to transected superior vestibular nerve from
where the tumor originated
may complicate decision making in patients who cannot
understand a complex set of options. Patient and family
biases for or against surgery or radiation may direct the
patient’s thinking contrary to the physician’s best judgment.
Access to the internet, influence from patients who have had
one form of therapy or another, and loyalty to a particular
institution may be relevant factors in decision-making.
One can guide the decision making by trying to simplify
principles. Explaining away misconceptions is a place to
start. Identifying patient and family biases and dealing
with them in a forthright way will also help. If it is per-
ceived that this discussion is simply a device to steer the
decision-making toward the surgeon or radiosurgeon’s
bias, confusion and mistrust can develop. If a patient har-
bors a tumor that may be amenable to either surgical
removal or radiosurgery, a simple construct can be pre-
sented to the family and patient to facilitate their decision-
making. Does the patient insist that the tumor be gone?
Benefits include diagnostic certainty and the lack of need
for long-term surveillance.
Ultimately patients will decide on what treatment option
they prefer with some guidance as to the risk/benefit ratio
from the physician. The surgical removal of acoustic neu-
roma has been refined over time to achieve impressive
results. However, obvious risk of major morbidity remains.
Radiosurgical methods are progressively less invasive and
less likely to cause major morbidity. However, large lesions
are clearly not amenable to this therapy and lifelong observa-
tion is a requirement, even for small lesions, and especially
in younger patients. No perfect algorithm exists and each
patient scenario has unique challenges. The first question the
physician and patient must answer is how important is the
removal of the tumor to one’s overall comfort. If knowing
the tumor is still present makes one unable to participate in
life activities then surgery seems logical. Otherwise the
radiosurgical alternatives must be explored. With sound
advice and research, the patient will ultimately decide his
own treatment algorithm.
352
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24 Acoustic Neuroma: Viewpoint—Surgery
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 Acoustic Tumors:
Viewpoint—Stereotactic Radiotherapy
Christopher J. Farrell and David W. Andrews
Introduction
With the widespread availability of MRI, patients with
acoustic neuromas are being increasingly diagnosed earlier
in their clinical course, and the need for high-quality data to
guide both patients and clinicians through the treatment deci-
sion-making process has become paramount [1, 2]. Complicating
this decision-making process is the unpredictable natural
history of acoustic neuromas with wide variability in terms
of growth rate and symptomatic progression. Several meta-
analyses have been performed demonstrating that only
43–54 % of tumors will show radiographic enlargement over
an observational period of approximately 3 years and that a
small percentage (4–6 %) of tumors will regress in size with-
out intervention [3, 4]. Many studies have attempted to more
accurately predict the natural history of untreated acoustic
neuromas; however, no resolute clinical or radiographic indi-
cators of progression have been identified. Hajoff et al. dem-
onstrated that extracanalicular tumors may be more likely to
fail conservative management compared to intracanalicular
tumors, while other studies have suggested that younger age
and growth within the first year of radiographic surveillance
may be predictive of subsequent progression [5–7]. Unfortu-
nately, these studies and others have consistently shown that
hearing may irrevocably deteriorate even in the absence of
radiographic tumor growth, contributing to the fear that an
observation-type approach may lead to missed opportunities
for hearing preservation [7, 8]. In a comprehensive review
of published studies containing hearing outcome data for
patients who underwent conservative management for
This is an adaptation of a chapter that was originally published in
Controversies in Stereotactic Radiosurgery edited by Jason P. Sheehan
and Peter C. Gerszten published by Thieme Medical Publishers, 2013.
C.J. Farrell, M.D. (*) • D.W. Andrews, M.D.
Department of Neurological Surgery, Thomas Jefferson University,
901 Walnut Street, 3rd floor, Philadelphia, PA 19107, USA
e-mail: Christopher.farrell@jefferson.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_25, © Springer Science+Business Media New York 2015
25
small- and medium-sized acoustic neuromas, Sughrue et al.
found that tumors exhibiting a growth rate of greater than
2.5 mm/year were significantly (75 % vs. 32 %) less likely to
retain serviceable hearing compared to those with slower
growing tumors [9]. In a large series of patients from
Denmark managed conservatively, Stangerup et al. identified
initial speech discrimination score as predictive of long-term
hearing retention. Among patients with a speech discrimina-
tion score of 100 % at the time of tumor diagnosis, 69 %
maintained good hearing after more than 10 years of obser-
vation compared to only 38 % of patients with a slight
discrimination loss at the time of initial diagnosis [10]. The
results of any radiation or surgical intervention aimed at
hearing preservation must be carefully balanced against the
anticipated rate of hearing maintenance during a period of
observation based on the individual clinical, radiographic,
and audiometric data.
Stereotactic Radiosurgery
Since Lars Leksell treated the first acoustic neuroma patient
with stereotactic radiosurgery (SRS) at the Karolinska
Institute in 1969, a steady increase in the utilization of radia-
tion therapy as either primary therapy or for residual disease
following microsurgical resection has been observed with
the results of modern SRS series consistently demonstrating
its efficacy and safety [11–18]. Stereotactic techniques cur-
rently employed include SRS and fractionated stereotactic
radiotherapy (FSR) with SRS most commonly delivered
using either a Gamma Knife (GK) or linear accelerator
(LINAC). Early experience with SRS delivered prescription
doses ranging from 16 to 20 Gy and achieved excellent rates
of local tumor control (89–100 %). However, the observed
rates of facial and trigeminal neuropathy were 29–67 % and
33–59 %, respectively, with multivariate analysis revealing
that tumor size and prescription dose correlated with the
development of cranial neuropathy [19–21]. Following intro-
duction of MRI-based treatment planning and reduction of
355
356
the prescription dose, facial and trigeminal nerve morbidity
was significantly decreased without change in tumor control
[22]. Multiple large SRS series with at least 5-year median
follow-up periods have yielded local tumor control rates of
89–100 % using prescription doses of 12–14 Gy; however,
attempts at further SRS dose reduction have met with unac-
ceptable levels of tumor recurrence [23].
While the efficacy and safety of SRS for small- and
medium-sized acoustic neuromas has been reliably estab-
lished, less clear has been the long-term results of SRS treat-
ment with regard to functional hearing preservation defined
as Gardner-Robertson (GR) classification I or II or American
Academy of Otolaryngology-Head and Neck Surgery (AAO-
HNS) class A or B hearing [24]. In a prospective study
assessing quality of life (QOL) measures in patients under-
going observational, surgical, and radiation therapy for
acoustic neuromas, nearly one-third of patients cited hearing
as the single most important factor affecting their QOL [25].
Similar to the natural history of hearing loss with these
tumors, hearing loss associated with SRS treatment has also
shown great variability with the overall results remaining
inconclusive in terms of their superiority relative to conser-
vative management. In a systematic analysis of the literature,
Yang et al. reported a hearing preservation rate following
SRS of 57 % with an average follow-up period of 41 months
[26]. The only significant variable found to positively corre-
late with hearing preservation was marginal treatment dose
≤12.5 Gy. Hearing loss may occur as early as 3 months fol-
lowing SRS with the potential to decline many years after
treatment [27, 28]. Chopra et al. reported that after 3 years of
follow-up, the hearing preservation rate was 74 % but had
declined to 44 % at 10 years [11, 21]. Similarly, Roos
reported a 5- and 10-year hearing preservation rate of 57 %
and 24 %, respectively [28].
Radiation therapy is believed to induce sensorineural
hearing loss (SNHL) via injury to the cochlea, cochlear
nerve, or brainstem auditory nuclei, and many recent studies
have focused on identifying patient-related and dosimetry
variables that may allow for improved preservation of func-
tional hearing. Several studies have demonstrated that
patients with GR class I were more likely to retain functional
hearing compared to GR class 2 patients suggesting that
interventions aimed at hearing preservation should be con-
sidered as early as possible, particularly for younger patients
[29–31]. Additionally, retrospective studies have also sug-
gested that radiation dose to the cochlea may be a critical
determinant of preserved hearing function. Kano et al.
reported the results of 77 patients treated with a marginal
dose of 12.5 Gy and found that after controlling for GR class,
patients who received a central cochlear dose <4.2 Gy were
more likely to retain serviceable hearing [31]. Unfortunately,
it is not always possible to limit the cochlear dose to a safe
C.J. Farrell and D.W. Andrews
level while still prescribing an effective dose necessary to
achieve tumor control [32–36]. Despite differences in dose
conformality and homogeneity, the results of LINAC-based
SRS are highly comparable to those of GK regarding both
tumor control and hearing preservation [16, 28, 37–40]. The
long-term decline in hearing experienced by patients
following SRS has led our group and others to investigate the
role of FSR to increase the therapeutic threshold and better
preserve function in patients with acoustic neuromas and
serviceable hearing.
Fractionated Stereotactic Radiotherapy
As summarized above, SRS represents the pioneering inter-
vention that broadened the treatment alternatives for patients
with acoustic neuromas. Originally practiced on the Gamma
Knife, radiosurgery techniques were soon adapted to retrofit-
ted LINACs [40] and subsequently to linear accelerators
designed for and dedicated to radiosurgery [41]. It was this
latter development that enabled the design of fractionated
stereotactic techniques with noninvasive relocatable frames
and marked the beginning of modern stereotactic techniques
described below. The sections below discuss the radiobio-
logical rationale and advantages of FSR as well as published
outcomes as they relate to acoustic tumors.
Radiobiologic Principles of Fractionation
for Selected Late-Responding Tissues
We previously reviewed the advantages of FSR and derived
a hearing RET formula as a formula to guide dose-
fractionation strategies [42] discussed below. SRS has made
the treatment of skull base tumors far more precise with
modern imaging and versatile three-dimensional treatment
planning software that, through dose-volume histograms,
maximizes dose to target with high conformality and mini-
mizes dose to contiguous normal structures. Two exceptions
are optic nerve sheath meningiomas and acoustic neuromas
where these cranial nerves are intrinsic to the target volume.
As special sensory cranial nerves, injury to sensory function
occurs much more frequently than either sensory or motor
function in mixed cranial nerves, reflecting a lower thresh-
old for injury. To make matters even more complicated
when considering acoustic neuromas, recent literature has
focused on the cochlea itself which may have a different
radiobiological tolerance [31]. We will advance arguments
based on published data that tumors involving or near spe-
cial sensory cranial nerves, when treatment is indicated,
should be treated with FSR utilizing daily low conventional
fraction sizes.
25 Acoustic Tumors: Viewpoint—Stereotactic Radiotherapy
The Example of Optic Nerve Sheath
Meningiomas
Single doses of 15 or 54 Gy in 30 daily fractions both result
in excellent control of meningiomas [43]. The SRS dose of
15 Gy, however, exceeds the generally accepted single-dose
tolerance of the optic nerves (8–10 Gy) and may be associ-
ated with a risk of optic neuropathy approaching 78 % [44].
For fractionated radiotherapy, decades of experience have
led to guidelines for normal tissue tolerance. For optic nerve
and chiasm, guidelines have evolved that have proven to be
extremely safe and are generally based on the optic RET
dose of 8.9 Gy recommended by Goldsmith et al. [45], later
corroborated by a large retrospective analysis by Parsons
et al. [46]. We adopted the observations set forth by Parsons
and dropped the daily dose to the optic nerve to 1.8 Gy and
the total dose to 54 Gy—both below the threshold for injury
established by the optic RET formula and corroborated by
Parsons. Our results yielded excellent tumor control and a
compelling preservation or improvement in vision in these
patients [47]. These were the first data supporting FSR as a
means of controlling a benign tumor while simultaneously
preserving or restoring the function of a special sensory cra-
nial nerve.
The Biologically Effective Dose
for Acoustic Neuromas
We previously noted that reports of hearing preservation are
not uniform, ranging from subjective hearing outcomes to
standard audiometric outcomes scales. The most widely
cited scale is the Gardner-Robertson scale [24], but despite
this scale there still exist disparities in reported outcomes
due to differences, for example, in the derivation of pure tone
average. We reviewed published literature and selected only
those studies that featured audiometric outcomes utilizing
the Gardner-Robertson scale confirmed by audiometric data
[42]. Other scales or outcomes based on subjective hearing
results were excluded. The most informative reports included
the actual audiometric data, but most reports did not. As we
previously noted, radiosurgery doses that reflected excellent
tumor control rates also reflected Gamma Knife dose de-
escalations over time to improve rates of cranial neuropathy.
Other than our recent publication [30], literature does not
reflect dose iterations for FSR. From past literature, high
rates of tumor control have been achieved for both a single
dose of 12–13 and 45–50 Gy in 1.8 to 2 Gy daily fractions,
suggesting a dose equivalence for treatment of acoustic neu-
romas. Unlike the optic apparatus, however, acceptably
low rates of hearing loss have not yet been generally
agreed upon. In our single-institution experience of dose
357
de-escalation for FSR, we have found the lower dose cohort
of 46.8 Gy achieves an excellent tumor control rate while
improving hearing preservation [30]. It remains unclear,
however, if further dose reductions improve hearing deficits
even more while still maintaining high rates of tumor
control.
To guide and optimize future treatments, we need to
understand the radiobiological rationale for fractionation for
acoustic neuromas. We must first acknowledge that the target
is a late-responding tissue radiographically inseparable from
a special sensory cranial nerve that could be compromised
by radiation treatment. Fractionation allows time between
fractions for normal tissues (i.e., cochlear nerve) to repair
sublethal damage, while tumor tissue is less efficient at repair
due to faulty repair mechanisms. This leads to the separation
of tumor and normal tissue cell survival curves, thereby min-
imizing normal tissue toxicity while maximizing tumor cell
kill. This is depicted in Fig. 25.1 below.
The radiobiology of high dose single fraction involves
more than sublethal damage, and the major effects have been
documented to involve both lethal DNA damage and endo-
thelial damage. While favorable for tumor cell kill, these
Fig. 25.1 Graph illustrating the effect of fractionation on the cell sur-
vival of tumor cells (A) as well as normal cells (B). Since normal cells
have intact repair mechanisms, whereas tumor cells do not, fraction-
ation effectively separates the cell survival curves for tumor cells and
normal cells, thereby sparing normal cells while killing tumor cells.
Published with permission from Balagamwala EH, Chao ST, Suh
JH. Principles of radiobiology of stereotactic radiosurgery and clinical
applications in the central nervous system. Technol Cancer Res Treat.
2012;11(1):3–13. Epub 2011/12/21. http://www.tcrt.org
358
dual effects may have adverse effects on the normal neuropil
and vasculature of the cochlear nerve.
To better understand an optimal dose regimen for the
treatment of acoustic neuromas, it is important to review the
concept of a biologically effective dose, or BED, which is
useful for quantifying treatment expectations [49] and is an
inherent part of the linear quadratic formula for radiation
effect. For a review of the derivation and significance of α/β
[alpha/beta] ratios and the linear quadratic equation, the
reader is referred to an excellent recent review by
Balagamwala et al. [48]. The radiation cell kill (or effect E)
can be expressed as:
(
Cell kill = E = n a [alpha ] d + b [ beta ] d 2 ) (25.1)
where α [alpha] and β [beta] are the radiosensitivity coeffi-
cients, n the number of fractions, and d the dose per fraction
such that the total dose (D) = nd.
Historically, radiosurgical dose reductions for acoustic
tumors have been performed empirically to improve hearing
outcomes. Consistent with this exercise, consider a progres-
sive reduction in d approaching but not reaching 0. Although
the number of fractions n will then need to be increased to
maintain the same effect, β[beta]d2 will be very small in
comparison to α[alpha]d, and when d is very small, the above
equation can be simplified to:
E = n a [alpha ] d = a [alpha ] D (25.2)
This demonstrates that the total dose D of radiotherapy
given at a very low dose per fraction represents the highest
total dose required to obtain a specific effect, in this case
simultaneously high rates of tumor control and hearing pres-
ervation. This total dose represents the biologically effective
dose or BED in situations where neoplastic cellular repopu-
lation can be ignored, which is the case for acoustic neuro-
mas. Equation (25.2) above can be redefined as:
BED = D = E / a [alpha ]
With this assumption, BED for any practical radiotherapy
application can be derived by first dividing both sides of Eq.
(25.1) by α [alpha] such that:
BED = E / a =
(
n a d + b d2 ) = nd é1 + d ù
(25.3)
a ê a / b úû
ë
It is perhaps difficult to understand that one BED can be
obtained by different dose/fractionation schedules. Drawing
from an analogy by Jones and colleagues [49], the height of
a mountain could be viewed as a BED. BED represents the
absolute height using the longest route (i.e., the lowest dose)
to the summit, but it is possible to climb to the summit by a
C.J. Farrell and D.W. Andrews
steeper and hence shorter route. Carrying the analogy
forward, the steeper route represents a shorter distance, or in
biological terms, the use of larger fractions results in a
shorter time course with a smaller total dose.
Currently, disparate focused radiation dose/fractionation
schedules are practiced worldwide for acoustic tumors,
including single fraction SRS, hyperfractionated FRS, and
hypofractionated FSR. Doses of 12 Gy in a single fraction,
46.8 Gy in 1.8 Gy daily fractions, or 18 Gy in three fractions
all achieve excellent tumor control rates with serviceable
hearing preservation rates that vary roughly from 60 to 80 %.
One might argue that these dose/fractionation schedules are
not biologically equivalent because of variable outcomes in
hearing preservation, but for purposes of this model, we will
assume they are. We can correspondingly assign values of
BED1, BED2, and BED3, respectively, to these dose/fraction
schemes. Assuming BED1 = BED2 for tissue of an unknown
α/β, or in terms of total dose D and fraction dose d:
D1[1 + d1/(α/β[alpha/beta])] = D2[1 + d2/(α/β[alpha/
beta])] or α/β[alpha/beta] = (D1 × d1 − D2 × d2)/D2 − D1
For acoustic neuromas using the assumption of equivalent
BED for 12 Gy in a single fraction (d1 = 12 Gy) and 46.8 Gy
in 26 fractions (d2 = 1.8 Gy):
a / b [alpha / beta ] = éë(12 ´ 12 ) - ( 46.8 ´ 1.8 ) ùû ( 46.8 - 12 )
= 1.72
and the corresponding BED based on this α/β[alpha/beta]
ratio is calculated as:
BED = 12 (1 + 12 / 1.72 ) = 46.8 (1 + 1.8 / 1.72 ) = 95.7 Gy1.72
Now having derived an isoeffective BED for acoustic
tumors, we can test an alternate dose-fractionation schedule
by substituting actual values from Eq. (25.3) above for BED3,
an actual dose-fractionation schedule recently reported [50]
to see if our derived α/β [alpha/beta] ratio actually yields the
same dose per fraction solving for d as the unknown:
é d ù
3d ê1 + ú = 95.7 Gy1.72
ë 1.72 û
which is rearranged to:
3d + 1.74 d 2 - 95.7 = 0
For a general quadratic equation such as ad2 + bd + c = 0,
the positive solution for d is given by:
-b + (b 2
- 4 ac )
2a
where in this case a = 1.74, b = 3, and c = −95.7. The solution
for d above is 6.6 Gy which is within a 10 % error of 6 Gy.
25 Acoustic Tumors: Viewpoint—Stereotactic Radiotherapy
As a working model, therefore, an α/β[alpha/beta] ratio of
1.72 yielding an isoeffective BED of 95.7 Gy is a reasonable
derivation from current literature regarding focused radiation
for acoustic neuromas.
While an α/β[alpha/beta] ratio of 1.72 is low and con-
sistent with late-responding normal CNS tissues [51], this
model has potential pitfalls including an oversimplification
of single Gamma Knife treatments which necessarily involve
multiple isocenter hot spots, and a two-target model (DNA
damage and endothelial cell apoptosis) may be necessary,
especially at high doses per fraction. In the former case, a
single one-point calculation will not be representative of the
biological effect throughout a larger acoustic tumor with
multiple hot spots, and multiple BED evaluations would be
necessary [49]. In the latter case, a modification of the linear
quadratic equation such as a generalized LQ (gLQ) [52] or a
universal survival curve (USC) [53] might be more appropri-
ate. As a starting point, however, we felt this model would be
useful for dose-fractionation schedules designed for treat-
ment of acoustic tumors. Its utility as a predictive model of
serviceable hearing loss, however, remains unclear due to the
significant variations in hearing outcomes mentioned above.
Derivation of a Hearing Ret Formula
for Acoustic Neuromas
We felt a more systematic approach to serviceable hearing
preservation would be the derivation and application of a
hearing RET formula [42]. A prospective trial by Pan et al.
[54] documented that for almost all cases in which significant
hearing loss occurred in the affected ear receiving radiation,
the dose was ≥45 Gy. Among published data available, we
were able to plot the log of dose versus the log of the number
of fractions drawing from Goldsmith’s model [3] for reports
with hearing preservation rates of at least 70 % based on
Gardner-Robertson criteria. The linear regression gave us a
formula for dose/fraction size regimens with a high correla-
tion coefficient (R2 = 0.9705). Drawing from Goldsmith’s
optic RET derivation, we postulated that dose/fraction
schemes with very high hearing preservation rates could be
represented by a parallel line on the same plot, intersecting a
point corresponding with the dosage/fraction scheme docu-
mented as safe. Data from Pan et al. [54] suggest that 45 Gy
in 25 × 1.8 Gy fractions (or less) is such a point. By substitu-
tion to the linear regression equation:
Intercept = log ( 4500 ) - 0.4308 ´ log ( 25 )
with an intercept at 3.051.
So the line equation is:
log D = 0.431 ´ log N + 3.051
359
where N is the number of fractions. This can be folded into:
D = 1,120 × N0.43 or 1,120 hearing RET = D × N − 0.43 for
dose/fraction schemes with high hearing preservation rates.
For one fraction: D = 11.2 Gy. This implies that the radio-
surgical dose should not exceed a threshold around 11.2 Gy
to obtain high rates of hearing preservation. Based on this
hearing RET formula, single fraction doses above 11.2 Gy or
a cumulative FSR dose above 45 Gy in a 25 fraction regimen
could result in higher rates of hearing loss. For SRS, any
dose below 13 Gy results in loss of tumor control [23], so
even with an approximate 60 % hearing preservation rate,
13 Gy may represent the most optimal dose achievable with
SRS. Based on our previous literature review, a median value
of 13 Gy has, in fact, resulted in reported serviceable hearing
losses ranging from 17 to 67 % [42]. A median FSR dose of
47.5 Gy, while maintaining excellent tumor control, has
resulted in reported serviceable hearing losses ranging from
29 to 43 % [42]. As noted in Fig. 25.2b below, the dose pre-
scription schemes with the highest yield of hearing preserva-
tion fall within the box that includes the 10 % variance of the
α/β [alpha/beta] ratio we derived. The single point represents
a recently published paper which describes a high probabil-
ity of hearing loss with a dose-fractionation scheme for
acoustic neuromas described as a total dose of 54 Gy in 27
fractions [55]. Applying an α/β [alpha/beta] ratio of 1.63 for
tumor control and the hearing RET formula as a guide
for hearing preservation, the total dose should not exceed
46.2 Gy for 27 fractions to maximize the chance of hearing
preservation while maintaining excellent tumor control.
Further Radiobiological Advantages:
The Example of Large Tumors
With the progressive shift in treatment patterns toward use of
radiation therapies for acoustic neuromas, some authors have
suggested that relative indications for microsurgical resec-
tion include the presence of medically refractory trigeminal
neuralgia, hydrocephalus, symptomatic mass effect includ-
ing disabling ataxia or hemiparesis, intractable headache,
and large tumor size. Although the definition of large tumor
size remains somewhat arbitrary, maximal tumor diameter
>3 cm has conventionally been used as a cutoff for SRS
treatment based on studies demonstrating rates of effective
tumor control as low as 57 % and increased risk of complica-
tion compared to SRS treatment of small- and medium-sized
tumors [56]. Milligan et al. described their experience using
SRS for tumors with volumes more than one standard devia-
tion above the mean during a 9-year period and demonstrated
a 5-year actuarial tumor control rate of 83 % [57]. Impairment
of facial nerve function was observed in 14 % of patients and
15 % required prolonged corticosteroid administration for sym-
ptomatic radiation-induced brainstem or cerebellum edema.
360
Fig. 25.2 (a) Logarithmic plot of total dose versus number of fractions
for cases reporting preservation of serviceable hearing; (b) plots of bio-
logically equivalent doses utilizing the linear quadratic formula with α/β
[alpha/beta] ratios as +10 % of the calculated α/β [alpha/beta] value, in
comparison with the hearing RET plot. The dose prescription schemes
predicting the highest yield of hearing preservation fall within the box at
Table 25.1 Results of the ANA surveys over three decades
Treatment reported by respondents 2007–2008 (%)
Translabyrinthine approach 33
RETrosigmoid approach 17
Middle fossa approach 10
Don’t know approach 0 0
Total, microsurgical resection 60
Stereotactic radiosurgery (SRS) 12
Fractionated stereotactic radiotherapy (FSR) 8 NA
Total SRS/FSR 20
Watch and wait 20
Don’t know what type of treatment NA
Total 100
Based on their results, the authors recommended consideration
of surgical resection for tumors larger than 2.7 cm in poste-
rior fossa greatest dimension. A group from the Netherlands
recently reported primary SRS treatment of 33 patients with
large tumors defined as tumor volume >6 cm3 with indenta-
tion of brainstem (Koos Grade III & IV). Patients with NF2,
symptomatic mass effect, or maximum extracanalicular
dimension ≥4 cm were excluded from primary SRS treat-
ment. A radiographic tumor control rate of 88 % was
reported over a median follow-up time of 30 months,
although 7 of 33 patients required further microsurgical
or SRS treatment for development of either progressive
neurologic symptoms or radiographic enlargement.
Transient facial and trigeminal neuropathy occurred in 9 %
and 14 % of patients, respectively, with good facial nerve
function (HB Grades I and II) preserved in all patients at
C.J. Farrell and D.W. Andrews
or below the hearing RET curve depending on which α/β [alpha/beta]
ratio is utilized. The black arrow represents the point beyond which dose-
fractionation schemes predict a higher likelihood of hearing preservation
for a lower α/β [alpha/beta] ratio, the gray arrow for a higher α/β [alpha/
beta] ratio. The black point represents a recent study which documented
a high rate of hearing loss [56] and falls above the hearing RET range
1998 (%) 1983 (%)
51 72
28 11
6 3
14
85 100
NA NA
NA
5 0
4 0
6 0
100 100
1 year posttreatment. Interestingly, of the 12 patients included
in the study who reported pretreatment symptoms of trigem-
inal hypoesthesia, 11 (92 %) experienced resolution of their
condition following SRS likely related to the 67 % inci-
dence of tumor volume shrinkage observed on radiographic
follow-up (Table 25.1).
The use of FSR has been recommended as an alternative
radiation modality for the treatment of larger tumors adja-
cent to the brainstem although minimal data exists to suggest
improved outcome relative to SRS for this population of
tumors. Mandl et al. reported a cohort of patients with tumors
>3 cm in diameter treated primarily with multisession SRS
using a maximum dose of 25 Gy delivered in 5 Gy fractions
[58]. The actuarial 5-year tumor control and facial nerve
function rates were 82 % and 80 %, respectively. We have
updated our review of FSR treatment for acoustic neuromas,
25 Acoustic Tumors: Viewpoint—Stereotactic Radiotherapy
Fig. 25.3 Serial magnetic resonance imaging scans (upper) with asso-
ciated audiograms obtained at same time (lower) in patient treated with
FSR to 46.8 Gy. (a) Pretreatment T1-weighted gadolinium-enhanced
axial image featuring right acoustic neuroma. Audiogram reflects pure
tone average of 22 and speech discrimination score of 95 %, represen-
ting Gardner-Robertson level 1 pretreatment serviceable hearing.
(b) Posttreatment T1-weighted gadolinium-enhanced axial image at 6
months featuring some enlargement and extensive central necrosis of
tumor. Audiogram at 6 months after treatment reflects some audiomet-
ric decay with pure tone average of 35 and speech discrimination score
and of 154 tumors treated in the 46.8 Gy cohort, 15 were
>6 cc in size. In this subgroup, we have documented no treat-
ment failures, and of 6 patients with serviceable hearing,
3 have maintained hearing in a serviceable range at a median
follow-up of 35 months. At conventional fraction sizes, we
have also noted no other cranial neuropathies in this sub-
group of patients. See Fig. 25.3 as an example.
The theoretical advantages of LINAC-based fractionation
for large tumors are depicted in Figs. 25.4 and 25.5 below.
For larger treatment volumes, the penumbra affecting con-
tiguous normal tissues is often judged to be prohibitive for
single fraction SRS that is substantiated in a broad literature.
In a review of 149 patients with posterior fossa tumors
treated with SRS, for example, factors that predicted cranial
nerve palsy included Dmax of >17.5 Gy, a prescribed isosur-
face dose of >12.5 Gy, length of cranial nerve of >16 mm,
and tumor volume of 1.7 cc [59]. Particularly for larger
acoustic tumors, both the dose prescription convention and
the design of multiple isocenters to achieve conformality
increase the likelihood of overdosing the cochlear nerve.
361
of 100 %, representing a decrease to Gardner-Robertson level 2 service-
able hearing. (c) Posttreatment T1-weighted gadolinium-enhanced
axial image at 42 months featuring marked diminution in tumor size.
Audiogram at 42 months after treatment reflects stable audiogram with
pure tone average of 30 and speech discrimination score of 92 %, back
to lowest range of Gardner-Robertson level 1 serviceable hearing. From
Andrews DW, Werner-Wasik M, Den RB, Paek SH, Downes-Phillips B,
Willcox TO, et al. Toward dose optimization for FSR for acoustic neu-
romas: comparison of two dose cohorts. Int J Radiat Oncol Biol Phys.
2009;74(2):419–26
We will first address dose prescription conventions (see
Fig. 25.4). While a Gamma Knife isosurface prescription is
classically at the 50 % isodose line, LINAC-based treatments
typically fall between an 85 and 95 % isodose line. Assuming
in both cases circular collimation is utilized, the 50 % isosur-
face yields a steeper dose gradient in the vicinity of the
cochlear nerve when compared to higher LINAC-based iso-
surface prescriptions and thus results in a higher dose to the
cochlear nerve (see Fig. 25.4). Our analysis is based on an
actual comparison of a multi-shot/high conformality Gamma
Knife SRS treatment to a single isocenter 5 dynamic arc FSR
treatment on a Novalis Classic. The dose distribution penum-
bra is a depiction of a circular collimator instead of a dynamic
arc penumbra to allow a uniform comparison of dose pre-
scription conventions with both techniques.
We will next address dose delivery conventions (see
Fig. 25.5). The prior section reviewed the advantages of frac-
tionation and staying within the hearing RET. Beyond con-
cerns of total dose and fraction size, the manner in which the
dose is delivered, particularly for larger tumors, will affect
362
Fig. 25.4 Comparison of dose distribution to the cochlear nerve with
Gamma Knife and FSR treatments based on isosurface prescription con-
ventions. (a) Axial T1 gadolinium-enhanced MRI scan of right acoustic
neuroma. (b) Artist’s rendering of translucent acoustic tumor with cra-
nial nerves VII and VIII adherent to the anterior and caudal surface of the
tumor, coursing to internal auditory canal. (c) Eight-shot Gamma Knife
radiosurgery treatment plan with a 12 Gy prescription to the 50 % iso-
dose line (yellow) for right acoustic neuroma. (d) Magnified sagittal view
of actual treatment plan in the distal porus acusticus [outer line (yellow)
is 50 % isodose prescription line; middle line (magenta) is tumor surface;
inner line (green) is 60 % isodose line]. Assuming cochlear nerve is
around the 7 o’clock position, the nerve is within a 10 % dose gradient
above isodose prescription. (e) Single-shot Novalis FSR treatment plan
with a 1.8 Gy prescription to the 90 % isodose line for a right acoustic
neuroma (tumor is shaded; outer line is 90 % isodose prescription line).
(f) Magnified sagittal view of actual treatment plan in the distal porus
the function of the organs at risk (OARs), in this case the
cochlea and the cochlear nerve. The latest innovation in
LINAC-based radiosurgery platforms is the use of mini-leaf
collimation. Rather than sphere packing with variably sized
shots from circular collimators, mini-leaf collimation auto-
mates target isosurface conformality with automated and
paired tungsten leaves which move dynamically through an
arc of radiation to match target geometry. This technique
eliminates the dose inhomogeneity within the cochlear nerve
C.J. Farrell and D.W. Andrews
acusticus (tumor is shaded; outer line is 90 % isodose 10 prescription
line; inner line is 95 % isodose line). Assuming cochlear nerve is around
the 7 o’clock position, the nerve is within a 5 % dose gradient above
isodose prescription. (g) Artist’s caricature of (d) (magnified sagittal
cross section of intracanalicular portion of tumor treated with Gamma
Knife). The VIII nerve at the 7 0’clock position is within the prescribed
isodose line and exposed to higher dose gradients. (h) Profile of a focused
radiation beam with typical isodose prescriptions at 50 % (Gamma
Knife) and 90 % (FSR). Vertical columns in either scenario could repre-
sent narrow location range of cochlear nerve relative to tumor (e.g.,
within 1 mm of tumor surface). Broad inferior horizontal bar represents
potential actual dose range delivered to cochlear nerve with 50 % isodose
prescription; narrow superior horizontal bar represents potential actual
dose range delivered to cochlear nerve with 90 % isodose prescription.
The potential dose gradient at a 50 % isodose prescription is more than
three times greater than 90 % prescription at the same distance
penumbra resulting from multiple shots yielding a much
more homogeneous dose of radiation to the cochlear nerve.
Dose homogeneity promises to minimize injury to the
cochlear nerve (see Fig. 25.5) and high conformality prom-
ises to minimize injury to the cochlea, a structure too small
for reliable dose-volume histograms.
The other important structure affecting hearing outcomes
is the cochlea itself and both SRS and FSRT techniques
achieve high conformality limiting dose to the cochlea.
25 Acoustic Tumors: Viewpoint—Stereotactic Radiotherapy
Fig. 25.5 Comparison of dose distribution to the cochlear nerve with
Gamma Knife and FSR treatments based on dose delivery conven-
tions. (a) Axial T1 gadolinium-enhanced right acoustic neuroma,
highlighted in red. (b) Cartoon of the same tumor now featuring the
cochlear nerve and cochlea (OARs are organs at risk). After a multi-
ple-shot, high conformality treatment, the dose penumbra including
the cochlear nerve necessarily includes hot spots from overlapping
Recent data suggests that a dose <4.2 Gy for an SRS
treatment [31] or 45 Gy for conventional radiation doses [54]
is favorable for cochlear function. We have since learned in
our experience that the dose fall off outside the PTV isosur-
face prescription is important when considering cochlear
dose, and an 80–85 % isosurface prescription for LINAC can
achieve the best dose distribution for both the cochlea and
cochlear nerve.
History and Progress in Clinical Outcomes
Utilizing FSR
In 1987, Wallner et al. described the use of fractionated con-
ventional radiation therapy (RT) for the treatment of acoustic
neuromas following subtotal resection. They demonstrated
that when doses ≥45 Gy were administered, the tumor recur-
rence rate could be significantly decreased. Several years
later, a group from France described their experience using
RT as primary therapy for acoustic neuromas, including a
small subset of patients with neurofibromatosis type 2 (NF2)
and preexisting unilateral deafness secondary to previous
surgical resection of a contralateral tumor. At an average
follow-up of 70 months, hearing was preserved in 3 of the 5
patients with no evidence of tumor progression. Based on
these encouraging early results, a number of groups posited
that combining the radiobiologic advantages of dose frac-
tionation with the precision of stereotactic techniques may
enable effective treatment of acoustic neuromas with reduced
cranial neuropathy and improved hearing preservation.
363
shots. 4.2 Gy is threshold beyond which injury to the cochlea results in
hearing loss [31]. (c) After a single isocenter dynamic arc treatment
with mini-multileaf collimation treatment, the dose penumbra includ-
ing the cochlear nerve is now much more homogeneous and close to
the isosurface prescription dose. A total dose of 45 Gy with conven-
tional fraction sizes is a threshold beyond which injury to the cochlea
results in hearing loss [55]
At the present time, a multitude of studies reporting
outcomes using FSR have consistently demonstrated excel-
lent tumor control rates comparable to those achieved with
SRS and low risk of cranial nerve morbidity. The optimal
dose and fractionation scheme for FSR remains uncertain
with the widespread variation in treatment practices at differ-
ent institutions, precluding definitive comparisons of FSR to
SRS. Several recent studies have described outcomes using
FSR with maximum doses ranging from 46.8 to 57.6 Gy,
typically administered in conventional 1.8–2 Gy fractions.
Overall, functional hearing preservation was observed in
61–94 % of patients over an average follow-up time of
approximately 50 months [60–67]. In 2001, our group at
Thomas Jefferson University performed a nonrandomized
prospective cohort analysis comparing outcomes after SRS
and FSR using a maximum dose of 50.4 Gy for 122 patients.
Tumor control, facial nerve preservation, and trigeminal
neuropathy rates were equivalent among the two cohorts;
however, hearing preservation rates were 2.5-fold higher in
the FSR group with a crude hearing preservation rate of
81 % compared to 33 % in the SRS cohort [60]. Limitations
of this prospective study included short-term length of audi-
ometry data and an SRS hearing preservation rate toward the
low range of reported outcomes. Combs et al. subsequently
reported their single-institution prospective experience com-
paring SRS to FSR using marginal dose of 57.6 Gy which
revealed no overall difference in terms of hearing preserva-
tion between the two modalities when the SRS prescription
dose was ≤13 Gy [68], but the FSR group represented only
10 patients.
364
Table 25.2 Summary of treatment outcomes for SRS and FSR 2004–2009
Treatment N Tumor volume (cc) Dose (Gy) Follow-up (months)
SRS 1,850 2.3 12.6 71
FSR 404 4.1 52.4 53
From: Arthurs BJ, Fairbanks RK, Demakas JJ, Lamoreaux WT, Giddings NA, Mackay AR, et al. A review of treatment modalities for vestibular
schwannoma. Neurosurg Rev. 34(3):265–77; discussion 77–9
Table 25.3 Summary of serviceable hearing outcomes from the 2007–2008 ANA survey
Treatment Hearing status (N) before treatment after treatment
SRS 108 22
FSR 84 41
Similar to the early stages of SRS, the optimal FSR
prescription dose necessary to achieve long-term tumor
control while minimizing damage to normal structures such
as the cochlea and cochlear nerve remains to be established.
We previously demonstrated that FSR dose reduction from
50.4 to 46.8 Gy enabled improved hearing outcomes without
sacrifice to tumor control. These results are consistent with
data using RT for nasopharyngeal cancer revealing that hear-
ing loss is significantly increased when the mean cochlear
dose is >48 Gy [30, 69]. Conversely, in the same patient
population, hearing is preserved for a mean cochlear dose
<45 Gy [54]. Importantly, hearing impairment after fraction-
ated RT appears to have a delayed time to onset relative to
SRS and longer-term data will be necessary to fully evaluate
this treatment modality [27].
Several groups have reported their experience using a
multisession SRS (≤5 treatment fractions) scheme in an
effort to balance the advantages of fractionation with the con-
venience of SRS. Hansasuta et al. described the extensive
experience of the Stanford group delivering 18 Gy over three
treatment sessions using the CyberKnife [50]. During a
median follow-up period of 3 years, they found a 98 % tumor
control rate and accompanying 76 % hearing preservation
rate. Meijer et al., however, reported the results of a pros-
pective cohort study comparing single versus multisession
LINAC-based SRS and observed no differences in either
tumor control or hearing preservation rates between the two
cohorts which were 75 % and 61 %, respectively, for service-
able hearing [67]. A slight but statistically significant reduc-
tion in trigeminal neuropathy incidence was noted with
multisession SRS.
As mentioned above, we have modeled the radiobiology of
fractionation for acoustic neuromas, including a hearing RET
formula as a guideline for treatment. Summarizing the above
literature, there remains no systematic application of radiobio-
logic principles to the treatment of acoustic neuromas. In fact,
none of the FSR or SRS papers we previously analyzed pro-
vided uniform treatment planning data such as MDPD (maximum
dose to prescribed dose) ratios or PTV (prescription to tumor
C.J. Farrell and D.W. Andrews
Tumor control rate (%) Hearing preservation rate (%)
89 60
95.8 79
Rate of serviceable hearing preservation (%)
20
49
volume) ratios as measures, respectively, of dose homogeneity
and dose conformality. For circular collimation, a uniform
reporting mechanism should include mean number of isocen-
ters stratified by tumor sizes, and these data might build a rela-
tionship between such variables as tumor size, serviceable
hearing loss, and mean number of isodose centers as a mea-
sure of conformality. Newer techniques such as mini-multileaf
collimation with dynamic arc or intensity modulation (Novalis/
TrueBeam) or non-isocentric smearing with pencil beams
(CyberKnife) [70] both promise to maintain conformality and
increase dose homogeneity, and should also include MDPD
and PTV values.
Despite a broad variety of dose-fractionation schedules
without a clear rationale, recent systematic literature review
by Arthurs and colleagues, however, favors FSR when
assessing hearing preservation [66] (see Table 25.2). These
data are remarkably similar to data we previously compiled
from published series [42].
Drawing from the patients’ perspective, we once again
refer to the ANA 2007–2008 patient survey, recognizing that
all data collected were self-reported by patients and reported
as is. Table 25.3 indicates the self-reported Gardner-
Robertson Class 1 and 2 results of respondents who under-
went either SRS or FSR.
If this survey is any indication, FSR provides a more
favorable outcome when assessing serviceable hearing
preservation.
Future Directions
Future treatment possibilities for acoustic neuromas remain
both challenging and hopeful. The challenge will remain the
design of appropriate prospective trials that guide practitio-
ners with useful level I data. While radiosurgery and FSR
have become common practice, physicians have become
entrenched in the commercial platform they use which
makes prospective randomized comparisons of different treat-
ment techniques on different platforms extremely difficult.
25 Acoustic Tumors: Viewpoint—Stereotactic Radiotherapy
Also, further refinements in our understanding of the
radiobiological tolerances of the cochlea and the cochlear
nerve, including the hearing RET formula, will be important
new information critical to the design of new radiation treat-
ment strategies. It has been well established that atrophy of
the cochlear nerve (loss of cochlear neurons) disproportion-
ately affects speech discrimination ability rather than pure
tone hearing thresholds [71–73]. Associating pure tone aver-
ages with cochlear doses and speech discrimination scores
with cochlear nerve doses might provide further insight into
the radiobiology of these structures and guide future treat-
ment plans. Uniform analyses of reliable audiometric data
immediately before and at routine intervals after treatment
will yield better outcome data. In one recent retrospective
analysis of temporal bone histopathology in 32 patients with
acoustic neuromas, the tumors caused significantly more
inner and outer hair cell loss, cochlear neuronal loss, precipi-
tate in endolymph and perilymph, and decreased pure tone
average, when compared with the opposite ear. Tumor size,
distance from the cochlea, and nerve of origin did not corre-
late with structural changes in the cochlea or the hearing
threshold [74]. With these provocative observations, cochlear
pathology rather than retrocochlear pathology may delineate
important prognostic groups prior to treatment.
The optimal treatment outcome will include the excellent
tumor control rates already achieved with better hearing pres-
ervation and possibly recovery of hearing. The latter achieve-
ment may include a combination of targeted chemotherapy and
radiation. In one recent application of chemotherapy, VEGF
blockade with bevacizumab improved hearing in some, but
not all, patients with neurofibromatosis type 2 and was associ-
ated with a reduction in the volume of most growing acoustic
neuromas [75]. The impact bevacizumab may have for spo-
radic tumors remains unknown. The molecular mechanisms at
play in sporadic tumors recently reviewed by Neff et. al., nota-
bly Merlin’s interactions with other proteins, and regulation of
the NF2 gene [76] could spawn new targeted molecular thera-
pies which may complement existing focused radiation strate-
gies or supersede them altogether.
Acknowledgment We thank our colleagues from the Department of
Radiation Oncology, Drs. Wenyin Shi and Haisong Liu, for their help-
ful comments during the preparation of this manuscript.
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 Stereotactic Radiosurgery
for Pituitary Adenomas
Jason P. Sheehan and Brian Williams
Introduction
Pituitary adenomas are common tumors found in approxi-
mately 10–27 % of the general population [1, 2].
Microadenomas which are less than 1 cm in maximum
dimension are typically diagnosed as a result of hormone
overproduction. Macroadenomas which are pituitary adeno-
mas greater than 1 cm in dimension may be discovered as a
result of direct mass effect leading to hypopituitarism, eleva-
tion in prolactin output, or a focal neurological deficit (e.g.,
cranial nerve dysfunction). Increasingly with the availability
of CT and MRI, pituitary adenomas are also being detected
incidentally. Microadenomas are divided fairly evenly
between functioning and nonfunctioning lesions, while non-
functioning lesions comprise approximately 80 % of all
macroadenomas [1]. Pituitary adenoma patients typically
exhibit symptoms of headache (40–60 %), visual distur-
bance, hypopituitarism, or rarely apoplexy [1, 2].
Pituitary adenomas remain difficult to cure with micro-
surgical techniques alone, and they often require multimo-
dality treatment, which includes surgery, radiation therapy,
radiosurgery, and medical management. In his seminal
work The Pituitary Body and Its Disorders, Harvey
Cushing recognized the limits of microsurgery and the
utility of ionizing radiation for the treatment of patients
with pituitary adenomas. He wrote “in view of the fact that
the surgical measures at our disposal are merely palliative
J.P. Sheehan, M.D., Ph.D. (*)
Department of Neurological Surgery, Health Sciences Center,
University of Virginia, Box 800212, Charlottesville,
VA 22908, USA
e-mail: jps2f@virginia.edu; jps2f@hscmail.mcc.virginia.edu
B. Williams, M.D.
Department of Neurosurgery, Health Sciences Center, University
of Virginia, Box 800212, Charlottesville, VA 22908, USA
e-mail: BJW6M@hscmail.mcc.virginia.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_26, © Springer Science+Business Media New York 2015
26
and directed toward neighborhood symptoms alone, and in
the case of an advancing struma are in no sense curative, it
is possible that radiotherapy should often be employed as a
supplementary measure” [3]. Later, Cushing and his col-
leagues used a device called a radium bomb to deliver
radiation therapy to intracranial tumors [4, 5]. Since that
time, neurological surgeons and radiation oncologists, in
conjunction with medical physicists, have utilized ionizing
radiation to treat patients with recurrent or residual pitu-
itary adenomas.
In the modern era, most centers have turned to stereotac-
tic radiosurgery (SRS) for treating patients with a recurrent
or residual pituitary adenoma. Tremendous effort in the field
of SRS has been placed on the preservation of surrounding
neuronal, vascular, and hormonal structures in an effort to
improve the therapeutic ratio. Technical refinements for
treating pituitary adenoma patients have been achieved
through advances in radiobiology, neuroimaging, medical
physics, and biomedical engineering. We review the contem-
porary role of SRS for pituitary adenomas.
Stereotactic Radiosurgical Concept
and Techniques
In 1951, SRS was described by Lars Leksell [6] as the
“closed skull destruction of an intracranial target using ion-
izing radiation.” In 1968, Leksell treated the first pituitary
adenoma patient with the Gamma Knife. Subsequently, SRS
has been utilized to treat thousands of patients with pituitary
adenomas.
SRS delivers a highly focused, large dose of radiation
to the target, while sparing surrounding structures from an
appreciable dose of radiation. Stereotactic image guid-
ance is utilized to achieve this. Radiosurgery is tradition-
ally delivered in a single session but may be delivered in
up to five sessions (i.e., fractions) [7]. It is characterized
by a steep dose falloff to the surrounding normal tissues.
369
370
For cobalt-based SRS devices, the steepest gradient index
(i.e., falloff) is achieved around a 50 % isodose line,
whereas for linear accelerator (LINAC)-based systems, it
is usually at the 80–90 % isodose line. Patients are immo-
bilized using rigid frames fixed to the skull or other immo-
bilization devices (e.g., aquaplast masks or bite blocks);
each immobilization device has its own stereotactic coor-
dinate system. Radiosurgery reliably achieves submilli-
meter accuracy in intracranial space. Onboard imaging
systems (OBI) may be used to further track and compen-
sate for sources of error (e.g., setup error, patient move-
ment, etc.).
There are several types of radiosurgical delivery devices,
including the Gamma Knife® (Elekta AB), modified LINAC’s
such as the CyberKnife (Accuray), Novalis (Brainlab),
TrueBeam STX (Varian), and Axesse (Elekta), or proton
beam units (e.g., IBA or Mevion). Single session radiosurgi-
cal margin doses for nonfunctioning adenomas range from
12 to 18 and 15 to 30 Gy for functioning adenomas. For
multi-session radiosurgery, these doses may be divided over
two to five fractions.
Gamma Knife radiosurgery involves the use of multiple
isocenters to achieve a highly conformal dose plan. The
number of isocenters or “shots” varies based upon the size,
shape, and location of the pituitary adenoma. With the cur-
rent version of the Gamma Knife Perfexion™, each isocen-
ter is comprised of eight independent sectors of 24 beams,
and each isocenter contains up to 192 simultaneous beams.
Beam diameters for the current Gamma Knife Perfexion unit
range from 0 (i.e., blocked) to 16 mm. Other cobalt-based
radiosurgical devices are also in use and include the Infini™
system (MASEP).
LINAC-based radiosurgery (e.g., CyberKnife®,
TrueBeam™ STx, Trilogy, Tomotherapy™, and Axesse™)
uses multiple radiation arcs to cross-fire photon beams at a
target volume [8]. Most systems use dynamic techniques in
which the arc is rotated around its radius to deliver radiation
that enters many different vantage points. Technical
refinements with LINAC-based radiosurgery include beam
shaping, intensity modulation, multileaf collimation, and
onboard CT or fluoroscopic imaging.
Proton therapy has been adapted as a radiosurgical tool
for intracranial pathology. It takes advantage of the inher-
ently superior dose distribution of protons compared with
that of photons because of the Bragg peak phenomenon [9].
Currently, there are a few centers using proton beam technol-
ogy to perform radiosurgery (one session treatment); many
proton centers perform fractionated stereotactic radiotherapy
(FSRT). The number of proton beam centers has increased
significantly in the past 10 years as the technology becomes
more cost-effective particularly with the advent of compact
proton beam units such as the one by Mevion Medical
Systems.
J.P. Sheehan and B. Williams
SRS for Pituitary Adenomas
SRS and Nonfunctioning Pituitary Adenomas
After a microsurgical resection most commonly through a
transsphenoidal approach, control of a pituitary tumor will
be achieved in 50–80 % of adenomas [10]. SRS is an excel-
lent treatment approach for patients who have progression or
recurrence. It may also be utilized in cases of residual tumors
that are known to be more aggressive (e.g., silent adrenocor-
ticotropic hormone (ACTH) or TSH adenomas). Based upon
the published literature, radiosurgery affords the vast major-
ity of pituitary adenoma patients with effective, long-term
tumor control as well as a low rate of complications [10].
In Table 26.1, we list the major radiosurgical series since
2002 that detail outcomes in nonfunctioning adenoma
patients [10–36]. Single session radiosurgery margin doses
of 12–18 Gy are generally used for nonfunctioning adeno-
mas. Tumor control rates with radiosurgery vary from 83 to
100 % (average 95.5 %) (Table 26.1). Neurological deficits
following radiosurgery are uncommon (average 2.7 %, range
0–7.1 %). The most common complication is hypopituita-
rism (average 13 %, range 0–39 %) which is a manageable
problem provided that it is detected and appropriate hor-
monal replacement therapy is initiated. At the University of
Virginia, we reported 90 % tumor control in a series of 140
patients with nonfunctioning pituitary adenomas [36]. Tumor
control was statistically less probable when the tumor vol-
ume treated was greater than 5 cm3 [36]. In a separate study,
we examined the outcomes of a smaller group of patients
with a minimum follow-up of 4 years after radiosurgery. The
overall progression-free survival was 83 %, and three-
quarters of the patients demonstrated a marked decrease in
the adenoma volume by at least 20 % or more [37]. This
same study demonstrated that tumor control was related to
treatment volume and that those patients with a treatment
volume of less than 5 cm3 were far more likely to have tumor
control after radiosurgery. In a recent analysis by the North
American Gamma Knife consortium, younger patient age,
smaller tumor volume, and no prior radiation therapy were
significantly related to the favorable outcomes of tumor con-
trol and neurological stability after radiosurgery for a non-
functioning pituitary adenoma. These findings underscore
the value of a maximum safe resection prior to SRS. Please
see Table 26.1 for a detailed summary.
SRS and Cushing’s Disease
In the vast majority of cases, endogenous Cushing’s syn-
drome results from oversecretion of ACTH from a pituitary
adenoma [38]. Although microsurgical resection is the mainstay
26 Stereotactic Radiosurgery for Pituitary Adenomas 371

Table 26.1 Summary of the literature review for the radiosurgical management of nonfunctioning pituitary adenomas
Mean/median Mean/median Radiologic control Neurological Delayed
Year Authors follow-up (months) margin dose (Gy) of tumor (%) deficit (%) hypopituitarism (%)
2002 Feigl et al. 55.2 15 94 NR 40
2002 Sheehan et al. 31.2 16 97.6 4.8 0
2002 Wowra and Stummer 57.7 16 93.3 0 10
2003 Petrovich et al. 34 15 100 3 NR
2004 Losa et al. 41.1 16.6 96.3 0 9.3
2004 Muacevic et al. 21.7 16.5 95 0 3.9
2005 Kajiwara et al. 32.1 12.6 92.9 7.1 7.1
2005 Picozzi et al. 40.6 16.5 96.1 NR NR
2005 Iwai et al. 36.4 12.3 93 0 7
2006 Mingione et al. 46.4 18.5 92.2 0 25
2006 Voges et al. 56.6 13.4 100 4.2 12.3
2007 Liscak et al. 60 20 100 0 1.4
2008 Pollock et al. 64 16 96.8 1.6 27
2009 Hoybye and Rahn 78 20 100 4.3 0
2009 Kobayashi 50.2 NR 96.7 2.8 8.2
2010 Castro et al. 42 12.5 100 0 0
2010 Hayashi et al. 36 18.2 100 0 0
2011 Gopalan et al. 95 18.4 83 6.3 39
2011 Iwata et al. 33 21 Gy/3 Fr 98 1 2
(CyberKnife) 25 Gy/5 Fr
2011 Park et al. 62 13 90 2.4 24
2012 Starke et al. 50.4 18 90 13.7 30.3
Average 48.7 16 95.5 2.7 13
NR not reported, FR fraction

of treatment for Cushing’s disease, many adenomas show
invasion of the surrounding dura and/or cavernous sinus
or are difficult to delineate on MRI, thereby making a
surgical cure unlikely. Radiosurgery proves a valuable
treatment option for patients with persistent Cushing’s
disease after a resection.
In Table 26.2, the major radiosurgical series for Cushing’s
patients since 2000 are listed (Table 26.2) [11–15, 18, 21, 23,
24, 27, 31, 33, 39–62]. In these studies, most authors utilized
the 24 h urinary free cortisol (UFC) or serum cortisol to
define an endocrine remission. In addition, radiosurgical
margin doses of 18 Gy to as high as 30 Gy were delivered to
the adenomas of Cushing’s disease patients.
The remission rates vary tremendously from 16.7 to
87 %, but the majority of reports note a remission rate of
greater than 50 %. In particular, the endocrine remission
rate after radiosurgery does not match the excellent rate of
radiologic control of the adenoma. Based on our institu-
tional experience, endocrine remission of Cushing’s disease
is typically achieved 12 months after SRS [46]. In most
series, after radiosurgery the rates of newly developed or
worsened cranial neuropathies, including visual deteriora-
tion, are low (average 3.4 %; Table 26.2). The risk of delayed
hypopituitarism after radiosurgery for Cushing’s disease
appears to be slightly higher (average 24.9 %; Table 26.2)
compared to that of nonfunctioning adenoma series; this
may be due in part to the higher margin doses delivered to
Cushing’s patients and the resulting higher doses to collat-
eral structures, such as the normal pituitary gland and stalk.
Long-term radiologic and endocrine follow-up is crucial
because late recurrences have been seen in several Cushing’s
disease series [46, 58]. Please see Table 26.2 for a detailed
summary.
SRS and Acromegaly
Acromegaly has an approximate prevalence of 60 per million
people [63]. Poorly controlled acromegaly is associated with
significant morbidity (e.g., hypertension, diabetes, cardio-
myopathy, and sleep apnea) and mortality [63]. Given the
potential for cure, surgical resection remains the initial treat-
ment for most acromegalic patients. Nevertheless, many
patients will not achieve a normalization of IGF-1 and
growth hormone after resection. Some of these patients
exhibit adenoma invasion of surrounding structures (e.g., the
dura or the cavernous sinus). Also, many patients with acro-
megaly have macroadenomas; complete resection is not
always feasible with the large, infiltrative lesions.
Table 26.3 details the major radiosurgical series for acrome-
galic patients published since 2000 (Table 26.3) [11–15, 18, 21,
24, 27, 31, 33, 40, 41, 44, 47, 48, 51, 52, 54, 58–61, 64–79].
372 J.P. Sheehan and B. Williams

Table 26.2 Summary of the literature review for the radiosurgical management of Cushing’s syndrome
Mean/median Mean/median Biochemical Neurological
Year Author margin dose (Gy) follow-up (months) remission (%) deficit (%) Hypopituitarism (%)
2000 Izawa et al. 23.8 26.4 16.7 0 0
2000 Sheehan et al. 20 39.1 63 2.3 16
2000 Shin et al. 32.3 88.2 50 6.3 16.7
2001 Hoybye et al. NR 16.8 44 0 68.8
2002 Feigl et al. 15 55.2 60 NR 40
2002 Kobayashi et al. 28.7 64 23.3 NR NR
2002 Laws et al. 20 NR 74 2.5 24
2002 Pollock et al. 20 42.4 78 22.2 16
2003 Choi et al. 28.5 42.5 55.6 0 0
2003 Petrovich et al. 15 34 NR 3 NR
2003 Wong et al. NR 38 100 0 20
2003 Witt 24 24 0 0 NR
2005 Devin et al. 14.7 42 49 0 40
2006 Voges et al. 16.4 58.7 52.9 4.2 12.3
2007 Castinetti et al. 29.5 54.7 42.5 5 15
2007 Jagannathan et al. 23 45 54 5 22
2007 Kajiwara et al. 26 38.5 50 0 50
2007 Petit et al. 20 62 52 0 52
2008 Pollock et al. 20 73 87 0 36
2008 Tinnel et al. 25 37 50 0 50
2009 Castinetti et al. 28 94 50 5.3 21
2009 Wan et al. 23 67.3 27.9 2.9 1.7
2009 Kobayashi 28.7 64.1 35 NR NR
2010 Hayashi 25.2 36 38 15.4 0
2011 Sheehan et al. 24 31 54 NR 22
Average 23 48.9 49.9 3.4 23.6
NR not reported

Similar margin doses of 18–30 Gy are routinely delivered to
the adenoma as part of single session radiosurgery. Endocrine
remission after radiosurgery is achieved in an average of
60.7 % of acromegalic patients (range 0–82 %). Neurological
deficits and hypopituitarism occur after radiosurgery in
1.8 % (range 0–11 %) and 14.7 % (range 0–40 %) of patients,
respectively. Temporary cessation of pituitary suppressive
medications near the time of radiosurgery appears to increase
the chance of endocrine remission in acromegalic patients
[80]. Also, patients who had a lower adenoma volume at the
time of radiosurgery were more likely to achieve endocrine
remission after radiosurgery [80]. Thus, for those acrome-
galic patients with a macroadenoma, maximal safe resection
should be attempted prior to radiosurgery.
At our center, the mean time to endocrine remission
after radiosurgery for acromegalic patients was 24 months
which is twice as long as the same milestone for Cushing’s
disease patients. This and other findings suggest a dif-
ferential response of various subtypes of functioning
adenomas to SRS [54]. Please see Table 26.3 for a detailed
summary.
SRS and Prolactinomas
Prolactinomas represent one of the more common types of
secretory pituitary adenomas. However, unlike patients with
acromegaly or Cushing’s disease, prolactinomas are usually
managed medically. For those patients with a medically
refractory prolactinoma or those suffering from side effects
of the medications, radiosurgery may be an option. Since
most patients are successfully managed with medical ther-
apy, patients that undergo radiosurgery likely represent a
more aggressive tumor biology.
The tumor control rate after radiosurgery for a prolacti-
noma is typically is over 90 %. However, the endocrine remis-
sion rates vary after radiosurgery [12, 15, 27, 40, 47, 54, 55,
58–60, 74, 81–90]. Biochemical remission of antisecretory
medications after radiosurgery ranges from 0 to 83 %. The
chance of biochemical remission of a prolactinoma after
radiosurgery tends to be lower than for those with Cushing’s
disease and acromegaly even when taking into account
pre-radiosurgical attributes such as tumor volume [54]. Some
of this variation in endocrine remission rates emanate from
26 Stereotactic Radiosurgery for Pituitary Adenomas 373

Table 26.3 Summary of the literature review for the radiosurgical management of acromegaly
Mean/median Mean/median margin Biochemical Neurological
Year Authors follow-up (months) dose (Gy) remission (%) deficit (%) Hypopituitarism (%)
2000 Izawa et al. 26.4 23.8 41.4 0 0
2000 Shin et al. 42.7 34.4 66.7 6.3 0
2000 Zhang et al. 34 31.3 36.8 2.9 0
2001 Fukuoka et al. 42 20 50 0 0
2001 Ikeda et al. 55.8 25 82 0 0
2002 Feigl et al. 55.2 15 60 NR 40
2002 Pollock et al. 42.4 20 42 0 16
2003 Attanasio et al. 46 20 23 0 6.6
2003 Choi et al. 42.5 28.5 50 0 0
2003 Muramatsu et al. 30 27.5 50 0 0
2003 Petrovich et al. 34 15 NR 3 NR
2003 Witt 24 24 25 0 NR
2005 Castinetti et al. 49.5 25 17 0 17.1
2005 Gutt et al. 22.8 18 47.7 0 NR
2005 Kajiwara et al. 53.5 13.5 0 0 0
2005 Koybayashi et al. 63.3 18.9 4.8 11.1 14.6
2006 Jezkova et al. 53.7 35 50 0 26
2006 Voges et al. 54.3 16.5 37.5 4.2 12.3
2007 Pollock et al. 63 20 50 2.2 33
2007 Roberts et al. 25.4 21 44.4 0 33.3
2007 Vik-Mo et al. 66 26.5 17 3.3 13.1
2008 Jagannathan et al. 57 22 53 4.2 34
2008 Losa et al. 69 21.5 60.2 0 8.5
2008 Pollock et al. 46.9 20 67 0 36
2008 Tinnel et al. 35 25 44.4 11 22
2009 Castinetti et al. 102 24 42 5.3 21
2009 Wan et al. (MASEP 67.3 21.4 36.9 1 1.7
GKS)
2009 Ronchi et al. 120 20 46.0 0 40
2010 Iwai et al. 84 20 38.0 0 8
2010 Hayashi et al. 36 25.2 40.0 0 0
2010 Poon et al. 73.8 20–35 75 0 11.4 % (GKS1);
27.3 % (repeat GKS)
2011 Sheehan et al. 31 24 53 NR 34
2012 Franzin et al. 71 22.5 60.7 0 7.8
Average 52.1 22.6 44.1 1.8 14.7
NR not reported, GKS Gamma Knife surgery, GKS1 first gamma knife procedure

selection biases at radiosurgical centers. As with acromegalic
patients, the chance of endocrine remission appears to be
enhanced when radiosurgery is delivered during a period of
temporary cessation of antisecretory medications [81, 84].
Please see Table 26.4 for a detailed summary.
SRS-Induced Endocrine Remission and Late
Recurrence
SRS yields hormone normalization within a period of time
that is longer than that achieved after surgical extirpation but
shorter than with radiation therapy [91]. After radiosurgery,
patients are typically bridged with suppressive medications.
They are periodically taken off of the antisecretory medica-
tion, and endocrine function is checked. Antisecretory medi-
cations can be halted at the time when a post-radiosurgery
endocrine normalization has been attained. The time interval
in which remission may occur varies from 3 months to 8
years [31, 57, 75]. The majority of radiosurgical reports indi-
cated endocrine remission in Cushing’s disease and acrome-
galic patients within 1–3 years.
Several investigators have identified factors that increase the
probability of endocrine remission. Castinetti and colleagues
[65] contended that preoperative GH and IGF-1 levels are
significantly associated with the rate of post-SRS remission.
374 J.P. Sheehan and B. Williams

Table 26.4 Summary of the literature for the radiosurgical management of prolactinomas
Mean/median Margin Biochemical Neurological
Year Authors follow-up (months) dose (Gy) remission (%) deficit (%) Hypopituitarism (%)
2000 Izawa et al. 28 22 20 0 NR
2000 Landolt et al. 29 25 25 0 NR
2000 Pan et al. 33 32 41 0 NR
2002 Feigl et al. 55 15 NR NR NR
2002 Pollock et al. 42 20 29 14 16
2003 Choi et al. 42.5 28.5 24 0 0
2003 Muramatsu et al. 30 15 0 7.7 0
2003 Petrovich et al. 41 15 83 0 NR
2005 Kajiwara et al. 35.3 17.5 33 4.7 9.5
2006 Pouratian et al. 55 18.6 26 7 28
2006 Voges et al. 56 20 15.4 4.2 18.3
2007 Ma et al. 37 26.1 40 NR 17.6
2008 Pollock et al. 48 30 18 2 45
2008 Tinnel et al. 19.5 30 50 11 22
2009 Castinetti et al. 85.5 30 46.6 5.3 21
2009 Jezkova et al. 75.5 49 37.1 0 14.3
2009 Wan et al. 67.3 35 23.3 1.7 1.7
2009 Kobayashi et al. 37.4 18.4 43.5 in 23 pts 0 0
2010 Tanaka et al. 60 25 17 8 42
2011 Sun et al. 48 23 0 0 0
2012 Liu et al. 36 15 27.3 0 4.5
Average 45.8 24.3 29.2 3.5 15
NR not reported, pts patients

Pollock and colleagues [75] evaluated 46 acromegalic
patients and identified two significant associations. A pre-
radiosurgical IGF-1 level greater than 2.25 times the upper
limit of normal range was significantly associated with a lower
rate of endocrine normalization (HR 2.9, 95 % CI 1.2–6.9).
For patients who had IGF-1 levels less than 2.25 times the
upper limit of normal and were not taking somatostatin ago-
nists at radiosurgery, the rates of biochemical remission
exceeded 80 %. A similar finding was noted by Landolt and
colleagues [92], who demonstrated that the post-SRS remis-
sion rate was lowered from 60 to 11 % for patients taking
octreotide during the radiosurgical period. Somatostatin ago-
nists may lower the radiosensitivity of adenoma cells because
of decreased cell division. Also, somatostatin agonists, such
as octreotide, can act as free radical scavengers and reduce
the DNA damage following ionizing radiation.
This counterproductive effect of antisecretory medica-
tions on radiosurgical outcomes is not exclusive to acromeg-
aly. Landolt and colleagues [92] found a trend toward worse
outcomes in prolactinoma patients on dopamine agonist.
Pouratian et al. [84] analyzed 23 patients with refractory pro-
lactinomas and noted a significant increase in the rates of
remission in patients who were not taking dopamine agonists
at the time of radiosurgery. We have also observed a similar
improvement in endocrine remission for acromegalic patients
who were taken off of pituitary suppressive medications at
the time of their radiosurgery [68].
The effect of pituitary suppressive medications on
radiosurgical outcome remains controversial. Reports have
not been entirely consistent regarding the importance of a
temporary cessation of suppressive medications at the time
of radiosurgery [55, 64, 65, 75, 76, 81, 92]. Two groups ana-
lyzed remission rates after radiosurgery among patients on
somatostatin agonists, and they failed to identify an associa-
tion between the use of somatostatin agonists and endocrine
remission [64, 65]. However, the definition of endocrine
remission has not been well defined across series [52, 66].
Second, the length of follow-up in retrospective series varies
widely. Pollock et al. [75] demonstrated that remission con-
tinued to occur for up to 5 years following radiosurgery,
whereas in the report by Castinetti and colleagues [65], 44 %
of their patient population received their final endocrine
evaluation less than 3 years after radiosurgery. At the
University of Virginia, we advocate the cessation of suppres-
sive medication for 6–8 weeks around the radiosurgery.
There does appear to be a differential radiosensitivity
between specific types of functioning adenomas [54, 59, 86].
Cushing’s disease demonstrates the highest rates of bio-
chemical remission, followed by acromegaly, prolactinomas,
and Nelson’s syndrome. This difference in response after
radiosurgery has been attributed to patient selection, tumor
volume, radiation dose, use of suppressive medications,
and duration of follow-up [54, 86]. Pollock et al. [54]
reviewed a retrospective series of 46 pituitary adenoma patients.
26 Stereotactic Radiosurgery for Pituitary Adenomas
This case-controlled study demonstrated variations in
endocrine remission after SRS for various types of secretory
adenomas. The study and others suggest a differential radio-
sensitivity for adenoma types, but the underlying cause for
this variable response remains unclear.
A few cases of recurrence following radiosurgical-
induced remission have been reported [46, 76]. However,
recurrence rates of up to 20 % have been reported. This
underscores the importance of long-term radiographic and
endocrine follow-up for patients with secretary pituitary
adenomas.
Adverse Events from Radiosurgery
Adverse events following radiosurgery for a pituitary ade-
noma occur in only a minority of patients. Hypopituitarism
is the most frequently occurring side effect from radiosur-
gery. Most radiosurgical series demonstrate that 30 % of
patients will eventually develop some form of pituitary defi-
ciency after radiosurgery. Post-radiosurgical dysfunction if it
occurs generally involves the anterior pituitary axis but can
involve the posterior pituitary axis or very rarely lead to pan-
hypopituitarism. Hypopituitarism has been correlated to the
radiosurgical treatment volume, with those patients having a
tumor volume ≤ 4.0 cm3 exhibiting an 18 % 5-year risk of
hypopituitarism versus 58 % for those with larger lesions
[54]. The risk of hypopituitarism after radiosurgery is likely
to be related to the pre-radiosurgical status of the normal
pituitary gland, the type and timing of prior treatments, the
radiosurgical dose delivered to the normal gland, the dose
delivered to the pituitary stalk, and the rigorousness and
length of the endocrine follow-up assessment period. An
absolutely safe radiosurgical dose or dose per volume so as
to avoid hypopituitarism probably does not exist. Some have
advocated surgical placement of a spacer between the resid-
ual adenoma and pituitary gland if postoperative radiosur-
gery is contemplated [93]. Delivery of an optimal dose to the
adenoma should not be compromised with the hope of avoid-
ing hypopituitarism. Adenoma progression or persistence of
Fig. 26.1 A 57-year-old male presented with a recurrent, nonfunction-
ing pituitary adenoma. He had two prior transsphenoidal resections. (a)
The patient underwent SRS in which 15 Gy was delivered to the tumor
margin. Four years later (b), the pituitary adenoma had decreased in
375
a hypersecretory state is a more significant threat to most
patients than delayed hypopituitarism. Hypopituitarism can
usually be managed with hormonal replacement.
The second most common toxicity is a cranial neuropa-
thy. Cranial nerves II, III, IV, V, and VI are located in the
parasellar or suprasellar regions and are at risk for injury
after radiosurgery. In the absence of tumor growth, such neu-
ropathies after radiosurgery occur in very few patients.
Improved conformality, steeper dose gradients, and adequate
shielding help to minimize this risk [91]. Other rare toxici-
ties include radiation necrosis of the adjacent parenchyma
[54, 59, 60, 76], internal carotid artery narrowing [76, 94],
and radiation-induced secondary malignancy [95]. No cases
of radiation-induced secondary malignancies have been
reported to date after SRS for pituitary tumors. Based upon
the available literature, the risk of serious and permanent
complications after radiosurgery for a pituitary adenoma is
quite low.
Conclusions
SRS plays a significant role in the contemporary manage-
ment of pituitary adenoma patients. SRS is typically per-
formed in patients with substantial residual tumor or
recurrence after resection. It is also used for patients with
functioning adenomas that fail to achieve endocrine remis-
sion after a prior resection. Even when the adenoma resides
in the cavernous sinus, neurological function after SRS is
usually preserved. Delayed hypopituitarism is the most com-
mon complication but still occurs in a minority of patients.
Permanent and uncorrectable complications after radiosur-
gery are rare. Long-term follow-up for pituitary adenoma
patients undergoing radiosurgery is recommended.
Case 26.1: A patient had a nonsecretory adenoma involv-
ing the right side of the sella and cavernous sinus (Fig. 26.1a).
The patient underwent Gamma Knife radiosurgery in 2005.
The adenoma was treated with 16 Gy to the periphery
(Fig. 26.1b). The patient had marked regression of his tumor
as shown on this MRI from 2013.
size and demonstrates diminished contrast enhancement. (c) Six and
one-half years after radiosurgery, the patient’s adenoma continues to
regress. All images are post-contrast, coronal MRIs
376
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 Pituitary Tumors: Viewpoint—Surgery
Khaled M. Krisht, William T. Couldwell,
and Martin H. Weiss
Introduction
Since the first recorded attempt at resection of a pituitary
tumor in an acromegalic patient via a staged lateral subtem-
poral approach by Caton and Paul [1], surgical approaches
to the sellar, suprasellar, and parasellar regions have under-
gone a profound evolutionary change, with refinements in
both microsurgical technique and instrumentation. In addi-
tion, the advent of both microscopic and endoscopic means
for improved visualization and understanding of the
nuances of sellar and suprasellar pathology has created an
algorithmic and structured approach to treating sellar
pathology, especially in dealing with pituitary adenomas.
The first successful removal of a pituitary tumor via a supe-
rior nasal transsphenoidal approach was reported in 1907
by Schloffer (Fig. 27.1) [2–4]. Owing to the disfiguring
effects of this approach, Cushing used the sublabial trans-
septal technique, which he later abandoned in favor of the
transcortical route in part because of the large number of
recurrent tumor cases he observed in his practice [5, 6]. It
was not until 50 years later that Guiot and Hardy further
refined and popularized the transsphenoidal technique,
reintroducing it back to the United States [7]. This chapter
will review the management strategies and decision making
K.M. Krisht, M.D. • W.T. Couldwell, M.D., Ph.D. (*)
Department of Neurosurgery, Clinical Neurosciences Center,
University of Utah, 175 North Medical Drive East,
Salt Lake City, UT 84132, USA
e-mail: neuropub@hsc.utah.edu
M.H. Weiss, M.D.
Department of Neurological Surgery, Keck School of Medicine,
University of Southern California, 1200 North State Street, Suite
3300, Los Angeles, CA 90089, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_27, © Springer Science+Business Media New York 2015
27
concerned with treating pituitary adenomas, with special
emphasis on surgical approaches and technique and the role
of stereotactic radiosurgery (SRS).
Indications for Surgery
The gold standard for treating both symptomatic extra-
glandular nonsecreting and glandular secreting pituitary ade-
nomas, with the exception of prolactin-secreting tumors, is
surgical resection. A trial of medical therapy with octreotide or
cabergoline for growth hormone (GH)-secreting tumors may
be warranted (especially in GH–prolactin (PRL)-cosecreting
tumors). Ketoconazole may be used for adrenocorticotropic
hormone (ACTH)-secreting tumors as an initial mode of ther-
apy in patients with multiple comorbidities or in those patients
who are reluctant to undergo surgery [8–12]. In patients who
fail to respond to medical therapy or those who experience
intolerable side effects, surgical resection becomes necessary.
In certain instances of progressive visual loss caused by
increasing mass effect or in cases of sudden onset of visual
loss or ophthalmoplegia associated with severe headache and
acute adrenal insufficiency as with pituitary apoplexy, emer-
gent surgical decompression of the optic apparatus along with
steroid replacement is warranted [13–16]. The general goals
of surgery are removal of the tumor mass with decompression
of the optic apparatus, normalization of hormonal hypersecre-
tion, and preservation of normal pituitary function (Fig. 27.2).
Radiation therapy, either fractionated radiosurgery or gamma
knife surgery, may be used as part of a planned combination
therapy for large tumors extending into the cavernous sinus
with internal carotid artery encasement, as a salvage treatment
for recurrent tumor, or as the primary mode of treatment for
patients who are poor surgical candidates [17–20].
379
380
Fig. 27.1 Schloffer’s transnasal transsphenoidal operation. (a) Incision
made along the left nasolabial furrow around the left ala nasi and con-
tinued up to the glabella. (b) The incision cuts through the skin, nasal
bone, philtrum, and the anterior part of the septum. The whole external
nose is reflected to the right, exposing the remainder of the septum. (c)
The rest of the nasal septum has been removed, exposing the rostrum of
the sphenoid sinus. (d) The anterior wall of the sphenoid sinus is
opened, the mucosa lining of the sinus is removed with a sharp spoon,
and the floor of the sella is removed with a small chisel or punch for-
ceps. (From: Cope VZ: The pituitary fossa, and the methods of surgical
approach thereto. Br J Surg 4:107–144, 1916)
Endocrinologic, Anesthetic,
and Radiographic Considerations
and Planning
The radiographic features of the pituitary tumor and its associ-
ated endocrinopathies have important medical, anesthetic, and
surgical implications. Before considering surgical intervention,
control and medical management of any preexisting medical
conditions and endocrinologic abnormalities should be insti-
tuted. This is best accomplished in an interdisciplinary manner
K.M. Krisht et al.
with the help of an endocrinologist. Hyperthyroidism should
be treated with thyroxine, with the aim of reducing cardiac and
sympathetic overactivity. Elevated blood sugar levels caused
by GH- and ACTH-secreting tumors should be managed.
Conversely, patients with hypoactive pituitary function should
receive appropriate replacement therapy to reestablish homeo-
stasis before undergoing surgery [12, 21, 22]. All patients
should have baseline fasting pituitary laboratory measurements
including prolactin, thyroid-stimulating hormone (TSH), free
T4, ACTH, and fasting AM cortisol; follicle-stimulating hor-
mone, luteinizing hormone, GH, and insulin-like growth factor
(IGF-1); and testosterone (in males) and estradiol (in females)
levels [11, 23, 24]. Patients with visual disturbance should
undergo a formal baseline visual field and acuity testing by a
neuro-ophthalmologist [25]. Special attention should be paid to
thyroid and steroid replacement; low levels of these hormones
may result in increased surgical and perioperative risk, and they
should be replaced accordingly. Hypocortisolemia may be
replaced acutely with intravenous corticosteroids, but thyroid
hormone deficit may take several days to replace.
In planning for surgery, the anesthesiologist should be
cognizant of the medical and physical stigmata of the pitu-
itary tumor–related endocrinopathies because they have
important implications with regard to preoperative care and
readiness. Patients on bromocriptine therapy may suffer from
gastroparesis and have occasional vomiting [16, 23, 26].
Such patients should be appropriately identified and suitable
measures taken to control their nausea and prevent aspira-
tion. Acromegalic patients should be evaluated for sleep
apnea, snoring, and airway changes prior to intubation
[27–29]. In addition, electrocardiography and a transthoracic
echocardiogram to evaluate for baseline left ventricular
function are warranted since patients with acromegaly are at
risk for hypertrophic cardiomyopathy [30, 31]. If an arterial
line is required throughout the case, especially in patients
with known hypertension, some anesthesiologists will advo-
cate placing the line in the dorsalis pedis artery since acro-
megalic patients may have an impaired ulnar artery
circulation. In the event that a radial arterial line is contem-
plated, an Allen test should be performed to document good
collateral flow [32]. Cushingoid patients with hypercorti-
solemia are easily bruised, and their peripheral veins can be
difficult to cannulate [16]. Special care in both positioning
and venous access should be practiced in such patients.
Intravenous hydrocortisone (100 mg) may be given at the
start of the procedure to prevent diabetes insipidus resulting
from antidiuretic hormone deficiency [23, 24, 33]. The anes-
thesiologist also needs to be mindful of the very short clo-
sure time involved at the conclusion of the resection to
adjust the anesthetic dose accordingly in preparation for
awakening. In the rare instance that air is to be injected
through a lumbar drain to elevate the cerebrospinal fluid
pressure and aid in the delivery and resection of a suprasellar
27 Pituitary Tumors: Viewpoint—Surgery
Fig. 27.2 (a) MR images of the brain with gadolinium enhancement
demonstrating a large sellar and suprasellar GH-secreting pituitary
macroadenoma in a 36-year-old acromegalic woman who presented
with a 4-year history of amenorrhea and a GH level of 60 ng/mL. Gross
total resection was achieved via a transnasal transsphenoidal resection.
(b) MR images of the brain with gadolinium enhancement showing a
sellar ACTH-secreting pituitary adenoma with extension into the region
component of the tumor (a practice that is not employed at
our facility), the anesthesiologist should eliminate nitrous
oxide from the anesthetic gas mixture to prevent tension
pneumocephalus [34].
The surgical route of choice is best determined by careful
inspection and evaluation of the morphology of the tumor of
interest and the area it occupies on thin-sliced coronal and sag-
ittal magnetic resonance images through the sellar region
while considering ease of access and patient safety. The vast
majority of pituitary tumors are removed via the transsphenoi-
dal approach. Lesions confined to the sella without any supra-
sellar extension can be easily resected via a transsphenoidal
route. Despite the suprasellar extension of some sellar lesions,
however, transsphenoidal surgery may still be used as long as
the tumor appears to be centrally located and symmetric. The
“hour-glass” or “dumb-bell” appearance of a tumor may
necessitate a combined approach for maximal safe resec-
tion, if the tumor does not descend from below [35–38].
Asymmetric extension of the tumor either anteriorly or
posteriorly may pose a challenge for the surgeon attempt-
ing to tackle it via a transsphenoidal approach but may be
381
of the left cavernous sinus in a 38-year-old Cushingoid woman who
presented with an elevated fasting serum cortisol level of 99 μg/dL and
significantly elevated 24-h urinary cortisol. The patient underwent a
microscopic transsphenoidal resection of her tumor with endoscopic
assistance. A cure was achieved with a drop in her postoperative
cortisol level to 1.7 μg/dL. She was subsequently placed on hormone
replacement therapy
amenable to transsphenoidal resection with wider removal of
the skull base for exposure. Some lesions are fibrous in consis-
tency, making them difficult to resect through a transsphenoidal
route, especially in cases where the tumor may be adherent to
important nearby neurovascular structures, or masking impor-
tant arterial feeders such as the superior hypophyseal artery sup-
plying the optic chiasm [35, 37, 39–41]. Another important
consideration is the proximity of the tumor to the intracavern-
ous carotid arteries. This is particularly important for identify-
ing deviations of the eccentric carotid arteries, which may
deviate into a midline trajectory and preclude a transsphenoidal
approach [37]. Fine-cut computed tomography (CT) of the head
with three-dimensional reconstruction helps identify important
bony landmarks, demonstrate the extent of sellar expansion,
and elucidate any evidence of tumor erosion through the sellar
wall. This becomes increasingly important in repeat transsphe-
noidal surgeries in which the normal anatomy is perturbed and
may therefore be misleading [37, 42]. In such a scenario, a
stereotactic CT scan is useful for stereotactic neuronavigation,
which helps to confirm midline and avoid inadvertent injury to
the carotid or violation of the anterior fossa space.
382
Surgical Approaches to the Pituitary
The Direct Microscopic Endonasal
Transsphenoidal Approach
Hirsch was the first to adopt the endonasal route to the
sphenoid sinus using multiple-staged operations including
resection of the middle turbinate and ethmoidectomy [43].
Despite his success, however, he changed his technique to a
transseptal approach. Almost eight decades later, in 1987,
Griffith and Veerapen revived the endonasal approach to the
sphenoid sinus [44].
The patient is placed in the supine “reflex” position with
the knee and body slightly bent at the mid-position to pre-
vent entrapment neuropathy, venous pooling, and patient
slippage (Fig. 27.3). The head is slightly tilted to the contra-
lateral side, the neck is flexed, and the head is extended at
the occipitocervical joint and slightly turned toward the
surgeon. This ensures that the face is parallel to the floor
Fig. 27.3 Patient and operating room positioning for the transsphenoi-
dal approach. The head is elevated 15° above to reduce venous bleeding.
The head is tilted toward the left shoulder to facilitate endonasal expo-
sure. (From: Couldwell WT, Weiss MH. The transnasal transsphenoidal
approach. In: Apuzzo MLJ, ed. Surgery of the third ventricle. 2nd ed.
Baltimore: Williams & Wilkins; 1998. p. 553–74, with permission)
K.M. Krisht et al.
and places the sphenoid ostia in the direct line of sight of
the surgeon. The head may be fixed in a three-point Mayfield
frame or on a horseshoe head holder and secured with tape.
At least 10 min prior to incision, the nostrils are packed with
oxymetazoline-soaked cottonoids to allow shrinkage of the
turbinates and to optimize hemostasis during initial expo-
sure. We no longer routinely prep the nose. The ipsilateral
thigh or abdomen is prepped and draped for harvest of fat
and fascia. Some surgeons use intraoperative C-arm fluo-
roscopy for guidance; however, we prefer to use such assis-
tance only in selected cases. The rostrum of the sphenoid is
identified at the level of the superior aspect of the distal
middle turbinate with direct vision using a handheld specu-
lum. The sphenoid ostium is found as the superior landmark
of the opening of the rostrum just at the level of the inferior
border of the superior turbinate. The perpendicular plate of
the ethmoid is fractured at the junction of the sphenoid
rostrum. A self-retaining nasal retractor is placed with the
remnant of the perpendicular plate of the ethmoid in the
midline. The mucosa are elevated away from each side of
the sphenoid rostrum. The sphenoid ostia should become
visible, and the sphenoid rostrum is removed with the aid of
micro rongeurs or a high-speed drill. The sella is identified,
and the bone over the sella is removed with micro rongeurs.
A #11 blade is used to create a durotomy in an X-fashion,
and then small, angled microscissors are used to further
open the dura to the extremes of exposure desired (Fig. 27.4).
With large tumors, the intracranial pressure helps deliver the
tumor when the dura is opened. First, the floor of the tumor
is removed with curettes. Then, the lateral aspects of the
tumor are removed to enable descent of the large center part
of the tumor. Four-quadrant curettage with various Hardy
ring curettes allows further tumor removal from lateral,
superior, and inferior recesses. Closure begins with packing
the resection site with adipose tissue. The septum is reduced
to the midline, and the authors elevate the middle turbinates
on both sides to ensure unimpeded drainage of the maxillary
sinuses. The authors employ well-lubricated, soft, curved
Rhino Rocket tubes covered with a piece of latex as airway
tubes, which are carefully placed posteriorly into the naso-
pharynx [45, 46].
Advancements in Endoscopic Surgery
The successful reintroduction of the pure endonasal route
paved the way for the use of endoscopic surgery in address-
ing sellar and suprasellar lesions [47, 48]. There are many
advantages to the employment of endoscopy as a sole or
supplemental tool for the resection of pituitary lesions. The
endoscope provides a panoramic view of the sphenoid sinus
and its important bony impressions. It also affords the
27 Pituitary Tumors: Viewpoint—Surgery
Diaphragm
Subfrontal arachnoid of sella
spaces
Hypothalamus
Dura
A
Sphenoid
sinus
Tumor
Window in
sella turcica
B
C
Fig. 27.4 Tumor removal. Tumor is readily removed with various
curettes and scoops. It is imperative that the integrity of the arachnoid is
preserved to minimize the potential for a postoperative cerebrospinal
surgeon with the ability to zoom in on areas of interest such
as the tumor–gland interface and obtain a sharpened close-up
view. Lenses of various angles on the endoscope allow the
operator to look into anatomic corners of the suprasellar
region that otherwise cannot be seen with the conventional
microscope. Additionally, there is no displacement of the
midline septum, and nasal packing and retraction are not
needed [49–52]. Notwithstanding the improved and versatile
visibility afforded by endoscopic transsphenoidal surgery,
the technique is not without pitfalls. In general, more of the
nasal septum is resected to allow adequate visual access.
With endoscopic surgery, the surgeon’s field of view is
383
Anterior Optic
cerebral a. chiasm Infundibulum
Tumor
Basilar a.
Arachoid
Dura
Arachnoid
Diaphragm
E
F
fluid fistula. (From: Couldwell WT, Weiss MH. The transnasal transsphe-
noidal approach. In: Apuzzo MLJ, ed. Surgery of the third ventricle. 2nd
ed. Baltimore: Williams & Wilkins; 1998. p. 553–74, with permission)
reflected on a screen as a two-dimensional image, which
results in loss of the sharp and focused stereoscopic view and
depth perception provided by the microscope. In addition,
there is a steep learning curve for the neurosurgeon inexperi-
enced in endoscopy [53–55]. In our hybrid practice, we have
been increasingly employing the endoscope as a supplemen-
tal tool for inspecting areas that are hidden from the field of
view of the microscope in all of skull base surgery. In lateral
and extreme anterior and posterior tumor rests, and those that
are buried behind redundant folds of suprasellar arachnoid as
well as in cases of tumor extending into the cavernous sinus,
the endoscope is a valuable tool.
384 K.M. Krisht et al.

Modifications of the Transsphenoidal Optic chiasm Dura of

Tumor tuberculum
Approach
Arachnoid Recess of sellae Circular
infundibulum sinus
The standard transsphenoidal approach is used in most cases A
of pituitary tumors with sellar and suprasellar extension;
however, regions of the skull base that were once thought
only accessible “from above” are now being approached
transfacially. With better knowledge of microsurgical anat-
omy and modern microinstrumentation, neurosurgeons have
Dura over
modified the transsphenoidal approach to gain better access
B pituitary
to regions such as the cavernous sinus and the suprasellar
cisterns.
Fraioli et al. [56] treated 11 patients with sellar tumors
invading the medial wall of the cavernous sinus with a trans-
maxillosphenoidal approach, which involves a unilateral, bilat-
eral, or Le Fort maxillary osteotomy and removal of the
medial wall of the maxillary sinus in addition to the standard Dural opening
transsphenoidal exposure. It allows direct visualization of the
C
intracavernous carotid artery during tumor resection but is
limited by extension of tumor lateral to the carotid artery. Sabit
et al. [57] described a safe, minimally invasive combined trans-
maxillary transsphenoidal approach to the cavernous sinus
that is both extradural and extranasal. This approach provides
adequate lateral-to-medial reach in the parasellar and infrasel- Tumor
Tumor seen
lar regions with visualization of the entire ipsilateral cavern- through arachnoid
ous sinus and the medial aspect of the contralateral cavernous Pituitary
sinus. The extended transsphenoidal approach to tumors of
Circular sinus
the tuberculum sellae and suprasellar cistern was first described
by Weiss [58]. Suprasellar tumors without sellar enlargement D Dural flap
have been successfully resected using a modified transsphe-
Fig. 27.5 (a–d) Modification of the transsphenoidal approach: expo-
noidal approach that involves a wide bone exposure of the
sure of the anterior skull base (extended transsphenoidal). A pure supra-
anterior surface of the sella and removal of the posterior por- sellar tumor may be approached by extending the bony resection
tion of the planum sphenoidale [59, 60]. This novel approach anteriorly over the tuberculum sellae, thus exposing the dura mater
has allowed resection of craniopharyngiomas, central nervous lying anterior to the circular sinus. An incision is made in the dura ante-
riorly and inferiorly to the circular sinus. The sinus is then coagulated
system hemangioblastomas, and ectopic ACTH-producing
and transected to gain a direct view of the suprasellar cistern without
adenomas arising from the pituitary stalk [59, 60]. disturbing the pituitary gland. (From: Couldwell WT, Weiss MH. The
Additional exposure of the skull base for lesions of the transnasal transsphenoidal approach. In: Apuzzo MLJ, ed. Surgery of
parasellar and clival region can be achieved by extended the third ventricle. 2nd ed. Baltimore: Williams & Wilkins; 1998.
p. 553–74, with permission)
transsphenoidal approaches [36]. Various portions of the
skull base may be exposed, and bone resection can be
extended by repositioning the patient’s head and the self- Jho and Carrau [52] reported encouraging results in a
retaining speculum. The standard transsphenoidal approach series of 50 patients who underwent endoscopic endonasal
can be extended anteriorly to resect suprasellar lesions, infe- transsphenoidal surgery. One of the main advantages of
riorly to expose clival lesions, and inferolaterally to access this approach is excellent panoramic visualization of the
cavernous sinus lesions (Figs. 27.5, 27.6, and 27.7) [36]. sellar and suprasellar anatomy with increased illumination
These variations on the transsphenoidal approach provide a and magnification [48]. Anatomic studies have demon-
minimally invasive technique that avoids prolonged surgery strated that the endoscope provides a volume of exposure
and brain retraction. superior to that of the operating microscope [54], but dis-
Technological advances in the areas of endoscope- advantages include the lack of stereoscopic vision, the
assisted microneurosurgery [47, 49] have been applied to lack of adequate instrumentation, the limited space of
the classical transsphenoidal operation in an attempt to working through one nostril [49], and a learning curve for
further decrease morbidity and mortality risks [47, 52, 55]. using this technique.
27 Pituitary Tumors: Viewpoint—Surgery 385

Sphenoid
sinus Rostrum Chordoma
Clivus

Soft
palate
Pharynx

Fig. 27.6 Modifications of the transsphenoidal approach: inferior exposure additional exposure to the mid and lower clivus requires more inferior
of the clivus. Exposure of the clivus is facilitated by slight flexion of the exposure. (From: Couldwell WT, Weiss MH. The transnasal transsphenoidal
patient’s head and repositioning of the nasal self-retaining retractor to point approach. In: Apuzzo MLJ, ed. Surgery of the third ventricle. 2nd ed.
inferiorly. The upper clivus lies directly posterior to the sphenoid sinus, but Baltimore: Williams & Wilkins; 1998. p. 553–74, with permission)

A B
Floor of Dura of sella
sella Floor of sella Dura over pituitary gland,
cavernous sinus, and ICA

Area of bone
removal

Sphenoid
sinus

Wall of sphenoid
Cavernous sinus
Pituitary
gland sinus
ICA
NII
Dural
NIII
incision
NIV
enlarged
NV

Sphenoid
sinus
Tumor
exposed
Area of
bone removal

Fig. 27.7 Modification of the transsphenoidal approach: inferolateral
exposure of the cavernous sinus. (a) After exposure of the dura overly-
ing the sella, the bone overlying the cavernous sinus, including that
overlying the carotid grooves, is carefully removed. This removal
defines the lateral extent of the exposure limited by the cavernous cra-
nial nerves. (b) The dura medial to the internal carotid artery is first
incised with a size 11 blade and opened with curved alligator microscis-
sors. Removal of the intracavernous portion of the tumor is carried out
with a microcurette. (From: Couldwell WT, Weiss MH. The transnasal
transsphenoidal approach. In: Apuzzo MLJ, ed. Surgery of the third
ventricle. 2nd ed. Baltimore: Williams & Wilkins; 1998. p. 553–74,
with permission)
386
Fig. 27.8 A giant hemorrhagic pituitary macroadenoma in a 44-year-
old man who presented with progressive left-sided weakness and
visual disturbance. There are areas of scant enhancement with exten-
sion into the suprasellar and prepontine cisterns exerting mass effect
Transcranial Surgery for Pituitary Tumors
With the increasing popularity of the transsphenoidal micro-
scopic or endoscopic approach, the indications for transcra-
nial approaches have become few. There are instances where
the transsphenoidal route cannot be employed despite agree-
able tumor morphology and location. Such is the case in
patients with severe sphenoid sinusitis or midline “kissing”
internal carotid arteries [40, 41]. In other instances, a large
eccentric suprasellar component of the tumor may be difficult
to access from a transsphenoidal approach without putting
the patient at risk (especially extensions lateral to the supra-
sellar carotid artery) (Fig. 27.8). For these scenarios, a tran-
scranial approach would be a safer and more suitable option.
The two most widely used transcranial approaches are the
pterional (frontotemporal) approach, which was first
described in detail and popularized by Yasargil [61], and the
anterior subfrontal approach. The pterional approach presents
the shortest transcranial trajectory to the suprasellar cistern
and should be the method of choice in a patient with a pre-
fixed chiasm since the tumor can be resected inferior, supe-
rior, and posterior to the chiasm. In the case of a postfixed
chiasm where the tumor lies between the two optic nerves,
the subfrontal approach gives the surgeon a straight frontal
trajectory with direct visualization of the tumor [35, 39–41].
In performing the latter approach, the surgeon has to be mind-
ful of the location of the frontal sinus to avoid a breach and to
make every effort to preserve the olfactory nerves. On rare
occasions when a large proportion of the tumor lies within the
third ventricle, an interhemispheric transcallosal approach
may be warranted either as a stand-alone approach or in com-
bination with a pterional craniotomy [36, 40, 41].
K.M. Krisht et al.
on the hypothalamus, right medial temporal lobe, and right basal
ganglia with encasement of bilateral cavernous carotid arteries. This
lesion was resected via a transcranial route using a standard pterional
craniotomy
Radiation Therapy and Radiosurgery
of Pituitary Tumors
Improvements in radiation techniques with the development
of medical linear accelerator systems and the enhancement in
stereotactic brain imaging have led to more effective and
safer radiation treatments. Today, both radiation therapy
(XRT) and SRS play an important role in treating recurrent
pituitary tumors in patients with hypopituitarism who may
not tolerate surgical re-resection and residual tumors invad-
ing the cavernous sinus [62–67]. In the latter case, fraction-
ated radiotherapy can provide excellent tumor control without
risking injury to the nearby cranial nerves. XRT has the
potential of delivering high dosages of radiation (up to 45 Gy)
directly to the tumor site while reducing radiation to the sur-
rounding structures. With fractionated radiotherapy, the
45-Gy dose is given over 5 weeks in fractionated doses of
1.8 Gy/day, 5 days a week [68, 69]. SRS uses stereotactically
focused high-energy proton particles generated by a cyclo-
tron to irradiate the tumor. The highest dose possible is deliv-
ered in a focused manner while keeping the dose to the optic
apparatus less than or equal to 8 Gy [69–71]. The preliminary
data for tumor control and normalization of hypersecretory
states after radiosurgery appears promising for GH- and
ACTH-secreting pituitary adenomas [69–73]. XRT and SRS,
however, rarely normalize prolactin levels in patients with
prolactinomas. In fact, radiotherapy may have the opposite
effect of elevating the prolactin level secondary to disruption
of the tuberohypophysial pathway [66, 70, 72]. Despite the
positive and encouraging results experienced with XRT, sur-
gical resection remains the initial mainstay treatment for both
27 Pituitary Tumors: Viewpoint—Surgery
Fig. 27.9 Pituitary transposition (hypophysopexy) with planned
radiosurgical treatment of residual cavernous sinus tumor. Acromegalic
young female with residual tumor within the cavernous sinus follow-
ing hypophysopexy. Coronal (a) T1-weighted gadolinium-enhanced
MR images demonstrating the relationship of the cavernous sinus
tumor (T), fat graft (F), optic chiasm (OC), and transposed pituitary
gland (P). Isodose curves on coronal image demonstrating doses deliv-
ACTH- and GH-secreting tumors [62–65, 67, 74, 75]. XRT
and SRS do not lead to any substantial visual improvement in
cases where the tumor is compressing the optic apparatus
[18, 71, 72, 76]. In such instances, immediate surgical decom-
pression is required. The reported improvements in hormonal
levels and anatomic features after radiotherapy of hyperse-
cretory tumors take up to 5 years to occur; however, since
metabolic effects of the glandular tumors may be taxing on
many organ systems, especially the cardiovascular system,
prompt and precipitous reduction in the hormonal level
through surgical resection remains an important first-line
treatment measure [70, 71]. Radiosurgery is, however, an
attractive treatment option for recurrent ACTH-secreting
387
ered to surrounding tissues on coronal (b) and axial images (c). Note
lateral displacement of the gland by the interposed fat graft on coronal
image. Diagram representing dosimetry target in relationship to brain-
stem and optic apparatus with transposed pituitary in green (d). (From
Couldwell et al., Hypophysopexy technique for radiosurgical treat-
ment of cavernous sinus pituitary adenoma. Pituitary 5:169–173, 2002;
used with permission)
tumors as a stand-alone treatment or in combination with a
planned transsphenoidal re-resection as well as in cases of
recurrent tumors with hypopituitarism and difficult to access
locations as discussed above [17–20]. The proximity of the
pituitary gland to the region of interest increases the risk for
developing hypopituitarism even with SRS. To curtail the
effect of radiation on the pituitary gland in a planned adjuvant
radiosurgery case after transsphenoidal resection, the authors
have developed a technique (hypophysopexy) to transpose the
pituitary gland away from the planned radiation site (residual
tumor within the cavernous sinus) [77–79]. This technique
involves interposing a fat graft between the pituitary gland
and the residual tumor in the cavernous sinus (Fig. 27.9).
388
Treatment of the residual tumor with SRS is facilitated by the
greater distance between the pituitary gland and the tumor,
therefore reducing the radiation exposure to the gland and the
likelihood for developing subsequent hypopituitarism.
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S, et al. The long-term efficacy of conservative surgery and radio-
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 Pituitary and Pituitary Region Tumors:
Viewpoint—Fractionated Radiation
Therapy
Jonathan P.S. Knisely and Paul W. Sperduto
Introduction
Fractionated radiotherapy for pituitary tumors and tumors
arising in the parasellar region has been used for over a cen-
tury. The multidisciplinary nature of optimal management of
tumors of the anterior skull base has been clearly established;
the expertise of endocrinologists, neurosurgeons, radiation
oncologists, neuroradiologists, neuro-ophthalmologists, and
laboratory medicine specialists is commonly required to
optimally manage tumors that arise in the pituitary or pitu-
itary region. The skull base structures surrounding the pitu-
itary gland are anatomically complex and include a number
of important vascular structures and cranial nerves [1], which
can present significant challenges to the surgical manage-
ment of pituitary region tumors. Complete resections with
acceptable operative morbidity can be difficult to achieve.
Iatrogenic damage may occur during the treatment of an
anterior skull base tumor that may result in endocrinologic,
visual, or other neurologic deficits. Radiation can induce
second tumors, accelerate atherogenesis, and cause endo-
crine insufficiencies. It is easy to appreciate the potential of
iatrogenic damage to decrease the quality of life for patients
that may live for decades after an intervention.
Treatment options include the use of microsurgery, medi-
cal therapy, and irradiation. Therapeutic goals include the
destruction of a tumor or control of its growth, controlling
hormonal hypersecretion (if present), and the restoration of
vision or lost function without injuring surrounding normal
neurovascular tissues or inducing pituitary hypofunction.
J.P.S. Knisely, M.D.
Department of Radiation Medicine, North Shore LIJ Health
System, Hofstra North Shore LIJ School of Medicine,
300 Community Drive, Manhasset, NY 11030, USA
P.W. Sperduto, M.D., M.P.P., F.A.S.T.R.O. (*)
Minneapolis Radiation Oncology & Gamma Knife Center,
University of Minnesota, 560 South Maple Street, Suite 10,
Waconia, MN 55391, USA
e-mail: psperduto@mropa.com
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_28, © Springer Science+Business Media New York 2015
28
A newer goal may be the avoidance of delivery of radiation
to the hippocampal structures, to avoid impairing their func-
tions in learning and memory. Radiation may be delivered in
a single radiosurgical dose or a variable number of smaller
doses. Radiation is frequently employed for incompletely
resected tumors, for recurrent tumors, and as a primary treat-
ment for medically inoperable patients and for patients who
refuse a surgical intervention.
This chapter will primarily review the use of convention-
ally fractionated photon radiation therapy (25–30 weekday
treatments, given over a 5- to 6-week time period, in doses of
approximately 1.8 Gy/day) for pituitary adenomas, meningi-
omas, and craniopharyngiomas, all benign anterior skull base
tumors arising in the sella and parasellar tissues. Many of the
management principles and concerns are largely the same for
other benign or for malignant tumors arising in this area.
Epidemiology and Histology
Pituitary Adenomas
Pituitary adenomas represent approximately 10–12 % of all
adult primary intracranial neoplasms; about half of these
pituitary adenomas are hormonally active [2]. Several
autopsy series have detected pituitary adenomas in as many
as 22–25 % of cases [3, 4]. Equal numbers of men and
women develop macroadenomas, and the incidence peaks in
the third and fourth decades of life. Only 10 % of cases arise
in children or adolescents. Individuals with multiple endo-
crine neoplasia type I have a hereditarily increased risk of
developing a pituitary adenoma, and kindreds with an
increased risk of pituitary adenomas without other endocrine
organ neoplasia have also been described.
Pituitary adenomas are classified as either functioning
(endocrine active) or nonfunctioning (endocrine inactive),
with functioning tumors subclassified by the endocrine axis or
axes upon which they act; nonfunctioning tumors are usually
classified as either oncocytic or non-oncocytic (Table 28.1).
391
392 J.P.S. Knisely and P.W. Sperduto

Table 28.1 Pituitary tumor classification recurrence rate that is very low, even if bone adjacent to the
Pituitary adenoma tumor is invaded.
cell type Hormone product Clinical syndrome
Corticotroph ACTH Cushing’s disease
Lactotroph Prolactin Galactorrhea/ Craniopharyngiomas
amenorrhea/impotence
Somatotroph Growth hormone Acromegaly, pituitary
Craniopharyngiomas are rare, representing only a few percent
gigantism
Somatotroph/ Growth hormone Acromegaly and
of all intracranial primary tumors [10]. Craniopharyngiomas
lactotroph and prolactin galactorrhea/amenorrhea arise from either embryonic remnants of an incompletely
Thyrotroph Thyrotropin Hyperthyroidism involuted hypophyseal-pharyngeal duct or from metaplastic
Gonadotroph FSH, LH Hypopituitarism ectodermal cells in the anterior hypophysis [11]. They account
Mixed cell None Hypopituitarism for a significant portion of the intracranial tumors of child-
(non-oncocytic) hood but are as common in adults as in children and adoles-
Oncocytic None Hypopituitarism cents [12]. The age distribution shows a bimodal pattern, with
FSH follicle-stimulating hormone, LH luteinizing hormone a first larger peak between the ages of 5 and 10 years and a
second less prominent peak in the fifth decade, and there is a
The detection of these hormones may be possible by testing very slight male preponderance reported in some large series.
peripheral blood or by doing immunohistochemical staining No recognized hereditary syndromes are associated with
of the tumor. craniopharyngiomas.
Two major histopathologic categories of craniopharyngi-
oma are recognized. There is evidence that they may have
Meningiomas different etiologies [10]. The adamantinomatous variant is
more commonly seen in pediatric patients, and papillary
Meningiomas represent approximately 18–20 % of all pri- squamous tumors are more commonly seen in adults and are
mary brain tumors. Twenty-five percent to 30 % of menin- apparently more likely to be durably controlled by surgery
giomas arise along the base of the anterior and middle alone. There is apparently some occasional intergrading of
cranial fossae in locations such as the cavernous sinus, craniopharyngioma tumor types [12].
tuberculum sellae, Meckel’s cave, or sphenoid wing [5].
The incidence of intracranial meningioma increases with
increasing age, and women are more commonly affected Clinical Presentation
than men by a ratio of approximately 2:1. Meningiomas
are more common in individuals with neurofibromatosis Pituitary Adenomas
type 2, in individuals who have a remote history of cranial
irradiation, and in patients with pulmonary lymphangi- Endocrine abnormalities are the most common presentation
oleiomyomatosis [6]. of pituitary adenomas. Functioning adenomas will manifest
Histopathologically, resected meningiomas from the skull themselves by causing one of the classic endocrine syn-
base should be graded as per the 2007 World Health dromes (Table 28.1). Hormonal insufficiency may arise from
Organization (WHO) guidelines [7]. If there are ≥4 mitoses compression of the normal pituitary gland or of the pituitary
per ten high-powered microscopy fields (HPF) or at least stalk. Insufficiencies may be more subtle than hypersecretory
three features believed to correspond with aggressiveness are states, but either can develop insidiously and only be discov-
seen—small cells, macronucleoli, hypercellularity, necrosis, ered after a protracted period of symptoms. Amenorrhea in
and sheeting architecture—a meningioma is deemed atypical young women and a decreased libido in men may be the signs
(grade II). Brain invasion is an indicator of grade II rather and signals that trigger an evaluation of the hypothalamic-
than grade III behavior in the absence of any histologic ana- pituitary axis.
plasia. A grade III meningioma must have frank anaplasia or Endocrine-active adenomas are more commonly diag-
a mitotic rate of >20/10 HPF. Four variants are considered nosed as microadenomas (<1.0 cm in diameter) than as mac-
innately more aggressive by definition: clear cell (grade II), roadenomas (≥1.0 cm in diameter), but somatotroph or
chordoid (grade II), papillary (grade III), and rhabdoid (grade lactotroph macroadenomas are common. Lateral extension
III). Grade II meningiomas recur at a rate of ~40% at 5 years of pituitary tumors into the cavernous sinus can cause diplo-
time, and grade III meningiomas have a median overall pia or facial sensory symptoms. Superior extension will
survival of <2 years [8, 9]. Grade I tumors have a short-term cause pressure on the optic nerves and chiasm, with a resul-
28 Pituitary and Pituitary Region Tumors: Viewpoint—Fractionated Radiation Therapy
tant bitemporal superior quadrantanopsia or bitemporal
hemianopsia. Frontal headaches may be caused by irritation
of meningeal sensory fibers as the adenoma enlarges.
Meningiomas
The presenting symptoms of meningiomas may be diverse in
these locations but are most commonly from mass effect
upon adjacent normal tissues. The exact symptoms will
depend upon what structures are compressed. The clinical
symptomatology may not be as distinctive as for a functional
pituitary adenoma, and high-quality imaging is frequently
required to determine whether a patient may have a pituitary
adenoma, a meningioma, a schwannoma, or other regional
pathology such as an aneurysm, sarcoid, or another condi-
tion. Involvement of the cavernous sinus will commonly
cause diplopia or facial sensory symptoms; a meningioma
arising from the optic nerve sheath will cause unusual visual
symptoms.
Craniopharyngiomas
These tumors most commonly are diagnosed as a result of
their mass effect upon the optic nerves or from mass effect
upon normal hypothalamic or pituitary function. As these are
generally slow-growing tumors, an insidious loss of function
may occur, so that the degree of compensation for loss of
vision or other deficits may be remarkable at the time of
diagnosis. Increased intracranial pressure may lead to head-
aches and projectile vomiting. The mass effect in adults usu-
ally results in amenorrhea for women and in loss of libido for
men, and if the tumor extends far enough into the cranial
vault, hypothalamic, frontal, or temporal lobe symptoms
may develop. Diabetes insipidus, obesity, and neurocogni-
tive or developmental abnormalities may result from a
craniopharyngioma.
Diagnostic Workup and Staging
All patients with tumors arising in this region should be
managed with a multidisciplinary approach. Not every spe-
cialist needs to see every case, but with a team of specialists
who are comfortable with multidisciplinary care and who are
aware of available therapeutic options, there will be less of a
chance of overlooking tests or therapies that could help
develop individualized safe and effective treatment plans
(Table 28.2).
393
Table 28.2 Diagnostic evaluation of patient with a sellar or parasellar
tumor
History and physical examination with particular attention to signs,
symptoms, and stigmata from hormonal hypersecretion or
hyposecretion and a detailed cranial nerve examination
Laboratory endocrine evaluation (for appropriate patients with
apparent endocrinologic problems, based on clinical assessment, or if
imaging reveals a tumor arising in or extending to the pituitary sella
or suprasellar-hypothalamic region)
Provocative testing of apparently affected axes, with assessment of:
• Serum prolactin level
• Fasting growth hormone level
• IGF-1 level and growth hormone dynamic testing with insulin
tolerance, glucose suppression testing, and thyrotropin-
releasing hormone testing
• Serum ACTH, 24-h urinary free cortisol and
17-hydroxycorticosteroid levels, and response
to dexamethasone suppression testing
• Gonadal function testing with serum LH, FSH levels,
and plasma estradiol and testosterone levels
• Thyrotropin (TSH), thyroxine, and triiodothyronine levels
• Complete blood count (CBC) and coagulation studies
Radiological evaluation including an MRI scan with coronal thin cuts
through the sphenoid bone with and without gadolinium contrast
and possibly also including CT imaging to evaluate bony changes.
Specialized neurointerventional imaging and petrosal venous sinus
sampling may be required in cases of Cushing disease with a
radiographically occult microadenoma
Neuro-ophthalmologic examination for patients with tumors that
impinge upon the optic apparatus or cause cranial nerve abnormalities
affecting vision
For tumors that present with mass effect, surgical debulk-
ing of the tumor may be needed promptly. A neurosurgeon
skilled in skull base and pituitary surgery and knowledgeable
about the use of fractionated irradiation and stereotactic
radiosurgery should be consulted. This surgeon should be
aware of the need to establish a distance between the rostral
surface of the tumor and the optic nerves.
High-dose glucocorticoids may provide temporary
improvement of mass effect while additional evaluations are
performed. An endocrinologic evaluation can determine
whether there are hormonal abnormalities that need to be
addressed before surgery and may also reveal that medical
management is possible as an initial therapy.
Discussion of each case with a neuroradiologist when
imaging studies are being ordered will facilitate obtaining
appropriately detailed studies. A dedicated pituitary mag-
netic resonance imaging (MRI) scan with and without
gadolinium contrast administration will show details of
the relation of the tumor to the optic nerves, chiasm, and
tracts and other critical structures that would affect radia-
tion management options being considered. Pulse
sequences that suppress the bright signal from fat can
394
clarify whether or not enhancing tumor extends into the
orbit. Computed tomography (CT) imaging may show
bone remodeling.
A neuro-ophthalmologic consultation is often warranted
to evaluate the patient for subtle funduscopic abnormalities
or tumor-related vision changes. Serial perimetry is able to
follow visual fields over time in a way that clinical exami-
nation cannot. Clinical evidence of injury to the cranial
nerves controlling extraocular motion should be docu-
mented by a careful observer; improvement is often seen
after irradiation.
When a patient appears to have long-standing neurocog-
nitive issues, it is worth the effort to have the patient evalu-
ated with neurocognitive testing appropriate to the clinical
situation. This can help identify learning issues that may be
addressable with interventions or therapy.
A radiation oncologist should also be asked to evaluate
the patient so that the strengths and shortcomings of different
radiation management strategies may be presented to arrive
at a satisfactory management approach.
Neurosurgical staging systems for anterior skull base
tumors have little applicability to radiation management
decisions [13–15]. The critical issues for radiation manage-
ment decisions for pituitary adenomas and all tumors in the
sellar and parasellar area are the proximity of the tumor to
the optic apparatus and the size of the tumor. Pituitary adeno-
mas and other tumors that are large or that very closely
approach the optic nerves or chiasm are not appropriate for
stereotactic radiosurgery. Fractionated irradiation can be
used for all tumors in this location. Not surprisingly, tumor
volume has been shown to be inversely correlated with long-
term control in patients with pituitary adenomas that are
treated with fractionated irradiation [16].
For meningiomas, the most common staging system
was developed over 50 years ago to provide some guid-
ance as to the risk of recurrence after surgical manage-
ment [15]. Molecular markers may be assessed to help
predict the risk for recurrence after surgical resection [17,
18]. Radiotherapy’s value in controlling meningioma
growth is broadly recognized. If a meningioma is less
than 5 mm from any part of the optic nerves or chiasm,
safe management with radiosurgery is extremely chal-
lenging and in the eyes of many experts carries an unac-
ceptable risk of radiation optic neuritis, although
fractionated radiation can be used.
There is no accepted staging system for craniopharyn-
giomas, which are frequently densely adherent to adjacent
normal tissues. Aggressive surgical resections may be
complicated by intraoperative damage to normal tissues
involved with the tumor. Irradiation may also cause mor-
bidity but generally is not as likely to cause an acute loss
of function. Radiation options include fractionated
J.P.S. Knisely and P.W. Sperduto
irradiation, stereotactic radiosurgery, and instillation of
radioisotope colloids into cystic tumors.
Usual Therapeutic Approaches
Radiation therapy is usually deferred until after any oper-
ative neurosurgical management has been completed.
This is because surgery is able to address both mass effect
(if present) as well as hormonal hypersecretion (if the
tumor in question is a hormonally active pituitary ade-
noma). For some pituitary adenomas (prolactinomas,
growth hormone-secreting adenomas, and thyroid hor-
mone-secreting adenomas), it is possible to use pharma-
cologic management with specific action at the
hypothalamic-pituitary axis and avoid or defer surgical
therapy or radiation therapy [19–21]. Neither meningio-
mas nor craniopharyngiomas have systemic management
options similar to those for functioning pituitary adeno-
mas. Meningiomas may be detected incidentally and
found to be without clinical signs or symptoms. As these
tumors are generally slow growing, documenting the rate
of growth prior to pursuing definitive interventions may
be useful, as no intervention is without risk. Some menin-
giomas and most craniopharyngiomas are detected
because of clinical signs or symptoms from the tumor’s
presence at the skull base. In some of these cases, a crani-
otomy may be needed to try to alleviate mass effect and
bring about a recovery of function, but it may not be
appropriate for all cases, when radiation management
options exist that are likely to be highly effective.
After an initial therapeutic intervention (usually surgery),
it is common to repeat many elements of the battery of tests
that were performed at the time of diagnosis to document any
changes in neurologic, ophthalmologic, or endocrinologic
function (Table 28.1). Documentation of improvements and
deficits will allow them to be accurately attributed to the
effects of the tumor, to the initial intervention, or to subse-
quent therapy.
If there is consideration being given to the use of stereo-
tactic radiosurgery for a tumor that preoperatively was docu-
mented to be very close to the optic nerves, volumetric
contrast-enhanced MRI must be repeated to ensure that the
tumor has been adequately debulked away from the optic
apparatus. This geometric separation of several millimeters
between the tumor and the optic apparatus is not as critical if
fractionated irradiation will be used as a postsurgical ther-
apy. The optic nerves will tolerate fractionated doses of radi-
ation to ~50–55 Gy used to durably control most tumors in
this area, while a radiation dose >8 to 10 Gy given to the
optic nerves in a single fraction will cause vision loss in an
unacceptably high number of patients [22–25].
28 Pituitary and Pituitary Region Tumors: Viewpoint—Fractionated Radiation Therapy
Radiation Therapy
The role of radiotherapy in the management of anterior skull
base tumors has waxed and waned over the past century.
Radiotherapy treatment for pituitary adenomas and parasel-
lar tumors is currently delivered with a very high degree of
precision, is extremely well tolerated, and provides excellent
outcomes by delivering a cytostatic or cytocidal dose of radi-
ation to the tumor while not exceeding the radiation toler-
ance of adjacent normal tissues.
Current radiation therapy techniques are greatly improved
relative to those of earlier eras. Superior resolution on imaging
of normal anatomy and pathology is a major component of
this, as tumors may be diagnosed earlier in their natural his-
tory. Modern treatment techniques reproducibly immobilize
patients to achieve setup accuracies of approximately 2 mm,
and radiation fields may be shaped to match tumor geometries
and include less normal tissues. Less normal tissue irradiation
will contribute to lower rates of late endocrine hypofunction
and other normal tissue damage. Temporal lobe damage has
been described as a complication associated with historical
radiation therapy techniques [26]. The use of higher-energy
photons and multiple treatment portals to treat centrally
located tumors should decrease the radiation dose delivered to
the temporal lobes. Using more radiation portals may attenu-
ate late neurocognitive sequelae, but the possibility exists that
late radiation-induced tumorigenesis may be increased with
treatment techniques that increase the volume of normal tis-
sues exposed to low doses of irradiation; useful data regarding
incidence rates and dose-volume histograms that might pro-
vide clinical guidance regarding this particular complication
are essentially nonexistent [27]. Despite these advances, if a
tumor is not clearly separated by several mm from any part of
the optic nerves or chiasm, it is generally safer to deliver frac-
tionated radiation therapy than radiosurgery.
Simulation and Radiotherapy Planning
Before radiation treatment can commence, preparatory steps
must occur, and the exact nature of these steps will vary
slightly with the equipment being used to treat the patient.
Radiotherapy treatment techniques have evolved from a dis-
tant era where the distance between the patient’s right and
left temple along the central axis of a pair of opposing X-ray
beams aimed at the presumed location of the tumor was the
critical factor involved in setting up, planning, and deliver-
ing radiation therapy. Current sophisticated radiotherapy
techniques use meticulous care in a series of steps before
any treatment is given to ensure that treatment will be deliv-
ered to the tumor being targeted only as prescribed by the
radiation oncologist.
395
Simulation is the process of determining the geometric
factors relating to fractionated irradiation delivery, and treat-
ment planning uses information about the radiation beams
and these geometric parameters to generate data on radiation
doses to the tumor and normal tissues. The first step in this
process is to fabricate a patient-immobilizing device that will
be used for all subsequent treatments. A thermoplastic mask
is commonly used for this purpose, together with a baseplate
that holds the patient’s head in a position that tucks the chin
to the chest. Many centers use baseplates that have the ability
to be set at a predetermined angle for reproducibly achieving
a high degree of chin tuck. A well-constructed mask and
baseplate pair should provide setup accuracies of ~2 mm.
More elaborate immobilization techniques that incorporate
custom-molded bite blocks and custom-molded posterior
head supports can provide immobilization accuracy that
approaches a millimeter or less [28]. Rigid and reproducible
immobilization techniques are mandatory for the most con-
formal radiation therapy delivery techniques. The position of
the patient’s head at the time of the fabrication of this device
will determine whether simple vertical beams or arcs can be
used with the couch in a neutral position. Inattention to this
point may reduce the ease of daily treatment or prevent some
well-characterized and simple treatment techniques from
being easily adopted.
For pituitary radiation therapy, a traditional simulation
method uses a fluoroscopic apparatus with the same geome-
try as a linear accelerator to set up an anterior and two lateral
radiation portals of approximately 4 × 4 cm, centered just
above the pituitary fossa. The immobilizing mask can be
marked with the entry points, central axes, and corners for
these fields. A contour of the skull is obtained along the line
that joins the central points of these fields. A dosimetrist can
use this contour information and X-ray beam data to calcu-
late radiation parameters with computerized treatment plan-
ning software. Obviously, the location of the radiation portals
and their size depends upon the size and location of the
tumor; the size of smaller portals is frequently limited by a
physicist’s ability to accurately measure the beam output
through a small and irregular aperture.
CT simulation simplifies some aspects of this process.
The patient needs to be immobilized in the treatment posi-
tion, and setup points need to be marked on the mask for later
reference. A noncontrast CT scan with fine cuts (1.25–
2.5 mm thick, extending from the vertex of the head to the
foramen magnum) is obtained. Contouring (identification of
structures in three-dimensional space in the imaging study)
needs to be done for all the important tissues, particularly if
intensity-modulated radiation therapy (IMRT) techniques
will be used to treat the patient. High-resolution treatment
planning CT studies generally show the pituitary fossa, optic
nerves, and lenses well enough that these structures can be
clearly defined. The radiation therapy portals are set up on
396
digitally reconstructed radiographs after the contouring pro-
cess has been completed, and from this information, a
dosimetrist can directly use this digital data to calculate the
beam weights and dosimetric parameters.
The use of image fusion software to register a high-quality
MRI study to the treatment planning CT scan may help in
delineation of the tumor and adjacent normal tissues. Image
fusion software rigidly registers the two imaging studies
through the use of normalized mutual information, chamfer
matching, or other algorithms and then reformats and redis-
plays the voxels from the MRI in the CT scan’s geometric
space. The MRI scan does not need to be done with the
patient in the immobilization mask. Structures better seen on
an MRI, like the hippocampi, can be contoured on the MRI
and can be transferred to the CT for calculation purposes.
Clinicians have realized from more detailed dosimetric
analyses that there can be areas of unacceptably high dose
(“hot spots”) that may injure normal tissues or areas of
Fig. 28.1 (a) Axial fractionated stereotactic radiation therapy (FSRT)
dose distribution. (b) Coronal FSRT dose distribution. (c) Sagittal FSRT
dose distribution. (d) Axial intensity-modulated radiation therapy (IMRT)
dose distribution. (e) Coronal IMRT dose distribution. (f) Sagittal IMRT
dose distribution. It is clear from these dose distributions (shown on MR
images) that for this patient with a pituitary adenoma, it was possible to
J.P.S. Knisely and P.W. Sperduto
incomplete coverage of intracranial target tissue (“cold
spots”) that can lead to tumor recurrences [29, 30].
Radiotherapy technology advances that permit more than a
few coplanar fields to be used to treat a tumor have been used
by researchers to determine an optimal number of radiation
beams for treatment of skull base tumors and to conformally
avoid unnecessary irradiation of normal tissues such as the
hippocampi [31–33].
Treatments that are three-dimensionally conformal to a radi-
ation target can be routinely delivered with a high degree of
precision. This has been termed 3DCRT (three-dimensional
conformal radiation therapy). The use of rigid, reproducible
immobilization and a large number of radiation beams or of arc-
ing beams has led some to term this approach fractionated ste-
reotactic radiation therapy (FSRT), although this terminology is
inaccurate in that true stereotaxy (in a neurosurgical sense) is
not achieved [34]. An example of an FSRT dosimetric plan for
a patient with a pituitary adenoma is shown in Fig. 28.1a–c.
develop a more conformal FSRT plan than an IMRT plan. Tissues outside
the target volume are treated to higher doses in the IMRT plan than in the
FSRT plan. Both plans would be acceptable for fractionated irradiation
using conventional fractionation, but neither could be accepted for radio-
surgical treatment, because the tolerance of the anterior visual pathways
would be exceeded by doses that would control the adenoma
28 Pituitary and Pituitary Region Tumors: Viewpoint—Fractionated Radiation Therapy 397

Software and hardware technology to dynamically con- Table 28.3 Results of radiation therapy for nonfunctional adenomas
trol the point-to-point intensity of incident radiotherapy No. of Results
beams has been developed and is known as IMRT. Radiation Reference patients Treatment End point Duration (%)
therapy plans generated and delivered using IMRT tech- Breen et al. [47] 120 S + RT, RT LC 10 y, 88;
niques are significantly different than plans developed in the 20 y, 78;
past. For an IMRT plan to be generated, a computer must be 30 y, 65
Tsang et al. [16] 160 S + RT LC 10 y, 87
told what the overall goals of the plan should be. These
Grigsby et al. [52] 111 S + RT, RT DFS 13 y, 84
include limitations of doses to certain structures, acceptable
Brada et al. [37] 252 S + RT, RT PFS 10 y, 97;
ranges of doses to other structures, and the basic parameters 20 y, 92
of beam energy and beam entry points. The computer soft- Woollons et al. [43] 50 S + RT PFS 5 y, 72
ware then selects radiation beam intensities that can achieve Park et al. [49] 44 S + RT PFS 5 y, 97.7;
the desired therapeutic goals. 10 y, 97.7
Better integration of these software and hardware advances Gittoes et al. [53] 66 S + RT PFS 15 y, 93
and faster computer microprocessors has allowed the use of Sasaki et al. [54] 65 S + RT LC 10 y, 98
changes in radiation beam intensity in multiple portals to Grabenbauer 50 S + RT LC 54 mo, 94 %
et al. [42]
achieve better radiation dose distributions, with fewer hot or
S surgery, RT radiation therapy, DFS disease-free survival, PFS pro-
cold spots inside the target volume and no hot spots outside the
gression-free survival, LC local control
target volume. These technological advances may decrease
treatment-related morbidity and improve treatment results
overall, but this has not yet been demonstrated to be the case Patients must understand the need of long-term close surveil-
for most intracranial tumors, including pituitary adenomas. An lance if radiation therapy is not employed as a routine
example of an IMRT dosimetric plan for a patient with a pitu- adjunctive therapy [48, 49].
itary adenoma is shown in Fig. 28.1d–f. Radiotherapy alone achieves control rates of approxi-
Proton beam therapy has been gradually increasing in mately 80–95 % at 10-year follow-up for recurrent nonfunc-
availability in some markets and there are now beginning to tional adenomas or for primary treatment of nonfunctional
be small series reported in the medical literature of patients adenomas [16, 37, 47]. Longer-term follow-up has docu-
treated with protons for pituitary adenomas, craniopharyn- mented continued progression up to >20 years from therapy,
giomas, and meningiomas. Modeling studies indicate that documenting the need for lifelong surveillance of patients
there may be significant benefit to the use of protons, but this with pituitary adenomas [50, 51].
has not yet been demonstrated in clinical series [35, 36]. A critical factor in the long-term local control after post-
operative irradiation of pituitary adenomas may well be the
postoperative volume of tumor. This may conceivably range
Radiation Therapy Results from a small amount of tumor remaining in a cavernous
sinus to a macroscopic suprasellar extension into the mid-
Pituitary Macroadenomas brain. Local control can now be more accurately determined
than in the past because of improvements in imaging tech-
Fractionated doses of approximately 45–50 Gy in daily nology and availability. Side-by-side comparisons can be
doses of 1.8 Gy are currently used for treating pituitary ade- made between studies obtained a decade or more apart, and
nomas at most centers because of the knowledge that has subtle changes in size can be detected. In addition to the pre-
been gained over the past decades about the low risk of caus- vention of adenoma growth, many radiotherapy series have
ing visual complications when these guidelines are followed, reported an improvement in mass effect and mass effect-
the dose response seen for doses lower than this range, and related symptoms such as vision, but neurosurgical manage-
the apparent absence of improved results and increasing rate ment is much more effective in promptly relieving mass
of visual and other complications when higher total doses effect. Several reports on fractionated irradiation for non-
and plans with hot spots are used [16, 37–42]. functioning pituitary adenomas are collected in Table 28.3
For patients who have undergone a surgical resection of a [16, 37, 42, 43, 47, 49, 52–54].
pituitary adenoma, long-term local control is improved when
radiation treatment is administered before a macroscopic
recurrence of tumor develops, though a patient with a com- Growth Hormone-Secreting Adenomas
plete resection of tumor may not require postoperative irra- (Acromegaly)
diation [16, 43–45]. The rates of recurrence are not at all
trivial in many series, and there is a very significant potential Acromegaly is still a common indication for fractionated
for progression at 5–10 years after surgical resection [46, 47]. irradiation. These tumors are frequently large, and as a result,
398
surgical debulking of suprasellar extension may be inade-
quate to permit consideration of stereotactic radiosurgery
because the tumor may still be in close juxtaposition to the
optic apparatus. There are some who believe acromegaly is
associated with a higher risk of radiation optic neuropathy
than for nonfunctional adenomas, with a cited risk of as high
as 1.4 % with conventional treatment techniques [25, 50]. A
large tumor mass and high pretreatment growth hormone
levels may predict a worse prognosis for patients with acro-
megaly [45, 55].
Older literature on the effectiveness of radiation therapy
for acromegaly cannot provide all the data that is believed
necessary to evaluate the effectiveness of the therapy. The
definitions of normal have been lowered with more precise
laboratory testing over the past several decades. Current
guidelines on the definition of cure include a random growth
hormone <1 μ[mu]g/L, or <0.4 μ[mu]g/L after an
oral glucose-tolerance test, and insulin-like growth factor 1
(IGF-1) levels that are within age-adjusted normative ranges
[56]. There is data that the IGF-1 levels after therapy may
correlate better with cure than GH values [57].
Modern multidisciplinary management for many patients
will include medical management with somatostatin receptor
ligands such as octreotide or lanreotide. Growth hormone
receptor antagonists such as pegvisomant are generally
reserved for patients who do not achieve biochemical control
with somatostatin receptor ligands [58]. The use of such
medical management strategies may alter the rate at which
conventionally delivered radiation can achieve durable con-
trol of hormonal excess and may provide additional opportu-
nities for improving the therapeutic ratio by effecting
regressions in tumor bulk prior to commencing definitive
irradiation [59].
Radiotherapy should be considered for all patients with a
postoperative basal GH level of >5 μ[mu]g/L, with medical
Table 28.4 Results of radiation therapy for growth hormone-secreting adenomas
Reference No. of patients Treatment
Eastman et al. [62] 87 S + RT, RT
Tsang et al. [38] 52 S + RT, RT
Milker-Zabel et al. [66] 20 S + RT, RT
Biermasz et al. [64] 40 S + RT
Thalassinos et al. [65] 46 RT
Dowsett et al. [55] 15 S + RT
Minniti et al. [63]
Roug et al. [61] 34 S + RT + M
González et al. [67] 40 S + RT + M
S surgery, RT radiation therapy, GH growth hormone, IGF insulin-like growth factor 1, M medical therapy, SD standard deviation
J.P.S. Knisely and P.W. Sperduto
management possibly used to help decrease tumor bulk
before commencing irradiation and also to help suppress
hormonal excess after irradiation while waiting for the even-
tual declines that are expected. As there is some data that
hormonal suppression prior to radiosurgery may depress the
ultimate control rates for some functional pituitary adeno-
mas, these agents may need to be evaluated for any protec-
tive effect in the setting of conventionally fractionated and
delivered radiotherapy [60]. There is little doubt that the use
of medical therapies can help patients while awaiting the
effects of radiotherapy [61].
Adequate follow-up has been obtained in several series
of patients with growth hormone-secreting pituitary ade-
nomas that document a progressive response over time
[38, 62–65]. The completeness of surgical resection
appears to contribute to the long-term results achievable
with radiation therapy [63, 65]. The results of FSRT are
only now becoming available; further follow-up will doc-
ument whether or not superior results are possible with
the technological advances that have been used to treat
these patients [66]. The results of several series of acro-
megalic patients treated with fractionated irradiation are
listed in Table 28.4 [38, 55, 61–67].
Prolactin-Secreting Adenomas
Prolactinomas are less commonly treated with irradiation
at present, and the role of surgical intervention in this dis-
order may also be declining with the availability of rea-
sonably well-tolerated medications that can be taken for
protracted periods of time. Historical series show that for
patients treated with irradiation, there is a decreased rate
of durable control without the addition of medical therapy
but that over time, the proportion of patients with hor-
Results
End point Duration (%)
GH <5 μ[mu]g/L 5 y, 30; 10 y, 53; 15 y, 77; 20 y, 89
GH <10 μ[mu]g/L 10 y, 46
“Normalized GH level”; 26 mo, 80; 25 mo, 45
“normalized IGF-1 level”
GH <5 μ[mu]g/L; “normalized 5 y, 75; 10 y, 76; 15 y, 87.
IGF-1 level” Last follow-up, 73
GH <5 μ[mu]g/L 5 y, 30; 10 y, 32; >10 y, 55
GH <5 μ[mu]g/L 3–5 y, 25; 5–10 y, 29; >10 y, 100 %
GH <1 μ[mu]g/L; IGF-1 < +2 SD 1 y, 24; 3 y, 38; 5 y, 64
GH <1 μ[mu]g/L; “normalized 5 y, 46; 10 y, 57; 5 y, 36; 10 y, 43
IGF-1 level”
28 Pituitary and Pituitary Region Tumors: Viewpoint—Fractionated Radiation Therapy 399

Table 28.5 Results of radiation therapy for prolactinomas

Results
Reference No. of patients Treatment End point Duration (%)
Ozgen et al. [69] 106 S + RT PRL <30 μ[mu]g/L Not stated, 58
Tsang et al. [38] 64 S + RT PRL <20 μ[mu]g/L 10 y, 25
Wallace and Holdaway [71] 25 S + RT Normal PRL 4 y, 33
Tsagarakis et al. [72] 36 RT PRL <360 mU/L 8 y, 50
Williams et al. [68] 28 RT Normal PRL Not stated, 29
Littley et al. [70] 58 S + RT, RT PRL <500 mU/L 10 y, 50 % (predicted)
Sun et al. [73] 7 S + RT PRL <20 ng/mL 21 mo, 100
PRL prolactin, S surgery, RT radiation therapy

Table 28.6 Results of radiation therapy for Cushing’s disease

Results
Reference No. of patients Treatment End point Duration (%)
Howlett et al. [80] 21 RT Normal mean serum cortisol 9.5 y, 57
Tsang et al. [38] 29 S + RT, RT Urinary free cortisol (UFC) <220 nmol/24 h 10 y, 53
Vicente et al. [74] 14 S + RT UFC <303.5 nmol/24 h 2 y, 70
Nagesser et al. [81] 86 RT and unilateral Low-dose dexamethasone suppression test 21 y, 64
adrenalectomy (serum cortisol <80 nmol/L)
Estrada et al. [83] 30 S + RT UFC <303.5 nmol/24 h; low-dose 42 mo, 83 %
dexamethasone suppression test normal
S surgery, RT radiation therapy, UFC urinary free cortisol

monal control without medical management does increase, Meningiomas

with perhaps 50 % of patients achieving a serum level
<500 mU/L at 10 years after irradiation [38, 68–70].
Hormonal normalization may only be achieved in many
patients with continuing medical management after sur-
gery and irradiation. Radiotherapy does reliably achieve
growth control, where this is an important goal (to avoid
visual or other complications). The results of several
series of prolactinomas treated with fractionated irradia-
tion are summarized in Table 28.5 [38, 68–73]. Recently
reported series are very small, in part because of the suc-
cess of medical management and in part because radiosur-
gical treatment is increasingly commonly used for patients
who need irradiation.
Radiotherapy has been shown to be highly effective at con-
trolling meningiomas in numerous series [30, 84–88]. Large,
recurrent, and histologically aggressive tumors are more
likely to progress after treatment [30, 86]. The morbidity
associated with fractionated irradiation is acceptably low,
particularly when compared with surgical series, but can cer-
tainly be minimized for individual patients by not using
radiotherapy plans that have dosimetric hot spots or cold
spots that may lead to radiation injury to normal tissues or
early recurrences [86–89].
Craniopharyngiomas

Adrenocorticotropic Hormone-Secreting Radiotherapy has been used in the treatment of craniopha-

Adenomas (Cushing’s Disease)
Adrenocorticotropic hormone (ACTH)-hypersecreting pituitary
adenomas should be irradiated if neurosurgical treatment is
unsuccessful [74–78]. Fractionated irradiation has historically
been used as primary therapy for Cushing’s disease as well, but
in current practice, only a rare case will be referred for irradia-
tion without a pituitary operation [78, 79]. In patients medically
unable to undergo microsurgery, medical therapy can suppress
cortisol excess until the effects of irradiation on hypercorti-
solemia can be achieved, commonly seen in a year or 2 [80–82].
The results of several radiotherapy series for Cushing’s disease
are detailed in Table 28.6 [38, 74, 80, 81, 83].
ryngiomas for many decades. Detailed evaluations of surgi-
cal outcomes and of radiation therapy outcomes have been
compiled [90–92]. Aggressive surgery has been associated
with higher rates of visual loss and diabetes insipidus, and
larger tumors are recognized to be more likely to recur [90].
The use of radiotherapy has been shown in retrospective
series to decrease the probability of recurrence requiring
additional surgery after a subtotal resection and has led to the
acceptance of the role of radiation therapy. Novel radiation
delivery technologies have been used over the years to treat
craniopharyngiomas [93–96] because of concern about
delayed radiation-related morbidity being added to some-
times considerable morbidity from the tumor and surgical
400
Table 28.7 Results of radiation therapy for craniopharyngioma
Reference No. of patients
Combs et al. [97] 40
Minniti et al. [98] 39
Smee et al. [99] 41a
Masson-Cote et al. [100] 53
S surgery, RT radiation therapy, FSRT fractionated stereotactic radiation therapy
a
Five of 41 patients received stereotactic radiosurgery or intracystic radiotherapy—results by treatment approach were not presented separately
management. More recently, stereotactic radiotherapy and
proton beam radiotherapy have been used increasingly fre-
quently. There is insufficient data to assess long-term results
of proton beam therapy at present. These treatment tech-
niques may limit the dose of irradiation given to contiguous
normal brain and pituitary, but as always, care must be taken
to avoid radiation injury to the optic apparatus [93] or not
irradiating the entire tumor (cysts may increase in size dur-
ing radiotherapy) [94, 95]. The results of several series of
patients irradiated for craniopharyngiomas are presented in
Table 28.7 [97–100].
Conclusion
Numerous advances in imaging and treatment delivery have
made fractionated irradiation for pituitary adenomas and
other anterior skull base tumors an extremely good therapeu-
tic option. Evaluation of radiation management approaches
for individual patients with tumors in the pituitary and para-
sellar region should bear in mind the potential for significant
complications from the attempt to use the most advanced
technology available. Not every patient should be treated with
radiosurgery or IMRT; extremely good and predictable results
are possible with highly conformal fractionated irradiation,
an option that should be nearly universally available.
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73. Sun DQ, Cheng JJ, Frazier JL, Batra S, Wand G, Kleinberg LR,
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74. Vicente A, Estrada J, de la Cuerda C, et al. Results of external
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75. Plowman PN. Pituitary adenoma radiotherapy—when, who and
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77. Mahmoud-Ahmed AS, Suh JH. Radiation therapy for Cushing’s
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80. Howlett TA, Plowman PN, Wass JA, et al. Megavoltage pituitary
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Acta Oncol. 2013;52(1):153–8.
 Pituitary Tumors: Viewpoint— Medical
Therapy
Rachel L. Hopkins
Introduction
The management of tumors originating from the pituitary
requires consideration of both hormonal functionality and mass
effect of the tumor. Tumors can arise out of any of the pituitary
cell types and each can produce a clinical syndrome with a typi-
cal corresponding response to therapeutic efforts. It is impor-
tant that endocrine function be evaluated prior to any treatment
because some pituitary tumors, such as prolactinomas, will
respond very well to medical treatment, obviating the need for
surgery. Even when surgery is the primary treatment for a pitu-
itary tumor, the nature of the tumor can determine what pre-
and postsurgical therapy will be indicated. In addition, large
tumors can cause hypopituitarism that needs to be addressed
before surgical intervention is attempted. Surgical and radiation
therapy can result in pituitary dysfunction that requires medical
management and replacement hormone therapy.
Diagnosis and Classification
By convention, pituitary tumors are usually classified into
microadenomas, those less than 1 cm in diameter, and mac-
roadenomas which are greater than or equal to 1 cm.
Microadenomas that are not hypersecreting hormones are
often discovered incidentally on imaging. Small or large
hypersecreting tumors usually come to attention because of
symptoms of a hormone excess syndrome such as acromeg-
aly or Cushing’s syndrome. In addition, macroadenomas
may present with symptoms such as visual changes, head-
aches, or cranial nerve dysfunction as a result of mass effect
of the tumor. Symptoms of pituitary hypofunction are often
R.L. Hopkins, M.D. (*)
Division of Endocrinology & Metabolism,
State University of New York Upstate Medical University,
3229 East Genesee Street, Syracuse, NY 13214, USA
e-mail: hopkinra@upstate.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_29, © Springer Science+Business Media New York 2015
29
found in these cases upon detailed questioning of the patient,
even when they are not the presenting complaints.
It is important to distinguish tumors of non-pituitary ori-
gin that can occur in the sellar region from those that arise
from the pituitary. Most lesions of non-pituitary origin have
classic radiologic appearance, including meningiomas, ham-
artomas, and craniopharyngiomas. Infiltrative processes
such as lymphocytic hypophysitis and sarcoidosis can usu-
ally be easily distinguished as well, but can look like tumors.
The relative role of surgical and medical therapy and
radiotherapy in pituitary adenomas depends on the specific
subtype of tumor. Many pituitary tumors require more than
one treatment modality, and optimal therapy involves
collaboration between the surgeon, endocrinologist, radia-
tion oncologist, and neuroradiologist.
Pituitary Tumor Subtypes
Prolactinomas
Diagnosis
Prolactinomas, or prolactin-secreting pituitary adenomas,
are the most common type of functioning pituitary lesion and
account for about 40 % of all pituitary tumors. In most cases,
patients present with typical signs and symptoms. In women,
these include amenorrhea and galactorrhea. Men most
often present with symptoms of hypogonadism including
decreased energy and sexual dysfunction. The prevalence of
prolactinomas is somewhat higher in women than in men [1].
Bone loss may occur as a result of suppression of sex steroid
production [2].
Diagnosis is usually easily established by the presence of
elevated serum prolactin levels. Levels greater than 500 μg/L
are essentially diagnostic of prolactinoma; those greater than
250 μg/L are usually prolactinomas (although some medica-
tions can cause elevations this high). Prolactin levels less
than 250 μg/L can result from stalk compression or other
causes, but can represent a small prolactinoma as well.
403
404
It is important to note that in the presence of a large pitu-
itary tumor, mildly elevated prolactin levels (<100–150 μg/L)
may be the result of stalk compression by the tumor. Prolactin
secretion is tonically suppressed by dopamine delivered to the
pituitary from the hypothalamus. Disruption of this pathway
by compression of the stalk results in elevated serum prolac-
tin levels. Treatment with medication in this situation will
decrease prolactin levels, but will not control tumor growth.
Management
Of all pituitary tumors, prolactinomas are the most respon-
sive to medical therapy. The goal of therapy is to normalize
prolactin levels and reduce tumor size, and this goal can usu-
ally be attained quickly with one of two dopamine agonists
available in the United States. Dopamine agonist therapy is
efficacious in treating even large tumors that are compress-
ing the optic chiasm and causing visual changes. This suc-
cess in treatment with medication has made surgery for
prolactinomas generally unnecessary, a development that has
occurred over the past several decades.
The two dopamine agonists available in the United States
are bromocriptine and cabergoline. Cabergoline is generally
preferred because of evidence of higher efficacy and a lower
side effect profile. Bromocriptine can be used in patients
who do not tolerate cabergoline or if cost is a significant con-
sideration, as cabergoline is a more expensive medication.
Over the past several years, there has been concern about
evidence of cardiac valve regurgitation in patients taking high
doses of dopamine agonists for treatment of Parkinson’s dis-
ease. The data are somewhat equivocal, but so far there is no
strong evidence that such damage occurs in patients taking
the significantly lower doses used to treat prolactinomas [3].
Surgical intervention is generally reserved for patients
with tumors resistant to, or for patients who are intolerant of,
dopamine agonists, patients considering pregnancy during
which tumors might increase in size, or those who suffer
pituitary apoplexy. Approximately 10 % of patients are resis-
tant to cabergoline therapy even after dose optimization.
Radiotherapy is recommended for patients who are intol-
erant of dopamine agonist therapy and in whom surgery has
failed to control tumor growth. There are rare cases of very
aggressive or malignant prolactinomas. These usually require
surgical and/or radiation therapy. Temozolomide therapy has
been used as chemotherapeutic treatment of malignant pro-
lactinomas as well.
Corticotroph Adenomas
Diagnosis
Cushing’s disease is defined as the condition of excess corti-
sol production caused by an adrenocorticotropic hormone
(ACTH)-secreting pituitary adenoma. In the absence of
R.L. Hopkins
treatment, this is a disease with high morbidity and mortality
largely due to cardiovascular effects and abnormal glucose
metabolism. Patients with cortisol excess, or Cushing’s syn-
drome, usually come to medical attention because of typical
clinical features. The most specific of these features are easy
bruising, facial plethora, proximal myopathy, and wide vio-
laceous striae on the abdomen or upper thighs. In addition,
there are a host of less discriminating features present in the
general population that, in the right clinical setting, might
prompt investigation for Cushing’s syndrome such as central
obesity and new-onset diabetes mellitus.
The diagnosis of Cushing’s disease involves first confirm-
ing the presence of hypercortisolism. Because none of our
current tests for hypercortisolism has 100 % specificity or
sensitivity, this is a process that requires multiple confirma-
tory tests, especially in more subtle cases [4]. Once estab-
lished, it must be determined whether the hypercortisolism is
ACTH dependent. This can usually be achieved with mea-
surement of a serum ACTH level.
The majority of ACTH-dependent hypercortisolism is
caused by corticotroph adenomas. However, evaluation of
possible Cushing’s disease is complicated by the high inci-
dence (about 10 %) of nonfunctioning pituitary incidentalo-
mas. It is possible to misattribute ACTH-dependent
Cushing’s syndrome to a nonfunctioning pituitary adenoma.
Care must be taken to avoid missing a diagnosis of ectopic
ACTH production (for instance, from a bronchial carcinoid),
which might result in unnecessary pituitary surgery and fail-
ure to cure the underlying process.
Management
The goal of therapy is to rapidly normalize serum cortisol
levels. Surgery is the primary treatment of corticotroph ade-
nomas. Reported rates of remission resulting from transsphe-
noidal surgery range from 69 to 98 % [5]. The highest
remission rates are in cases of noninvasive microadenomas,
while lower rates of success are seen in macroadenomas with
invasion into the cavernous sinus. Conventional radiotherapy
and stereotactic radiotherapy are used as adjuvant therapy,
but their effects are slow and do not achieve prompt control
of hypercortisolism.
There are a number of medical therapies that decrease
either ACTH or cortisol secretion. Most have significant side
effect profiles that can limit their use, but they may prove
beneficial in certain situations. In particular, medical therapy
is often employed in patients who have received radiation
therapy and are awaiting the often delayed results of that,
those who are not candidates for surgery or in whom the
source of ACTH is uncertain, in very ill patients to ameliorate
the effects of hypercortisolism before surgery, or in patients
with recurrent or persistent hypercortisolism after surgery.
Inhibitors of steroidogenesis include ketoconazole,
metyrapone, mitotane, and etomidate. Ketoconazole has
29 Pituitary Tumors: Viewpoint—Medical Therapy
been used extensively in control of cortisol secretion. It is
often well tolerated, but use can be limited by derangements
of liver enzymes. Metyrapone inhibits 11-beta-hydroxylase
activity. Its use is limited by androgenic effects in women
and mineralocorticoid-related adverse effects. It is also not
available commercially and the producing company must be
contacted directly to obtain it. Mitotane has significant gas-
trointestinal and neurologic adverse effects. Also, once
taken, it is stored in adipose tissue for about 2 years.
Etomidate is used often in induction of anesthesia and is gen-
erally too sedating for practical long-term use.
Centrally acting agents include cabergoline and pasireo-
tide. While cabergoline, a dopamine agonist discussed previ-
ously, does have a relatively low side effect profile, it is
generally not very efficacious in controlling serum cortisol
levels and any effect seen is not always sustained [6].
Pasireotide is a somatostatin receptor ligand that has shown
some potential for use in Cushing’s syndrome, but results of
ongoing research are pending [7]. There is some evidence
that combined therapy with cabergoline, pasireotide, and
ketoconazole may be useful. The glucocorticoid receptor
antagonist mifepristone (RU486) has proven useful in some
cases of hypercortisolism [8].
Bilateral adrenalectomy is necessary in some patients with
refractory hypercortisolism or who have been intolerant to
several other interventions, or in whom the source of ACTH
overproduction cannot be identified. This option is compli-
cated by the risk of Nelson’s syndrome (enlargement of the
pituitary adenoma secondary to lack of suppressive feedback
from circulating cortisol). If bilateral adrenalectomy is
employed, lifelong steroid replacement will be required.
Somatotroph Adenomas
Diagnosis
Growth hormone-secreting, or somatotroph, adenomas cause
gigantism in children and acromegaly in adults. Acromegaly
is a rare disease associated with increased morbidity and early
mortality. Clinical onset can be insidious and the disease can
take years to be recognized. Suspicion for the condition
should be raised in patients with two or more of the following
comorbidities: new-onset diabetes, diffuse arthralgias, new-
onset or difficult-to-control hypertension, cardiac disease
including biventricular hypertrophy and diastolic or systolic
dysfunction, fatigue, headaches, carpal tunnel syndrome,
sleep apnea syndrome, diaphoresis, loss of vision, colon pol-
yps, and progressive jaw malocclusion [9]. The finding of an
elevated insulin-like growth factor-1 (IGF-1) level, combined
with suspicious clinical features and a pituitary lesion on
MRI, is sometimes adequate to make the diagnosis of acro-
megaly. However, in equivocal cases an oral glucose tolerance
test with serial growth hormone (GH) measurements is used
405
to confirm the diagnosis. Inadequate suppression of GH on
this test indicates the presence of a somatotroph adenoma.
Management
The goal of treatment is both tumor shrinkage and biochemi-
cal control of IGF-1 levels. Because of the insidious clinical
onset, most patients present with macroadenomas at the time
of diagnosis. As a result, the surgical cure rate is relatively
low, around 50 %, in cases of macroadenomas greater than
2 cm in size. In microadenomas showing no invasion into the
cavernous sinus, the surgical cure rate is as high as 80 % [9].
When surgery is not curative, radiotherapy, medical ther-
apy, and quite often both are used as adjunct treatment. First-
line medical therapy usually involves somatostatin analogs
(SSAs), either octreotide or lanreotide. Some tumors resis-
tant to usual doses of SSAs respond well to dose optimiza-
tion using higher-than-usual doses [10]. The dopamine
agonists cabergoline and bromocriptine have proven useful
in some cases of acromegaly, even those without cosecretion
of prolactin. Cabergoline is preferred because there is more
evidence of efficacy [9, 11].
Pegvisomant is a human growth hormone analog that
blocks the action of GH at the site of its cognate receptor and
is quite successful at decreasing IGF-1 levels. Because of its
mechanism of action, treatment with pegvisomant actually
causes an increase in GH levels. There is concern about
reflex increase in tumor size resulting from the lack of nega-
tive feedback from IGF-1. This has proven to be an uncom-
mon event that has not been clearly attributable to
pegvisomant itself [12]. Nonetheless, patients being treated
with pegvisomant should undergo regular surveillance with
MRI during initial treatment. It is also prudent to avoid its
use in the setting of large tumors near the optic chiasm.
Primary medical, as opposed to surgical, therapy may be
appropriate in patients with macroadenomas showing no evi-
dence of mass effect in which cure is very unlikely, those
who carry a high surgical risk and those who for their own
reasons prefer medication over surgery.
The question has been raised as to whether use of SSAs
to debulk large tumors prior to surgeries will improve out-
comes. At this point the data are mixed and it is not clear
whether there is any advantage to this approach. Further
research is needed to explore this issue [9, 13].
Thyrotropin Adenomas
Diagnosis
Thyrotropin, or TSH-producing, adenomas are quite rare rep-
resenting less than 2 % of pituitary adenomas. Classically, pre-
senting symptoms are those of hyperthyroidism and patients
almost always have a goiter. Patients may also present with
symptoms of mass effect of the lesion or hypopituitarism.
406
The diagnosis is suggested by an elevated TSH level in
the setting of elevated thyroxin or free thyroxin as opposed
to the suppressed TSH that would be found in primary hyper-
thyroidism. This lab pattern is also seen in the syndrome of
resistance to thyroid hormone (RTH). In this condition, fam-
ily history will reveal other family members with thyroid
problems. Studies that can help differentiate between these
two conditions include the TRH stimulation test and the T3
suppression test in which lack of response would indicate a
thyrotropin adenoma. In addition, a high alpha-subunit to
TSH molar ratio is seen with these lesions. Genetic testing
can evaluate for the presence of RTH. It is important to rule
out RTH even if a pituitary lesion is seen on MRI because of
the previously mentioned 10 % incidence of nonfunctioning
pituitary adenomas in the general population.
The diagnosis of thyrotropin adenomas can be delayed by
the coexistence of autoimmune hypothyroidism [14] or
hyperthyroidism, both of which are far more common.
Classically, by the time of diagnosis, most patients with TSH-
producing adenomas have had a long history of thyroid dys-
function and usually have quite large tumors often with
suprasellar extension or sphenoidal sinus invasion. This may
be changing with the advent of highly sensitive TSH assays.
There is some evidence that more thyrotropin adenomas have
been diagnosed as microadenomas in the past decade or so,
although not all centers have found this to be the case [15, 16].
Management
Surgery is the primary treatment for thyrotropin adenomas.
When tumors are large at diagnosis, complete surgical resec-
tion of these tumors is often quite difficult. Adjunct therapy
with radiation is considered when there is significant resid-
ual tissue or persistent hyperthyroidism after surgery.
Medical therapy with the long-acting SSAs octreotide
LAR and lanreotide has been reported with fairly high suc-
cess. The combination of surgery and radiation therapy
results in complete normalization of thyroid hormone levels
about 1/3 of the time, while 1/3 of cases achieve a level of
control considered adequate [17]. Treatment with SSAs is
successful in about 95 % of patients. Dopamine agonists
cabergoline and bromocriptine have been used to treat TSH-
secreting adenomas with far less consistent results.
Treatment with either thyroidectomy or thyroid ablation
with radioactive iodine is generally not advised because of
concern that absence of thyroid hormone feedback suppres-
sion will result in tumor expansion (much as in Nelson’s syn-
drome). One case report following two patients over 8–12
years saw no such response [18]. Nonetheless, this is still not
considered to be a standard approach to treatment.
Successful control of hyperthyroidism may result in per-
manent or transient central hypothyroidism, and levothyrox-
ine replacement therapy may be necessary after surgery and/
or radiotherapy.
R.L. Hopkins
Gonadotroph and Nonfunctioning Adenoma
Diagnosis
Gonadotroph adenomas are the most common pituitary mac-
roadenomas and represent the majority of nonfunctioning
adenomas. Many of these benign tumors are discovered inci-
dentally on imaging obtained for other reasons, and others
come to medical attention when they grow large enough to
cause symptoms of mass effect. Usually circulating levels of
follicle-stimulating hormone (FSH) and luteinizing hormone
(LH) are normal because most gonadotroph adenomas
secrete inefficiently or variably. However, circulating levels
of the free alpha-subunit component of these hormones are
often elevated.
Patients being evaluated for incidentally discovered pitu-
itary adenomas, or those who present with symptoms of
mass effect, should undergo biochemical evaluation for pos-
sible hormone hypersecretion or hyposecretion. In patients
with large adenomas, symptoms of mass effect are often
more obvious, but careful clinical evaluation and testing may
reveal hypopituitarism in many. Replacement of pituitary
hormones is an important aspect of the medical management
of pituitary adenomas.
Hypersecreting gonadotroph adenomas are rare but do
occur. There are several case reports of ovarian hyperstimu-
lation syndrome (OHSS) in patients shown to have FSH-
hypersecreting pituitary adenomas [19]. Diagnosis of
hyperfunctioning gonadotroph adenomas is based on mea-
surement of elevated FSH and/or LH in the setting of ele-
vated estradiol or testosterone levels.
Management
Clinically nonfunctioning pituitary microadenomas do not
generally require surgery as long as they are not causing
mass effect or endocrine dysfunction. Most nonfunctioning
microadenomas will not grow significantly, but some will.
Therefore, patients should be followed clinically and with
repeat imaging, usually at yearly intervals. Macroadenomas
are more likely to grow, and for those that don’t initially
meet criteria for surgery, follow-up imaging is recommended
6 months after initial presentation. Evaluation for pituitary
hypofunction should also be repeated periodically in
macroadenomas.
For nonfunctioning tumors that are causing compression
of the optic chiasm or other mass effect, surgery is the first
line of treatment. Endocrine function needs to be carefully
monitored after surgery to look for both resolution of preop-
erative pituitary deficits and the development of new hypopi-
tuitarism as a result of surgery. In addition, long-term
surveillance is necessary because nonfunctioning pituitary
adenomas can recur after transsphenoidal surgery [20, 21].
The risk of recurrence is thought to be highest in cases with
incomplete resection leaving residual tumor. In these cases,
29 Pituitary Tumors: Viewpoint—Medical Therapy
adjuvant radiation therapy might lower the recurrence rate,
although some argue for observation without radiotherapy in
these patients [21]. In patients who undergo prophylactic
radiation therapy, there is some risk of developing hypopitu-
itarism so these patients need to undergo long-term monitor-
ing of endocrine function. Decline in endocrine function
may occur months or even years after radiation treatment.
No drug therapy has been shown to consistently control
tumor growth in nonfunctioning adenomas [22, 23]. New
medical treatments are being explored, but have not been
through adequate clinical trials to be included in routine
practice [24]. Therefore, the main role of medical therapy for
nonfunctioning pituitary adenomas is to address pituitary
hypofunction caused by either the tumor itself or by surgical
or radiation therapy.
Tumors causing gonadotropin hyperfunction are treated
primarily with surgery and radiotherapy as above. There
have been reports of hormonal control with dopamine ago-
nists, but again, only rare tumor shrinkage [22].
Although the majority (about 80 %) of nonfunctioning
pituitary adenomas are of gonadotroph origin, all of the other
pituitary tumor subtypes can present as nonfunctioning ade-
nomas as well. There is emerging evidence that these differ-
ent subtypes may follow quite different clinical courses [25].
A subtype referred to as silent corticogonadotroph adenomas
in particular seems to have a more aggressive clinical course
with a higher rate of both recurrence and development of
postsurgical hypopituitarism [26]. Immunostaining of
resected nonfunctioning pituitary tumors may aid in guiding
postsurgical management of patients with nonfunctioning
pituitary adenomas.
Conclusion
The role and success of medical therapy for pituitary tumors
varies tremendously depending on the tumor cell type.
Medical therapy is most successful for prolactinomas where
available drugs are both tolerable and highly effective. For
all other tumors, neurosurgery is the primary modality of
treatment. In these cases radiation and drug therapy play
adjuvant roles. Monitoring for hypopituitarism is crucial
both pre- and postoperatively, especially in macroadenomas,
and after radiation treatment to the pituitary. Medical man-
agement is crucial in achieving appropriate pituitary hor-
mone replacement therapy which is both life sustaining
and leads to improved quality of life in patients with
hypopituitarism.
Finally, advances in drug therapy targeted to more spe-
cific receptor subtypes in pituitary tumors may lead to even
more successful medical therapy of the pituitary tumor sub-
types. Currently, a multidisciplinary approach affords the
best advantage to the patient.
407
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 Pediatric Radiosurgery
Arthur K. Liu
Introduction
In the 1950s, Drs. Leksell and Larsson first described the use
of stereotactic radiosurgery (SRS), a technique to deliver an
ablative dose of radiation to an intracranial target [1, 2]. Since
then, extensive experience has been obtained with SRS in
adults, demonstrating safety and efficacy in benign and
malignant diseases [3–5]. Over the past three decades, there
has been increasing interest in the use of SRS in pediatric
patients. In this chapter, we discuss the treatment of children
with SRS and review existing pediatric SRS literature.
Radiosurgery
The goal of radiosurgery is to deliver high doses of radiation
to a discrete target while minimizing radiation to surrounding
tissue. This requires accurate patient and tumor localization,
and the ability to have steep dose falloff from the target.
Radiosurgery can be delivered with a Gamma Knife system
and with linear accelerator (linac)-based systems.
The Gamma Knife system accomplishes this by directing
multiple (approximately 200 cobalt-60 sources, with the spe-
cific number of sources depending on the type of system)
beams of gamma rays to a single target. The gamma rays are
directed to the targets by collimators ranging in size from 4
to 18 mm that focus the beams of radiation from the source
to the target with an accuracy of 0.3 mm at the isocenter.
Using a stereotactic head frame, the target is placed at the
isocenter. Depending on the complexity of the target shape,
there may be multiple isocenters that are treated to ade-
quately cover the target.
A.K. Liu, M.D., Ph.D. (*)
Department of Radiation Oncology, University of Colorado
Cancer Center, 1665 Aurora Court, Suite 1032 MS F-706,
Aurora, CO 80045, USA
e-mail: arthur.liu@ucdenver.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_30, © Springer Science+Business Media New York 2015
30
Linac-based radiosurgery uses a single X-ray source
which is moved around the patient. Collimation can be
accomplished using cones or multi-leaf collimators.
Treatment can be delivered using static fields or moving arcs.
Patient head positioning uses either an invasive frame similar
to the frame used for Gamma Knife radiosurgery, or non-
invasive frames. Additional positioning accuracy is obtained
with robotic couches that allow for correction of both trans-
lational and rotational errors.
Unique Aspects of Radiosurgery in Children
There are some unique practical aspects of delivering radio-
surgery in children. In children less than 24 months old, the
lack of skull thickness complicates the fixation of a stereo-
tactic localization frame to the skull. Skull thickness is not an
issue when using a non-invasive frame. An inappropriately
applied head frame pin may penetrate the skull of a young
child. To avoid this complication, some institutions utilize a
special torque wrench that allows accurate measurement of
torque force applied to a child’s skull during head frame
placement, which should be no more than 2–4 inch-pounds
of torque for younger children and slightly more for a child
over 3. Another potential complication of a child’s thin skull
is that it is deformable. This may result in a loss of position-
ing accuracy. In younger children (2–10 years of age), preci-
sion is maintained by using special posts of the head frame
that are tailored to the curve of a small child’s head. Often,
longer pins are used because of their small head circumfer-
ence, making placement of the frame more critical than in
adolescents and adults. Because of the need to use long pins,
special care must be used when moving the child during the
procedure.
Most adult patients receive Gamma Knife radiosurgery
under local anesthesia with light sedation. However, many chil-
dren younger than 12 years old cannot tolerate the procedure
awake and therefore undergo radiosurgery using general anes-
thesia. This requires special expertise with anesthesiologists
409
410
who are comfortable with imaging and treating patients under
general anesthesia [6]. For Gamma Knife SRS, the anesthe-
tized child is moved multiple times during planning and treat-
ment with the head frame in place.
The anesthetic concerns are decreased for linac-based
radiosurgery. Treatment planning scans are typically per-
formed on a different day, eliminating the need to move chil-
dren under general anesthesia. However, it is still critical to
closely coordinate with the anesthesia team to maintain a
safe environment for treatment of the child.
Finally, there is a significant difference in normal tissue
tolerance between children and adults. There is mixed data
showing cognitive deficits in adults who receive radiation to
the brain [7]. However, there are multiple studies showing
significant neurocognitive deficits in children, with increasing
risk and severity for younger children and high doses [7, 8].
Published Experiences of Pediatric SRS
SRS has been used in children with arteriovenous malforma-
tions, malignant brain tumors, and benign brain tumors.
Some reports are specific to pediatric patients, but many also
include adult patients. Whenever possible, the pediatric spe-
cific data is presented. Current literature is reviewed here and
grouped by diagnosis.
Arteriovenous Malformations
Arteriovenous Malformations (AVM) are congenital vascu-
lar abnormalities that are at risk of hemorrhage. Primary
management is typically surgery, with embolization as an
option. SRS is a well-accepted treatment option when surgi-
cal risk is unacceptable. The earliest descriptions of SRS for
children with AVMs come from Italy [9], the University of
Pittsburgh [10], and Children’s Hospital, Boston and
Brigham and Women’s Hospital [11]. Since that time, there
have been numerous publications reporting the experience of
using SRS for children with AVMs, demonstrating both effi-
cacy and safety. The largest series are reviewed here.
The largest pediatric SRS experience for AVMs comes
from the UK [12]. Three hundred and sixty three children
underwent 410 treatments, including 4 with planned two-
stage treatments and 43 who were retreated. The most com-
mon presentation was hemorrhage seen in 80 % of the
children. Mean SRS dose was 22.7 Gy (range 15–25 Gy).
Follow-up duration for the group was not specified.
Obliteration rates were calculated from 220 children with
sufficient follow-up, while toxicity was reported for the
entire cohort. For children treated upfront, the obliteration rate
was 71 % and the mean obliteration time was 32.4 months.
For children retreated, the obliteration rate was 62.5 %
A.K. Liu
and the mean obliteration time was 79.6 months. Radiation
necrosis was seen in 1.1 % of patients. Another large series
from the University of Virginia reported on 186 children
[13]. Similar to the UK experience, hemorrhage was the
most common presenting sign, seen in 71.5 % of children.
Mean initial SRS dose was 21.9 Gy. In 41 children who
underwent repeat SRS for incomplete obliteration, the mean
SRS dose at retreatment was 20.7 Gy. With a mean follow-up
of 98 months, complete obliteration was seen in 49.5 % after
initial SRS and 58.6 % after repeat SRS. Small nidus volume
and higher SRS dose were associated with higher rates of
obliteration. MRI changes were seen in 37.8 %, but were
accompanied by symptoms in only 7.2 %. Another series
from the University of Pittsburgh reports on 135 children.
The median SRS dose was 20 Gy. With a median follow-up
of 71.3 months, the obliteration rate at 5 years was 67 %. On
multivariate analysis, only higher SRS dose was associated
with improved obliteration rates. Adverse radiation effects
were seen in 5.9 %. There are two other series with 100 or
more children, one from Taiwan [14] and the other from
France [15], that report similar results.
The extensive use of SRS in children with AVMs has
allowed some comparisons between pediatric and adult
patients. Hemorrhage as a presenting symptoms is more
common in children [16]. While the overall obliteration rate
is comparable between children and adults, it appears that
children respond earlier to SRS [16, 17]. There may also be
a differential response based on the size of the AVM. The
group from Taiwan found that AVMs smaller than 3 cm and
larger than 20 cm have similar obliteration rates between
children and adults, with much better response in smaller
AVMs [14]. However, children with AVMs of intermediate
size between 3 and 10 cm had lower obliteration rates than
adults with similarly sized AVMs.
Ependymoma
While ependymomas make up a relatively small proportion
of pediatric brain tumors, they may be well suited to treat-
ment with SRS. The standard management of these tumors is
maximally safe resection followed by postoperative fraction-
ated radiation therapy. Chemotherapy may be of limited
effectiveness and is currently being studied in a randomized
trial by the Children’s Oncology Group. Local failures occur
in approximately 2/3 of recurrences and typically occur
within the treatment field [18]. SRS has been used in both
residual tumor and recurrent disease.
In the upfront setting, at St. Jude Children’s Research
Hospital five children received an SRS boost (median dose
10 Gy) after conventionally fractionated radiation (50.4–
52.2 Gy) for residual disease [19]. At a median follow-up
of 24 months, one child had a local recurrence and died
30 Pediatric Radiosurgery
of progressive disease. No significant toxicities were seen.
In another series from Boston, three children with ependy-
momas received SRS (dose 10–15 Gy) as part of initial
management after conventionally fractionated radiation [20].
Two of those children are alive with no evidence of disease
30 and 62 months from SRS.
There are larger series with ependymoma treated at
recurrence. Twenty six patients (12 were under 18 years at
diagnosis) with 49 lesions were treated at the Mayo Clinic
[21]. The median SRS dose was 18 Gy. With a median fol-
low-up of 3.1 years, local control at 3 years was 72 % and
median overall survival was 5.5 years. Two patients devel-
oped radiation necrosis. At the University of Pittsburgh,
39 patients (median age 22.8 years, ranging from 2.9 to
71.1 years) received SRS to 56 lesions [22]. Median SRS
dose was 15 Gy. With a median follow-up of 23.5 months,
PFS at 3 years was 45.8 % and OS at 3 years was 36.1 %.
Three patients developed radiation necrosis.
While these two series show good local control with min-
imal toxicity, there are other reports with less promising
results. The Boston series reports on 90 children treated
with SRS (median dose 12.5 Gy) included 25 children with
ependymoma treated at recurrence and the three children
treated upfront mentioned earlier [20]. For children with
ependymomas treated with SRS, median PFS was
8.5 months and local control at 3 years was 29 %. Radiation
necrosis and neurologic symptoms requiring surgery
occurred in 19 of the 90 patients. A smaller series of six
children with recurrent ependymoma receiving SRS (median
dose 18 Gy) at St. Jude Children’s Research Hospital had a
median PFS of 15 months and median OS of 65 months.
Four patients died of disease. One patient was alive 10 years
after SRS, but with symptomatic radiation necrosis requir-
ing surgery and hyperbaric oxygen. The last patient died
from radiation necrosis.
There are other series that include small numbers of pedi-
atric patients. The Indiana University experience reported on
eight patients (five were children) with 13 tumors, treated
upfront and at recurrence. Median SRS dose was 14 Gy and
median follow-up was 30 months. Three year in field control
was 61 % and OS was 75 %. Two patients, both of whom
received prior radiation therapy, developed symptomatic radi-
ation necrosis. The Washington University experience of SRS
(dose ranged from 14 to 20 Gy) for nine patients with epen-
dymoma included an 11 and an 18 years old [23]. The older
child treated definitively is alive with no evidence of disease
56 months after SRS. The younger child had a local failure
and died 27 months after SRS. A series from Texas included
three children with ependymoma [24]. All three recurred
within 16 months, and two died from progressive disease.
Two children were treated in Japan to 16 lesions with local
control for 21 months and no reported toxicity [25].
411
Embryonal Tumors
Embryonal tumors include medulloblastoma, primitive neuro-
ectodermal tumors (PNET), medulloepithelioma, pineoblastoma,
ependymoblastoma, and atypical teratoid/rhabdoid tumor
(ATRT). Standard treatment for these embryonal tumors
includes surgical resection, chemotherapy, and radiation ther-
apy. Radiation treatment for these tumors typically includes
craniospinal irradiation due to a risk of dissemination through-
out the CNS, along with a boost to initial sites of disease. SRS
has also been used in both initial therapy and recurrent disease.
The Boston SRS series includes 21 children with medullo-
blastoma and PNET, with six children being treated upfront
with SRS (median dose 12.5 Gy) [20]. Median PFS was 11
months and 3 year local control was 57 %. A report from the
University of Heidelberg on 20 patients with 29 lesions
included 6 patients under 14 years [26]. All patients had recur-
rent disease after receiving prior chemotherapy and radiation
therapy. Eight lesions were treated with SRS with a median
dose of 15 Gy. There were no local failures or symptomatic
radiation necrosis. However, the follow-up for the SRS lesions
was not specified. A series from Austria included 12 children
with embryonal tumors [27]. Mean dose was 18.8 Gy. With a
mean follow-up of 32 months, local control was 50 %. At the
University of Pittsburgh, seven children with recurrent disease
received SRS (median dose was 14.5 Gy) to 15 lesions [28].
With a median follow-up of 25.8 months, local failure was
seen in 5 children. No radiation necrosis was seen. All children
died from progressive disease, with a median survival of
15 months from SRS. A series from Texas included seven chil-
dren with embryonal tumors (medulloblastoma, PNET, and
ATRT) who received SRS (median dose of 17 Gy) to 15
lesions [24]. With a median follow-up of 11.5 months, there
was one in field failure and two cases of radiation necrosis.
There are other small series of SRS in pediatric embryo-
nal tumors. A report from Denmark included three children
with embryonal tumors who received SRS (15–18 Gy) [29].
Two children are alive with distant disease at 76 and 70
months from SRS and one died from metastatic disease at 13
months from SRS. At the University of Arizona, two chil-
dren with medulloblastoma received SRS (4.5 and 6 Gy) for
a boost after fractionated radiation therapy. At 51 months
and 16 months of follow-up, both children have no evidence
of disease and no radiation necrosis was seen.
High-Grade Gliomas
High-grade gliomas are WHO grade III and IV tumors.
These are typically very aggressive with poor clinical out-
comes. Standard therapy includes resection and adjuvant
412
radiation and chemotherapy. In these children, SRS has been
used as initial therapy and at recurrence.
The pediatric SRS experience from Boston reports 18
children with high-grade gliomas (median SRS dose 12.5 Gy
for the entire series) [20]. With a median follow-up of 24
months, PFS at 3 years was 12 months and local control at
3 years was 50 %. An early series from the University of
Pittsburgh of 25 children who received SRS included five
children with high grade gliomas [30]. Mean SRS dose for
the entire group was 15.2 Gy. Two have no evidence of dis-
ease, one had local progression only, one had disseminated
disease, and one died of disease.
Two children with anaplastic astrocytomas treated to
three lesions were included in the series from Texas [24].
SRS dose ranged from 17 to 19 Gy. With a follow-up of
16–18 months, there was no progression and one child had
asymptomatic radiation necrosis.
Low-Grade Gliomas
Low-grade astrocytomas are WHO grade I or II and include
pilocytic astrocytomas and fibrillary astrocytomas. These
tumors are typically slow growing. With a complete resec-
tion, adjuvant therapy is usually not required. For incom-
pletely resected tumors, adjuvant chemotherapy and radiation
therapy are treatment options. SRS has been used as initial
therapy and at recurrence.
The largest series of children with low-grade gliomas
comes from the University of Pittsburgh [31]. Fifty children
with juvenile pilocytic astrocytomas received SRS (median
dose 14.5 Gy) at initial diagnosis for residual tumor (n = 16) or
recurrence (n = 34). With a median follow-up of 55.5 months,
PFS at 3 years was 82.8 %. Longer PFS was seen with solid
tumors, smaller target volumes (<8 cc), treatment upfront
(versus at recurrence), and no brainstem involvement. Two
children developed asymptomatic radiation necrosis and three
had symptomatic radiation necrosis. At the Karolinska
Hospital in Sweden, their series included 16 children (of 19
patients total in the report) with pilocytic astrocytomas who
received SRS (median dose 10 Gy). With a median follow-up
of the children of 5 years, there were no local failures. Three
children had asymptomatic radiation necrosis and two had
symptomatic radiation necrosis, with one requiring surgery.
A series reporting SRS in children from Austria included 12
children with low-grade gliomas [27]. Mean SRS dose was
15.2 Gy. With a mean follow-up of 38 months, tumor progres-
sion was seen in two children and one child developed edema
requiring steroids.
A small series from Washington University includes
six children with pilocytic astrocytomas that received SRS
(median dose 15.5 Gy) [32]. Median follow-up for the
SRS patients was not specified. PFS at 5 years was 80 %.
A.K. Liu
Another series from Texas included three children with
pilocytic astrocytomas who received SRS (dose of 10–25 Gy)
[24]. No local failures were seen with a follow-up ranging
from 1 to 27 months.
There are a number of reported series of SRS for patients
with low-grade astrocytomas that include children. However,
these do not report specific results for the children. A series
from Japan of 12 patients with WHO grade I and 39 WHO
grade II patients included some children (mean age of 9.8
and 30.9 years for patients with WHO grade I and WHO
grade II tumors, respectively) [33]. Mean SRS dose was 12.5
and 15.7 Gy for patients with WHO grade I and WHO grade
II tumors, respectively. For patients with WHO grade I
tumors with a mean follow-up of 24.8 months, local control
was 91.7 %. For patients with WHO grade II tumors with a
mean follow-up of 28.5 months, local control was 87.2 %.
Post-SRS edema was seen in 16.7 % of WHO grade I patients
and 41 % of WHO grade II patients. Another series from
Taiwan of 21 patients with low- grade astrocytomas (includ-
ing both WHO grade I and II tumors) includes nine children
[34]. For the entire cohort, the median SRS dose was 14.5 Gy.
With a median follow-up of 67 months, PFS at 10 years was
65 %. Eight patients (40 %) developed mild to moderate
adverse radiation effects. The University of Pittsburgh sepa-
rately reported their SRS experience for 25 patients (median
age of 30 years, range 8–68 years) WHO grade II astrocyto-
mas [35]. Sixteen patients were treated at initial presentation
and nine were treated at progression. Median SRS dose
was 14 Gy. With a median follow-up of 65 months, PFS at
10 years was 37 %. No permanent treatment-related morbid-
ity was seen.
Craniopharyngioma
Craniopharyngiomas are benign tumors that arise in Rathke’s
pouch. Typical management involves surgical resection with
adjuvant fractionated radiation therapy used for residual dis-
ease. There are reports of SRS for either residual or recurrent
disease.
The largest report of SRS in pediatric patients with cra-
niopharyngioma comes from Japan [36]. Their report of 107
patients includes 38 children <15 years at diagnosis. For the
entire cohort, mean SRS dose was 11.5 Gy and mean follow-
up was 65.5 months. Progression-free survival and overall
survival at 10 years were 53.8 % and 91 %, respectively.
Response was reported separately for children and adults,
with 32 % of children progressing compared to 13 % of
adults. A 37 patient series from the University of Virginia
included 17 children <18 years at diagnosis [37]. Median
SRS dose was 14.5 Gy and median follow-up was 50 months.
Progression-free survival and overall survival at 5 years were
67 % and 75.6 %, respectively, with only one death attributed
30 Pediatric Radiosurgery
to tumor progression. In this group, local progression was
not associated with age. Another study from Sweden included
both children (11 under 16 years) and adults [10, 38]. Median
follow-up was 3.5 years. In children, the median SRS dose
was 5 Gy (range 2.5–15 Gy). Local progression was seen
in 82 % of the children, compared to 50 % of adults. This high
rate of progression was attributed to the low SRS dose. A report
on 12 patients with recurrent craniopharyngioma from the
University of Miami included 10 children <18 years [39].
Mean SRS dose was 14 Gy. With a mean follow-up of 39
months, two local failures (one in a child and one in an adult)
were seen. Other series that included children report similar
response, with tumor control rates of 68–87 % [27, 40, 41].
Other Tumors
There are numerous reports of SRS for other diagnosis in
children. In general, these are either very small or do not
specify results for the pediatric patients. These include
meningiomas [24, 27, 42, 43], pituitary adenomas [44–50],
and vestibular schwannomas [51–57]. In general, these stud-
ies show minimal toxicity with good tumor control.
Summary
SRS in children has been reported for many diagnoses. The
most robust data supporting SRS as a treatment option in
children exists for AVMs. Overall obliteration rates appear
similar between adults and children, although children may
respond earlier.
For malignant or benign brain tumors, the data is more
limited. The majority of reports are small with short follow-
up. The largest series exist for craniopharyngioma, low-
grade glioma, and recurrent ependymoma. These reports
taken together suggest low toxicity but efficacy is difficult
to interpret given the small numbers and limited follow-up.
At this time, SRS in children with brain tumors can be con-
sidered in patients with recurrent or residual disease, but
ideally requires multi-disciplinary evaluation by neurosur-
gery, radiation oncology, and medical oncology.
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 Pediatric Disorders:
Viewpoint—Surgery
Stephanie L. Da Silva and Mark D. Krieger
Introduction
The pediatric brain is different from the adult brain in many
ways. Plasticity, myelination, and tolerance to radiation dos-
ages vary greatly with age. Furthermore, pediatric disorders
of the brain differ significantly from those in adults. These
considerations are important in the discussion of the use of
stereotactic radiosurgery in children. This chapter will focus
on the treatment of tumors and vascular malformations of the
pediatric brain from a surgical perspective.
In contrast to brain tumors representing only 1–2 % of
all new cancers in adults [1], pediatric tumors of the central
nervous system represent 20 % of all childhood cancers
with an incidence of 2.5 per 100,000 children under the age
of 15 [2]. Central nervous system (CNS) tumors are the
most common solid tumors in children and second most fre-
quent of childhood malignancies after leukemia. Differences
are also apparent between pediatric and adult patients in the
tumors’ sites of origins, histological features, and clinical
presentation. A majority of childhood brain tumors origi-
nate infratentorially in the cerebellum, brainstem, or fourth
ventricular region, while adult tumors have a proclivity to
arise in the cerebral cortex. Pathology of pediatric brain
tumors varies by age, with the heterogeneity of these tumors
attributed to their unique natural history, treatment options,
and prognosis. Surgery and extent of resection plays a large
role in the management of these tumors. Radiation therapy
is used more cautiously given concerns about its effect
on the developing brain and on patients with long life
expectancies.
S.L. Da Silva • M.D. Krieger, M.D. (*)
Division of Neurosurgery, Children’s Hospital Los Angeles,
1300 N. Vermont Ave., Los Angeles, CA 90027, USA
e-mail: mkrieger@chla.usc.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_31, © Springer Science+Business Media New York 2015
31
Surgical Management Overview: Pediatric
Brain Tumors
Pediatric brain tumors are extremely heterogeneous. A team
approach is usually taken and includes the pediatric neuro-
surgeon, neuro-oncologist, radiation oncologist, psycholo-
gist, and radiologist among others. In cases of low grade
tumors, surgical intervention is recommended to obtain a tis-
sue sample for diagnosis and to maximally resect the tumor
while limiting morbidity. However, surgical management
may not be the best method of treatment for highly invasive,
malignant tumors or benign tumors that may infiltrate the
visual pathways of a child. Factors such as age, histology,
and tumor location are generally considered in determining
the appropriate treatment, though in certain incidences these
factors may be weak predictors of outcome.
Low-Grade Tumors
Low-Grade Gliomas
The most common primary central nervous system malig-
nancies affecting the pediatric population are low-grade
gliomas, with an annual incidence of 0.6 cases per 100,000
children under 18 years of age [3]. Fortunately, the prognosis
for children with these tumors is excellent; long-term
progression-free survival (PFS) is reported as high as 80–90 %
at 10 years [3]. Juvenile pilocytic astrocytomas (JPAs), the
most common of these low-grade gliomas in children, are
characterized by early age of onset, lack of invasiveness, and
favorable prognosis in patients [4]. Cerebral hemispheric
and cerebellar JPAs are optimally treated by surgical resec-
tion as these tumors tend to be well-circumscribed with rea-
sonably well-defined borders [5]. As these tumors are usually
curable upon complete removal, surgical resection is not
generally followed by adjuvant therapy. Even with incom-
plete tumor resection, pilocytic astrocytomas are associated
415
416
with prolonged survival. In a series of 361 pediatric patients
with low-grade gliomas (63 % pilocytic astrocytomas),
Armstrong et al. [6] determined the 10-and 20-year overall
survival rates to be 87 % and 82 %, respectively. However,
prolonged survival in this series did not come without a cost,
especially when these tumors are closely associated with
critical brain structures. A substantial number of these long-
term survivors experienced poor outcome in other areas, such
as cognitive deficit, hearing loss, blindness, and endocrine
abnormalities. In patients with JPAs that cannot be totally
resected or exhibit tumor regrowth, adjuvant therapy is needed.
Though radiation therapy may be used for older children, it is
undesirable in young patients due to conventional side effects
of radiation, and in these patients chemotherapy is utilized
more frequently. For patients with newly diagnosed unresect-
able, progressive, or recurrent JPAs, stereotactic radiosurgery
(SRS) is now considered a valuable option to control tumor
progression or long-term remission. As reported by Kano et al.
[5] in a series of 50 pediatric patients, newly diagnosed patients
receiving SRS who had either biopsy or subtotal resection had
a significantly better progression free survival at 10 years when
compared to patients who underwent delayed SRS for recur-
rent tumors after initial total or subtotal resection (STR)
(88.9 % and 44.5 %, respectively, p = 0.049).
While the mainstay of treatment for low-grade gliomas is
maximal surgical resection, tumors that arise within critical
brain regions such as the brain stem or basal ganglia are gener-
ally not resectable without the risk of significant morbidity.
In these gliomas, minimally invasive neurosurgical techniques
including stereotactic biopsy for diagnosis and endoscopic
third ventriculostomy for cerebrospinal fluid (CSF) diversion
have been beneficial for surgical management [7–9]. Appro-
priate adjuvant therapy is given once a diagnosis has been
made. For tumors considered to be accessible, however, surgery
should be pursued. In St. Jude’s experience of 52 patients with
low-grade focal brainstem gliomas, 48 % of patients had surgi-
cal resection as the primary treatment with a 5- and 10-year
PFS and overall survival of 59 %/98 % and 52 %/90 %, respec-
tively [10]. These results are comparable to other studies who
found 5-year survival rates between 87 and 100 % [11, 12],
though disease progression is not uncommon in these tumors.
Yen et al. [13] reported their use of Gamma knife surgery as an
alternative to surgical resection for 20 patients with focal brain-
stem gliomas, finding that the tumors disappeared in 4 patients
and shrank in 12. Thus, they concluded that gamma knife sur-
gery may be effective as a primary treatment or adjunct to open
surgery for focal brainstem gliomas [13].
Craniopharyngioma
In pediatric neurosurgery, the surgical management of cra-
niopharyngiomas is one of the most highly controversial top-
ics. Craniopharyngiomas, comprising approximately 5–10 %
S.L. Da Silva and M.D. Krieger
of brain tumors in children [14, 15], are epithelial tumors
varying in size that tend to arise in the sellar or suprasellar
location. Surgery is indicated in mostly all cases, with the
goal being to establish a tissue diagnosis and to remove as
much tumor as is safely possible by limiting morbidity. With
the technological advancements in surgical tools including
ultrasonic aspiration, image-guiding techniques, and neuro-
endoscopy, surgical success in resecting craniopharyngio-
mas generated a wave of enthusiasm through publications by
Hoffman et al. [16], Choux and Lena [17], Pierre-Kahn et al.
[18], Caldarelli et al. [19], and Zuccaro [20]. This enthusi-
asm, however, was short-lived, as associated mortality was
reported to occur in up to 50 % at 10 years and was followed
by a high rate of recurrence (50 % in some cases) [21].
Following aggressive resection, complications ensued as
patients suffered peri-operative injury to the hypothalamus
leading to memory, behavioral, and endocrine disorders.
As injury to the hypothalamus was found to be the main fac-
tor associated with morbidity, surgical treatment modalities
were developed to avoid hypothalamic dysfunction by
approaching the tumor via the trans-nasal route [21]. A pre-
operative grading system was devised by Puget et al. [22] to
balance the benefits of aggressive surgical resection with the
risk of significant morbidity in children, dividing tumors into
three types based on extent of invasion of the hypothalamus.
Gross total resection (GTR) was proposed to be attempted in
type 0 tumors (representing no hypothalamic involvement)
and type 1 tumors (distorting or elevating the hypothalamus).
In type 2 tumors, in which the hypothalamus is no longer
visible, STR is recommended, leaving only the hypothalamic
component. Radiation therapy would be the preferred
therapy. In a series by Jane et al. [23] in 2010, among 22
pediatric patients with some sellar component to their cra-
niopharyngioma, transsphenoidal resection resulted in a high
rate of GTR with a low risk of recurrence (2 of 15 patients
after GTR). It was noted, however, that a majority of cases
approached via this route were infra diaphragmatic in
location [23].
In cases where gross total resection is not safely possible,
subtotal resection may be followed by radiation therapy.
Patients in either case are followed by serial MRIs and clini-
cal monitoring of pituitary and visual functioning. In patients
with residual disease who had previously undergone subtotal
resection or in those with recurrence following an initially
thought GTR, stereotactic radiotherapy, both in the form
of radiosurgery or fractionated stereotactic radiotherapy,
is increasingly showing encouraging results. Kiehna and
Merchant [24] recently published a review of the literature
for studies including radiation therapy for pediatric cranio-
pharyngioma, reporting modern studies with 90 % disease
control in a 5-year follow-up and more than 85 % favorable
functional outcome [22, 24–27]. However, long-term follow-
up beyond 5–10 years is necessary to assess tumor control
relative to quality of life and functional outcome as these
31 Pediatric Disorders: Viewpoint—Surgery
Fig. 31.1 Sagittal contrast-enhanced T1-weighted MRI scan showing
a large cystic craniopharyngioma
children remain vulnerable to late treatment failures and
side effects from radiation therapy [24] (Case Study 31.1,
Figs. 31.1 and 31.2).
Neurofibromatosis-1 (NF-1)
Neurofibromatosis-1, or von Recklinghausen NF, is one of
the most common autosomal-dominant CNS disorders with
an incidence of about 1 per 2,500–3,000 live births [28, 29].
About half of all cases are inherited; the other half arise de
novo. The most common genetic abnormality associated
with NF results in the loss of a tumor suppressor gene. NF-1
patients are prone to the development of pilocytic astrocyto-
mas and gliomas involving the optic pathway in children
[30]. An estimated 15–20 % of children with NF-1 are
afflicted with an optic pathway glioma (OPG), with a major-
ity of symptomatic children diagnosed before the age of 6 [3,
31, 32]. Rodriguez et al. [30] reported that in NF-1 patients
with pilocytic astrocytomas and indeterminate subtype low-
grade astrocytoma, extent of resection was not significantly
associated with recurrence, radiographic progression, or
tumor location. However, patients who undergo GTR have a
better overall survival (OS) rate than those who undergo STR
or biopsy (100 % vs. 52 % and 65 % at 10 years, respec-
tively) [30]. Chemotherapy is considered a first-line therapy
in children with NF-1 and afflicted with low-grade gliomas.
A Children’s Oncology Group phase III trial of 401 children
treated with different chemotherapy regimens revealed
5 year OS rates of 98 % for patients with NF-1 vs. 86 % for
417
Fig. 31.2 On last follow-up 1 year after Gamma knife radiosurgery for
residual tumor, the patient remains stable and the tumor controlled
non-NF-1 children, suggesting a more favorable prognosis in
the context of NF-1 [33]. Radiation therapy in patients with
NF-1 is limited due to the increased risk of second malignan-
cies [34] and radiation-related cerebral vasculopathies [35].
Sharif et al. [34] reported a high incidence of second nervous
system tumors in NF1 OPG patients, with an increased risk
in irradiated patients (4 malignant peripheral-nerve sheath
tumors in 12 irradiated NF-1 OPG patients vs. 3/48 NF-1
controls).
Neurofibromatosis-2 (NF-2)
Neurofibromatosis-2, or bilateral acoustic NF, is more rare
than NF-1 with an incidence of 1 in 25,000 live births [36–38].
Though NF-2 is often associated with adult onset, Evans
et al. [39] showed that at least 18 % of NF-2 patients present
in childhood and are likely to have a more severely debilitat-
ing disease course. Furthermore, 10–18 % of children pre-
senting with a meningioma or schwannoma are likely to have
NF-2 with prolonged follow-up [39]. Eighth nerve dysfunc-
tion is a much more common symptom in children than in
adults. Nunes and MacCollin [40] reported that hearing loss
owing to vestibular tumors affected 9/12 children and 11/24
ears by age 18 years. Treatment for NF-2 is primarily surgi-
cal; optimal management includes presymptomatic resection
for vestibular schwannomas [40]. Vestibular schwannomas
in NF-2 patients are more difficult to treat than those with
sporadic unilateral VS given the association with the eighth
cranial nerve (vestibulocochlear) and as such surgery almost
418
always leads to loss of the cochlear nerve and total deafness
[41]. Depending on the location of the tumor, surgical resec-
tion via a middle fossa or retrosigmoid approach with partial
or complete tumor removal may preserve hearing [42]. SRS
is a controversial treatment of vestibular schwannomas in
NF-2 and is currently being extensively debated [43]. While
radiosurgery may preserve hearing function and arrest tumor
growth, the presence of acoustic neuroma is still of threat to
the patient [42].
Meningioma
Meningiomas are rare in children, accounting for 0.4–4.6 %
of all CNS tumors in the pediatric population [44, 45].
As previously discussed, meningiomas within the pediatric
age group are often the first sign of neurofibromatosis 2 [46].
Pediatric meningiomas are most commonly intracranial
(90 %), followed by intraspinal (6 %), intraorbital (2 %), and
elsewhere (2 %). These tumors are frequently located in the
cerebral convexity, followed by intraventricular, falcine,
parasagittal, anterior, and middle cranial fossa [47]. Perry
et al. [48] noted that meningiomas in the pediatric population
have a high frequency of brain invasion and are more pheno-
typically and genotypically aggressive when compared
to adults. Surgical management is difficult in children due to
location of tumors, larger size at presentation, relatively less
blood volume in children, and risks inherent in long opera-
tions such as massive blood transfusions and hypothermia
[49]. The goal of treatment is considered gross total resec-
tion with resection of the dural origin or attachment recom-
mended to lower the risk of recurrence [45, 50]. In the largest
series of 87 pediatric patients by Rushing et al. [50], mortal-
ity rate and recurrence rate were reported as 10.6 % and
19.4 %, respectively. There is limited data on the use of SRS
in children, reported only in case reports. In one such report,
SRS was used to successfully treat a child with recurrent
meningioma in association with meningioangiomatosis [51].
Recurrent meningioma has also been successfully treated in
three children using Gamma knife radiosurgery [52, 53].
High-Grade Tumors
Treatment for high-grade tumors without brain stem invol-
vement in children is generally approached by surgical
resection followed by adjuvant therapy. The main goals of
surgery for these malignant tumors include obtaining a his-
tological diagnosis and reducing the burden of the tumor by
decreasing mass effect. High-grade tumors that have the
treatment option of stereotactic radiosurgery following surgi-
cal resection include glioblastomas, ependymomas, medul-
loblastomas, ependymoblastomas, pineoblastomas, and CNS
S.L. Da Silva and M.D. Krieger
primitive neuroectodermal tumors (PNETs). GTR is achieved
less for eloquent brain areas such as the thalamus and the
basal ganglia than noneloquent areas such as the superficial
cortical locations not associated with essential functions
(63 % vs. 91 %, respectively) [54].
Glioblastoma
Glioblastomas are the most malignant astrocytic neoplasm
and characteristically have zones of coagulation necrosis and
areas of vascular hyperplasia [55]. These tumors represent
3 % of CNS tumors in children with a 5-year survival of
about 20 % [56]. Due to the aggressive nature of glioblasto-
mas, prognosis is poor; the median survival of these patients
is only 12 months [55]. Glioblastomas are more commonly
found in the superficial cortex than in deep structures [57],
and often as a consequence of intratumoral hemorrhage,
approximately 5–10 % of these children present as the result
of sudden deterioration in their neurological status [58]. In
order to significantly increase overall survival of the patient,
gross total resection should be the goal. However, this may
be more feasible in children than adults. In a study of 37
pediatric patients with glioblastoma not of the brainstem,
Yang et al. [57] reported a median OS of 45.1 months in
patients with GTR vs. <1 year in patients who had STR or
biopsy only. Furthermore, at 5 years, 42 % of patients who
had GTR were still alive, whereas none of the patients with-
out GTR survived [57]. Extent of resection but not location
of the lesion was reported as an independent predictive factor
of OS in a multivariate analysis performed by Song et al.
[59]. Though radiation and chemotherapy exist as current
treatment options, glioblastomas have an inherent resistance
of conventional therapy. Therefore, SRS is thought to be
more advantageous due to its improved set-up accuracy in
treating recurrent glioblastomas [60]. However, to date there
is no prospective study reviewing the efficacy of SRS in
pediatric patients with glioblastoma.
Ependymoma
Ependymomas are the third most common intracranial tumors
in children, representing up to 10 % of all CNS tumors in the
pediatric age range with a peak incidence between birth and
4 years [61]. The greatest determinant of survival in children
with ependymoma is extent of resection. Supratentorial epen-
dymomas, constituting about 30 % of ependymomas in chil-
dren [62], have a better prognosis than infrantentorial
ependymomas [63–65]. GTR of supratentorial ependymomas
is more likely to be achieved when compared to those in the
infratentorial location [66, 67], especially those which do not
invade the ventricular system [68, 69]. In these patients with
31 Pediatric Disorders: Viewpoint—Surgery 419

100% Following maximal safe resection, postoperative MRI should

90% be performed to radiologically confirm the extent of resec-
80% tion. If there is residual tumor found with no dissemination,
70% second-look surgery is strongly advised. Even with maximal
resection, however, recurrence rates may be as high as 50 %.
% survival

60%
50%
Adjuvant radiation therapy of 54–55.8 Gy to the tumor
bed is a commonly accepted postsurgical treatment for chil-
40%
dren over the age of 3 years old. One series from UCSF
30%
GTR showed that radiation therapy has been found to improve
20%
STR PFS even after adjusting for extent of resection and also
10% interestingly in those who received GTR when compared to
0% those without radiation therapy [70]. The adverse effects of
0 6 12 18 24 30 36 42 48
radiation on children under 3 years of age have traditionally
Months after surgery
limited this type of treatment, though a series by Koshy et al.
Fig. 31.3 Percent progression-free survival vs. months after surgery [71] used data from Surveillance Epidemiology and End
for ependymoma patients following GTR and STR Results of 184 children younger than 3 years to show
that postoperative radiation therapy significantly improved
100% 3-year overall survival when compared with those who did
90%
not receive RT (81 % and 58 %, respectively, p = 0.005).
Grundy et al. [72] reported in his series of 89 children
80%
younger than 3 years that primary postoperative chemother-
70%
apy led to a 5-year OS of 63.4 %, without radiation therapy
% survival

60%
50%
40%
30%
20% GTR
10% STR
0%
0 6 12 18 24 30 36
Months after surgery
Fig. 31.4 Percent overall survival vs. months after surgery for ependy-
moma patients following GTR and STR
supratentorial ependymomas who undergo complete resection
and exhibit no evidence of metastasis, surgery alone may
be acceptable treatment option and radiation therapy can be
avoided without affected OS, as evidenced by Venkatramani
et al. [68].
Gross total resection has been found to dramatically
increase OS and PFS. In one study at Children’s Hospital Los
Angeles, 28 children with a mean age of 43 months (range
5–51 months) were surgically treated for ependymomas in a
10-year period [61]. Twenty-one (75 %) patients underwent
GTR, whereas 7 (25 %) underwent STR or biopsy. In a
median follow-up period of 30 months (range 1–95 months),
the 28 patients had 3- and 5-year PFS rates of 21.4 % and
10.7 %, respectively, and 3- and 5-OS rates of 39.3 %
and 17.9 %, respectively. Patients receiving radiographically
confirmed GTR had a much higher PFS and OS (33 and 44
months, respectively), than those receiving STR (6.5 and
15 months, respectively), as shown in Figs. 31.3 and 31.4.
in 42 % of those treated for nonmetastatic disease. Currently
under clinical evaluation is a randomized phase III trial
studying how well maintenance chemotherapy works in
comparison with observation following induction chemo-
therapy and radiation therapy in treating newly diagnosed
pediatric ependymoma.
Patients with recurrent ependymomas may also want to
42 48 consider stereotactic radiosurgery. In evaluating the utility
of SRS in treating childhood ependymomas, two factors
must be considered: efficacy in disease control and toxicity
[73]. In 2008, Merchant et al. [74] described their expe-
rience with reirradiation for childhood ependymomas at
St. Jude’s Hospital. Six of the 38 patients in their series were
treated with stereotactic radiosurgery for recurrence, with
age at time of initial presentation ranging between 1 and 6
years. At the time of initial disease presentation, all patients
received radiation therapy while three received chemother-
apy. Notably, only two of the patients treated with SRS had
prior gross total resection. Using a median dose of 18 Gy,
ranging between 15 and 20 Gy, only one of the six patients
survived. Four patients had local progression, though two of
these patients had a longer PFS after SRS than after initial
adjuvant therapy. This finding may suggest that SRS is bet-
ter for temporizing local disease progression than standard
radiotherapy when repeat surgery is not feasible. An even
more encouraging result came from Liu et al. [75], who
used hypofractionated re-irradiation, “staged radiosurgery,”
to treat locally recurrent ependymomas in six children.
All patients survived with no evidence of disease at median
follow-up of 28 months from the time of re-irradiation
(range 6–56 months), though it is important to note that five
420
Fig. 31.5 Axial contrast-enhanced T1-weighted MRI scan showing a
large right calcified and hemorrhagic paraventricular mass, diagnosed
after biopsy as a supratentorial ependymoma
of the six patients had GTR upon disease recurrence prior
to re-irradiation. Following re-irradiation, three of the six
patients were reported to have a longer second disease-free
interval than the time to initial progression. In both the
Merchant and Liu series, however, evidence of radiation
necrosis was described in a few patients and thus remains a
risk in radiosurgical treatment (Case Study 31.2, Figs. 31.5
and 31.6).
PNET (Medulloblastoma, Ependymoblastoma,
Pineoblastoma)
Although there is some controversy surrounding the histo-
pathological classification of childhood CNS embryonal
tumors such as CNS primitive neuroectodermal tumors
(PNETs), medulloblastoma, ependymoblastoma, and pineo-
blastoma (usually grouped with tumors of the pineal region),
determining the appropriate surgical management plan and
treatment is similar. Dissemination at the time of diagnosis
for medulloblastomas and pineoblastomas to other intracra-
nial sites and spinal cord is reported to occur in 10–30 %
of patients and results in a worse prognosis [76–81]. CNS
PNETs account for 4.8 % of childhood brain tumors [82].
Even with multimodal treatment, including maximal safe
resection, fractionated neuraxis radiation therapy, and sys-
temic chemotherapy, local and metastatic recurrences occur
in 30–40 % of pediatric patients [83]. Five-year survival
for standard-risk and high-risk patients are 70–80 % and
S.L. Da Silva and M.D. Krieger
Fig. 31.6 The patient remains stable with no evidence of disease 5 years
after surgical resection followed by intensity-modulated radiation therapy
and concomitant chemotherapy
55–76 %, respectively [84]. Gamma knife surgery (GKS) has
been found in anecdotal case series to have potential benefits
especially for young children unsuitable for initial or addi-
tional fractionated radiation therapy, which carries the risk
of neurotoxicity and poor neurocognitive outcome [85, 86].
Flannery et al. [87] showed that patients who had a smaller
tumor volume were more likely to respond to GKS treat-
ment. The longest survival, 126 and 67 months, occurred in
two patients who had repeat maximal resection followed by
early GKS.
Medulloblastoma
Medulloblastomas account for 20 % of pediatric CNS tumors
and 40 % of posterior fossa tumors in children, with an inci-
dence of 0.6 per 100,000 cases [88]. These tumors are most
commonly found in fourth ventricle and tend to invade nor-
mal cerebellar tissue, with 15 % of cases infiltrating the brain
stem [89]. Medulloblastomas are often seen as a midline
hyperdense cerebellar vermian mass upon review on a CT
scan [90], and ventriculomegaly is noted in approximately
85–90 % of all cases [91, 92]. Though the peak incidence of
children diagnosed with medulloblastomas is between 5 and
7 years, 10 % of cases are diagnosed in the first year of life
[93]. Patients with these tumors can be divided into standard
risk and high risk. Standard risk patients are those over the
age of 3, have no evidence of neuraxis dissemination on the
brain and spine MRI and lumbar CSF, and have less than
31 Pediatric Disorders: Viewpoint—Surgery 421

1.5 cm2 of residual tumor on post-MRI scans. In contrast,

high-risk patients are those with disseminated disease, ana-
plastic histology, postoperative CSF cytology, and a post-op
MRI showing greater than 1.5 cm2 residual tumor [93, 94].
For children with medulloblastoma, surgery is usually the
primary indication for treatment to remove as much of the
tumor as safely possible while also confirming histological
diagnosis. Maximal surgical resection has been associated
with improved rate of survival, chiefly in those with no
evidence of dissemination at the time of diagnosis [95, 96].
In infants, treatment is particularly challenging due to the
vascular nature of tumor, high incidence of leptomeningeal
spread, and lower chance of achieving a gross total resection
[93]. Patrice et al. [97] was the first to propose the SRS tech-
nique as an effective and safe treatment in the management
of medulloblastoma, showing that SRS was capable of con-
trolling small, locally recurrent disease in 5 out of 11 patients
with a median survival from the time of SRS of 10 (range 5
to 59+) months. The six remaining patients died of progres-
Fig. 31.7 A sagittal contrast-enhanced T1-weighted image reveals a
sive disease. Furthermore, this series proposed that SRS was an large preoperative pineoblastoma in the pineal region
effective addition to craniospinal irradiation for patients with
newly diagnosed medulloblastoma, as all three patients were
alive at last follow-up without evidence of disease [97]. worse prognosis for children aged ≤5 years compared with
older children; these patients had a 5-year survival rate of
15 % and 57 %, respectively (p < 0.00001). Among all
Ependymoblastoma patients, 5-year survival rate increased with degrees of resec-
tion: 29 % for debulking, 53 % for STR, and 84 % for GTR
Ependymoblastomas are considered a subgroup of CNS [100]. For children under the age of 3 years, the prognosis is
PNETs, most frequently located in the supratentorial region, even worse, with a survival rate at 1 year of 0 % [102].
but may also arise in the infratentorial or spinal sites [98]. Radiotherapy may have a significant impact on survival.
These tumors are classified as WHO grade IV due to their A series by Hinkes et al. [102] indicated that six older children
aggressive behavior with rapid growth and proclivity to dis- (median 6.75 y, range 3.6–16.9 y) who underwent radiother-
seminate into the craniospinal region [99]. Gerber et al. [99] apy in a maintenance chemotherapy regimen brought all
reported in their series of 10 patients a median OS survival of those who had not been in complete remission into remission
12 months, with longer survival of those with radiotherapy and kept all others in remission with no evidence of remain-
or chemotherapy. If intraventricular chemotherapy was part ing tumor (Case Study 31.3, Figs. 31.7 and 31.8).
of treatment, a subcutaneous reservoir with an intraventricu-
lar catheter was implanted in the anterior horn of lateral ven-
tricle. In this series, 5 year PFS and OS were 36.4 ± 14.5 % Vascular Malformations: Arteriovenous
and 30.3 ± 15.9 %, respectively, though all patients eventu- Malformation
ally died of tumor progression [99].
The most dangerous congenital vascular malformations are
arteriovenous malformations (AVMs). Prevalence in adults
Pineoblastoma is about 18 per 100,000 and AVMs account for between 1
and 2 % of all strokes, 3 % of strokes in young adults, and
Pineoblastomas are pineal region tumors that can metasta- 9 % of subarachnoid hemorrhages [103]. AVMs usually
size along the neuroaxis and may be locally invasive, spread- present between ages 10 and 40 with the most common
ing outside the pineal region through the subarachnoid space symptoms being headache, seizures, focal neurologic defi-
[100]. These tumors are relatively rare, accounting for 0.6 % cits, and intracranial hemorrhage; however, at least 15 % of
of all childhood brain tumors [82]. The standard treatment people affected by AVMs are asymptomatic [103]. The long-
includes maximal surgical resection followed by adjuvant term crude annual case fatality rates are between 1 and 1.5 %
cranial-spinal irradiation and systemic chemotherapy [101]. [103]. After a hemorrhage, the annual mortality can be as
A literature review of patients with pineoblastoma revealed a high as 18 % [104]. Ninety percent of AVMs in the brain are
422 S.L. Da Silva and M.D. Krieger

Fig. 31.8 The patient remains without residual tumor following surgi-
cal resection and chemotherapy at last follow-up
Fig. 31.9 An axial contrast-enhanced T2-weighted MRI shows the
appearance of a right temporal lobe hematoma secondary to underlying
located supratentorially, while the rest are located in the AVM
posterior fossa. The Spetzler-Martin Intracranial AVM grading
scale [105] was devised based upon size, location, and deep
venous drainage. The lesion grade (I–V) is derived by sum-
ming assigned points in each category. Complete surgical
excision of a grade I lesion (small <3 cm, located in a non-
eloquent region such as the anterior frontal lobe, and with
solely superficial drainage) would have very little risk of any
resulting morbidity or mortality. On the other hand, a grade
V lesion (larger than 6 cm, located within or adjacent to elo-
quent brain areas and with some drainage into the deep
venous system) would have significant morbidity and mor-
tality [105]. Surgical resection is the treatment of choice for
grade I–III AVMs, due to its high cure rate (reported from 89
to 98.4 %) and low morbidity and mortality [106, 107].
In children, AVMs are most frequently located in the basal
ganglia, thalamus, corpus callosum, brainstem, or within the
motor, speech, or visual cortex [108, 109] and are the most
frequent cause of intracranial hemorrhage in children [110–
112]. Mortality from AVM hemorrhage in the pediatric pop-
ulation is much greater for cerebellar AVM than for AVM
in the cerebral hemisphere (57 % to 4.5 %, respectively,
p < 0.0001) [113]. While surgery is the mainstay of treatment Fig. 31.10 A year after recurrence and subsequent Cyber knife radio-
for AVMs, endovascular embolization has become a useful therapy, an axial contrast-enhanced T2-weighted MRI scan shows no
evidence of residual AVM
additional technique along with radiosurgery as an alterna-
tive for high-risk lesions. After primary stereotactic radiosur-
gery, Pan et al. [114] reported a pediatric AVM obliteration Gamma knife radiosurgery, as Dinca et al. [115] reported
rate of 65 % at 48 months following the procedure. When 71.3 % for a one time treatment and 82.7 % overall. Thus,
needed, additional SRS led to a total obliteration rate of GKS is considered to be a valid active management option
81 % [114]. Kano et al. [110] showed an even higher total for pediatric AVM, though limitations include delayed effect
obliteration with SRS of 70 % with at least 4 years of with persistence of bleeding risk for 2–4 years posttreatment
follow-up. Similar obliteration rates were obtained with [115] (Case Study 31.4, Figs. 31.9 and 31.10).
31 Pediatric Disorders: Viewpoint—Surgery
Case Studies
Case 31.1
The patient is a 15-year-old young man, who presented
with an indolent history of progressive visual loss and
headaches. Imaging studies revealed a large cystic cra-
niopharyngioma (Fig. 31.1). A pterional craniotomy
was then completed. Multiple cystic areas were resec-
ted and aspirated. This was a very prolonged and diffi-
cult dissection given the tumor’s investment in the
surrounding optic chiasm, contralateral optic nerve,
and posterior fossa. Two years later, the patient had evi-
dence of tumor recurrence in the temporal lobe. Using
microsurgical dissection techniques, the multiple cysts
of the tumor were removed in this location. Two and a
half years after the second resection, there was again
evidence of recurrence, which required tumor removal
in the medial portion of the sylvian fissure. Five months
later, he underwent Gamma knife radiosurgery. The
tumor remains controlled 1 year after radiosurgery at
last follow-up (Fig. 31.2).
Case 31.2
A 6-year-old young man presented with left-sided
hemiparesis, headache, nausea and vomiting, and
lethargy. Imaging studies revealed a right parietal
tumor that was later diagnosed as a supratentorial
ependymoma (Fig. 31.5). The large hemorrhagic and
calcified tumor was removed in its entirety using
microsurgical dissection techniques and the Stealth
frameless stereotactic system to confirm complete
resection. Postoperatively, the patient became pro-
gressively more lethargic and was found to need a
ventriculoperitoneal shunt to manage new onset
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thoracic spine and a L1–L2 spinal cord lesion within a
span of 9 months that were each resected. At last fol-
low-up 3 years later, the lesion has been stable with no
changes in the fourth ventricular lesion and lumbar
lesions on MRI of the brain (Fig. 31.6) and spine.
423
Case 31.3
A 2-year-old boy presented with signs and symptoms of
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 Pediatric Disorders: Viewpoint—
Fractionated Radiotherapy
Thomas E. Merchant and Erin S. Murphy
Introduction
Childhood cancer is the most common cause of disease
related death among children ages 0–19 years. It has not
been defined as a public health problem because fewer than
12,500 cases are diagnosed each year. CNS tumors represent
21 % of childhood cancers or about 2,700 cases per year [1].
This rare group of tumors is comprised of astrocytoma 56 %,
embryonal tumors including medulloblastoma, supratento-
rial primitive neuroectodermal tumor, and pineoblastoma
20 %, ependymoma 7 %, craniopharyngioma 3 %, germ cell
tumors 3 %, and tumors involving the spinal cord, pituitary,
and choroid plexus 11 %.
As recent as 15 years ago, radiotherapy avoidance was
the primary objective of clinical trials developed for CNS
tumors in children. Most treatment morbidity was attributed
to radiation therapy and there was a major focus on cogni-
tive effects and second malignancies. These concerns were
justified based on the results of the time and the available
treatment. After decades of pursuing radiotherapy avoid-
ance, investigators found that side effects remained despite
the omission of radiation therapy and follow-up reports
demonstrated that disease control was inferior without radi-
ation therapy as a component of frontline management.
Additionally, functional outcomes were relatively unchanged
among long-term survivors: patients would pursue radio-
therapy avoidance, experience side effects associated with
those treatments, suffer progression of disease, and eventually
T.E. Merchant, D.O., Ph.D. (*)
Department of Radiological Sciences, St. Jude Children’s Research
Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
e-mail: thomas.merchant@stjude.org
E.S. Murphy, M.D.
Department of Radiation Oncology, Cleveland Clinic,
Cleveland, OH 44106, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_32, © Springer Science+Business Media New York 2015
32
require further surgery, radiation therapy or both. Based on
published reports demonstrating major reductions in acute
side effects associated with radiation therapy for adult can-
cers, 3-dimensional (3D) radiation was introduced incre-
mentally to the pediatric population. For pediatric patients
with CNS tumors, age has been the major driving force
behind the inclusion or exclusion of radiation therapy and
the sequencing of treatment. The age minimum of 3 years
has often been used to determine whether a child should
receive radiation therapy as part of their frontline treatment.
The embryonal tumors and ependymoma serve as pertinent
examples. For other tumors, such as low-grade astrocytoma,
the age at which radiation therapy has been considered
acceptable has varied from 3 years to 10 years of age. For
CNS germ cell tumors, craniopharyngioma and high-grade
glioma, age has been considered important factor, although
most patients with these diagnoses tend to present at an
older age.
With the objective of reintroducing radiation therapy for
the treatment of young children, defined by the National
Cancer Institute as children under the age of 3 years, and
improving outcomes for all patients, investigators have
looked at ways in which the total prescribed dose might be
reduced, the prescribed volume of radiation might be lim-
ited, or how newer methods of focal radiation delivery
might be implemented to increase conformity of the high-
est isodose volumes. To achieve the aforementioned goals,
clinical trials have been designed to test the safety of lower
doses and reduced target volumes for a variety of tumors
and to study radiation-related treatment effects focusing on
objective measures including neurologic, endocrine, and
cognitive function. Because newer methods of radiation
therapy planning yield information about the 3D distribu-
tion of dose in normal tissues, the long-term goal of many
investigations has been to correlate treatment dosimetry
with functional outcomes and to model the effects of radiation
dose on normal tissues.
427
428
Contrasting Fractionated Irradiation
and Radiosurgery
Although this chapter is meant to focus on the applications
of fractionated irradiation, the use of radiosurgery in pediat-
ric CNS tumors requires comment. Radiosurgery is often
proposed as an alternative to fractionated irradiation for pri-
mary pediatric CNS tumors based on the assumption that it
would be less toxic. Most investigators would agree that
indications exist for the use of radiosurgery in the frontline
adjuvant treatment of craniopharyngioma and certain low-
grade astrocytomas, supplemental boost treatment in con-
junction with fractionated irradiation of pineal region
tumors, and recurrent or metastatic disease. The usual cave-
ats regarding tolerance of critical normal tissue structures
apply, namely, tolerance of optic chiasm, nerves, brain stem,
and diencephalic structures to high-dose single-fraction
irradiation.
The true value of radiosurgery in the treatment of pediatric
patients is unknown because of a lack of prospective experi-
ence and long-term outcomes. For example, the published
series that include pediatric patients with pilocytic astrocyto-
mas are all retrospective with median follow-up ranging from
2 to 8 years, patient numbers ranging from 12 to 50, a variable
number of patients who had undergone prior radiotherapy,
marginal prescription dose ranging from 10 to 15 Gy, and
no consensus of appropriate target volume [2–5]. The same
groups reported rates of tumor cyst expansion ranging from
11 to 25 %. Due to the lack of common inclusion criteria,
target volume, and prescription dose, the applicability of this
data to patient treatment strategies is difficult.
The potential benefits of radiosurgery are often overshad-
owed by poor patient selection or when long-term therapeu-
tic goals or the natural history of the tumor is not considered.
For the treatment of pediatric CNS tumors, radiosurgery has
not been proved to be equivalent to surgery or fractionated
irradiation in terms of outcomes and side effects. Questionable
applications of radiosurgery include the following: low-dose
(<12 Gy) single-fraction irradiation in lieu of a full-dose
fractionated treatment course regardless of tumor size; irra-
diation of a tumor bed without an identifiable target; target-
ing macroscopic residual tumor within a tumor bed known to
contain microscopic disease with no plan for fractionated
irradiation of the tumor bed; primary radiosurgery in lieu of
craniospinal irradiation for seeding tumors; radiosurgery in
lieu of relatively simple surgery when feasible; radiosurgery
to the solid component of a cystic/solid tumor complex;
boost treatment with radiosurgery with subtherapeutic dose
attenuation of the fractionated component. Finally, the pedi-
atric caregiver requires advance notice that imaging changes
are prone to occur after radiosurgery that should not be inter-
preted as progressive disease.
T.E. Merchant and E.S. Murphy
Medulloblastoma
Historically, the treatment for medulloblastoma has consisted
of surgery, postoperative radiation therapy, and during the
past 15 years, systematic post-irradiation chemotherapy for
those older than the age of 3 years at the time of diagnosis.
Surgery followed by chemotherapy, in an effort to delay or
avoid radiation therapy, has been the path followed by most
children under the age of 3 years.
For decades, radiation therapy for older children con-
sisted of craniospinal irradiation to 36 Gy followed by
“boost” treatment of the anatomic posterior fossa to 54 Gy.
These guidelines were developed in an era where adjuvant
therapy consisted of radiation therapy alone and they
remained the standard until it was eventually demonstrated
that the craniospinal dose could be reduced for low-risk
patients (i.e., no evidence of neuraxis dissemination and
residual tumor measuring <1.5 cm2) with the addition of
multiagent chemotherapy [6]. Patients with neuraxis dissem-
ination or substantial residual tumor continue to receive
craniospinal irradiation to dose levels ≥36 Gy despite the
addition of multiagent chemotherapy.
Evolution of Treatment and Impact
on Cognitive Effects
Fear of craniospinal irradiation and its effects on cognitive
function have always been and remain justifiable. The
expectation for a child who receives craniospinal irradiation
at an early age is a loss of IQ at a rate of approximately 3.9
points per year without plateau over the time period of the
reported data, about 6 years [7]. These data were derived
from the St. Jude experience that included children initially
treated postoperatively with chemotherapy that eventually
required conventional dose craniospinal irradiation.
Craniospinal doses of 35.2 Gy and posterior fossa doses of
54–55.8 Gy were prescribed for these patients with a median
age of approximately 3.2 years. Until this article by Walter
et al. [7], the data in the available literature was not mod-
eled, included few subjects, did not include acceptable fol-
low-up, and suffered from significant attrition. Working on
the assumption that the craniospinal dose and treatment vol-
ume were largely responsible for the effects observed in
these children, investigators sought ways to reduce the dose
of craniospinal irradiation from 36 to 23.4 Gy for selected
average-risk patients using adjuvant chemotherapy. In the
largest study reported for that time, and using longitudinal
psychology data from the CCG-9892 trial, Ris et al. [8]
showed a decline in IQ of 4.3 points per year among patients
between the ages of 3 and 7 years treated with craniospinal
irradiation to 23.4 Gy, posterior fossa irradiation to 55.8 Gy,
32 Pediatric Disorders: Viewpoint—Fractionated Radiotherapy
Fig. 32.1 (a) Classic lateral portal film outlining the posterior fossa boost for a patient with medulloblastoma (lower): composite craniospinal,
posterior fossa, and primary site dose distribution for a standard-risk patient with medulloblastoma treated on the St. Jude SJMB96 protocol
and adjuvant chemotherapy. In other words, reducing the
craniospinal dose to 23.4 Gy did not improve cognitive out-
comes in young patients with average-risk medulloblas-
toma. This lack of improvement should have come as no
surprise given the volume of normal brain subtended by the
treatment of the entire posterior fossa. It has been estimated,
depending on the individual patient, that nearly 40 % of the
entire brain receives the prescription dose of 54–55.8 Gy
when the posterior fossa is the target and conventional radi-
ation therapy planning is used.
The more recent focus for investigators has been the tar-
get volume for the “boost” component of treatment after cra-
niospinal irradiation in an attempt to alter treatment from the
entire posterior fossa to the primary site with a limited mar-
gin. Although there are a number of single institution reports
that appear to have accomplished this goal, the largest study
of its kind was the SJMB96 trial conducted at St. Jude
Children’s Research Hospital and collaborating centers at
Texas Children’s Hospital, the Royal Children’s Hospital in
Melbourne, and the New Children’s Hospital in Sydney from
1996 to 2003 [9] (Fig. 32.1).
This study included patients with a variety of embryonal
tumors and presentations including average and high-risk
medulloblastoma, supratentorial PNET, and atypical teratoid
rhabdoid tumor. All patients received similar post-irradiation
high-dose chemotherapy with peripheral stem cell support
and all patients received postoperative craniospinal irradia-
tion that was uniquely risk adapted. For example, patients
classified as average-risk (no evidence of metastases, resid-
ual tumor <1.5 cm2), regardless of embryonal tumor type or
location, received 23.4 Gy craniospinal irradiation, 36 Gy
posterior fossa irradiation (infratentorial tumors only), and
primary site irradiation using an anatomically confined 2 cm
clinical target volume margin surrounding the postopera-
tive tumor bed and residual tumor and 0.3–0.5 cm planning
target volume margin. Patients with high-risk tumors received
36–39.6 Gy craniospinal irradiation and primary site irradiation
429
using a similarly defined clinical and planning target volume
margins. This small and step-wise reduction in primary site
targeting did not affect the rate or patterns of failure for
patients with average-risk medulloblastoma. The 3-year
event-free survival was reported at 78 ± 6 %. Although the
gross tumor volume was significantly smaller than the ana-
tomic posterior fossa in these patients, with the additional
2 cm clinical target volume margin and 0.3–0.5 cm planning
target volume margin, the final target approached, and in
some cases exceeded, the anatomic posterior fossa for these
same patients. The volumetric details from this study pro-
vided some insight into the effect of the actual postoperative
primary site volume, location, and targeting guidelines on
our ability to further reduce the volume of irradiation after
the craniospinal component. Despite the small reduction
in the volume of irradiation, the decline in IQ for patients
with average-risk medulloblastoma, ages 3–7 years, was
significantly improved to approximately –2.4 points per year.
Indeed, the psychology data from this study forms the largest
data set for patients treated with craniospinal irradiation for
medulloblastoma and provides data from which parents and
caregivers may estimate the effects of craniospinal irradia-
tion. In summary, eliminating posterior fossa irradiation and
treating the primary site with a limited margin after cranio-
spinal irradiation does improve cognitive outcomes for
patients with medulloblastoma.
The next step taken by the St. Jude consortium and sepa-
rately by the Children’s Oncology Group was further dose
and volume reduction. The recently completed St. Jude trial
known as SJMB03 (clinicaltrials.gov, NCT00085202)
includes identical risk-based craniospinal dosing and
post-irradiation chemotherapy as the SJMB96 trial with
newer targeting guidelines for the primary site boost. The
clinical target volume margin is an anatomically confined
margin of 1 cm surrounding the postoperative tumor bed and
residual tumor. The planning target volume margins remain
0.3–0.5 cm. The Children’s Oncology Group is conducting
430
Fig. 32.2 Schema from
the COG standard risk
medulloblastoma trial
ACNS0331 (clinicaltrials.
gov, NCT00085735)
a medulloblastoma trial (ACNS 0331, clinicaltrials.gov,
NCT00085735) for patients 3–8 years of age and 8–21 years
of age (Fig. 32.2). The younger children are enrolled on an
ambitious four-arm trial with two steps of randomization.
Postoperatively patients are randomized to 23.4 Gy cranio-
spinal irradiation with concurrent vincristine versus 18 Gy
craniospinal irradiation and boost treatment of the anatomic
posterior fossa to 5.4 Gy (total 23.4 Gy posterior fossa) and
concurrent vincristine. Patients are further randomized to
primary site treatment that may include 55.8 Gy to the con-
ventional posterior fossa volume or 55.8 Gy conformal pri-
mary site irradiation using a 1.5 cm clinical target volume
margin. All patients receive post-irradiation chemotherapy
consisting of cisplatin, CCNU, cyclophosphamide, and vin-
cristine every six weeks for a total of nine cycles. The che-
motherapy regimen was designed based on the equivocal
results from the A9961 intergroup study that compared plati-
num, CCNU, and vincristine to cyclophosphamide, cisplatin,
and vincristine. The older patients all receive 23.4 Gy cranio-
spinal irradiation and concurrent vincristine followed by a
randomization to 55.8 Gy to the conventional posterior fossa
volume or 55.8 Gy conformal treatment of the primary site
using a 1.5 cm clinical target volume margin. They will
then receive post-irradiation chemotherapy identical to the
younger patients.
A number of important questions should be answered
after completion of the Children’s Oncology Group study in
late 2013:
• In the context of conventional chemotherapy is it possible
to eliminate irradiation of the entire anatomic posterior
fossa?
T.E. Merchant and E.S. Murphy
• Will 18 Gy craniospinal irradiation prove to be as
effective (similar disease control) as 23.4 Gy craniospinal
irradiation?
• Are the volumetric differences between the different
treatment arms sufficiently large to detect a difference in
cognitive or audiometric outcomes?
Figure 32.3 shows a graphical representation of the dose
distribution for the total brain volume that would be expected
for a typical patient planned and treated using conformal
radiation therapy on the Children’s Oncology Group trial.
There are several regions of these curves that are notable
moving from lowest to highest doses. The total brain is
expected to receive the entire craniospinal dose as prescribed,
18 or 23.4 Gy. The dose to the total brain falls steeply and the
curves separate according to those who receive conventional
posterior fossa irradiation (parallel opposed portals in the
example) or those who receive conformal treatment of the
primary site—who tend to have an increase in the volume
that receives the intermediate doses. The curves come
together at the point where 30 % of the total brain receives
approximately 40 Gy, and for the remainder of the high dose
region, the curves diverge based on conventional targeting
and treatment of the posterior fossa versus conformal treat-
ment of the primary site. These curves demonstrate the volu-
metric effects of craniospinal dose reduction, the volumetric
effects of conformal irradiation, and finally volumetric
effects of the reduction in the targeted volume from the ana-
tomic posterior fossa to the primary site with the prescribed
clinical target volume margin of 1.5 cm. Based on the
improvement shown for the SJMB96 trial over conventional
radiation therapy, one would anticipate an improved outcome
32 Pediatric Disorders: Viewpoint—Fractionated Radiotherapy
Fig. 32.3 Graphical
representation of the
whole-brain dose
distribution for
representative cases
planned for treatment on
each of the four arms of
the COG standard-risk
medulloblastoma trial
ACNS0331 (clinicaltrials.
gov, NCT00085735)
for those treated with 18 Gy craniospinal irradiation and
perhaps those treated on the other arms.
Emerging data strengthen the association between the dis-
tribution of dose to regional volumes of normal brain and
decline in cognitive function in several domains. The negative
impact on IQ and academic test scores associated with increas-
ing mean dose was shown for the entire brain volume, supra-
tentorial brain volume, left and right temporal lobes, and left
hippocampus (IQ, math, and reading scores) [10]. Figure 32.4
shows example IQ scores modeled based on SJMB96 data.
Proton therapy is an excellent measure to reduce extra-CNS
and CNS dose in these patients: Photon dose volume data
associated with a decline in IQ are graphically inferior to
proton dose volume data for similar patients [11].
Early data from a prospective proton therapy trial for
patients with medulloblastoma with a median follow-up of
3.2 years demonstrates a 3-year progression-free survival of
83 % and 76 %, respectively, for standard- and high-risk
children [12]. Fifty-one children underwent neurocognitive
evaluations at baseline and 31 received follow-up testing.
Full scale, verbal, and performance IQ evaluations were not
significantly different, but there was a decline in processing
speed. Long-term neurocognitive outcome data is awaited to
be able to compare proton data with that of modern photon
data for which we have longer follow-up.
Neurovascular Effects
An important and devastating side effect of radiation therapy
is CNS necrosis. Among 148 patients who received 23.4 Gy
craniospinal irradiation and 88 patients who received more
than 36 Gy craniospinal irradiation, the cumulative incidence
431
of CNS necrosis at 5 years was 3.7 % (SD, 1.3 %) [13].
Those patients for whom CNS necrosis was observed had the
largest infratentorial volumes receiving dose in excess of 50,
52, and 54 Gy, providing new limits of tolerance for children
with medulloblastoma and other CNS embryonal tumors
treated with aggressive surgery, craniospinal irradiation, and
intensive chemotherapy.
Endocrine Effects
Baseline and prospective endocrine evaluations were per-
formed for children on the risk-adapted SJMB96 trial
described above. The 4-year cumulative incidence of growth
hormone deficiency, thyroid-stimulating hormone (TSH)
deficiency, adrenocorticotropic hormone (ACTH) defi-
ciency, and primary hypothyroidism was 93 ± 4 %, 23 ± 8 %,
38 ± 6 %, and 65 ± 7 %, respectively [14]. Radiation dosime-
try to the hypothalamic-pituitary axis was associated only
with the development of TSH deficiency; the 4-year cumula-
tive incidence was 44 ± 19 % and 11 ± 8 % for those receiving
a median dose to the hypothalamus of <42 Gy compared
to ≥42 Gy, respectively.
Treatment for Young Children
Reintroducing radiation therapy to very young children
under the age of 3 years with embryonal tumors has meant
omitting craniospinal irradiation from their treatment
regimen. The obvious advantages of CSI elimination, com-
bined with conformal radiation therapy (CRT) of the poste-
rior fossa and/or primary site, are apparent. The Children’s
432
Fig. 32.4 Modeled IQ scores in children with medulloblastoma treated with craniospinal irradiation on the SJMB96 trial (clinicaltrials.gov,
NCT00003211)
Oncology Group Study P9934 demonstrated the advantage
of the addition of CRT to postoperative chemotherapy when
compared postoperative chemotherapy alone for children
with nonmetastatic medulloblastoma between the ages of 8
and 36 months [15]. Seventy-four children on this trial
underwent maximal surgical resection followed by four
cycles of induction chemotherapy (cyclophosphamide, vin-
cristine, cisplatin, and etoposide) followed by age and
response-adjusted CRT to the posterior fossa (18 or 23.4 Gy)
and tumor bed (cumulative 50.4 or 54 Gy) and maintenance
chemotherapy (four alternating cycles of cyclophosphamide
and vincristine followed by oral etoposide). The 4-year EFS
and OS was 50 ± 6 % and 69 ± 5.5 %, respectively, which
compared favorably to results from Pediatric Oncology
Group (POG) 9233 trial which included postoperative mul-
tiagent chemotherapy alone and resulted in EFS and OS of
25 ± 5.5 % and 46 ± 6 %, respectively. It is important to note
that the P9934 study included more patients with a gross
total resection and desmoplastic or nodular histology, which
are known to be good prognostic factors compared to POG
9233. Of note there was no significant or consistent decline
in either cognitive or motor function that could be attributed
to the chemotherapy or CRT. The majority of children did
exhibit a significant delay in development at baseline, most
likely due to the tumor itself.
The current trial sponsored by the Children’s Oncology
Group (ACNS0334, clinicaltrials.gov, NCT00336024) for
children with high-risk primitive neuroectodermal tumors
randomizes children under the age of 3 years who have
undergone maximal surgical resection to the addition of
T.E. Merchant and E.S. Murphy
methotrexate to an intensive induction chemotherapy regi-
men of vincristine, etoposide, cyclophosphamide, and cispl-
atin. The induction regimen is followed by second surgery if
less than a complete response or consolidation chemotherapy
with stem cell rescue. Radiotherapy is not a part of this clini-
cal trial but age, risk, and response-adapted guidelines are
suggested after the completion of consolidation. CSI is
avoided for patients without metastatic disease and the target
volume includes the tumor bed with a 1 cm clinical target
volume margin with a total dose of 50 Gy (45 Gy < 24 month)
for complete response or 54 Gy (50 Gy < 24 month) for par-
tial response or stable disease. Patients presenting with meta-
static disease are recommended to receive reduced dose CSI
of 18 Gy followed by the same tumor bed boost as above.
Primary Brain Tumors That Require Focal
Irradiation
The ICRU-50 Report Guidelines published in 1993 [16] and
more recently the ICRU-62 [17] Report Guidelines pub-
lished in 1999 have been taken to heart by those involved in
the design and conduct of brain tumor trials for children. The
definitions of the gross tumor volume (GTV), clinical target
volume (CTV), and planning target volume (PTV) follow
closely those of the ICRU with one notable exception. The
GTV includes the tumor bed in addition to the residual
tumor. In the ICRU-50 report, the tumor bed is not meant as
part of the GTV and the CTV margin is the margin surround-
ing the GTV in consideration of microscopic extension.
32 Pediatric Disorders: Viewpoint—Fractionated Radiotherapy
Because margins are not assessed for brain tumors, all mar-
gins of the tumor bed are considered to be at risk and likely
to harbor microscopic disease with extension into surround-
ing normal tissues. Until the day when neurosurgeons biopsy
the operative cavity and the pathologists determine margins
or the neuroradiologists have the means to identify subclini-
cal microscopic disease, the margin of the tumor bed will be
considered to be the basic volume at risk and defined as
the GTV.
The governing principals of target volume definitions and
beam’s eye view treatment planning, whether forward or
inverse, are similar in children and adults. After the target
volume definition, the next step in the planning process is the
definition of normal tissue volumes or so-called critical
structures. These volumes take on additional meaning in the
treatment of younger patients where there is an incentive to
minimize dose to normal tissues and spare these patients
from the late effects of radiation on the central nervous
system. For children destined to receive central nervous
system irradiation, planners should have at minimum, dose
volume data for the entire brain, supratentorial brain or
temporal lobes, hypothalamic-pituitary unit, cochleae, optic
chiasm, cervical spinal cord, and brainstem. These patients
are at risk for radiation-related CNS effects including abnor-
malities in neurovascular function affecting hearing, vision,
and gross neurologic function, cognitive effects involving
learning, memory, attention, behavior, academic achieve-
ment, and global IQ, endocrine function affecting growth
hormone secretion, thyroid hormone secretion, ACTH secre-
tion, and the gonadotropins. Patients who receive hypotha-
lamic irradiation are at risk for hypothalamic obesity. Patients
treated with large volume cranial, superficial cranial, or cra-
niospinal irradiation are at risk for abnormalities in growth
and development including deformity of the calvarium,
facial bones, and spine [18].
The true value of past, present, and future 3D treatment
trials will be the correlation of 3D radiation dosimetry with
functional outcomes. Three-dimension radiation planning
has greatly improved our understanding of radiation dose
distributions in tumor and normal tissues. The most practical
way for those involved in treatment planning to view dose
volume data is with the 2D dose volume histogram (DVH),
which is a reduction of the 3D dose volume information
based on the assumption that all elements of the brain vol-
ume in question are functionally similar. In other words, the
dose-volume histogram lacks spatial information. The cumu-
lative DVH graphs the percent volume of a normal tissue
structure receiving a specified dose in a cumulative manner.
While this is helpful to the planner, the most important graph
is the differential DVH, which represents the percent volume
of the normal tissue structure (y-axis) receiving the given
dose on the x-axis. Integrating these data one can determine
the distribution or burden of radiation therapy to the normal
433
tissue volume in question and when using advanced
modeling procedures, one may integrate dose over speci-
fied intervals and treat these data as clinical variables in a
multivariate analysis. Most modeling procedures have used
specific doses chosen along the dose volume curves and
entered these values into one of the many models meant to
determine the probability of a specific effect.
In consideration of radiation-related CNS effects, four
important points should be understood: (1) pre-irradiation
morbidity has not been systematically studied; (2) most
reports describing radiation-related side effects are outdated;
(3) most studies include small numbers of subjects and have
large rates of attrition; and (4) radiation has been treated as a
categorical variable in most analyses. The governing hypoth-
esis for current clinical trials involving children with CNS
tumors that require only focal irradiation is that irradiation of
smaller volumes will reduce radiation-related side effects
without affecting tumor control. In support of this hypothesis,
current studies include statistical monitoring of rate and
patterns of failure and comparison of disease control rates to
those achieved for patients treated using historic guidelines.
In support of this hypothesis, most studies include longitu-
dinal assessment to evaluate patients for CNS effects and
include baseline assessments and some prospect of compar-
ing results with historical controls, although, as mentioned
earlier, there are limited data for such a comparison. In a land-
mark study conducted at St. Jude Children’s Research
Hospital from 1997 to 2003, patients with localized primary
brain tumors were treated on a Phase II study to estimate the
local control and patterns of failure for pediatric patients with
localized primary CNS tumors treated with 3D conformal and
intensity-modulated radiation therapy. The study also sought
to quantify radiation-related CNS effects looking at pre-
irradiation morbidity and estimating the time to onset of
CNS effects, specifically evaluating the effects of radiation
dose and volume on longitudinal functional outcomes. This
study, known as RT-1 (clinicaltrials.gov, NCT00187226),
included patients as young as 12 months of age and up to age
25 years, tumors that required only focal irradiation, biopsy
proven tumors except for optic pathway glioma, no evidence
of dissemination (patients requiring craniospinal radiation
were not eligible), no prior fractionated external beam irradi-
ation history, and prior chemotherapy was not exclusionary.
Patients were required to have a minimum performance status
and parents were required to sign a protocol consent indicat-
ing that they understood the risks of target volume reduction
including an increase in the rate of failure. Notably, patients
with brainstem glioma because of their poor prognosis and
patients treated with craniospinal irradiation were excluded
because the whole-brain component of this treatment pre-
cludes a high degree of normal tissue sparing (Fig. 32.5).
The RT-1 protocol had two strata. The first included a
1 cm CTV margin for ependymoma, WHO Grade I and
434
Fig. 32.5 (a) Axial T2-weighted MR image of cerebellar pilocytic astrocytoma. (b) Axial T2-weighted MR image of optic pathway glioma.
(c) Axial T2-weighted MR image of diffuse pontine glioma. (d) Axial T2-weighted MR image of gliomatosis cerebri
Grade II astrocytoma, and craniopharyngioma. The second
included a 2 cm CTV margin for Grade III and IV astrocy-
toma. Planning target volume margins for all tumors were
0.3–0.5 cm based on the methods of immobilization of the
time that included vacuum-bag and thermoplastic technol-
ogy, relocatable stereotactic head frames, and frameless
stereotaxy using radiocamera systems. During the time
period of the study, additional developments included
improved IV-administered general anesthesia, routine use of
prone position general anesthesia, spiral CT, non-coplanar
multi-field conformal irradiation, routine MR registration,
linear accelerator treatment automation with independent
gantry and couch movement, micro-leaf collimation
(<1 cm), widely available inverse planning, and intensity-
modulated radiation therapy. One of the key success factors
in radiation planning has been the introduction of MR regis-
tration into the planning process: treatment standards should
include multi-sequence MR registration. MR-only planning
has been proposed for patients with CNS tumors.
Compared to prior treatment eras, dose prescriptions for
patients with pediatric CNS tumors are now similar or identi-
cal to those used for adults. One example is ependymoma:
postoperatively, 59.4 Gy is prescribed with dose reductions
to 54 Gy only for children under the age of 18 months who
have undergone gross total resection. The dose reduction for
those less than 18 months of age is not based on experi-
mental data, rather concerns about late effects in very young
children who have not previously been irradiated as a part of
their frontline management. Grade I and II astrocytoma and
craniopharyngioma are prescribed 54 Gy and Grade III and
IV astrocytoma 59.4 Gy. The data showing no difference in
dose for adults with low-grade glioma [19] does not apply to
children for pediatric patients are more likely to have juve-
nile pilocytic astrocytoma (WHO Grade I) compared to
adults who are more likely to have WHO Grade II astrocy-
toma. One important aspect of dose prescription for local-
ized brain tumor protocols in children is the tolerance doses
T.E. Merchant and E.S. Murphy
for the spinal cord and optic chiasm. At our own center, we
routinely prescribe 54 Gy to the upper cervical spinal cord
which is meant to include the upper 10 cm3’s of spinal cord
defined as 30 2 mL CT slices multiplied by the area of the
cross-section of the spinal cord ranging from 3–5 cm2. No
neurologic deficits ascribed to the spinal cord have been
identified in patients treated in this manner. Similarly, dose
levels of 54–55.8 Gy to the optic chiasm have also been pre-
scribed in patients who have tumors adjacent to or involving
this critical normal tissue structure. Again, no delayed vision
loss has been observed in this patient population. It is impor-
tant to note that while we limit doses to the tolerance levels
as described, regardless of the method of volume reduction
or “cone down,” these structures will continue to receive
additional dose. In our own practice, we have limited the
cone down dose objective to be less than 70 % of the daily
prescription dose. Although a point for more lengthy discus-
sion, the variances in PTV or normal tissue (unspecified
tissue) inhomogeneity, while often included in cooperative
group or institutional guidelines, are unsupported by data.
There are a number of critical aspects to planning (pre-
treatment), treatment (on treatment), and post-treatment
imaging. At the present time, thin slice CT (<2 mm) is the
fundamental data set. CT is used for radiation dose calcula-
tion as well as to define cochlea and spinal cord. As poste-
rior fossa tumors are the most common site for CNS tumors
in children, the cervical spinal cord is often subtended by
the irradiated volume and needs to be precisely defined.
The cochlea, an adjacent and important structure, is easily
defined within the temporal bone and needs to be precisely
defined. Because these structures are small and prone to the
errors of registration (e.g., flexion or extension errors for
the spinal cord when registering diagnostic MR and treatment
planning CT), it is our suggestion, while CT remains the
fundamental data set, to define the cochleae within the tem-
poral bone and the cervical spinal cord beginning below the
foramen magnum on CT. MR imaging is, of course, used to
32 Pediatric Disorders: Viewpoint—Fractionated Radiotherapy
define target volumes and other normal tissue structures.
Gadolinium-enhanced T-1-weighted MR imaging works
well for most tumor systems to identify post-operative tumor
bed, enhancing residual tumor and normal tissue structures.
The post-contrast T-1-weighted imaging sequence should be
acquired three dimensionally to improve spatial resolution
and to minimize errors in registration. Certain low-grade
astrocytomas, most high-grade astrocytomas, and nearly all
brainstem gliomas are best seen on T-2-weighted and fluid-
attenuated inversion recovery (FLAIR) imaging. Fortunately
T2-weighted and FLAIR sequences may now be required
3-dimensionally with high resolution at 1.5 T. In developing
targeting guidelines, the imaging must have resolution lower
than the prescribed margins.
Imaging during treatment is a concept that requires care-
ful study and discussion. Imaging during treatment may be
critical for patients with craniopharyngioma and cystic low-
grade astrocytoma. These patients are prone to cyst expan-
sion during radiation therapy and in the setting of highly
focused small margin irradiation have the potential to expand
outside of the prescribed isodose volume. On the St. Jude
RT-1 protocol, imaging was performed at weeks 3 and 5 of
irradiation therapy in order to acquire experimental data for
quantitative measure of the MR T1 value in normal tissues.
This maneuver proved to be critical for patients with cranio-
pharyngioma, the majority of which required cyst aspiration
during radiation therapy either stereotactically or through
imbedded catheter and reservoir systems. Despite aggressive
aspiration, 15 % of patients required replanning. In addition,
several cases of expansive low-grade astrocytoma were noted
during treatment. Given the standard to perform MR imaging
at some point in time prior to the initiation of radiation ther-
apy, often 2–3 weeks, followed by 6 weeks of radiation
therapy and the usual 6-week follow-up after radiation,
nearly 4 months may elapse between preplanning MRI and
posttreatment MRI. Posttreatment imaging on the RT-1 pro-
tocol includes scans every 3 months for 2 years, every 6
months for an additional 3 years followed by yearly imaging.
Patients with potentially seeding tumors such as ependy-
moma underwent MR imaging of the spine every 12 months.
Over a 5.5 year period of time, from July 1997 to January
2003, 202 patients with localized CNS tumors were
enrolled on the RT-1 protocol including 88 children with
ependymoma, 49 children with low-grade astrocytoma, 35
patients with high-grade astrocytoma, and 28 patients with
craniopharyngioma. There were two additional patients
eligible for study; one with a CNS germ cell tumor, the
other with a choroid plexus tumor. The rates and patterns of
failure for all these patient groups have been previously
reported or presented and fell within the expected range of
failure noted for patients treated in the conventional radia-
tion therapy era.
435
Ependymoma
Focusing on children with ependymoma treated on the RT-1
protocol, and as previously reported, there were 88 children
treated from July 1997 to January 2003. The age at the time
of irradiation was 2.85 years (median) with a standard devia-
tion of 4.47 years. Seventy-four patients underwent gross
total resection, six underwent near total resection, and eight
subtotal resection. Thirty-two patients underwent second
surgery prior to the initiation of radiation therapy. Sixteen
patients had pre-irradiation chemotherapy and 20 patients
had supratentorial tumor location. As reported in the Journal
of Clinical Oncology the 3-year event-free survival was
75 ± 6 % with a cumulative incidence of local failure of
14 ± 4 % [20]. The median time to failure was 16 months
ranging from 6 to 26 months. These data compared favorably
to the CCG9942 study, which reported a 5-year event-free
survival of 57 ± 6 % for children 3–21 years of age with intra-
cranial ependymoma [21]. Through the RT-1 trial the volume
of irradiation for ependymoma was shown to be reducible to
a 1 cm clinical target volume margin without effecting tumor
control. The improved tumor control rate was attributed to
the high rate of gross total resection, improved targeting
through MR and CT registration, the relatively high total
dose 59.4 Gy, and the relatively high tolerance dose for the
cervical spinal cord (54 Gy). Based on the RT-1 study, the
Children’s Oncology Group initiated a study (ACNS0121,
clinicaltrials.gov, NCT00027846) in August 2003 and it
completed patient enrollment in January 2010, the results are
not yet reported.
Cognitive Effects
Patients on the RT-1 protocol submitted to a battery of psy-
chology testing including measures of intelligent, academic
achievement, attention, impulsivity and reaction time, mem-
ory, auditory learning, problem, and adaptive behavior.
Testing was performed at baseline and serially at 6, 12, 24,
36, 48, and 60 months. As previously reported, children
under the age of 3 years had a statistically lower baseline
IQ. Both younger and older patients showed no change in IQ
with time after irradiation. These data are an improvement
compared to historic St Jude data where much older children
had a decline in IQ of approximately 2.4 points per year.
Academic achievement, memory, verbal learning, and adap-
tive behavior have been stable in these same patients [22]
(Fig. 32.6).
The DVH data for the total brain, supratentorial brain,
left and right temporal lobes were acquired for 86 of the 88
ependymoma patients included on the RT-1 protocol.
436
Fig. 32.6 Prospective evaluation of children receiving focal irradiation
demonstrates essentially stable IQ and adaptive behaviors, but a signifi-
cant decline in communication scores
These data were partitioned into three intervals representing
the percent volume receiving less than 20 Gy, the percent
volume receiving 20–40 Gy, and the percent volume
receiving 40–60 Gy. The DVH data were combined with
clinical data to form a linear aggression model estimating
IQ as a function of time [23].
Initially the correlation involved dosimetry and the IQ data
for all patients. A total brain dose volume estimating equation
was produced that included in the intercept age and in the
slope time and dose volume. No other clinical variables were
included in the equation. A similar equation was developed
for the supratentorial brain; however, no correlation could be
developed for the temporal lobes or with any of the clinical
co-variants. It is important to note in the total brain volume
dosimetry estimating equation that the low dose coefficient (v
0–25 Gy) was negative and small, the high dose coefficient (v
45–65 Gy) was negative and small, and the intermediate dose
volume term v 20–40 or v –25 to 45 was similar in weight to
the high dose coefficient but with a positive term. To increase
the specificity of our model we performed a correlation only
with infratentorial patients and developed three equations;
one for the total brain, another for the supratentorial brain,
and one for the left temporal lobe. The dose volume equations
have similar coefficients, negative low dose, positive interme-
diate dose, and negative high dose terms. The low dose terms
were not statistically significant for the total brain or left tem-
poral lobe equations. Age continued to affect the intercept
and time affected for the slope.
A recent study evaluated the impact of cerebellar radia-
tion dosimetry on cognitive and academic abilities for chil-
dren with infratentorial ependymoma receiving adjuvant
conformal radiotherapy (54–59.4 Gy) [24]. Seventy-six chil-
dren underwent cognitive and academic testing at baseline,
6 months post-conformal radiotherapy, and annually for
5 years. Overall for this population, the IQ scores at 5 years
T.E. Merchant and E.S. Murphy
post-radiotherapy fell within population norms. There was a
correlation between mean infratentorial dose and IQ, math,
reading, and spelling scores. When evaluating specific
sub-volumes of the cerebellum, there was a correlation
between mean anterior cerebellum dose and reading scores
and mean posterior cerebellum dose and math, spelling, and
visual-auditory learning scores.
Endocrine Effects
Patients on the RT-1 study also underwent provocative endo-
crine testing to measure growth hormone secretion, thyroid
hormone secretion, ACTH reserve, and gonadotropin secre-
tion in appropriate patients. These tests were performed at
baseline and 6, 12, 36, and 60 months after the initiation of
irradiation. In the first report of its kind, 46 of 68 initial
patients were found to have preexisting hormone deficien-
cies including 16 of 32 patients with posterior fossa tumors
[25, 26]. Among these patients specific deficiencies included
growth hormone secretion abnormality in 38 %, thyroid hor-
mone secretion abnormality in 43 %, ACTH secretion
abnormality in 22 %, and GNRH abnormality in 18 %. There
was one patient with hyperprolactinemia. Among children
with ependymoma, the baseline rate of growth hormone defi-
ciency using the ATT/L-dopa test was 29 %, thyroid hor-
mone abnormality using the TSH surge 27 % or TRH
stimulation test 10 %, ACTH secretion abnormality using the
1 μg ACTH test 12 %, and metyrapone test 12 %.
Change in peak growth hormone levels following ATT/L-
dopa have been studied in children from baseline through 12
months after irradiation. The falloff in growth hormone for
25 “normal” patients was shown to be exponential and a
population-based estimating equation was developed for
which all dose terms (low, intermediate, and high) were sta-
tistically significant and negative. The effect of low dose was
smallest and the effects of intermediate and high doses were
similar. Similar changes in peak growth hormone after ATT/
L-dopa were developed specifically for ependymoma.
Other Long-Term Side Effects
The data gathered from the St. Jude prospective trial of
conformal radiotherapy for children with ependymoma
has allowed us to better counsel our patients and their fami-
lies on the long-term side effects of modern radiotherapy.
The 7-year cumulative incidence of brainstem radionecrosis
was found to be 1.6 % [27]. The 7-year cumulative incidence
of any secondary malignancy and second malignant brain
tumor was 4.1 % and 2.3 %, respectively. The secondary
malignancies included two glioblastoma and one papillary
thyroid cancer. Only 1 of 153 patients required a revascular-
32 Pediatric Disorders: Viewpoint—Fractionated Radiotherapy
ization surgery and this patient’s high dose target volume
encompassed the Circle of Willis.
In summary, the results of recent trials for localized brain
tumors have made radiation therapy more acceptable for
young children with brain tumors. Improved targeting may
increase tumor control rates for some tumors, which will in
turn increase the validity of numerous prognostic factors.
The next generation of volume reduction trials is currently
underway for patients with medulloblastoma and localized
brain tumors. We also anticipate outcomes from children
with these brain tumors being treated with proton therapy.
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2. Boëthius J, Ulfarsson E, Rähn T, Lippitz B. Gamma knife radiosur-
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5. Hallemeier CL, Pollock BE, Schomberg PJ, Link MJ, Brown PD,
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 Pediatric Brain Tumors:
Viewpoint—Chemotherapy
Nathan J. Robison
Introduction
Recent decades have seen significant advances in the treatment
of childhood brain tumors [1]. Despite these, the outcome for
many tumors remains extremely poor, while long-term survi-
vors often face significant long-term sequelae. For many
better-prognosis pediatric brain tumors, a major aim of
recent clinical innovation has been to decrease late effects,
particularly the neurocognitive effects consequent to irradi-
ating eloquent areas of the developing brain [2]. Various che-
motherapeutic approaches have been used to allow reduction
in radiation dose and field, or to replace irradiation entirely.
Stereotactic radiosurgery (SRS) has the potential to address
some of these problems as well: SRS allows treatment of
focal areas of disease with high-dose radiation, with signi-
ficantly reduced risk of injury to the surrounding brain.
Anecdotal experience lends support to the safe use of SRS in
combination with other modalities as a radiation-limiting
strategy [3, 4]. The risk of radiation necrosis and subsequent
injury to eloquent areas of the brain must be considered [5, 6].
This chapter discusses the relative roles and limitations of
SRS and chemotherapy in the treatment of specific pediatric
brain tumors.
Low-Grade Glioma
Low-grade gliomas include pilocytic astrocytoma, which
is the most common brain tumor in children, as well as a
heterogeneous collection of rarer histologic entities [1].
Complete resection, where feasible, is usually curative.
However, even for non-resectable tumors, very long-term
N.J. Robison, M.D. (*)
Children’s Center for Cancer and Blood Diseases, Children’s
Hospital Los Angeles, University of Southern California Keck
School of Medicine, 4650 W. Sunset Blvd, MS #54,
Los Angeles, CA 90027, USA
e-mail: nrobison@chla.usc.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_33, © Springer Science+Business Media New York 2015
33
survival is quite favorable, and spontaneous malignant
transformation exceedingly rare [7]. Disease- and treatment-
related morbidity are therefore of primary concern. Histori-
cally, radiation therapy has been considered definitive
therapy for non-resectable disease [8, 9]. However, as data
continues to accrue regarding the long-term radiation-
related morbidities in this population, post-radiation disease
progression, and the probability of very-long-term survival
without radiation, significant doubt has been cast on the
appropriateness of radiation in many cases.
Low-grade gliomas, pilocytic astrocytoma especially, are
usually responsive to a number of relatively low-intensity
chemotherapeutic regimens [1]. A randomized clinical trial
comparing carboplatin and vincristine (CV) with thioguanine,
procarbazine, lomustine, and vincristine (TPCV) showed
similar outcomes with both regimens; event-free and overall
survival rates for the entire cohort were 45 and 86 %, respec-
tively, at 5 years [10]. The high rate of eventual disease
progression does not necessarily reflect a poor long-term
prognosis, as response rate to salvage therapy is high, even
with multiply recurrent disease, as the high long-term overall
survival indicates [11]. Chemotherapy should generally be
considered standard front-line therapy for non-resectable
tumors requiring treatment as well as for recurrent disease.
Besides CV and TPCV, regimens that have been used with
success in the treatment of newly diagnosed or recurrent
low-grade glioma include cisplatin and etoposide [12], temo-
zolomide [13], monthly carboplatin [14], or weekly vinblas-
tine [15], among others.
SRS in the treatment of low-grade gliomas has been used
anecdotally and in several small series with generally favor-
able results [6, 16–22]. A retrospective series of 50 children
who underwent SRS for unresectable disease showed a
10-year progression-free survival (PFS) of 89 % for patients
treated at the time of diagnosis and 45 % for patients treated
at time of recurrence/progression [23]. This is similar to out-
come seen after treatment with chemotherapy. Adverse radi-
ation effects are reported to 10–35 % of LGG patients treated
with SRS [18, 23]. The risk of second malignancy after SRS
439
440
is thought to be reduced, but is not yet well-defined [24].
Efficacy of SRS in tumors progressive after prior fraction-
ated radiotherapy appears to be limited [22].
Patients with neurofibromatosis type 1 (NF1) have a high
incidence of low-grade glioma, especially optic pathway gli-
oma. Low-grade gliomas typically follow an indolent course in
this population [25]. Radiation therapy is generally contraindi-
cated in patients with NF1, due to extremely high risk of
second malignancy and radiation-induced vascular disease
[25–28]. Observation alone is appropriate for most asymptom-
atic patients, even in the setting of radiographic progression
[29, 30]. NF1 patients are also at increased risk of secondary
leukemia after treatment with alkylating agents such as cyclo-
phosphamide or nitrosureas [31]. For this reason, treatment
with non-alkylating chemotherapy is recommended for NF1
patients with symptomatic low-grade gliomas.
High-Grade Glioma
High-grade gliomas include grade III astrocytoma (anaplastic),
grade IV astrocytoma (glioblastoma), and other rarer entities
such as anaplastic oligodendroglioma and oligoastrocytoma.
Although relatively rare in children, high-grade gliomas
nonetheless contribute substantially to pediatric cancer-
related mortality. Because long-term survival is the excep-
tion, late effects concerns have not played an important role
in guiding therapeutic strategies.
The mainstay of therapy for high-grade glioma is maxi-
mal resection where feasible, followed by involved field
radiation. High-grade gliomas are relatively chemotherapy-
resistant. Adjuvant chemotherapy, typically temozolomide
monotherapy, concurrent with and following radiation, has
been shown to have benefit in adults with glioblastoma [32]
and may have benefit in children [33]. Temozolomide
appears to be active only in tumors characterized by MGMT
methylation [34]. The antiangiogenic agent bevacizumab is
effective in the management of recurrent disease in adults;
initial pediatric experience is less promising [35, 36]. The
potential role of SRS in the management of high-grade
glioma includes treatment of very small tumors [20] and
treatment of larger tumors as an adjunct to fractionated
radiotherapy [17]. SRS also may have a role in palliative
local tumor control at recurrence [5, 37, 38].
Glioblastoma in infants has unique clinical features and is
often responsive to chemotherapy. Sustained responses have
been described in a substantial portion of infants treated with
surgery and chemotherapy alone, without radiation [39].
Diffuse intrinsic pontine glioma (DIPG) is a uniquely
chemotherapy-resistant disease, with an abysmal prognosis.
Although radiation has palliative benefit, the disease remains
universally fatal, with a median overall survival of 11 months
from diagnosis. Over 200 clinical trials have failed to
N.J. Robison
demonstrate any role for adjuvant chemotherapy [40].
The diffusely infiltrative nature of DIPG precludes SRS as a
viable option.
Ependymoma
Ependymomas account for about 9 % of pediatric intracra-
nial tumors [41]. They occur most commonly in the posterior
fossa, and less commonly in the cranial hemispheres or the
spinal cord. Prognosis is highly dependent on the degree of
surgical resection, with long-term PFS rates of 60–77 % for
patients with completely resected vs. 9–34 % for those with
incompletely resected tumors [42–45]. Tumor grade (ana-
plastic vs. non-anaplastic) may also have prognostic implica-
tions [44–46]. Best outcome for localized tumors has been
achieved with maximal surgical resection, followed by
involved field radiotherapy [45]. For completely resected grade
II supratentorial ependymoma, observation alone without
adjuvant radiotherapy may be appropriate [47, 48]. Historically,
the role of adjuvant chemotherapy in the management of
this disease has been unclear [42, 43, 49]. Attempts to use
dose-intensive chemotherapy instead of radiation have been
unsuccessful, with PFS rates of 9–26 % [50–52]. However,
ependymomas are known to be chemotherapy-responsive in
the short term, and combination chemotherapy may have a role
either in delaying definitive radiation therapy in young chil-
dren [39, 53] or as post-surgical, pre-radiation therapy for
patients with incompletely resected tumors [41]. The use of
SRS in conjunction with fractionated radiotherapy to treat
small residual non-resectable ependymoma has been proposed,
with anecdotal reports of success [54, 55]. SRS may also have
a role in the management of recurrent ependymoma. A retro-
spective review of 26 patients treated with SRS for ependy-
moma recurrence showed a 3-year PFS of 66 %, and a 3-year
local control rate of 72 % [56]. In another series of 21 patients
treated with SRS for recurrent ependymoma, the local control
rate was similarly high, but the distant failure rate was 80 % at
3 years [57].
Embryonal Tumors
Medulloblastoma is the most common histologically malig-
nant brain tumor of childhood [58]. Standard therapy in most
cases includes maximal surgical resection, cranial spinal
irradiation with boost to tumor bed, and chemotherapy [59].
The addition of chemotherapy before, after, and/or during
radiation has led to increased survival for high-risk (meta-
static, incompletely resected, and/or anaplastic) disease
and allowed dose-reduction of craniospinal irradiation for
standard-risk disease. With this approach, long-term PFS
exceeds 80 % for patients with standard risk tumors and
33 Pediatric Brain Tumors: Viewpoint—Chemotherapy
approaches 70 % for patients with high-risk disease [58].
For infants and young children, dose-intensive chemother-
apy regimens without radiation have been used. Survival
outcomes for young patients treated without radiation are
quite favorable for those with desmoplastic histology, but
more guarded for those with classic and anaplastic histology
[60–62].
Anecdotal experience supports the uses of SRS in medul-
loblastoma in certain settings [20]. In theory, SRS has utility
either in the treatment of concerning lesions persistent after
definitive therapy, or in the palliative or adjuvant manage-
ment of small tumors at recurrence. The marked propensity
of embryonal tumors towards distant recurrence and lepto-
meningeal dissemination limits the utility of SRS in most
cases [20].
Pineoblastoma and primitive neuroectodermal tumor of
the central nervous system are less common embryonal
tumors occurring outside of the posterior fossa. Treatment is
similar to that of medulloblastoma, but with a less favorable
prognosis. Atypical teratoid rhabdoid tumor is a more
recently described embryonal tumor, initially thought to
have an extremely poor prognosis. Long-term survival
exceeding 40 % has been reported in AT/RT patients treated
with an intensive anthracycline-based chemotherapy regi-
men and fractionated radiotherapy [63].
Germ Cell Tumors
Germ cell tumors of the central nervous system are classi-
fied either as pure germinoma or as nongerminomatous
germ cell tumor (NGGCT), the latter typically representing
mixed-histology tumors. Standard treatment for CNS ger-
minoma includes radiation, either of the entire craniospinal
axis or limited to the ventricular fields. Platinum-based
chemotherapy regimens have been used as an adjuvant
modality to reduce radiation dose and/or volume, while
still maintaining excellent long-term survival [64].
Attempts to treat germinoma with chemotherapy alone
have been less successful [65]. NGGCT has historically
had a poorer prognosis, although recent trials have shown
significantly improved outcome with the use of dose-inten-
sive pre-radiation platinum-based chemotherapy [66].
High-dose myeloablative chemotherapy with autologous
stem cell rescue has been used with success as a salvage
regimen in patients with recurrent germ cell tumors [67].
SRS has been used anecdotally in patients with germinoma,
either in combination with fractionated radiotherapy for
primary management of small tumors, or in combination
with dose-intensive myeloablative chemotherapy with
stem cell rescue and conventional radiotherapy for relapsed
disease [68, 69].
441
Craniopharyngioma
Craniopharyngiomas are believed to arise from ectodermal
nests within the pituitary stalk [70]. Although histologically
benign, they are often associated with substantial morbidity,
both disease-related and iatrogenic. Standard therapy includes
either surgical resection alone, or partial resection with
involved field radiotherapy. Successful use of SRS has been
reported: in a series of 100 pediatric and adult patients treated
with SRS for postoperative residual or recurrent craniopha-
ryngioma, the 10-year PFS was 60 % [71]. Another similar
series of 46 patients with craniopharyngioma showed a 5-year
PFS of 68 % [72]. Risk of visual compromise from optic
nerve irradiation is an important consideration [73]. There is
currently no established role for chemotherapy in the treat-
ment of craniopharyngioma. However, systemic interferon
alpha-2b may have activity in this disease [74].
Conclusion
SRS has a role in the management of pediatric brain tumors.
The propensity of many pediatric neural malignancies either
to disseminate along CSF channels or to infiltrate surround-
ing brain limits the utility of SRS as monotherapy. Its most
promising role is as an adjuvant to surgery, chemotherapy,
and/or conventional fractionated radiation in the management
of localized residual disease. With notable exceptions, most
data on the use of SRS in children is from small retrospective
series. Further prospective analysis is needed.
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 Pineal Region Tumors
Gregory P. Lekovic and Andrew G. Shetter
Introduction and Background
The pineal gland is situated at the geographic center of the
brain between the posterior and habenular commissures. Its
central location, as well as its solitary nature in an organ com-
prised of paired structures, led early anatomists and physiolo-
gists to impart to it singular importance (e.g., famously
asserting that the pineal was the seat of the human soul).
As cited by Baumgartner and Edwards [1], the first
description of a lesion in the pineal region is attributed to
Virchow in 1865. By the early twentieth century, neurosurgi-
cal pioneers had devised approaches to the pineal region,
variants of which are still in use today, including the trans-
callosal approach of Dandy and Fedor Krause’s supracere-
bellar infratentorial approach. These early experiences with
surgery for pineal regions were highly morbid, a fact that is
not surprising given the technological limitations of the time
[2]. At the same time, the radiosensitivity of germinomas,
the most common pineal region tumor, was beginning to be
appreciated. Gradually, surgical approaches were given up in
lieu of empiric treatment with radiotherapy. With the advent
of the era of microneurosurgery, interest in the surgical man-
agement of pineal region tumors remerged, and empiric
treatments with radiotherapy are now obsolete.
Most recently, the development of chemotherapy and
radiosurgery has added additional variables to the treatment
algorithm of these tumors. Chemotherapy has been used suc-
cessfully to lower radiation doses used to treat patients with
germinoma. This is especially important in the treatment of
G.P. Lekovic, M.D., Ph.D.
House Clinic, Good Samaritan Gama Knife Radiosurgery Center,
2100 West Third Street, Los Angeles, CA 90057, USA
A.G. Shetter, M.D. (*)
Section of Functional Stereotactic Neurosurgery, Division
of Neurological Surgery, Barrow Neurological Institute, St.
Joseph’s Hospital and Medical Center,
350 W. Thomas Road, Phoenix, AZ 85013, USA
e-mail: neuropub@dignitiyhealth.org
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_34, © Springer Science+Business Media New York 2015
34
children, for whom whole brain irradiation carries significant
morbidity. Gamma knife radiosurgery (GKRS) offers a simi-
lar advantage in providing highly conformal targeting with
maximization of delivered dose to the therapeutic target and
concomitant minimization of dose exposure to neighboring
structures. Although the role of radiosurgery in the manage-
ment of pineal region tumors is still evolving, it is safe to say
that radiosurgery plays an important role in the multimodal-
ity management of these lesions.
Anatomy
The pineal region is broadly defined as the region lying
between the splenium of the corpus callosum and tela cho-
roidea dorsally, and the quadrigeminal plate and tectum ven-
trally, and between the posterior third ventricle rostrally, and
cerebellar vermis caudally. The pineal gland itself is situated
between the habenula dorsally and posterior commissure
anterior-inferiorly (Fig. 34.1).
The pineal region is notable in that it is a region rich in
vasculature, especially the deep cerebral veins. The vascular
supply to the pineal gland proper is predominantly from the
medial posterior choroidal arteries, with contributions from
the lateral posterior choroidal and quadrigeminal arteries as
well [3]. However, the pineal is surrounded by the deep
venous drainage of the brain on all sides—the velum inter-
positum, containing the internal cerebral veins, lies rostral
and dorsal to the pineal gland (to which it is often attached to
pineal region tumors by thick arachnoid adhesions) [4], the
basal veins of Rosenthal are located at either flank, and the
vein of Galen lies posterior and superior to it. For this reason,
stereotactic biopsy of the pineal region is viewed with trepi-
dation by some.
The cellular constituents of the pineal region include
pinealocytes, astrocytes, and sympathetic nerves. The sym-
pathetic innervation comes from the superior cervical gan-
glion. The physiological role of the pineal is thought to be
concerned with the regulation of circadian rhythms.
445
446
Fig. 34.1 Midsagittal section demonstrating the anatomy of the pineal
region. Labeled structures include the pineal body (PB), the subforni-
ceal organ (SFO), choroid plexus (CP), area postrema (AP), neurohy-
pophysis (NH), median eminence (ME), and organum vasculorum of
the lamina terminalis (OVLT). Used with permission from Barrow
Neurological Institute
Ontologically and embryologically the pineal is related to
photoreceptor organs. Indeed, this role persists in certain
reptiles where the pineal is known as the “parietal eye.”
Because of this shared evolutionary background, pineoblas-
tomas are sometimes seen in association with retinoblastoma
(so-called “trilateral retinoblastoma”).
Pineal Region Tumor Presentation
and Natural History
Although the physiological role of the pineal in humans is
still somewhat obscure, it is an important locus of pathology.
Broadly speaking, there are four categories of lesions occur-
ring in the pineal region: germinoma (including pure germi-
noma, teratoma, and nongerminomatous germ cell tumors,
NGCTs), pineal parenchymal tumors (pineocytoma and
pineoblastoma), glial tumors, and miscellaneous tumors
(including metastases, meningioma, and ependymoma).
Although pineal region tumors are relatively rare
(accounting for less than 1 % of all intracranial neoplasms),
they are much more common in Asia [5]. It is well known
that there is a higher incidence of germ cell tumors (GCTs)
in Asian populations than in North American or European
populations. GCTs typically account for the majority of
pineal region tumors, with pineal parenchymal tumors sec-
ond and miscellaneous tumors third.
G.P. Lekovic and A.G. Shetter
In Western populations, GCTs account for 0.3–0.5 % of
all primary intracranial neoplasms, but comprise approxi-
mately 3.0 % of those encountered in children. In contrast, in
Asia, GCTs comprise at least 2.0 %, and up to 9–15 %, of all
intracranial neoplasms and pediatric neoplasms, respec-
tively. In Japanese and Korean populations, 80 % of pineal
region tumors in patients aged 15–35 years of age are germi-
noma [6]. In contrast, out of 370 French patients undergoing
stereotactic biopsy of pineal region tumors, only 51 % of
patients under the age of 30 had radiosensitive tumors
(germinoma + pineoblastoma) [7].
The most common presentation of pineal region tumors is
from symptoms attributable to local mass effect, principally
increased intracranial pressure related to aqueductal com-
pression and/or to mass effect on the quadrigeminal plate
(e.g., Parinaud’s syndrome). The growth pattern of pineal
region tumors tends to reflect the underlying histology, with
benign, well-encapsulated tumors filling the posterior third
ventricle, quadrigeminal cistern, and displacing the anterior
cerebellum [4]. Malignant tumors are more likely to dif-
fusely infiltrate the midbrain, thalamus, or other neighboring
structures.
Importantly, there is tremendous variation in the natural
history of pineal region tumors depending on their histology.
The management of tumors of this region, therefore, is
extremely dependent on an accurate diagnosis. In most cases,
this necessitates a tissue diagnosis, whether through stereo-
tactic, endoscopic, or open biopsy. This issue will be dis-
cussed in greater detail below.
Pathology
Germ Cell Tumors
Pure germinoma, the most common central nervous system
GCT, consists of large undifferentiated cells arranged in
monomorphous sheets. Nuclei are round and typically cen-
trally positioned amidst abundant clear cytoplasm. Mitoses
are common and necrosis uncommon. Some tumors may
incite an inflammatory response that is evident on histology
by the presence of either many lymphocytes or occasionally
fibrous tissue. Immunohistochemical positivity for placental
alkaline phosphatase is typical.
Nongerminomatous Germ Cell Tumors
The group of tumors that together comprise the nongermino-
matous germ cell tumors (NGGCTs) include teratoma
(mature and immature), yolk sac tumors, embryonal carci-
noma, and choriocarcinoma. Only teratoma is commonly
34 Pineal Region Tumors
encountered as a pure tumor type, with most NGGCTs hav-
ing regional variations in histology suggestive of multiple
tumor subtypes.
By definition, teratomas recapitulate somatic elements from
endodermal, mesodermal, and ectodermal lines. Differentiated
teratomas include well-formed, fully differentiated elements
such as rests of skin, hair, teeth, or cysts of mucosal epithelia.
Immature teratomas are much more common, and contain
incompletely differentiated tissue. Occasionally, a carcinoma
or sarcoma can arise from within a teratoma (so-called tera-
toma with malignant transformation).
Yolk sac tumors are characterized by a reticular epithe-
lium set in a myxoid matrix; classically these may form
papillae known as Schiller–Duvall bodies. Embryonal carci-
noma is composed of sheets of large cells with prominent
nucleoli, many mitoses, and abundant cytoplasm. Necrosis is
common. Trophoblastic elements, such as syncytiotropho-
blastic cells (which may be seen scattered with other CNS
GCTs) indicate tumor trophoblastic differentiation and
hence choriocarcinoma.
The immunohistochemistry of GCTs is helpful in differ-
entiating tumor types. Typically, cell membranes and/or
cytoplasm are positive for placental alkaline phosphatase in
germinoma; beta-HCG and human placental lactogen in cho-
riocarcinoma, and alpha-fetoprotein in yolk sac tumor and
teratoma.
Pineal Parenchymal Tumor
Pineocytomas (aka, pinealocytoma) are slow growing neo-
plasms of the pineal gland composed of small uniform sized
cells. Characteristically, the cells exhibit cytoplasmic pro-
cesses that are said to resemble club-like endings. Unlike
pineoblastomas, there is some preservation of the lobular
architecture of the normal pineal gland.
Pineoblastomas are members of the family of small blue
cell primitive neuroectodermal tumors, similar to medullo-
blastoma or retinoblastoma. Like these tumors, they are
highly cellular neoplasms with a high nucleus to cytoplasm
ratio, characterized by the presence of either Homer–Wright
or Flexner–Wintersteiner rosettes, the latter being a mark of
retinoblastic differentiation. True to the oncologic common-
ality between the pineal and photoreceptor organs, pineal
parenchymal tumors stain positively for interphotoreceptor
retinoid binding protein.
True intermediate tumor classification is relatively rare,
with only about 8 % of pineal parenchymal tumors belong-
ing to this category (WHO). These tumors are highly cellular
with numerous mitoses and nuclear atypia, but without
pineocytomatous rosettes. Even more rarely, a pineal paren-
chymal tumor may have within it areas of both pineocytoma-
tous and pineoblastomatous differentiation.
447
Because many tumors of the pineal region are histologically
heterogeneous (especially the NGGCTs), the ability of the sur-
geon to avoid sampling errors in obtaining tissue for histopath-
ological examination is paramount. In general, this need for
accurate histological diagnosis of disparate regions of tumor
has been commonly cited as support for open or endoscopic
biopsies, during which regions of tumor appearing grossly dis-
similar can be biopsied separately.
Imaging
Magnetic resonance imaging (MRI) with and without gado-
linium contrast enhancement is the diagnostic imaging
modality of choice. Pineocytomas are typically hypointense
on T1-weighted images, and hyperintense on T2-weighted
sequences. Pineoblastomas are heterogeneous, and can be
either hypo- to isointense on T1-weighted MRI. GCTs are
typically well circumscribed, iso- to hyperdense relative to
grey matter, and intensely enhancing. However, no certain
method exists for differentiating pineal region tumors on the
basis of imaging studies alone.
Tumors of the pineal region enhance variably, as does the
normal pineal gland due to the absence of a blood–brain bar-
rier. Incidental calcification of the pineal is common,
although such calcifications are also associated with “brain
sand” seen in pineocytomas. The diagnosis of GCT is sug-
gested if the neoplasm appears to surround or engulf the nor-
mal pineal gland calcifications, whereas pineal parenchymal
tumors are said to cause an “explosion” of pineal calcifica-
tions to the periphery of the lesion as the mass expands. On
the other hand, hemorrhage (pineal apoplexy) is suggestive
of choriocarcinoma. In general, tumors arising from the col-
licular plate are more likely to be of glial origin [1], and the
presence of fat signal is characteristic of lipoma, mature tera-
toma, or dermoid tumors. The presence of mature teratoma-
tous elements such as hair or teeth may also be evident on
imaging studies.
Management of Pineal Region Tumors
Because of the varied natural history of pineal region tumors
and the lack of diagnostic specificity of imaging studies, the
importance of obtaining a tissue diagnosis cannot be over-
emphasized. Therefore, a biopsy, whether stereotactic, endo-
scopic, or open (see discussion below) should be obtained as
the initial step in the management of tumors of this region in
all cases, except where cerebrospinal fluid (CSF) is positive
for markers of malignant germinoma (i.e., BHCG or alpha-
fetoprotein), in the case of new metastatic lesions (where the
tissue diagnosis is already known), or perhaps in patients
who are too frail to undergo even a biopsy. As discussed in
448
more detail below, there is no role for empiric radiation ther-
apy in the management of these tumors, at least not in occi-
dental populations.
Whether it is better to perform an open biopsy, coinci-
dent with attempted gross total resection or cytoreductive
surgery, or to perform a minimally invasive (i.e., stereotactic
or endoscopic biopsy) is controversial. Proponents of open
biopsy cite the relative safety and low morbidity of
approaches to the pineal region given modern instrumenta-
tion and microsurgical technique. Because of the histopath-
ologic heterogeneity common to tumors of this region, the
ability to minimize sampling errors with open biopsy may
yield more accurate specimens for diagnosis. Benign tumors
may be completely respectable; therefore, an open approach
offers the potential for cure of these lesions. Moreover, even
malignant tumors and radiation sensitive tumors may bene-
fit from cytoreduction.
On the other hand, minimally invasive approaches avoid
the risks of craniotomy, and have high diagnostic yield.
Because of the pineal region’s proximity to the deep cere-
bral veins, some authors argue that stereotactic biopsy of
this region is a relatively higher risk. However, Regis et al.
[7] reviewed 370 stereotactic biopsies of the pineal region
from 15 Fr neurosurgical centers. They reported a 1.3 %
mortality and 0.8 % severe neurological morbidity attrib-
utable to stereotactic biopsy. This was believed not to
reflect an increased risk of death or neurologic injury over
other intracranial sites. Overall, diagnostic tissue was
obtained in 94 % of patients. However, 2.3 % of biopsied
patients underwent repeat biopsy or subsequent open sur-
gery and were found to have been initially misdiagnosed.
Sampling errors were felt to contribute to about half of
these cases (i.e., about 1 % diagnostic error due to sam-
pling errors).
The endoscopic approach to the pineal region for the pur-
poses of biopsy was first described by Fukushima [8, 9]. The
advantages of an endoscopic approach include direct visual-
ization of the biopsy site which could lessen sampling errors
and lead to greater diagnostic accuracy [10]. In addition,
because many patients with pineal region tumors either pres-
ent with, or are at high risk of hydrocephalus, a CSF diver-
sionary procedure may be required. An endoscopic biopsy
affords the possibility of simultaneously performing an
endoscopic third ventriculostomy at the same operative sit-
ting. Oi et al. reported their experience with 20 consecutive
patients followed prospectively who underwent endoscopic
biopsy in the initial management of their pineal region
tumors [11]. Importantly, they reported the endoscopic
detection of spread of tumor not visualized in preoperative
neuroimaging. This suggests that endoscopy may have ben-
efit as a diagnostic tool per se. Nevertheless, the proper role
of the endoscope in the management of pineal region lesions
remains controversial.
G.P. Lekovic and A.G. Shetter
The Role of Surgery
Pineal region tumors can be successfully resected with
microsurgical techniques at tolerable levels of morbidity and
mortality. Approaches to the pineal region include both
supratentorial (interhemispheric transcallosal and occipital
transtentorial) and infratentorial (supracerebellar infratento-
rial approach, Fig. 34.2). Bruce and Stein [12] described
their experience with 160 pineal region tumors. They
achieved a gross total resection in 46/53 benign pineal region
tumors, with overall mortality and morbidity of 4 % and 3 %,
respectively. Their results are comparable to other major sur-
gical series for whom mortality rates range from 2 to 11 %
and serious morbidity from 3 to nearly 30 % (for a recent
review, see [13]).
The role of surgery for maximal debulking and/or resec-
tion is best established for benign lesions, where gross total
resection may be curative. Conversely, these are also the
lesions best suited to radiosurgical treatment. The argument
for surgery for benign pineal region tumors is that gross total
resection is often possible, and that this may afford a perma-
nent cure and obviate the need for CSF diversion.
Whether surgical resection or debulking plays a signifi-
cant role in the management of malignant tumors is much
more hotly debated. Aggressive malignancies, especially
those that on preoperative imaging are seen to invade the
brainstem or other neighboring structures, are unlikely to
be amenable to complete resection. Nevertheless, some
studies have shown benefit of cytoreduction even in these
cases, although these data have not reached statistical
significance [14, 15]
Fig. 34.2 Surgical approaches to the pineal region. Midsagittal section
of the human brain demonstrating the surgical corridors to the pineal
region, the transcallosal, occipital transtentorial, and the supracerebel-
lar infratentorial. Used with permission from Barrow Neurological
Institute
34 Pineal Region Tumors
Finally, some centers advocate “second-look” surgery if
imaging abnormalities persist after initial treatment of
NGGCTs with chemotherapy and radiation [13]. The major-
ity of these surgeries find either necrosis or, in the case of
mixed NGGCTs, rests of mature teratoma.
Role of Radiation
It has been known for decades that radiation is curative for
intracranial germinoma [16], with 5-year survival rates of up
to 95 % reported for pure germinoma and up to 76 % for
NGGCTs. Indeed, radiation remains the mainstay of treat-
ment of most pineal region tumors, whether as primary treat-
ment modality or as adjuvant therapy. Nevertheless, radiation
has significant morbidity. Efforts at reducing radiation expo-
sure have included avoiding whole brain and prophylactic
craniospinal irradiation, the use of chemotherapy, and
radiosurgery.
Traditionally, germinoma was treated with craniospinal
irradiation, given estimates of spinal cord metastasis or seed-
ing after surgery range of 13–40 %. However, as the sequelae
of prophylactic craniospinal irradiation have become more
appreciated, efforts have been made to delay or avoid spinal
irradiation, and to limit cranial irradiation from whole brain
to local field. The effectiveness of partial brain fields
comprising tumor plus a 2-cm margin was shown initially by
Dattoli and Newall in 1990 [17]. In this retrospective study,
12 patients were treated with partial brain irradiation, con-
sisting of either fields comprising tumor plus a 2-cm margin
(n = 10), or fields comprising the ventricular system with a
boost to the tumor (n = 2). Nine out of ten patients treated
with partial brain irradiation were complete responders;
however, one patient relapsed and ultimately succumbed to
the disease. This patient, however, also received a reduced
dose of less than 40 Gy. Thus, the authors concluded that
whole neuraxis radiation could be safely avoided in the
majority of patients, provided that sufficient tumoricidal
doses of radiation were delivered.
Because gonadal GCTs respond well to chemotherapy,
chemotherapy has been advocated as a means to further
reduce the amount of radiation necessary to obtain control of
the tumor. In this regard, the rationale for chemotherapy
anticipates the argument made for radiosurgery. Balmaceda
et al. [18] enrolled 71 patients with GCTs (including both
pure and NGGCTs) in an international cooperative study
comprising 31 institutions in 6 countries, and demonstrated
that chemotherapy could not be used alone for the treatment
of GCTs. They employed a high-dose regimen of carbopla-
tin, etoposide, and bleomycin. Although 41 of the 71 patients
were successfully managed with chemotherapy alone initially,
35 patients showed evidence of recurrence or progression.
449
Furthermore, 7 of 71 patients treated died of chemotherapy
related toxicity.
In contrast, Buckner et al. [19] reported the results of a
Phase II trial of primary chemotherapy followed by reduced-
dose radiation for the treatment of CNS GCT in which the
partial brain dose was reduced to 30 from 54 Gy. All patients
were alive without progression at 51-month mean follow-up.
One patient relapsed distally (spinal cord) and was salvaged
with spinal irradiation. Thus, the prevailing paradigm at the
present time is to use chemotherapy as an adjuvant therapy in
combination with reduced-dose radiation. Spinal irradiation
should be reserved for those cases presenting with dissemi-
nated disease or in the case of relapse.
The Role of Radiosurgery
The role of radiosurgery in the management of pineal region
tumors remains controversial. Traditionally, pineal region
tumors have either been approached surgically with the goal
of gross total resection and cure (if benign), or with conven-
tional radiation if the tumor is of a histology known to be
radiosensitive and/or malignant. Radiosurgery, on the other
hand, has the potential to be used either as a “boost” modal-
ity in conjunction with conventional radiotherapy, or even as
an alternative to radiotherapy and/or surgery altogether.
Table 34.1 summarizes the results of reports in the English
language literature, including three from our institution, on
the use of stereotactic radiosurgery in the treatment of pineal
region tumors. Several factors, however, make it difficult to
draw easy comparisons or conclusions from these studies,
including relatively small sample sizes and because of the
heterogeneity of diagnoses included within individual series.
Backlund et al. [20] first reported the treatment of two
cases of pineocytoma with GKRS in 1974. The patients were
treated with peak dose of 50 Gy. At 13 and 36 months fol-
low-up neither patient had displayed evidence of tumor pro-
gression. Subach et al. [21] included eight patients with
pineocytoma (out of 14), with three tumors demonstrating a
complete response to GKRS, three a partial response, and
two no change. GKRS mean marginal doses for all tumor
types treated were 15.4 Gy, and all tumors were treated to the
50 % isodose line. Hasegawa et al. [22], however, reported a
distant recurrence of pineocytoma after GKRS, although
100 % local control was achieved. A complete response of
pineoblastoma to GKRS was demonstrated by Manera et al.
[23] in one patient and a partial response in another.
However, Hasegawa et al. [22] experienced three distant
failures following GKRS for pineoblastoma treated with a
mean marginal dose of 15.3 Gy to the 50 % isodose line.
Kano et al. retrospectively reviewed 13 patients with pineo-
cytoma treated with a median marginal dose of 15 Gy [24].
 450

Table 34.1 Summary of pineal region tumors in literature

Mean
follow-up
Reference No. and diagnosis Biopsy (months) Prior treatment Radiological results Dosimetry Progression Complication
Backlund et al. 2 pineocytoma 2 SB 13 and 36 None Regression of tumor GKRS 50 Gy None None
(1974) [20]
Dempsey and 4 meningioma, 2 4 SB, 5 OB 20.7 4 primary, 5 OR, 6 partial or complete GKRS mean None 3 new
Lunsford anaplastic (3–32) 4 with previous responses, 3 no marginal dose of neurological
(1992) [32] astrocytoma, 1 WBRT, 1 change (all 16.6 Gy (10–2- Gy) deficits
ependymoma, 1 chemotherapy meningioma) at 50–60 % isodose
craniopharyngioma, line
1 pineocytoma
Manera et al. 1 pineocytoma, 1 7 SB, 4 NO 12.3 1 OR 3 complete responses GKRS mean None None
(1996) [23] astrocytoma, 2 (2–34) (1pinealoblastoma, 2 marginal
germinoma, 2 germinoma), 5 partial, dose = 9.3 Gy
pinealoblastoma, 3 2 no change, 1 (6–20), 40–50 %
meningioma insufficient follow-up isodose line
Subach et al. 8 pineocytoma, 9 SB, 2 OB, Mean 1 55 Gy EBRT, 1 4 complete responses GKRS marginal 1 (embryonal 1 new Parinaud’s,
(1998) [21] 2pineoblastoma, 2 3 NO imaging subtotal OR, 2 (3 pineocytoma and 1 doses 15.4 (12–20), carcinoma) 3 deaths (only 1
germinoma, 2 follow-up chemotherapy pineoblastoma), 6 all treated to 50 % attributed to
NGGCT 21 partial (3 isodose line mean progression)
pineocytoma, 1 volume 6.4 cm3
pineoblastoma, 2
germinoma)
Kobayashi et al. 8 germinoma, 4 11 NO N/A Germinoma: 8 8 complete response, GKRS marginal 8 7 deaths
(2001) [26] STGC, 13 chemotherapy, 5 overall response dose = 16.8 Gy for attributable to
malignant GCT, 3 OR malignant rate = 73.3 %, For germinoma, 13.4 Gy progression
pineocytoma, 2 GCT: 10 OR, germinoma and for malignant GCT,
pineoblastoma, 2 chemotherapy pineocytoma 100 % 17.5 Gy for PPT and
unknown 10, EBRT 8 control rate others
Hasegawa et al. 10 pineocytoma, 2 10 SB, 4 OB 52 4 OR, 4 EBRT (2 4 complete response, GKRS mean 4 distant treatment 2 new deficits, 5
(2002) [22]a mixed histology, 4 as boost and 2 8 partial, 2 no change, marginal failure (1 pineocytoma, deaths (4
pineoblastomas after recurrence) 2 no imaging dose = 15.3 Gy at 3 pineoblastomas) attributable to
follow-up, local 50 % isodose line progression)
control = 100 %
Hasegawa et al. 4 NGGCT 1 SB, 2 OB, 25 2 OR 2 partial, 1 no change, 12–16 Gy marginal 1 (death) None
(2003) [28]a 1 CSF 1 progression dose to 50 %
isodose line
G.P. Lekovic and A.G. Shetter
 34

Deshmukh 5 pineocytoma 5 OR 14.6 5 OR 4/5 partial response GKRS marginal None None
et al. (2004) 100 % local control dose 14–16 Gy
[33]
Casentini et al. 6 germinoma 5 yes 27.6 “Inverse boost” Complete response Varian LINAC None 1 periprocedural
(1990) [25] (1–58) paradigm with (marginal dose death (unrelated)
extended field 10–11 Gy, peak
radiotherapy: doses 10–12.5)
mean 31 Gy,
range 24–36)
Pineal Region Tumors

Kano et al. 13 pineocytoma, 5 20 with OB 54.1 6 OR, 3 EBRT, 3 26 % complete, 47 % GKRS mean 6 deaths, 5-year No permanent
(2009) [24] pineoblastoma, 2 or SB chemotherapy, 2 partial, 11 % “stable,” marginal dose 15 Gy progression-free morbidity
mixed histology EBRT and 11 % local survival 89 %
chemotherapy progression
Mori et al. 38 germ cell tumor, Biopsy in 13 33.5 13 OR, 20 EBRT, NR Mean marginal dose Progression-free 1 optic
(2009) [27] 9 PPT, 2 unknown germ cell 27 chemotherapy 15.5 Gy survival at 10 years neuropathy
tumors, OB 68 % for germ cell
in 9 PPT tumors, 67 % for PPTs
Wilson et al. 14 pineocytoma 12 OB, 2 EB 53 12 OR, 5 with 5 complete resection, Mean marginal dose Progression in 3 None for GKRS
(2012) [30] gross total 9 residual tumors of 14.6 Gy with patients with subtotal
excision postoperatively GKRS in 5 patients excision, none in
patients with gross
total excision or GKRS
Yianni et al. 11 PPT, 2 germ cell 16 SB, 62.5 17 OR, 10 EBRT, NR Mean marginal dose
8 deaths, progression- None
(2012) [31] tumors, 2 papillary 11 EB, 17 4 chemotherapy 18 Gy free survival 27 %
epithelial tumors, 9 OB at 5 years
gliomas, 20 with no
histologic diagnosis
Used with permission from Barrow Neurological Institute
GKRS Gamma knife radiosurgery, NR not reported, NGGCT nongerminomatous germ cell tumor, SB stereotactic biopsy, OB open biopsy (craniotomy), EB endoscopic biopsy, STGC germinoma
with syncytiotrophoblastic giant cells, OR surgery, EBRT external beam radiation therapy, PPT pineal parenchymal tumor
a
Patients partially included in previous reports
451
452
Overall survival after GKRS was 92.3 % at 5 years, with
23 % of tumors treated demonstrating a complete radio-
graphic response.
Although germinoma is highly curable by external beam
irradiation, efforts to reduce the dose of EBRT radiation have
gained momentum because of concerns of the toxicity of
even partial brain irradiation (especially in children). In
1990, Casentini et al. [25] reported their results using Varian
LINAC radiosurgery as an “inverse boost” paradigm for the
treatment of germinoma, with all six patients so treated dem-
onstrating a complete response. Kobayashi et al. [26]
included eight patients with the diagnosis of germinoma who
were treated with chemotherapy prior to GKRS. They
obtained a 100 % control rate for these tumors with a mar-
ginal dose of 16.8 Gy. Mori et al. [27] treated 18 germinomas
with GKRS, the largest case series to date. Marginal doses
ranged from 9.9 to 25.7 Gy, and all but one patient received
fractionated external beams radiation therapy as well. The
progression-free survival rate at 5 years was 63 %. The sin-
gle patient who received GKRS as the initial therapy experi-
enced CSF dissemination at 15 months.
Increasingly, GKRS is being reported in the treatment
of NGGCTs. The number of reported cases is now well
over 50. However, due to the heterogeneity of diagnoses in
the reported series it is difficult to draw comparisons.
Nevertheless, it is clear that NGGCTs are less responsive
to GKRS than are germinoma or pineocytoma. Mori et al.
[27] used adjuvant GKRS for 16 NGGCTs with marginal
doses similar to those for GCTs. The progression-free sur-
vival rate at 5 years was 37 % [27]. Neither of the two
NGGCTs reported by Subach et al. [21] demonstrated a
response to GKRS. Hasegawa et al. [28] treated four
NGGCTs with between 12 and 16 Gy at the 50 % isodose
line. At a mean follow-up of 25 months, one tumor pro-
gressed, one demonstrated no change, and two tumors par-
tially responded. Kobayashi et al. [26] reported the results
of 13 malignant GCTs treated with GKRS. Follow-up data
was obtained in 12 patients, of whom 3 demonstrated a
complete response, 3 a partial response, and 6 had pro-
gressed. Five patients were deceased at a mean follow-up
of 12.6 months.
Barrow Neurological Institute GKRS
Experience
We recently reported our experience with GKRS for pineal
region tumors in 17 patients with non-metastatic tumors of the
pineal region [29]. Diagnoses included pineocytoma (n = 8), as
well as choroid plexus papilloma, neurocytoma, anaplastic
astrocytoma, PNET, low-grade astrocytoma, pineoblastoma,
NGGCT, malignant teratoma, and pineal parenchymal tumor
of intermediate differentiation (n = 1 each).
G.P. Lekovic and A.G. Shetter
All patients were treated using Leksell Gamma Plan treat-
ment planning software, with a mean marginal dose of
14.06 Gy (range 12–18 Gy). All doses were prescribed to the
50 % isodose line. Seven to 27 isocenters (mean 11.4) were
used to treat a mean target volume of 7.42 cm3 (range
1.2–32.5 cm3).
Fourteen patients were treated with GKS as either the pri-
mary radiation modality or as a salvage treatment for a recur-
rence after conventional EBRT failed. Two patients, one with
an NGGCT and another with an anaplastic astrocytoma,
were administered a 15- and 12-Gy GKS boost to the pineal
region after receiving reduced-dose craniospinal radiation
therapy (3,600 cGy).
There were no complications attributable to GKRS. There
were three mortalities after GKRS. One patient died 6 days
after radiosurgery (this patient was excluded from further
analysis), one died 2 months after radiosurgery, and the third
died after developing widespread metastatic disease. These
latter two patients demonstrated local control of tumor,
despite of their clinical progression. Upon latest follow-up
imaging, local control was established in 100 % of the
patients.
Wilson et al. examined a subset of 15 patients with histo-
logically proven pineocytomas treated at the BNI over a
12-year interval [30]. The mean clinical and radiographic
follow-ups were 44 and 53 months, respectively. Gross total
tumor excisions were achieved in five patients with no known
recurrences, although two of those patients were lost to
radiographic follow-up. Of the nine patients who underwent
subtotal tumor excisions or endoscopic biopsy, three received
initial GKRS and six were observed. None of the patients
treated with “up-front” radiosurgery recurred. The remaining
six patients demonstrated recurrence at varying intervals.
Four received subsequent radiosurgery and developed no
further signs of tumor progression. The authors concluded
that adjuvant GKRS is an effective treatment for pineocyto-
mas when complete surgical excision is not feasible, and that
radiosurgery can be successful in controlling recurrent dis-
ease. Their data also suggests that subtotal pineocytoma
excision plus radiosurgery may yield results equivalent to
gross total surgical excision, although greater patient num-
bers and larger follow-ups will be needed before this finding
can be stated with certainty.
Conclusions
Although tumors in this region are relatively rare, the pineal
region is an important site of a wide range of pathological
processes. Because of the wide variation in natural history of
these tumors depending on this histological heterogeneity,
obtaining a tissue diagnosis prior to instituting definitive
therapy is paramount. Exceptions to this rule may be in met-
34 Pineal Region Tumors
astatic disease (where the presumptive tissue diagnosis is
already known) and in patients that are truly too poor surgi-
cal candidates. In our experience, open craniotomy with
attempted resection or at least debulking of tumor with
biopsy has been the favored approach to obtaining a diagno-
sis. Endoscopic biopsy potentially spares the patient the risk
of craniotomy if the tumor is found to be radiosensitive. In
addition, endoscopy does afford the theoretical advantage of
being able to perform an endoscopic third ventriculostomy at
the same surgery as that for obtaining a biopsy; however, in
our series all patients’ third ventriculostomies eventually
failed, ultimately requiring ventriculoperitoneal shunting.
Other centers have reported good results using stereotactic
biopsy to obtain a histologic diagnosis [7, 31].
The role of radiosurgery in the management of pineal
region tumors remains controversial. We have found it help-
ful to dichotomize our approach to the appropriateness of
pineal region tumors based on the grade of tumor involved.
For benign lesions, i.e., those with an indolent natural his-
tory, that are relatively radioresistant, and curable with gross
total surgical resection, radiosurgery competes with conven-
tional surgery in the treatment options. Despite advances in
microsurgical approaches to the pineal region, surgical
extirpation of tumors occurring in this region is often impos-
Case Examples
Patient #1
A 12-year-old boy presenting with progressive headache,
nausea, and vomiting for 5 days underwent computed
tomography (CT) of the head revealing a pineal region
mass with hydrocephalus at an outside institution and was
subsequently transferred to the our institution for defini-
tive care. The patient had a prior history of strabismus but
was otherwise previously healthy. On admission exami-
nation, the patient was awake, alert, and fully oriented. He
complained of diplopia but his extraocular movements
were intact to examination except for some divergence of
gaze looking upwards. There were no other cranial nerve
findings, and motor examination revealed 5/5 motor
strength throughout without drift. Imaging revealed a
pineal region tumor with hydrocephalus. Serum markers
were positive for an elevated alpha-fetoprotein of 213,
although CSF markers were absent.
The patient underwent stereotactic wand-guided endo-
scopic biopsy and third ventriculostomy. However, endo-
scopic biopsy material was nondiagnostic, and so the
patient subsequently underwent a suboccipital craniotomy
453
sible. Moreover, the sensitivity of pineal region tumors to
radiation tends to weigh against surgical aggressiveness.
Nevertheless, because surgery does offer at least the poten-
tial for cure, we believe radiosurgery may be reserved in
these cases for poor surgical candidates or for the treatment
of residual or recurrent disease. For malignant lesions, the
role of radiosurgery is perhaps less well defined. Many
malignant lesions are surgically incurable, and likely
treatable with radiotherapy and chemotherapy alone.
Nevertheless, like surgery, radiotherapy has significant mor-
bidity that may be ameliorated by using radiosurgery as
either a boost modality or as an alternative treatment alto-
gether. The rationale for radiosurgery for radiation sensitive
tumors is therefore analogous to that of chemotherapy (i.e.,
to avoid, delay, or at a minimum to reduce the dose of, con-
ventional external beam radiation therapy). However, enthu-
siasm for the role of radiosurgery in malignant disease must
be tempered, in our experience, by the fact that we have
found that Gamma knife as a primary radiation modality in
the treatment of malignant disease may lead to distal failure.
Of course, in this case the possibility of salvage with either
repeat radiosurgery or radiotherapy remains. In such case,
radiosurgery may still be of value in delaying the exposure
to whole brain external beam radiation therapy.
for supracerebellar infratentorial approach for biopsy and
tumor debulking 2 days later. Despite third ventriculos-
tomy, the patient developed recurrent symptoms of hydro-
cephalus and eventually required ventriculoperitoneal
shunting. Pathological examination was consistent with a
malignant mixed GCT.
After surgery, the patient was begun on induction che-
motherapy with a 3-day course of VePesid, carboplatin,
cytotaxin, and bleomycin followed by high-dose Neupogen
and Procrit. He returned for subsequent cycles of chemo-
therapy every 3 weeks for a total of four cycles. Repeat
imaging demonstrated persistent disease.
The patient then underwent craniospinal irradiation
with planned Gamma knife boost to the pineal region. The
brain was treated with shaped-opposed 6 MV photon
beams with dose calculated at midplane. The brain was
treated to 3,600 cGy in 20 fractions. The spine was treated
with two separate fields, one including the cervical and
thoracic spines primarily, and the other comprising the
lumbar region. Both fields were treated to a depth of
4.5 cm to 3,600 cGy.
(continued)
454
(continued)
Fig. 34.3 A 12-year-old boy presented with hydrocephalus secondary to pineal region NGGCT. Axial (a) and sagittal (b) gadolinium-
enhanced MRI demonstrating complete of response of pineal region NGGCT 6 years after GKRS boost to craniospinal irradiation
The patient tolerated both chemotherapy and cranio-
spinal irradiation well and was felt to be an excellent can-
didate for GKRS boost to the pineal. Two days after the
completion of his course of craniospinal irradiation, the
patient underwent GKRS. The prescription dose was
15 Gy prescribed at the 50 % isodose line. The target vol-
ume was 1.2 cm3, and was covered in a single matrix with
two 4-mm collimator isocenters and 6 8 mm isocenters.
Patient #2
A 20-year-old man presented with 3 weeks of persistent
headache, dizziness, and diplopia. CT demonstrated an
enhancing pineal region mass. The patient underwent a
suboccipital craniotomy for supracerebellar infratentorial
approach for resection of the mass. Pathological examina-
tion was consistent with pineoblastoma. The patient sub-
sequently underwent ventriculoperitoneal shunting.
The patient was begun on emergent whole brain radio-
therapy, and an initial response was found after seven
treatments. The patient was therefore administered cranio-
spinal irradiation, with 3,600 cGy prescribed to the brain
and spine with an IMRT boost to the pineal, for a total of
G.P. Lekovic and A.G. Shetter
Follow up imaging studies demonstrated the complete
response of the tumor to treatment at 1 year of follow-up.
Six years after GKRS, the patient’s MRI scan continues to
show no evidence of tumor (Fig. 34.3). He is performing
in high school at his grade level, and he has been off treat-
ment for 5 years, although he continues to require pitu-
itary replacement therapy.
5,580 cGy to this location. In addition, the patient under-
went GKRS to the residual tumor, with a prescription dose
of 14 at the 50 % isodose line. The defined target volume
was 23.00 cm3, and 22.00 cm3 were covered within the
dose matrix with a combination of three 8-mm collimator
isocenters and twelve 18-mm collimator isocenters.
The patient tolerated craniospinal irradiation and
GKRS well. There were no treatment-related complica-
tions. The patient has been followed with serial imaging
which at 4.5 years post GKRS demonstrate stable tumor
with loss of central enhancement and without evidence of
growth (Fig. 34.4). Clinically, the patient has a KPS of 100
and has returned to work full-time.
(continued)
34 Pineal Region Tumors
(continued)
Fig. 34.4 A 20-year-old man presented with pineoblastoma, treated
with GKRS boost after craniospinal irradiation. Sagittal gadolin-
ium-enhanced MRI at the time of GKRS (a), compared to that on
Patient #3
A 52-year-old woman, a nursing home resident with
severe psychiatric disease, was found to have a diminish-
ing level of consciousness and incontinence of bowel and
bladder. She denied headache and her neurological exam
was nonfocal. Imaging studies revealed a large (>5 cm)
contrast enhancing lesion in the pineal region. The patient
underwent endoscopic third ventriculostomy and biopsy.
Pathological examination demonstrated a low-grade
appearing lesion with preserved pineal glandular architec-
ture; the MIB labeling index was less than 0.1 %. Because
of the benign pathological appearance of the tumor, the
patient was taken back to the operating room for resection
of the tumor via a suboccipital craniotomy and supracer-
455
follow-up imaging (b) demonstrates stable tumor size with a promi-
nent loss of central enhancement
ebellar infratentorial approach. In addition, she eventually
required ventriculoperitoneal shunting after failure of her
third ventriculostomy.
After surgery, the patient was evaluated for GKRS to
residual tumor. The defined target volume was 7.33 cm3.
The prescription dose was 14 Gy to the 50 % isodose line.
The target dose volume histogram volume was 7.22 cm3;
the treatment plan included five 8 mm and five 14-mm
collimator isocenters. The patient tolerated the treatment
well and there were no treatment-related complications.
After treatment, the patient returned to her care facility
in her usual state of health. On 25-month follow-up, MR
imaging demonstrated slight shrinkage of the tumor
(Fig. 34.5).
456
(continued)
Fig. 34.5 A 52-year-old woman presented with a large (>5 cm)
pineocytoma. The patient underwent subtotal resection with
treatment of 7.3 cm3 of residual tumor with GKRS (a). Two years
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 Pineal Region Tumors: Viewpoint—
Surgery
Adam M. Sonabend, Alfred Ogden, and Jeffrey N. Bruce
Introduction
Since the seminal articles that described safe and effective
approaches to the pineal region in the early 1970s [1, 2],
numerous surgical series have established open surgery as a
critical tool in the treatment of pineal region lesions
(Table 35.1) [3–15]. Although the difficulties and perils of
pineal surgery were considered prohibitive during the
nascent years of neurosurgery [16–18], the advent of the
operating microscope, microneurosurgical techniques, mag-
netic resonance imaging (MRI), and the development of neu-
rologic intensive care as a specialty have all helped to develop
pineal region surgery within a reasonable degree of safety
(Table 35.1).
Open surgery is the treatment of choice for benign tumors.
Depending on specific histology, open surgery has a variable
role in the treatment of malignant tumors and tumors with
mixed elements, either as a means of cytoreduction prior to
chemotherapy and/or radiation [15, 19, 20] or as the best
option to eradicate benign elements in mixed tumors after
chemotherapy/radiation [7, 21]. Additionally, through imme-
diate removal of obstructing lesions, open surgery can obvi-
ate the need for permanent cerebrospinal fluid (CSF)
diversion. Open surgery also offers comprehensive tissue
sampling for a group of tumors that can be of mixed histology
and are notoriously difficult to diagnose.
A.M. Sonabend, M.D.
Department of Neurological Surgery, Bartoli Brain Tumor
Research Laboratory, Columbia University Medical Center,
New York Presbyterian Hospital, 710 W 168th Street, New York,
NY 10032, USA
A. Ogden, M.D. • J.N. Bruce, M.D. (*)
Department of Neurological Surgery, Bartoli Brain Tumor
Research Laboratory, Columbia University Medical Center,
New York Presbyterian Hospital, 710 W 168th Street, New York,
NY 10032, USA
e-mail: jnb2@columbia.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_35, © Springer Science+Business Media New York 2015
35
The management strategy for achieving control of tumor
growth is strongly dependent on histology. While benign
tumors are often cured by surgery, germinomas, on the
other extreme, are exquisitely radiosensitive and best man-
aged with radiation therapy [22]. Most malignant pineal
region tumors benefit from a combination of surgical resec-
tion followed by chemotherapy and/or radiation. In rare
instances of mixed tumors containing both benign and
malignant elements, surgical resection may be necessary to
remove benign elements after prior chemotherapy/radiation
has eradicated the malignant portion. Open surgery also
facilitates comprehensive tissue sampling reducing the risk
of sampling error given the rarity, diversity, and similar
radiographic appearance of different of pineal tumor his-
tologies (Fig. 35.1).
Stereotactic radiosurgery has an unproven role as an
adjunct or even an alternative to open surgery. The great
variety of tumors that occur in the pineal region and the
need to direct adjuvant therapy based on histopathologic
diagnosis mandate that, with few exceptions, treatment,
including stereotactic radiosurgery, should not be pursued
without a tissue diagnosis. Stereotactic biopsy followed by
stereotactic radiosurgery may prove to be a reasonable
alternative to open surgery in selected cases, but this strat-
egy is currently most appropriate for patients with signifi-
cant medical contraindications to open surgery. Stereotactic
radiosurgery may also have an additional role as an alterna-
tive to whole-brain radiation in the treatment of select
radiosensitive tumors or in the adjuvant setting following
surgical resection. Retrospective series of patients with
pineal region tumors treated with stereotactic radiosurgery
report variable outcomes [23, 24]. The interpretation of
treatment efficacy in these studies is complicated as the
patient populations include different or unknown histology,
and nonuniformity of additional treatments including crani-
otomy and radiation therapy. Predictors of poor outcome
following stereotactic radiosurgery include radiographic
signs of tumor necrosis, prior radiation treatment and high
grade histology [23].
459
460 A.M. Sonabend et al.

Table 35.1 Results of large microsurgical series for pineal region tumors
Percent
of patients Major Permanent
No. of with GTR Mortality morbidity minor morbidity
Authors Year cases Approach Patient population Pathology (%) (%) (%) (%)
Hoffman et al. [8] 1983 61 TCIH/ITSC Pediatric All NA 20a NA NA
Neuwelt et al. [9] 1985 13 OTT Adult/pediatric All 60 0 0 20
Lapras et al. [10] 1987 86 TCIH/OTT Adult/pediatric All 65 5.8† 5.8† 28
Edwards et al. [11] 1988 36 TT/OTT/ITSC Pediatric All NA 0 3.3 3.3
Pluchino et al. [12] 1989 40 ITSC Adult/pediatric All 25 5 NA NA
Luo SQ et al. [13] 1989 64 OTT Adult/pediatric All 21 10 NA
Vaquero et al. [14] 1992 29 TCIH/ITSC/OTT Adult/pediatric All NA 11 NA NA
Herrmann et al. [87] 1992 49 IHTC/ITSC Adult/pediatric All NA 8 NA NA
Bruce and Stein [6] 1995 160 ITSC/TC/OTT Adult/pediatric All 45 4 3 19
Chandy et al. [88] 1998 48 ITSC/OTT Adult/pediatric “Benign 55 0 NA NA
lesions”
Kang et al. [89] 1998 16 OTT/ITSC/TCIH Adult/pediatric All 37.5 0 0 19
Shin et al. [90] 1998 21 OTT Pediatric/adult All 54.5 0 0 5
Konovalov et al. [3] 2003 201 OTT (54 %) Adult/pediatric All 58 10‡ NA >20
ITSC (34 %)
Bruce [91] 2004 81 ITSC/TCIH/OTT Adult/pediatric All 47 1 2 NA
Hernesniemi et al. [4] 2008 119 ITSC (93 %)/ Adult/pediatric All 88 0 1 4.9
OTT (7 %)
TCIH transcallosal interhemispheric, ITSC infratentorial supracerebellar, OTT occipital transtentorial, TT transcortical transventricular
a
All except one mortality prior to 1975

Surgical Management: An Overview

Initial management of a pineal region mass includes evalua-

tion for hydrocephalus, which is present in most patients.
Although ventriculoperitoneal shunting is acceptable, endo-
scopic third ventriculostomy is preferred, achieving the same
end without exposing a patient to the potential problems of
shunt malfunction, shunt infection, and abdominal seeding
of a malignancy. After CSF diversion, a procedure to obtain
tissue is indicated, either via a stereotactic, an endoscopic, or
an open approach. Either diverting procedure provides a con-
venient opportunity to assay CSF for malignant germ cell
tumor markers (α[alpha]-feto-protein or β[beta]-HCG) and
cytology, which can in very rare cases obviate the need for
tissue sampling. If these markers are elevated in either CSF
or serum, then by definition a malignant nongerminomatous
germ cell tumor (NGGCT) is present, and chemotherapy and
radiation therapy can proceed without the need for histologic
confirmation.

Stereotactic Biopsy

Although safe, stereotactic biopsy in the pineal region requires

Fig. 35.1 Similar imaging characteristics of pineal lesions with differ-
ent histologies. T1-weighted MRIs, precontrast (left panels) and post-
contrast (right panels), of three patients with pineal region tumors: (a)
ependymoma, (b) pineocytoma and (c) germinoma
more care and planning than biopsies of most other areas of
the brain. An anterolateral approach is favored with a pre-cor-
onal entry point just behind the nexus of the superior temporal
line and the hairline (Fig. 35.2). Using image guidance, the
35 Pineal Region Tumors: Viewpoint—Surgery
Fig. 35.2 Eighteen year-old male presented with headache, nausea and
vomiting. MRI revealed a pineal lesion (a), with dissemination into the
third ventricle (a, red arrow). Following endoscopic third ventriculos-
trajectory can be adjusted to enter a gyrus at the pial surface,
avoid the lateral ventricle, and steer clear of any obvious vas-
culature that may be distorted into the path of the biopsy nee-
dle by the tumor itself [25].
Close proximity of the target to the deep venous system
and a lack of adjacent tissue turgor should theoretically
increase the likelihood of a significant biopsy-induced hem-
orrhage. In fact, such hemorrhages appear to be mildly more
common in the pineal region, but they are rarely of any clini-
cal significance [26, 27]. Some series have suggested a
higher morbidity associated with pineal region biopsies
compared with routine biopsies, whereas others do not.
In any case, overall complication rates are low and are
almost always a function of transient exacerbations
of existing symptoms [25, 28–31]. A rare, but nonethe-
less reported complication of stereotaxic biopsy is meta-
static seeding of a pineoblastoma along the biopsy
tract [32]. The major drawback to biopsies is the limited
tissue sampling that makes definitive diagnosis difficult
when dealing with these widely diverse and often
heterogeneous lesions.
461
tomy, a stereotaxic needle biopsy was obtained. Stereotaxic needle tra-
jectory with a pre-coronal and slightly lateral entry point was chosen to
avoid the ventricular system, and eloquent cortical territory (b)
Endoscopic Biopsy
Some authors have advocated obtaining tissue specimens
endoscopically during the same operation as the third ven-
triculostomy. Although a potentially elegant one-step solution
to CSF diversion and tissue diagnosis, such a strategy neces-
sarily biases tissue sampling towards one quadrant of the
tumor capsule. Also, unless a flexible endoscope is used,
endoscopic biopsy and third ventriculostomy must be per-
formed through two separate burr holes and as such offers no
less “invasiveness” than stereotactic biopsy and third ventric-
ulostomy. Recent studies have demonstrated the feasibility of
both biopsy and third ventriculostomy through a single burr
hole positioned midway between the two trajectories [33].
Craniotomy for Open Resection
Although diagnostic biopsies are a suitable first option in
some cases, an open approach is generally preferred. The
advantages of an open resection are numerous, including
462
Fig. 35.3 Fifty two year-old female presented with nausea and vomit-
ing over the course of few weeks. MRI revealed a pineal region
lesion with no involvement of the third ventricle but with inferior
extension dorsal to the brainstem, and obstructive hydrocephalus
generous tissue sampling, potential obviation of a shunt, and
the ability to proceed with a radical resection if indicated
after intraoperative pathology consultation [34]. The relative
advantages of pursuing radical resection depend on an accu-
rate histopathologic diagnosis and must be weighed against
rates of morbidity and mortality from radical surgery.
Complications from open surgery can be serious and even
catastrophic typically resulting from postoperative hema-
toma, venous infarction from vein sacrifice, thalamic injury
from dissection of the anterior tumor capsule, and visual
deficits if the occipital transtentorial approach is used.
However, when complete tumor removal can be achieved,
the risk of postoperative hemorrhage into a subtotally
resected tumor is reduced. Minor complications include
infection and exacerbation of existing ataxia or Parinaud
phenomena. Pineal region surgery is certainly not trivial, but
within the past 25 years, major morbidity and mortality from
published surgical series have improved dramatically and
over the past quarter century has dropped to 0–2 % [35]
(Table 35.1).
A craniotomy is performed when cytoreductive radical
resection is the goal, and as mentioned above, this surgery
provides significantly more reliable material for histological
diagnosis. There are a series of approaches to access the
pineal region, and the selection of a particular one depends
on factors such as the surgeon’s experience, and anatomical
factors. In general, the approaches can be divided into supra-
tentorial and infratentorial [35–37].
Supratentorial approaches provide a wider lateral expo-
sure, and are preferred when the tumor mass extends signifi-
cantly into the supratentorial compartment, or has grown
A.M. Sonabend et al.
(a). Following endoscopic third ventriculostomy, the patient underwent
a craniotomy through occipital transtentorial approach (trajectory
shown with red arrow in a), and postoperative imaging showed gross
total resection (b)
laterally away from the natural reach achieved with a midline
trajectory from the infratentorial supracerebellar (ITSC)
approach. The supratentorial approaches include the occipi-
tal transtentorial (OTT) (Fig. 35.3), the transcallosal inter-
hemispheric (TCIH), and the rarely used
transcortical-transventricular (TT) approach which is limited
to the setting of ventricular dilatation and tumor extension
into the lateral ventricle [10, 34, 35, 38, 39]. Some of the
surgical morbidity can be related to deficits specific to a
given approach. One of the major inconveniences of the
supratentorial approaches is that important deep venous
structures such as the vein of Galen and the internal cerebral
veins lay between the surgeon and the lesion. The presence
of these veins in the field increases the risk of venous infarct,
and might obstruct the operative field limiting.
Infratentorial access to the pineal region is obtained
though the ITSC corridor (Fig. 35.4). With the patient prefer-
ably in the sitting position, the superior surface of the cere-
bellum is dissected from the tentorium and the precentral
cerebellar vein is divided, allowing the cerebellum to fall by
gravity clearing an unobstructed pathway to the pineal region
[35, 40]. With the sitting position, gravity minimizes retrac-
tion, and prevents blood from pooling in the microsurgical
field. Additionally, the deep venous structures lie superior to
the tumor mass, facilitating resection of the lesion. This
approach is favorable for removing tumor extending into the
third ventricle and velum interpositum. Disadvantages of the
approach include limited access to lateral and supratentorial
areas. Also, the sitting position carries a risk of air embolism,
pneumocephalus and subdural hematoma, although proper
precautions can minimize the risk [35, 41].
35 Pineal Region Tumors: Viewpoint—Surgery
Fig. 35.4 Twenty five year-old female presented with Parinaud’s syn-
drome and headache. MRI revealed a pineal region lesion with exten-
sion into the posterior portion of the third ventricle (a). A craniotomy
Treatment Results by Tumor Histology
The field of oncology is predicated on the belief that any
treatment modality must be evaluated on the basis of efficacy
in treating groups of patients bound by a common diagnosis.
This diagnosis is almost always made on the basis of tissue
histology. Pineal region tumors can arise from any of the myr-
iad cell types that normally occur in and around the pineal
gland, as well as from the range of ectopic tissues that can be
trapped near the pineal gland during embryogenesis. Because
few places in the body can match such cellular diversity and
biopsies of pineal lesions have been demonstrated to be safe,
histologic diagnosis of pineal region tumors is mandatory
unless tumor markers are positive. MRI is excellent at defin-
ing the relationship between tumor and adjacent anatomic
structures but is not able to distinguish between tumors of
different histologies (Fig. 35.1).
Tumors in the pineal region can be categorized as benign
or malignant. Alternatively, they can be classified into one of
four broad histologic categories: (1) pineal cell; (2) germ
cell; (3) glial cell; and (4) miscellaneous. Although surgical
results significantly influence the outcome for these patients,
individual prognosis is heavily dependent upon tumor type.
The rarity of individual histopathologic types within the
pineal region makes it difficult to generate sufficient num-
bers of patients treated to evaluate individual therapies, how-
ever some generalizations can be made.
Benign Pineal Region Tumors
Benign tumors account one third of the masses found
in pineal region [6]. These are composed mainly of
well-differentiated ependymomas, meningiomas, teratomas,
463
with an infratentorial supracerebellar approach was performed for
tumor resection (trajectory shown with red arrow in a), and postopera-
tive imaging showed gross total resection (b)
pineocytomas, and rare pilocytic astrocytomas. In each case,
radical resection is the standard of care if it can be performed
within a reasonable degree of safety. Gross total resection
provides the best chance for a cure or extended remission but
this goal must be weighed against the risks associated with
radical resection. Surgical series demonstrate good outcomes
over a range of pathologies, although there is a need in the
literature for surgical outcomes to be analyzed according to
specific histology. Only a few small surgical series are dedi-
cated to benign pineal lesions of a single histological type
[42–44].
Glial Tumors
Glial neoplasms encountered in the pineal region can present
in three different categories: (a) brainstem astrocytomas,
usually tectal lesions that extend rostrally, (b) “true” pineal
astrocytomas that arise from the supporting astrocytes of the
pineal gland itself, and (c) ependymomas associated with
the third ventricle. Brainstem astrocytomas that grow into the
pineal region are solid and, although they may be “low
grade,” are generally invasive. These are not amenable to
aggressive resection and require irradiation after biopsy [36,
45]. The “true” pineal astrocytomas are often cystic, encap-
sulated, and resemble pilocytic astrocytomas on histology
[46]. These can be completely resected and have excellent
long-term results. Anaplastic gliomas and glioblastomas
have also been encountered in the pineal region [3, 4].
Surgical outcomes from ependymomas are binary, depend-
ing on the degree of anaplasia. Pineal region ependymomas
with low cellularity and few mitoses have excellent long-
term outcomes although they may recur more readily than
ependymomas associated with the lateral ventricles [47].
464
Pineal Parenchymal Tumors
Arising from the melatonin-producing cells of the pineal
gland, pineal parenchymal tumors exist along a histopatho-
logic continuum from benign and indolent pineocytomas to
malignant and aggressive pineoblastomas. Tumors of inter-
mediate grade are referred to as mixed pineal parenchymal
tumors, and various classification schemes that are tied to
prognosis have been proposed [42, 48–52]. Making an accu-
rate pathologic diagnosis is difficult even with generous tis-
sue sampling. The rarity of these tumors makes the
aggregation of sufficient numbers of patients for an instruc-
tive clinical trial difficult. Further complicating matters is the
variable behavior of tumors with similar histopathologies
depending upon age of presentation.
Amidst the paucity of data to direct clinical decisions,
certain general treatment guidelines are apparent. The goal
for well-differentiated pineocytomas should be a cure, at
least in adults. There is some evidence that this standard is
unrealistic in pediatric cases where pineocytomas may
behave more aggressively [53].
The reported low recurrence rates with gross total resec-
tion of pineocytomas (overall survival approximately
100 % at 40 months median follow-up) has established a
new standard of care for these low grade tumors [3, 4, 42].
Outcomes following radiosurgical treatment of pineocy-
toma have been favorable as well [54–56], although the few
reported adult cases had only had a short follow-up [56]
and included at least one adult treatment failure resulting in
death from CNS metastasis [55]. One pediatric pineocy-
toma radiosurgical series reported four of seven treatment
failures resulting in death during a follow-up of 3 months to
4 years [57], although recently, more favorable results have
been reported [23].
At the other end of the neoplastic spectrum are pineoblas-
tomas. Although pineoblastomas often appear identical to
pineocytomas on MRI, they are histologically indistinguish-
able from primitive neuroectodermal tumors (PNETs) and
behave in a similar clinical fashion. Like PNETs, they tend to
be more aggressive in children than in adults [58], and within
the pediatric population they are increasingly aggressive
with decreasing age of presentation [59–66]. Although some
indication of increased survival exists in both adults [19] and
children [20] undergoing open surgery, no statistically rigor-
ous study has examined the impact of extent of resection
on survival or disease progression. In the absence of such
studies, it seems logical to follow the standard of care for
medulloblastoma (pinealoblastoma, shares phonotypical
characteristics of PNET) for which significant survival ben-
efits are apparent after reduction of tumor mass under 1.5 cm3
[67]. The few published cases of stereotactic radiosurgery
for pineoblastoma report poor results with the most recent
A.M. Sonabend et al.
showing local tumor control of 30 % at 2 years from diagno-
sis [24, 54–57], likely reflecting their malignant nature and
potential to spread through CSF. The relative utility of radio-
surgery cannot be ascertained based on a few published cases
except to say that radiosurgery does not appear to be a “magic
bullet” for these lesions, and it does not address the meta-
static potential of these tumors. Ultimately, prognosis for
pineoblastoma is most predicted by age of presentation and
disease dissemination at the time of diagnosis. Although far
from comprehensive, evidence suggests that resection has a
beneficial impact on survival.
Intermediate-grade pineal parenchymal tumors behave in
an unpredictable fashion. Treatment successes and failures
have been reported from a range of treatment strategies, and
there is little helpful data to direct clinical decisions [19, 51,
52]. Although patients with pineoblastoma are routinely irra-
diated after surgery, it is unclear whether this is universally
required in cases of intermediate-grade pineal parenchymal
tumors. Recently, some immunohistochemical markers have
been shown to be of prognostic value [68]. Clinical studies
that tie adjuvant therapy to tumor grade and outcome are
required with long-term outcome as tumors can recur more
than 5 years from diagnosis [19].
On the whole, pineal parenchymal tumors present a for-
midable challenge to clinicians. Treatment optimization will
only be possible with systematic and expert pathologic diag-
nosis that is not restricted by availability of tissue. Ideally,
this tissue should be sought via open surgery as radical resec-
tion loosely correlates with long-term survival.
Papillary Tumor of the Pineal Region
Papillary tumor of the pineal region (PTPR) was first
described in 2003 [69], and introduced as a distinct tumor
entity in the 2007 WHO classification of brain tumors. The
cells of origin for these lesions are presumed to be special-
ized ependyma of the subcommissural organ [69–71]. Due to
their recent identification as a separate entity, and their rarity,
not much is known about their clinical behavior. Fevre-
Montange et al.’s retrospective study of 31 patients is the
largest published series of these tumors and reported an age
range from 5 to 66 years (median age, 29 years) and slight
female predominance [15]. Gross total resection was per-
formed on 21 or 31 patients, and in 15, adjuvant radiotherapy
was given. Despite aggressive treatment, the majority of
patients had recurrences. Overall, the 5-year survival was
73 % with progression free survival of 27 % [15]. Details on
their histological and immunohistochemical profile, as well
as reliable methods for distinguishing between papillary
tumors, choroid plexus papillomas, and metastatic carcino-
mas have been reported [15, 69, 70, 72, 73]
35 Pineal Region Tumors: Viewpoint—Surgery
Germ Cell Tumors
Germ cell tumors are considered and studied in two separate
groups, germinomas and NGGCTs. The latter group consists
of endodermal sinus tumors, choriocarcinomas, embryonal
carcinomas, mature teratomas, and immature teratomas. The
role of open surgery for these lesions is perhaps as well
defined as for any pineal region tumors.
Germinomas are the most common of pineal region
tumors, especially in adolescent boys and young men. In
Japan and Korea, for reasons that are not understood, germ
cell tumors in general and germinomas in particular are more
prevalent than in any other part of the world including neigh-
boring China [62]. Because they do not secrete a specific
tumor marker and they cannot be distinguished radiographi-
cally from other types of tumors that call for different treat-
ment paradigms, diagnosis should be made with tissue
confirmation regardless of age of presentation.
Cytoreduction from open surgery has not been shown to
improve the excellent outcomes with radiation alone [63] and
thus the overwhelming majority of germinomas are diagnosed
by open or stereotactic biopsy and treated with whole-brain
radiation. Historically, the relatively high prevalence of ger-
minomas, their exquisite radiosensitivity, and the perceived
dangers of pineal region biopsy all contributed to the practice
of up-front radiation without tissue diagnosis for all pineal
region tumors. This approach was still commonly pursued in
the Far East as recently as 1992 [64, 65]. Although it is diffi-
cult to take issue with cure rates that today are over 90 % [66,
74–77], improvements in the treatment of intracranial germi-
noma can still be made. A small percentage of patients fail
radiation and suffer CSF dissemination that is ultimately fatal.
Treatment failure is much more likely when syncytiotropho-
blastic giant cells (STGCs) are mixed within the usual histo-
logic features, and failure rates within this histologic subtype
have been reported as high as 40 % [78–80]. Because these
are the rare germinomas that secrete β[beta]-hCG to produce
mildly elevated serum levels, their diagnosis should be
straightforward with adequate biopsy tissue and standard
assays of serum markers. As such, they should be considered
in a separate category from “pure germinomas” and the sub-
ject of separate clinical trials to reexamine all treatment
modalities, including radiosurgery and surgical cytoreduc-
tion. A study of stereotactic radiosurgery showed 72 and 62 %
local tumor control at 3 and 5 years from diagnosis [24].
Because many patients with intracranial germinoma have
long-term remission, the extended sequelae of whole-brain
radiation, particularly in the pediatric population, are another
major concern. Strides in chemotherapy have been made in
trials composed of children too young to receive full doses of
whole-brain radiation [81, 82]. Radiosurgery is a theoreti-
cally attractive alternative because of relatively limited radia-
tion exposure to adjacent brain tissue. Over the last decade,
465
stereotaxic radiotherapy for germinomas has been performed,
with local tumor control rates at 3 and 5 years of 82 %, and
72 %, respectively although 62 % germinomas with STGCs
had 5-year control rate of 62 % [24]. Some authors propose
the use of stereotactic radiosurgery as an effective adjunct for
pure germinomas to reduce cumulative radiation doses [54].
This hypothesis could be ethically tested in the pediatric
population.
NGGCTs have historically had a much worse prognosis
than germinomas. Because the individual types are so rare and
they are frequently of mixed histology, they have been lumped
together in retrospective analyses and clinical trials. These are
the only pineal region tumors that should be treated without a
tissue diagnosis as elevated levels of markers in the serum and/
or CSF are pathognomonic for specific histopathologies.
Although open surgery in a pre-adjuvant therapy cytoreductive
role has been examined with variable results [81, 83, 84], the
best results seem to occur when radiation and/or chemotherapy
is followed by “second look” surgery when a persistent radio-
graphic lesion exists [7, 81, 82, 85]. Using this approach, only
residual teratomatoma elements or scar tissue has been found,
and 5-year survival rates have improved dramatically to >90 %.
Stereotactic radiosurgery has an undefined role for
NGGCTs. One report [86] of four patients who received
radiosurgery along with fractionated radiation and chemo-
therapy showed tumor regression in three patients after a
follow-up of 2 years.
Conclusion
Despite sharing a common anatomic location and similar
imaging characteristics, pineal region tumors are extremely
heterogeneous with respect to histopathology, natural his-
tory, and response to therapy. Except for cases of marker-
secreting germ cell tumors, a tissue diagnosis is required to
direct therapy. In the absence of elevated markers, in most
cases, open surgery is the best initial therapeutic option.
Benign lesions can be cured with gross total resection, and in
experienced hands gross total resection can be achieved with
low complication rates. Stereotactic biopsy followed by ste-
reotactic radiosurgery is a potential alternative that is most
appropriate in patients with tumor seeding or medical con-
traindications to open surgery. The most effective treatments
for malignant lesions will likely require a combination of
modalities that will be directed by histopathologic diagnosis.
The merit of this approach is apparent in the example of
NGGCTs whose prognosis has vastly improved after numer-
ous clinical trials that were predicated on cohorts of patients
with specific diagnoses. Further progress will depend on
consistent histologic confirmation of these rare tumors rather
than empiric up-front conventional radiation or stereotactic
radiosurgery as some authors have proposed [57].
466
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 Pineal Tumors: Viewpoint—
Fractionated Radiation Therapy
William G. Rule and Steven E. Schild
Introduction
An estimated 22,910 primary brain/CNS tumors will be diag-
nosed in the United States in 2012. Of these, approximately
13,700 will result in death [1]. Pineal tumors make up only
0.4–1 % of all brain tumors and demonstrate an overall male
to female predominance of 3 to 1 [2, 3]. The pineal gland
region is unusual given the wide variety of primary tumors
that can arise from this site [4–9]. Benign cysts can also occur
in this site, as can ordinary brain tumors such as astrocytomas
or meningiomas. However, these are not as common as the
germ cell tumors (GCTs), which make up approximately two
thirds of the malignancies of the pineal gland.
It is assumed that germ cells migrate during embryogene-
sis and can lodge at the ectopic pineal region site, becoming
malignant GCTs later in life. The most common of these are
the germinomas, which are histologically indistinguishable
from testicular seminomas and ovarian dysgerminomas.
Nongerminomatous germ cell tumors (NGGCTs) also occur
in pure and mixed forms. Histologic varieties of nongermino-
matous GCTs include teratomas, embryonal carcinomas, yolk
sac tumors (endodermal sinus tumors), choriocarcinomas, or
combinations referred to as mixed GCTs. Teratomas typically
include cell types derived from all three germ cell layers:
endoderm, mesoderm, and ectoderm. Mature teratomas con-
tain fully differentiated cells. Immature teratomas consist of
cells and tissues resembling those of the developing fetus. By
convention, tumors in which mature and immature compo-
nents coexist are classified as immature. Other teratomas with
malignant epithelial or mesenchymal elements are considered
to be teratomas with malignant transformation. Embryonal
carcinomas contain large, primitive-appearing epithelial cells
W.G. Rule, M.D. (*) • S.E. Schild
Department of Radiation Oncology, Mayo Clinic College
of Medicine, Mayo Clinic Arizone, 5777 East Mayo Boulevard,
Phoenix, AZ 85054, USA
e-mail: rule.william@mayo.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_36, © Springer Science+Business Media New York 2015
36
that form sheets, cords, and gland-like arrangements. In rare
instances, they contain plate-like miniature embryos or
embryoid bodies. Yolk sac tumors are epithelial tumors that
contain compact sheets, ribbons, cords, or papillae. Schiller–
Duval bodies are diagnostic of yolk sac tumors. They contain
tufted epithelium-covered vessels projecting into clear spaces.
In addition to Schiller–Duval bodies, yolk sac tumors often
have a loose-knit vitelline pattern. Choriocarcinomas contain
a bilaminar arrangement of both syncytiotrophoblasts and
cytotrophoblasts. Combinations of any of these tumor types
are referred to as mixed GCTs. One specific mixed GCT, the
teratocarcinoma, contains elements of both embryonal carci-
noma and teratoma [4–9].
Some GCTs produce markers such as AFP (α[alpha]-
fetoprotein) or β[beta]-HCG (β[beta]-human chorionic
gonadotropin). Yolk sac tumors (endodermal sinus tumors)
can produce AFP, choriocarcinomas can produce β-HCG,
and embryonal tumors can produce both markers. Pure ger-
minomas can produce β-HCG but usually not in very high
levels. These markers are generally found in higher concen-
tration in the cerebrospinal fluid (CSF) than in the serum and
can aid in identifying the tumor type, as well as monitoring
the effects of therapy.
Tumors may also arise in the pineocytes forming a group
of tumors called pineal parenchymal tumors (PPTs), which
compose 15–30 % of all pineal tumors. These can be classi-
fied into four groups: pineocytomas, mixed PPTs, PPTs with
intermediate differentiation, and pineoblastomas [4, 6, 8, 9].
Pineocytomas are well-circumscribed masses that compress
surrounding structures. They are composed of mature-
appearing cells arranged in sheets or ill-defined irregular
lobules. Fibrillary processes with club-like endings project
from these cells, which take up silver stains. Pineocytomatous
rosettes are formed around collections of these fibrillary
processes. Pineoblastomas are grossly invasive and micro-
scopically highly cellular with small, mitotically active,
poorly differentiated cells with scant cytoplasm arranged
in pattern-less sheets similar to other primitive neuro-
ectodermal tumors (PNETs) and small blue cell tumors.
469
470
They resemble retinoblastomas and medulloblastomas.
Flexner–Wintersteiner rosette formation is a prominent
feature of pineoblastomas. These are rosettes of cells form-
ing around small lumens. Pineoblastomas occurring in
patients with bilateral retinoblastomas are called trilateral
retinoblastomas.
Symptoms from pineal masses are related to the anatomy
of the region. They often obstruct the sylvian aqueduct caus-
ing hydrocephalus and can result in increased intracranial
pressure, which can lead to headaches, nausea, vomiting, cog-
nitive dysfunction, and incontinence. Additionally, they can
cause pressure on the superior colliculus (midbrain) causing
Parinaud syndrome or dorsal midbrain syndrome with a triad
of signs consisting of vertical gaze palsy, light-near dissocia-
tion of the pupils, and convergence retraction nystagmus.
A major scientific advance took place in 1973: computed
tomography (CT) was first used in major US medical cen-
ters. This tool made the diagnosis and localization of pineal
tumors easier, leading to a resurgence of surgical interven-
tion with greater safety. Further improvements took place
with the introduction of magnetic resonance imaging (MRI),
which aided in localization as well as staging of the entire
central nervous system (CNS).
Prior to 1973, the operative risks of a biopsy or resection
were substantial, with mortality rates as high as 50 % [10–
12]. At that time, many experts recommended operative inter-
vention be reserved for CSF shunting in patients with
hydrocephalus and for the treatment of tumors that pro-
gressed after radiotherapy. Conservative therapy, including
CSF shunting and radiotherapy, resulted in a generally favor-
able 5-year survival rate of approximately 70 % [10–12].
However, therapy can only be customized to the specific
tumor type if the exact tumor histology is known. Additionally,
obtaining histologic confirmation, prior to therapy, allows
one to avoid irradiating benign lesions such as cysts [13, 14].
Over the past several decades, advances in CT imaging, MRI,
stereotactic techniques, operating microscopes, neurosurgi-
cal techniques, and postsurgical care have dramatically
decreased the morbidity and mortality previously associated
with biopsy or resection of pineal region tumors [15].
We evaluated a multi-institutional cohort of 135 patients
with histologically verified pineal region tumors [8]. Thirty-
five females and 100 males with ages ranging from 3 days to
77 years and a median age of 17 years were included in this
study. This series was not pure in that primary sites included
the pineal gland in 81 patients, the suprasellar region in 31
patients, and the cerebrum in 23 patients. Gross total resec-
tions were performed in 26 patients, subtotal resections were
performed in 49 patients, and biopsies were performed in 60
patients. There were two groups of neoplasms included in
this series: PPTs and GCTs. The PPTs included 15 pineo-
blastomas (PB), 2 mixed PPTs (mixed PPT), 4 PPTs with
intermediate differentiation (PPTID), and 9 pineocytomas.
W.G. Rule and S.E. Schild
Table 36.1 Probability of spinal seeding at diagnosis according to
tumor type
No. with spine seeding/
Histologic types total no. of patients (%)
1. Mature and immature teratoma 0/20 (0 %)
2. Mixed NGGCT 1/26 (4 %)a
3. Other NGGCT 0/11 (0 %)
4. Germinoma 2/48 (4 %)b
5. Pineocytoma 0/9 (0 %)
6. Pineoblastoma, PPTID, mixed PPT 4/21 (19 %)c
Total 7/135 (5 %)
a
This patient had a mixed germ cell tumor, composed of immature tera-
toma and germinoma, and had positive CSF cytology
b
Of these two patients with evidence of seeding at diagnosis, one had a
positive CSF cytology and the other had radiographic evidence of spi-
nal metastases
c
Of the four patients with evidence of seeding at diagnosis, two had
pineoblastomas (one with clinical evidence of spinal cord compression
and one with radiographic evidence of spinal seeding) and two had pineal
parenchymal tumors with intermediate differentiation (one with positive
CSF cytology and one with radiographic evidence of spinal seeding)
Note: All seven patients with evidence of spinal seeding at diagnosis
received craniospinal irradiation and of these only one (with a pineoblas-
toma) had a subsequent treatment failure at the primary site and the spine
The GCTs included 48 germinomas, 26 mixed GCTs, 11
mature teratomas, 9 immature teratomas, 6 malignant terato-
mas (with carcinomatous or sarcomatous components), 2
yolk sac tumors, and 3 choriocarcinomas. At the time of
diagnosis, 7 (5 %) of the 135 patients were found to have
evidence of spinal seeding (Table 36.1). Spinal seeding most
commonly occurred in patients with pineoblastomas.
One hundred patients underwent radiotherapy (Table 36.2).
Regions treated included the craniospinal axis in 35 patients,
the whole brain in 26 patients, and the partial brain in the
remaining 39 patients. Doses delivered to the primary tumor
bed ranged from 4,500 to 6,480 cGy (median dose, 4,132 cGy)
in 150- to 200-cGy fractions. Eleven patients treated during
the earlier years of this study received total doses of less than
3,000 cGy. When treated, the whole brain received 2,000–
5,040 cGy and the spine received 2,000–3,800 cGy.
Chemotherapy was administered to 35 patients as a compo-
nent of initial therapy (Table 36.2). These patients received
various combinations of the following agents: BCNU,
CCNU, cyclophosphamide, prednisone, vincristine, vinblas-
tine, cisplatin, etoposide, dactinomycin, bleomycin, chloram-
bucil, thiotepa, procarbazine, and melphalan.
Patients were followed for 0.25–37.3 years or until death
(median follow-up, 5.3 years). The survival rate for the entire
group of patients was 62 % at 5 years. Survival was worse for
patients treated during the early years of this study. Patients
diagnosed before 1973 had a 5-year survival rate of 34 %
compared with 66 % for those patients diagnosed more
recently (p = 0.0002). Twelve of the patients who were
operated on between 1936 and 1950 died in the immediate
36 Pineal Tumors: Viewpoint—Fractionated Radiation Therapy 471

Table 36.2 Summary of therapya Therapy

Histologic type RT No RT Chemotherapy No chemotherapy
1. Mature teratoma 2 5 1 6
2. Immature teratoma 2 7 0 9
3. Mixed NGGCT 19 6 17 8
4. Other pure NGGCT 5 4 3 6
5. Germinoma 48 0 8 40
6. Pineocytoma 6 1 0 7
7. PB, PPTID, mixed PPT 18 0 6 12
Surgical procedure
Histologic type Biopsy Subtotal resection Gross total resection
1. Mature teratoma 0 3 4
2. Immature teratoma 3 2 4
3. Mixed NGGCT 3 12 10
4. Other pure NGGCT 4 3 2
5. Germinoma 29 16 3
6. Pineocytoma 3 4 0
7. PB, PPTID, mixed PPT 9 6 3
RT radiotherapy, NGGCT nongerminomatous germ cell tumor, PB pineoblastoma, PPTID pineal parenchymal
tumor with intermediate differentiation, mixed PPT mixed pineal parenchymal tumor
a
Excludes 12 of the 135 patients who died postoperatively during the early years of the study

postoperative period. These patients were excluded from
the remainder of the analysis because their deaths were
more likely a result of operative complications than of
progressive disease.
Tumor histology was evaluated for its relationship to sur-
vival. The 5-year patient survival rate was 86 % for those
with mature teratomas, 86 % with pineocytomas, 80 % with
germinomas, 67 % with immature teratomas, 49 % with
PPTs other than pineocytomas (PB, PPTIDs, and mixed
PPTs), 38 % with mixed GCTs, and 17 % with the other pure
NGGCTs (p = 0.0001). Age, sex, and tumor location were
not associated with survival.
The extent of resection was evaluated for its effect on
patient survival. NGGCTs were the only tumors for which
survival was associated with extent of tumor resection. The
3-year survival rate was 0 for patients having a biopsy, 36 %
for patients having a subtotal resection, and 73 % for patients
having a gross total resection (p = 0.0002).
The relationship between the administration of chemo-
therapy (as a component of initial therapy) and survival was
evaluated. Patients who received chemotherapy had a 5-year
survival rate of 45 % compared with 65 % for those patients
who did not (p = 0.37). However, the administration of che-
motherapy was associated with improved survival rates in
patients with NGGCTs other than mature and immature tera-
tomas. Patients with NGGCTs who received chemotherapy
had a 3-year survival rate of 56 % compared with 8 % for
patients who did not receive chemotherapy (p = 0.0001).
Most of the patients (100 of 123) received radiotherapy.
However, only four patients with either mature or immature
teratomas received radiotherapy. Therefore, the effect of
radiotherapy in patients with mature and immature teratomas
could not be assessed. Patients with NGGCTs, other than
mature and immature teratomas, who received radiotherapy
had a 3-year survival rate of 46 % compared with 11 % for
patients who received no radiotherapy (p = 0.0089). There
was an association between the dose of radiation adminis-
tered and survival in patients with NGGCTs other than
mature and immature teratomas. Patients who received
≤5,000 cGy had a 3-year survival rate of 21 % compared
with 55 % for patients receiving higher doses (p = 0.02). The
dose of radiation administered correlated with survival rates
in patients with PPTs. Patients with PPTs receiving doses of
≤5,000 cGy had a 3-year survival rate of 56 %, and patients
who received higher doses had a 3-year survival rate of 94 %
(p = 0.03). There was also an association between the dose of
radiation administered and survival in patients with germino-
mas. Those patients with germinomas receiving doses of
≤4,400 cGy had a 5-year survival rate of 70 % compared
with 92 % for patients who received higher doses (p = 0.04).
There was no association between patient survival and radia-
tion field arrangement (partial-brain irradiation, whole-brain
irradiation, or craniospinal axis irradiation).
Spinal seeding was the predominant pattern of distant
failure. The outcome for patients with evidence of spinal
seeding at the time of diagnosis is summarized in the foot-
notes of Table 36.1. The risk of spinal failure relative to both
tumor type and radiotherapy field arrangement for patients
without evidence of spinal seeding at diagnosis is shown in
Table 36.3. Patients with PPTs (other than pineocytomas)
and GCTs (other than mature and immature teratomas) had
the greatest risk of spinal failure.
472 W.G. Rule and S.E. Schild

Table 36.3 Probability of spinal failure in patients without evidence of spinal seeding at diagnosis
Histologic types No. with spine failure/total no. of patients (%)a
1. Mature and immature teratoma 0/16 (0 %)
2. Mixed NGGCTb 1/24 (4 %)
3. Other NGGCTb 3/9 (33 %)
4. Germinoma 8/46 (17 %)
5. Pineocytoma 0/7 (0 %)
6. Pineoblastoma, PPTID, mixed PPT 8/14 (57 %)
Total 20/116 (17 %)
Probability of spinal failure according to the radiotherapy fields in patients without evidence of spinal seeding at
diagnosisc (including only seeding malignancies) (%)
Histologic types PB WB CSPRT Total
1. NGGCTd 2/4 (50 %) 0/8 (0 %) 1/11 (9 %) 3/23 (13 %)
2. Germinoma 7/25 (28 %) 1/11 (9 %) 0/10 (0 %) 8/46 (17 %)
3. PPTe 2/3 (66 %) 2/5 (40 %) 4/6 (66 %) 8/14 (57 %)
Total 11/32 (34 %) 3/24 (13 %) 5/27 (19 %) 19/83 (23 %)
PB partial-brain fields, WB whole-brain fields, CSPRT craniospinal irradiation, NGGCT nongerminomatous germ cell
tumor, PPT pineal parenchymal tumor, RT radiotherapy
a
Some of these patients received no RT
b
Of the NGGCT patients with spinal failure, three of these patients had teratomas with malignant transformation and one
had a yolk sac tumor. Not all of the patients with NGGCTs received RT
c
This included only patients with potentially seeding tumors (NGGCTs excluding mature and immature teratomas, pineal
parenchymal tumors excluding pineocytomas, and germinomas) who received RT. One patient with a NGGCT received
no RT and later had a spinal failure
d
NGGCTs excluding mature and immature teratomas
e
Excluding pineocytomas

Only one patient developed distant metastases outside the
central nervous system. This individual had a mixed GCT
with a component of malignant teratoma. After placement of
a ventriculo-peritoneal shunt for the treatment of tumor-
induced hydrocephalus, he developed peritoneal metastases
and died.
Conclusion
Pineal region tumors are rare and include a large variety of
lesions. Many studies included patients whose tumor types
were not histologically verified because of the risks associ-
ated with operative intervention [10, 11, 16–18]. As a result,
these series may have included patients with benign pro-
cesses such as cysts and vascular lesions. Prognosis is clearly
dependent upon tumor histology. This finding has been
reported by many investigators [19–32], with patients with
pineocytomas, germinomas, and mature teratomas demon-
strating the most favorable survival rates.
Jennings et al. found that survival was dependent upon the
extent of tumor, which emphasizes the importance of careful
staging [25]. The staging workup should include a careful his-
tory and physical examination, MRI of the brain and spine,
spinal fluid cytology, complete blood cell count, chemistry
panel, baseline ophthalmologic exam, and tumor marker stud-
ies (AFP and β[beta]-HCG from both the CSF and serum).
Caution should be exercised when obtaining CSF from
patients with increased intracranial pressure, because hernia-
tion of the brain may occur if pressure is rapidly reduced.
The treatment of pineal and other primary CNS GCTs
requires a precise knowledge of tumor histology. Obtaining a
histologic diagnosis is important because optimal therapy for
the various tumor types differs significantly. Improvements
in surgical technique and postoperative care have decreased
the morbidity once associated with resection or biopsy of
these tumors. Popovic and Kelly reported on 34 patients with
pineal lesions who underwent 66 stereotactic procedures at
the Mayo Clinic (including 37 biopsies and 10 resections)
[15]. Diagnostic tissue was obtained in 33 of the 34 patients.
No mortality or permanent morbidity was observed. Because
the survival of patients with NGGCTs appears dependent
upon the extent of resection, total resection should be
attempted in all cases where it can be safely performed.
Obtaining tissue for diagnosis is recommended in all patients
with pineal region tumors whenever possible.
Platinum-based multiagent chemotherapy has dramati-
cally improved the outcome in patients with NGGCTs [11].
Our series revealed that a significant increase in survival was
associated with the administration of chemotherapy to
patients with NGGCTs other than mature and immature tera-
tomas. Many other authors have recommended the use of
platinum-based multiagent chemotherapy for the treatment
of NGGCTs of the brain [20, 21, 25, 26, 32–36].
36 Pineal Tumors: Viewpoint—Fractionated Radiation Therapy
Radiotherapy should be administered to all patients with
pineal region tumors other than possibly the mature and
immature teratomas for which little data exist regarding
radiotherapy. Careful consideration should be given to the
dose, because survival in patients with NGGCTs (other than
mature and immature teratomas), PPTs, and germinomas is
dependent upon the dose of radiation administered to the pri-
mary tumor. The extent and dose of radiation should be tai-
lored to the particular tumor type as outlined below.
Patients with PPTs (other than pineocytomas) have a high
risk of spinal failure, and craniospinal axis radiotherapy
would appear reasonable (particularly in pineoblastomas).
However, patients with PPTs of intermediate differentiation
with no spinal metastasis can be given whole-brain irradia-
tion because the risk of spinal seeding appears no greater
after whole-brain irradiation than after craniospinal irradia-
tion (Table 36.3). In general, pineoblastomas are treated
similarly to medulloblastomas, with craniospinal axis irradi-
ation with a subsequent boost, followed by adjuvant chemo-
therapy. The primary tumor should receive 5,040–5,400 cGy,
and spinal metastases should receive 5,040 cGy in 180 cGy
fractions. Prophylactic therapy can include the delivery of
3,000–4,500 cGy to uninvolved high-risk areas. Patients with
pineocytomas can be irradiated to the local tumor alone.
None of the pure pineocytomas we studied metastasized.
It appears that the radiation dose (>5,000 cGy versus
≤5,000 cGy) delivered to the primary tumor was the most
significant factor affecting survival in patients with PPTs.
Patients with germinomas but no spinal seeding still have a
modest risk of spinal failure. Historically, children with non-
disseminated germinomas were treated with craniospinal irra-
diation (3,600 cGy) followed by a boost to the primary tumor
(total dose of 5,000–5,400 cGy). Lower doses of craniospinal
irradiation and lower boost doses have demonstrated good
efficacy in retrospective as well as prospective settings [37–
39]. Replacing craniospinal irradiation with whole-brain or
whole-ventricular-irradiation has also been shown to yield
good results, with low spinal failure rates [5, 37, 40–43]. In
our study, no patient who received craniospinal irradiation had
a spine failure and only 1 of 11 (9 %) patients treated with
whole-brain irradiation failed (Table 36.3). While the rate of
spinal failure in patients who received partial-brain fields was
substantial in our study, multiple other series have demon-
strated very good outcomes with whole-ventricular-irradiation
[37, 38, 41, 42, 44, 45]. The standard radiation therapy alone
arm in the Children’s Oncology Group (COG) ACNS0232
protocol was structured to deliver 2,400 cGy in 150 cGy frac-
tions to whole-ventricular fields, with a 2,100 cGy boost in
150 cGy fractions subsequently delivered to regions of gross
disease (total tumor dose of 4,500 cGy). Patients with spinal
seeding were to receive 2,400 cGy in 150 cGy fractions to the
craniospinal axis, followed by a 2,100 cGy boost in 150 cGy
fractions to regions of gross disease.
473
Given the good response rates of germinomas to chemo-
therapy, attempts have been made to use chemotherapy alone
in order to avoid radiotherapy. However, the chemotherapy-
only approach has been shown to yield unacceptably high
tumor recurrence rates [45–47]. In an attempt to strike an
ideal balance between disease-related outcomes and long-
term treatment-related sequelae, current work is aimed at
exploring the best combination of pre-radiotherapeutic che-
motherapy with reduced dose radiation (in the disseminated
and non-disseminated settings). When possible, every effort
should be made to enroll patients with germinomas in cur-
rent cooperative group clinical trials.
Based on our series, patients with NGGCTs (other than
immature and mature teratomas) but no spinal seeding can
be treated with either whole-brain or craniospinal irradiation.
Spinal failure occurred in two of the four patients treated
with partial brain fields. There was a low risk of spinal fail-
ure with either whole-brain or craniospinal irradiation
(Table 36.3). In other studies, whole-ventricular-irradiation
has shown some promise as a potentially reasonable alterna-
tive in selected patients [48–50]. As discussed above, it
has been shown that NGGCT patients also experience
improved survival with the administration of chemotherapy.
Chemotherapeutic regimens typically include cisplatin (or
carboplatin) and etoposide, with some regimens also adding
cyclophosphamide or ifosfamide. The potential benefits of
prophylactic spinal irradiation must be carefully weighed
against potential toxicity in patients requiring platinum-
based multiagent chemotherapy. Craniospinal irradiation
and systemic chemotherapy should be considered for patients
who present with spinal seeding. The primary tumor should
receive 5,040–5,400 cGy and spinal metastases should
receive 5,040 cGy in 180 cGy fractions. Prophylactic ther-
apy can include the delivery of 2,400–3,600 cGy to unin-
volved high-risk areas. Second-look surgery should be
considered for patients with persistent masses/residual tumor
after a course of chemotherapy and radiation. As with germi-
nomas, enrollment in clinical trials should be strongly con-
sidered for NGGCT patients.
Immature and mature teratomas should be resected, if this
can be safely achieved. We cannot make definitive recom-
mendations regarding the efficacy of radiotherapy or chemo-
therapy for patients with immature and mature teratomas,
because of the small number of patients in our series treated
with these modalities. If progression occurs, further surgical
intervention, radiotherapy, and/or chemotherapy should be
considered.
Table 36.4 lists the relative advantages of stereotactic
radiosurgery (SRS) versus fractionated external beam irradi-
ation. Stereotactic radiotherapy and radiosurgery have poten-
tial roles in the treatment of pineal tumors. These techniques
would have the greatest potential as a single treatment modal-
ity in non-seeding tumors. The advantages for radiosurgery
474 W.G. Rule and S.E. Schild

Table 36.4 Advantages of stereotactic radiosurgery (SRS) versus fractionated external beam radiotherapy (FRT)
Advantage Disadvantage
Effectively address those at ↑ risk of CSF seeding FRT SRS
Most effectively minimizes RT dose to surrounding normal brain SRS FRT
More radiobiologically effective in the treatment of small, non-seeding tumors SRS FRT
Marrow suppression in patients who in some cases receive chemotherapy SRS FRT
May be an effective alternative to resection in histologies in which resection is believed to improve survival SRS FRT
Requires less patient time SRS FRT
Proven long-term efficacy FRT SRS
Germinomas FRT SRS
Nongerminomas FRT SRS
Pineocytomas SRS FRT
Other PPTs FRT SRS
Note: Ultimately, one might consider the following paradigm for future investigation in seeding pineal tumors (all those other than pineocytomas,
mature teratomas, and immature teratomas): Biopsy first (and shunting if needed), followed by FRT followed by a specialized boost (SRS, IMRT,
heavy ions …), and chemotherapy when appropriate. In non-seeding tumors, one might consider: Biopsy first (and shunting if needed) followed
by a specialized boost technique. The major rationale for this approach is the opinion that complete resection of a pineal tumor incurs a substan-
tially greater overall risk to the patient than does SRS. Additionally, the specialized boost would provide greater local control than FRT alone in
unresected tumors

in these cases are a shortened course compared with fraction-
ated external beam irradiation, and, more importantly, a
reduction in radiation exposure to surrounding normal struc-
tures. The latter is especially advantageous in pediatric
patients. Pineocytomas and teratomas (both mature and
immature) represent tumors in which this approach would be
most applicable as they do not generally seed the CSF. There
are examples in the literature where pineocytomas have been
reported to seed, but this may represent confusion regarding
the classification of PPTs, which should be subdivided into
four groups [4, 6, 8]. The risks of radiosurgery are likely sub-
stantially less than resection. Regarding PPTs, the University
of Pittsburgh experience with Gamma Knife radiosurgery
would support these contentions. Hasegawa et al. reported
that the 5-year survival of ten patients with pineocytomas
was 90 % utilizing Gamma Knife radiosurgery [34]. In con-
trast, the results of Gamma Knife treatment with pineoblas-
tomas were poor, with death occurring in four of six patients.
Complications including upward gaze paralysis occurred in
2 of 16 (12.5 %) and was likely due to the dose delivered to
the superior colliculus, which lies in direct contact with
pineal tumors. Pineocytomas are round, circumscribed
tumors that are generally not large at diagnosis because they
cause symptoms as soon as pressure is exerted on the sylvian
aqueduct or the superior colliculus. However, PPTs with
intermediate differentiation and mixed PPTs are often dif-
fuse, invasive, and seeding. These should be treated with
either whole-brain radiation therapy followed by a boost to
the tumor in cases without seeding or craniospinal radiation
therapy in cases with seeding followed by a boost to areas of
gross disease. The options for the boost include external
beam irradiation, stereotactic radiotherapy, or radiosurgery.
Which boost technique option offers the best outcome is
unknown. Pineoblastomas, variants of supratentorial PNETs,
are, in general, treated similarly to medulloblastomas. For all
other pineal tumors with seeding potential, radiosurgery or
stereotactic radiotherapy could be used as a boost to gross
disease after other therapy. Hasegawa et al. also reported on
a small series of four patients treated for nongerminomatous
GCTs of the brain [35]. These patients received a Gamma
Knife boost after other therapies, and three of four were alive
without disease at last follow-up. Although this is a small
series, it does show potential and should lead to further
investigation. The specialized radiation techniques might
also be considered as salvage therapeutic maneuvers when
other treatments have failed.
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Lunsford LD. The role of radiosurgery for the treatment of pineal
parenchymal tumors. Neurosurgery. 2002;51(4):880–9.
35. Hasegawa T, Kondziolka D, Hadjipanayis CG, Flickinger JC,
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36. Herrmann HD, Westphal M, Winkler K, Laas RW, Schulte
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region. Neurosurgery. 1994;34(3):524–9. discussion 9.
37. Bamberg M, Kortmann RD, Calaminus G, Becker G, Meisner C,
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 Pineal Region Tumors:
Viewpoint—Chemotherapy
Christopher Dardis and Roy A. Patchell
Introduction
Tumors involving the pineal gland are uncommon, accounting
for 4–11 % of intracranial tumors in children and 0.4–1 % of
such tumors in adults [1]. As noted in preceding chapters, the
conventional classification system divides them into four
broad histologic types, and treatment is generally based
on this type (rather than anatomic location). These types are:
(1) germ cell, (2) pineal cell, (3) glial cell, and (4) miscella-
neous. Speaking generally, chemotherapy has an adjunctive
role in most of these tumors.
Regarding glial tumors, little will be said here as the che-
motherapeutic management is not different for those arising
in the pineal as opposed to elsewhere; interested readers are
referred to Chap. 20 in the current volume. The following
may also be seen here: meningiomas, choroid plexus papil-
lomas, neuronal cell tumors, ependymomas, lipomas, and
metastases. Again, the reader is referred to the appropriate
chapters.
As noted elsewhere in the current volume, biopsy of
pineal tumors is strongly recommended prior to the start
of therapy. In occasional cases, magnetic resonance imaging
(MRI) of the brain with cerebrospinal fluid (CSF) sampling
may be sufficient to establish a diagnosis of certain hormone-
secreting germ cell tumors (GCTs). (β[beta]HCG for chor-
iocarcinoma, α[alpha]FP for yolk sac, and embroyonal
carcinoma) An MRI of the entire spine is recommended to
look for “drop metastases” in the case of pineoblastoma.
Recent years have seen substantially increased interest in
the role of chemotherapy for these conditions. At the time of
C. Dardis, M.D.
Barrow Neurological Clinics, 500 W. Thomas Rd.,
Suite 300, Phoenix, AZ 85013, USA
R.A. Patchell, M.D., F.A.A.N. (*)
National Brain Tumor Center, Capital Institute for Neurosciences,
Capital Health Medical Center-Hopewell, Two Capital Way,
Suite 456, Pennington, NJ 08534, USA
e-mail: rpatchell@capitalhealth.org
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_37, © Springer Science+Business Media New York 2015
37
writing, the NIH lists over 50 studies including patients
affected by one of these tumors, the majority of which include
a chemotherapeutic element. Overall, regimens tend to be
similar in adults and children, reflecting a belief in the simi-
larity of tumor biology across the lifespan. Likewise, given
their rarity, the tendency has been to lump rather than split in
retrospective reviews and in designing effective regimens.
Germ Cell Tumors
Primary GCTs account for approximately half of pineal
tumors. Central nervous system (CNS) GCTs mostly arise in
the midline: 80 % or more arise in structures near the third
ventricle, with the region of the pineal gland being the most
common site of origin. Multifocal disease is common. CNS
GCTs are seen most commonly in childhood and young
adulthood. These tumors can be divided into germinomas
(aka seminomas, also the most common type of testicular
cancer) and nongerminomatous GCTs, which include tera-
toma (from Lt. teratos = deformity, consisting of tissues
derived from all three embryonal layers), embryonal cell
carcinoma (or stem cell, arising from a portion of cells with-
out which embryogenesis cannot continue), yolk sac tumor
(from O.E. geolu = yellow), and choriocarcinoma (from Gk.
khorion = membrane enclosing the fetus).
Germinomas
For germinomas, conventional is to aim for subtotal resec-
tion where possible, with adjuvant radiation. As they are par-
ticularly sensitive to radiation, this remains the cornerstone
of treatment, typically involving ventricular irradiation with
a local boost [2]. Five-year survival in a series of 49 germi-
nomas was reported as 88 ± 5 % for such an approach. At one
time complete craniospinal irradiation was employed pro-
phylactically; however, given the rates of adverse sequelae
with this approach, surveillance is now preferred [3].
477
478
Generally these tumors are also sensitive to chemotherapy
and the following agents have all been used with some
success: alkylating agents (cisplatin, carboplatin, cyclophos-
phamide, ifosphamide) as well as etoposide, vinblastine,
adrimycin, and bleomycin. A platinum-based agent with
etoposide is most commonly employed. Given how sensitive
they are to carboplatin in particular, it was hoped at one point
that this single agent may be able to replace radiation com-
pletely, although this no longer is a widely-advocated
approach [4].
Neo-adjuvant chemotherapy with a platinum-based
regime has been advocated by a number of centers, although
it remains to be seen whether this is of additional benefit by
comparison with the regimen proposed above [5]. A phase II
study by Allen et al. in 1994 showed complete response rates
in 7 of 11 pediatric patients receiving carboplatin (150 mg/
m2 weekly, 2–4 cycles) [6].
In cases with dissemination there is clearly a role for
craniospinal irradiation and for adjuvant chemotherapy.
Likewise, in cases of local or systemic relapse, adjuvant che-
motherapy is generally recommended. Given the relatively
low incidence of any of these complications, decisions are
typically based on small retrospective studies. Plantinum and
etoposide-based regimens are commonly employed, although
bleomycin and cyclophosphamide have also been used [7].
Cyclophosphamide with re-irradiaiton had previously been
suggested as optimal monotherapy for recurrence, with
response rates of up to 5 months [8].
Recent trials have also explored the possibility of reducing
radiation dosing by giving adjuvant chemotherapy. One study
using cisplatin and etoposide (up to six cycles) following
whole brain or ventricular irradiation in 16 pediatric patients
has shown promising results [9].
It bears noting that there have been attempts to eliminate
radiation therapy altogether from the treatment regimen. The
largest of these was initiated by the international CNS GCT
study group.
This was a trial with a common protocol for all GCTs
[10]. Of 71 patients enrolled, 45 had germinomas. Induction
chemotherapy consisted of four cycles of carboplatin, etopo-
side, and bleomycin chemotherapy, a regimen adapted from
systemic GCT experience. (Cisplatin is considered more
effective than carboplatin for systemic disease.) Those
achieving complete remission (CR) were given an additional
four cycles. An intensified regimen was offered to those not
achieving complete remission. Of the germinomas, 37 of 45
achieved complete response. However, the relapse-free sur-
vival was disappointing, with approximately 50 % of patients
with each pathologic subtype experiencing relapse or pro-
gression. Twenty eight of 55 patients in complete remission
without irradiation subsequently developed tumor recur-
rence at a median time of 18 months from diagnosis.
C. Dardis and R.A. Patchell
From this experience, it appears that aggressive chemo-
therapy alone can induce durable complete remissions in only
approximately 50 % of patients. Given the superior results
with radiation for germinomas, the use of chemotherapy with-
out radiation cannot be considered routine for these patients.
Non-germinomatous GCTs
Mature teratoma, like germinoma, tends to have a favorable
prognosis and remission may be achieved with resection
alone. However, given the generally unfavorable prognosis
of the other tumors in this class, chemotherapy is not
controversial.
Historically non-germinomatous GCTs have been ana-
lyzed together rather than separately and so relatively little is
known about their relative response to chemotherapy, i.e.,
whether regimes should include the particular histology in
their design. Of the group, choriocarcinomas tend to have a
significantly worse prognosis than the others.
A consensus has emerged that adjuvant chemotherapy
should generally include a platinum-based agent. A recent
review advises first line adjuvant treatment with POMB-
ACE (cisPlantin, vincristine (Oncovorin), methotrexate,
bleomycin, actiomycin-d, cyclophosphamide, etoposide) or
EMA/CO (etoposide, methotrexate actinomycin-d, folinic
acid, cyclophosphamide, vincrisite (Oncovorin)) [11].
Other proposed adjuvant regimes include cisplatin, ifos-
phamide, and etoposide [12], PVB (cisplatin, vinblastine,
bleomycin) and PIV (cisplatin, ifosphamide, bleomycin) [13].
Earlier approaches with neo-adjuvant cisplantin and etopo-
side followed by adjuvant carboplatin, etoposide, bleomycin,
and vinblastine also confirmed improvement with this
multimodality approach [14]. These are typically selected on
the basis of tolerability and employed over 4–6 cycles. All of
the platinum-based regimens have improved prognosis for
these tumors. However, given that this tends to remain rather
dismal (3-year survival rates reported as 30 % for adults,
60 % for those age under 16), clearly there remains room for
improvement in these regimes [13]. In all cases, following
hormonal markers, typically in serum, it is advised to assess
response to treatment.
For recurrence, further chemotherapy is advocated, typi-
cally platinum-based and more aggressive than before,
although a consensus has yet to emerge on an optimal
regimen.
Metastases have been reported with these tumors, most
commonly when mixed (i.e., a non-germinomatous element
is present). These can occur as a result of transit through a
VP-shunt or independently—presumably hematogenously.
If well localized, these may be treated with irradiation, typi-
cally with a platinum and etoposide combination.
37 Pineal Region Tumors: Viewpoint—Chemotherapy
The frustratingly high relapse rate and the initial
refractoriness of nongerminoma GCTs to chemotherapy has
led to the use of high-dose chemotherapy (HDC) and autolo-
gous stem cell transplant for either relapse disease or to con-
solidate partially responsive disease. This strategy is based
on experience with systemic GCTs, as well as the increasing
experience with other high-risk primary brain tumors, such
as medulloblastoma. One of the largest such experiences was
published by Modak et al. [15], a group based in New York
and one of the leaders in the field of high-dose therapy and
stem cell rescue for brain tumors. Like the CNS GCT trial
above, it included all germ-cell tumors, in this case 21 patients
with CNS GCTs who had either relapsed or progressed,
despite receiving chemotherapy and/or radiation therapy. They
received high-dose thiotepa with another agent, typically eto-
poside, often with carboplatin. Resection after chemotherapy
was undertaken when practical. Posttransplant radiation ther-
apy was added focally or to the entire neural axis whenever
feasible. Four of 12 patients with non-germinomatous GCTs
achieved CR with a range of 24–55 months at time of publica-
tion. One was alive with residual disease at 51 months (7 of 9
patients with recurrent germinomas survived disease-free,
with a range of 6–87 months, median 48).
These encouraging results suggest that long-term remis-
sions can be obtained even in a group of patients initially
refractory to chemotherapy. It remains to be seen whether
adopting this as the approach at time of diagnosis will offer
additional benefits over current regimens.
Teratomas
Given their relative rarity, a consensus on the role of adjuvant
chemotherapy for immature teratomas has yet to emerge. One
large retrospective series showed a good response to chemo-
therapy, typically platinum-based, when signs of recurrence
developed [16]. This did not, however, apply to those in the
highly malignant subgroup, for whom no salvage therapies
were effective.
Pineal Parenchymal Tumors
These tumors arise from the pineocyte. They are classified by
the WHO into pineocytoma (grade I), pineal parenchymal tumor
of intermediate differentiation (grade II-III), and pineoblastoma
(grade IV). They are considered to represent a spectrum.
Pineocytomas
Chemotherapy is far from standard of care for these tumors.
A review in 2010 looking at outcomes for all English-
language cases of pineocytoma concluded that optimal
479
management consists of total resection and postoperative
radiation, with 1- and 5-year survival rates of 91 % and 88 %,
respectively [17]. No significant improvement in survival
was found in the addition of radiation to subtotal resection,
although this is likely to remain standard practice in most
cases; chemotherapy was not considered further. It was sug-
gested as far back as 2004 that platinum-based chemother-
apy could have a supportive role to play, although this has
not been explored further with clinical trials [18]. Sensitivity
to nimustine (ACNU) has also been reported [19].
Certain variants are more aggressive and, given the poor
prognosis, should generally be offered chemotherapy. The
papillary variant is particularly aggressive [20]. Meningeal
metastases also tend to have a poorer prognosis and ACNU
and vincristine has been suggested as a reasonable approach
for such cases [21].
Pineoblastomas and Pineal Parenchymal
Tumors of Intermediate Differentiation
Pineoblastomas (PBs) and pineal parenchymal tumors of
intermediate differentiation (PPTIDs) are very rare in adults.
To date, no prospective studies analyzing different chemo-
therapy regimens are available. A recent multicenter review
indicated the poorer outcomes of these entities compared
with pineocytomas [22].
Primary or secondary failure (relapse) rates were about
50 % at 10 years, with the worse outcomes seen among
patients who present with disseminated disease or who have
large-volume residual disease. PB histology compared with
PPTID also had worse outcomes.
Conventional approaches to adjuvant chemotherapy for
these tumors typically involves use regimens similar to those
used for medulloblastoma (which pineoblastoma resembles
histologically), such as cisplatin, carboplatin, etoposide,
cyclophosphamide, and vincristine [23].
Given the poor prognosis treatment with HDC and autolo-
gous stem-cell rescue (ASCR) in patients with newly diag-
nosed PB remains a possible alternative [24]. In the largest
trial to date on this subject (2004), 12 patients (6 children
and 6 adults) underwent biopsy or complete resection (5 of
12) of primary tumor at the time of diagnosis.
All patients received induction chemotherapy with one of
three regimens.
Stem cells were harvested from bone marrow and/or
peripheral blood after the first or second cycle of induction
chemotherapy after using granulocyte colony-stimulating
factor (G-CSF).
All patients, except two infants, received craniospinal
irradiation at a median dose of 36 Gy with a boost to the
pineal region boost.
Eleven patients received HDC with cyclophosphamide
50 mg/kg daily for 4 days followed by melphalan 60 mg/m2/day
480
for 3 days or busulfan 1 mg/kg every 6 h for 16 total doses over
4 days followed by melphalan 60 mg/m2/day for 3 days.
After HDC and ASCR, nine patients were disease-free
at a range of 28–125 months (median 62), including three
of four with metastatic disease at presentation and the two
infants who did not receive radiotherapy. Two of eight
patients with localized disease and one of four patients with
metastatic disease developed progression and died.
This outcome in this small sample of patients using HDC
after induction chemotherapy and radiation are superior to
less-aggressive regimens.
Subsequent trials have tended to confirm these initial
results, although the numbers with pineoblastoma were gen-
erally small and tended to be grouped with high-grade recur-
rent CNS tumors [25–27].
Conclusion
Chemotherapy has an established role to play in GCTs, par-
ticularly non-germinomatous and pineoblastomas. At present,
the agents in use are relatively nonspecific. Given their prog-
nosis, future developments will likely focus on higher doses
of these agents, with stem-cell rescue as required, or on more
targeted biological agents, possibly based on molecular char-
acteristics of the tumor. New modalities such as stereotactic
radiosurgery may improve the response rates to adjuvant
treatment, although it does not appear likely to replace it
entirely for now. When classifying outcomes, the issue of
“splitting” vs. “lumping” remains to be clarified, particularly
in relation to the response to chemotherapy in the pediatric
and adult forms of these tumors and also in variable responses
to subtypes of non-germinomatous GCT.
Treatment decisions should be made in a multi-
disciplinary context and that given their rarity, centralization,
co-ordination of services, and detailed reporting of outcomes
are key goals to facilitate future improvements in care.
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 Skull Base Tumors
Reinhart A.J. Sweeney and Matthias Guckenberger
Introduction
This chapter will focus on the rarer skull base tumors not
discussed in detail in the respective meningioma, pituitary,
and schwannoma chapters.
These skull base tumors can be divided into those that are
unique to a particular region and those that can occur through-
out the skull base. These tumors may derive from the bone,
paranasal sinuses, nasopharynx, inner ear, dura, cranial
nerves, or brain. They may be primary tumors invading local
structures, or metastatic disease. They can also be divided
into benign and malignant lesions.
Unfortunately, even benign lesions can become life
threatening if critically located, rendering them unresectable
or otherwise not amenable to effective local therapy.
Tumors of the skull base pose the greatest challenge to
neurosurgeons as they tend to grow around and invade criti-
cal structures such as cranial nerves and vessels, hindering
complete resections as the risk of neurologic deficits and
morbidity is high. Especially here, the advantages of mod-
ern, high-precision radiosurgery with its high rate of local
control with minimal risk due to optimal sparing of these
critical structures become an attractive alternative. Primary
radiosurgery can also be an alternative for inoperable patients
or a palliative alternative for those with a poor prognosis. For
these, symptom relief such as tumor-related facial pain is
common. In general however, the goals of radiosurgery are
long-term prevention of tumor growth, maintenance of
R.A.J. Sweeney, M.D., B.Sc. (*)
Department of Radiation Oncology, MVZ Immed, Klinik Bad
Trissl, Bad-Trissi Str. 76, Oberaudorf, Germany
e-mail: reinhart.sweeney@klinik-bad-trissl.de
M. Guckenberger, M.D.
Department of Radiation Oncology, University Würzburg,
Josef-Schneider Street 11, 97080 Würzburg, Germany
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_38, © Springer Science+Business Media New York 2015
38
patient function and quality of life, as well as prevention of
new neurologic deficits. Very few complications occur after
stereotactic radiosurgery, such as perifocal edema, delayed
intratumoral hemorrhage, or radionecrosis requiring neuro-
surgical intervention [1, 2].
In general, single-fraction stereotactic radiosurgery is
used for small localized lesions under 3 cm in diameter by
using external stereotactic techniques such as Gamma Knife
which requires the applications of an invasive stereotactic
frame attached to the skull with four pins. The same tech-
nique has also been adapted to linac-based systems and
charged-particle therapy such as protons. However, in the
last decade, noninvasive alternatives have emerged, using
noninvasive fixation, most commonly thermoplastic masks
or a vacuum-mouthpiece [3–5]. This allows temporal separa-
tion of the imaging, planning, and treatment sessions as well
as the option of fractionation should this be required. The
inherent repositioning inaccuracy and intrafraction motion
of noninvasive fixation systems are fully compensated by
image guidance and, in many cases even six degrees of free-
dom treatment couches [6]. As of late, it has become possi-
ble to fractionate treatment with the Gamma Knife as well,
using the abovementioned vacuum-mouthpiece [5, 7].
Linac-based radiosurgery can be performed with various
techniques, such as the traditional arc-based approach with
circular collimators [8], static beams [9]. Dynamic Circular
Arc (DCA) [10] and intensity-modulated techniques (IMRT/
IMSRS) [11]. When circular collimators are used for irregu-
lar treatment volumes (Gamma Knife, but also so equipped
Linacs), multiple isocenters are usually required. These
result in overlapping beams which in turn cause substantial
dose inhomogeneity within the treatment volume. This inho-
mogeneity may damage organs at risk (OAR), in cases where
these OARs are located within the treated volume. This can
be of special relevance at the base of skull where cranial
nerves abound [12]. The introduction of (micro-) multileaf
collimation in linac radiosurgery improved conformity and
homogeneity [13].
483
484 R.A.J. Sweeney and M. Guckenberger

Table 38.1 Advantages of different radiosurgical techniques; a literature review

First Author (year)
Bourland et al. (‘94) [9]
Hamilton et al. (‘95) [99]
Shiu et al. (‘97) [100]
Kubo et al. (‘97) [101]
Kramer et al. (‘98) [102]
Yu et al. (‘99) [14]
Cardinale et al. (‘98) [103]
Benedict et al. (‘01) [104]
Leavitt et al. (‘01) [105]
Yu et al. (‘02) [10]
Perks et al. (‘03) [13]
Baumert et al. (‘03) [11]
Ernst-Stecken et al. (‘05) [106]
NA not available, CI conformity index, HI homogeneity index, IMSRT intensity-modulated stereotactic radiotherapy, IMSRS intensity-modulated
stereotactic radiosurgery, OAR organ at risk, DCA dynamic conformal arc
Methods compared
Noncoplanar circular arc vs.
conformal fixed beam
Noncoplanar circular arc vs.
conformal fixed beam
Noncoplanar circular arc vs.
conformal fixed beam
Noncoplanar circular arc vs.
conformal fixed beam
Noncoplanar circular arc vs.
IMSRT
Noncoplanar circular arc vs.
IMSRT vs. conformal fixed beam
Noncoplanar circular arc vs.
conformal fixed beam vs. IMSRT
Noncoplanar circular arc vs.
conformal fixed beam-IMSRT
DCA vs. IMSRS/IMSRT
3D conformal fixed beam vs.
DCA vs. IMSRT
Gamma Knife vs. Conformal
Fixed Beam vs. DCA
DCA vs. IMSRS
DCA vs. IMSRS
Patients (N) PTV (cm3) Results
NA NA Smaller high-dose volume and
better homogeneity for fixed
beam
1 3.5 Smaller high-dose volume and
better homogeneity for fixed
beam
2 4.5–9 Smaller high-dose volume and
better homogeneity for fixed
beam
11 0.4–17.6 Lower doses to normal tissues
and shorter planning time for
fixed beam
1 NA Better CI, lower max. Dose,
better HI, but larger penumbra
in IMSRT
3 9.6–36.7 IMSRT: better CI, lower dose
to normal brain than others
3 11.5 Depending upon shape: IMSRT
better conformity and OAR-
sparing (irregular) or arcs better
(ellipsoid)
4 2.3–3.5 IMSRS: lower dose to OAR,
lower volume normal brain
receiving >50 % of prescr. Dose
3 8.7–55 Lower dose to OAR in IMSRS/
IMSRT
50 Large volumes, no SRS DCA: best conformity, lower
dose to normal tissues than
conformal beam but not IMSRT
8 0.3–10.6 Gamma Knife: best conformity,
fixed beam and arc : better
homogeneity
10 15–43 IMSRS: better coverage and
lower OAR dose, but higher
low-dose regions in the normal
brain
6 1.1–10.4 IMSRS: lower volume of
normal brain receiving >90 %
of PD but higher integral dose.
RTOG criteria best met by DCA

Table 38.1 summarizes the evolution of techniques with

their inherent advantages and disadvantages in the form of a
literature review; initially, static beams showed superior con-
formality compared to circular collimator arc treatment [14].
Perks et al. showed that more beams don’t necessarily trans-
late into better normal brain sparing as four to six noncopla-
nar beams yielded similar results as plans using up to 30
fields [15]. Then followed the next level of conformality in
the form of DCA therapy, where the beam is continually
MLC-shaped during gantry rotation [16]. Most recently,
IMSRS has been shown to offer superior treatment volume
(PTV) coverage and lower OAR doses for irregular and con-
cave targets [11].
Dose Limitations at the Skull Base
Radiosurgery in the region of the skull base poses special
challenges, as many critical structures converge there,
most notably the optic apparatus and cranial nerves.
Table 38.2 summarizes the current data from literature,
which can assist in determining the feasibility of radiosur-
gery itself or a given plan. We cannot emphasize enough
that these data are to be used with utmost caution as, with
exception of the RTOG 90–05 data, they are not the result
of dose escalation or randomized trials but stem originate
mostly from retrospective clinical outcome data, with not
38 Skull Base Tumors 485

Table 38.2 Summary of radiosurgical tolerance doses at the base of skull

Organ # fx Vol. cm3 Vol. % Vol. limit (Gy) Max. limit (Gy)
Major vessels 1 0.035–10 31–37 37
3 5–10 21–39 45
4 1–10 35–43 49
5 10 47 53
Pituitary gland 1 NA
Brainstem 1 1 10 15
3 1 18 23
5 1 26 31
5 100 20
Brain 5 100 20
Chiasm 1 8–15 10 Gy safe → 77 % chance
of RON above 15 Gy
3 0.2 15
5 0.2 100 20 25
Cranial nerves 1 20–30 Fifth cranial nerve 20 Gy max
Cochlea 1 12
3 20
5 27.5
Lens 1 2–3
2 3–6
3 3–7
5 3–7
Retina and lacrimal gland 1 5
2 5–10
3 5–15
5 5–15
Neurovascular bundle 5 20–50 38
Optic nerve 1 8–15
2 10
3 0.2 15 19.5
5 0.03–0.5 12.5–25 25–30
Area postrema 6.2
Adapted from Grimm J, LaCouture T, Croce R, Yeo I, Zhu Y, Xue J. Dose tolerance limits and dose volume histogram evaluation for stereotactic
body radiotherapy. Journal of Applied Clinical Medical Physics/American College of Medical Physics. 2011; 12(2): 3368; (open source journal)

only limited long-term outcome data but also small patient
collectives.
From these data, one can surmise that the most critical
structures are the optic pathways. The risk of clinically sig-
nificant radiation optic neuropathy for patients receiving
SRS for skull base tumors is 1–2 % following doses to optic
chiasm below 10 Gy and this percentage may significantly
increase for higher doses [17, 18]. Leber et al. reviewed 50
patients having SRS for benign skull base tumors in which
the optic nerves or chiasm were exposed to 4.5 Gy or more.
For patients receiving 10–15 Gy and greater than 15 Gy, the
risk of radiation-induced optic neuropathy was 26.7 % and
77.8 %, respectively, however no optic neuropathy was
observed when a dose less than 10 Gy was delivered to the
optic apparatus [19]. Stafford et al. found that the risk of
developing a clinically significant optic neuropathy was
1.1 % for patients receiving a maximum point dose of 12 Gy
or less [20] and similar results have been reported by others
[21]. Considering an effective dose of 13–16 Gy to achieve
local control of a given tumor and a recommended dose of
8 Gy as the maximum for the optic chiasm this means that in
clinical practice a distance between tumor margin and optic
apparatus should be at least of 2–3 mm to avoid visual
deterioration.
The auditory apparatus is second in line with 12–15 Gy
SRS tolerance using a single fraction or 18 Gy in three frac-
tions. Then follows the trigeminal nerve and finally the motor
cranial nerves [2, 4, 6, 7, 9–12] which have rarely been
reported having a deficit using doses under 16 Gy.
Considering these data and published risks of optic neu-
ropathy for conventionally fractionated radiotherapy,
α/β[alpha/beta] ratios in the range of 0–1 seem reasonable
for estimating radiosurgery dose equivalents for optic and
cranial nerves.
486
Re-irradiation at the Skull Base
This often represents a relatively high-risk treatment, as criti-
cal tolerance doses have usually been applied in the first
course of treatment. Historically, most radiation oncologists
have refused re-irradiation due to concern about the risks of
late central nervous system toxicity, especially radionecro-
sis, which may appear several months to years after treat-
ment. Re-irradiation of brain tumors has recently attracted
more interest as our understanding of the tolerance of the
brain to radiation evolves, and developments in radiation
technology and imaging make highly accurate targeting of
biologically relevant tumor volumes possible. Prospective
data addressing this approach is however lacking.
Obviously, the applicable doses depend to large extent on
time since initial treatment, treatment volume, fractionation
used and location as well as individual factors such as histol-
ogy, location, and imminent danger to the patient, so that
individual recommendations are well beyond the scope of
this book.
However, it seems reasonable to apply the same rationale
to re-irradiation in the base of skull regions as is applicable
to the brain itself; own and other published clinical experi-
ences have yet to describe any major untoward effects of
such re-irradiation if certain radiobiological principles are
followed:
Although available data come mainly from animal spinal
models, the pathogenesis of radiation toxicity and recovery
potential in the brain is assumed to be similar with a similar,
low α/β[alpha/beta] [22]. Animal spinal cord models suggest
that significant recovery follows irradiation; conservative
estimates being up to 50 % recovery within 1–2 years after
initial exposure [23, 24]. An increasing body of evidence is
available (mainly for re-irradiation of gliomas) resulting in a
solid clinical rationale should re-irradiation be required. But
there may also be a case to be made for repeat radiosurgery
in the base of skull region, i.e. for acoustic neuromas [25].
In summary, re-irradiation at the skull base remains a
complex procedure and should be left to centers with exten-
sive experience herein. With developments in molecular-
targeted therapy, further exploration of the role of
re-irradiation on its own or in combination with novel agents
is needed.
Clinical Entities
Skull base tumors are relatively rare. Approximately 0.1 %
of all intracranial tumors are chondrosarcomas and also
approximately 0.1 % of all intracranial tumors are chordo-
mas. For benign tumors of the skull base such as glomus
R.A.J. Sweeney and M. Guckenberger
tumors, local control rates of 90–100 % have been reported.
On the other end of the spectrum, local control rates for chor-
domas range from 50 to 70 %.
On the following pages, the radiosurgical options for
primary malignant and benign skull base tumors will be
discussed.
Angiofibroma
Disease Pathophysiology
Juvenile angiofibroma is one of the most common benign
nasal tumors affecting males between 9 and 19 years of age
accounting for 0.05 % of all head and neck tumors [26]. In
the USA it is the most common Head and Neck tumor of
adolescence [27]. The tumor originates from the broad area
of the posterolateral wall of the nasal cavity in the region of
the sphenopalatine foramen [28]. The etiology is still unclear,
however recent electron microscope studies suggest it is
rather a vascular malformation, possibly associated with
incomplete regression of the first brachial artery, than a
tumor [29]. They often act in a malignant manner by eroding
into the surrounding sinuses developing an aggressive growth
pattern. Intracranial extension is noted in 10–20 % of cases.
Different staging systems based on tumor extension have
been proposed [30].
Typical clinical symptoms are frequent epistaxis, nasal
obstructions, and rhinorrhea. Chronic rhinosinusitis, swell-
ing of the cheek, alteration of olfaction are possible; unilat-
eral otitis media may result by eustachian tube blockage. By
eroding into the cranial fossa, diplopia may occur as well as
symptomatic pressure of the chiasm and optic nerves.
Treatment Options
After CT/MRT and bilateral angiography for staging and
determination of blood supply, treatment of choice in
patients with primary and recurrent juvenile nasopharyn-
geal angiofibroma is surgical resection as sole treatment of
early-stage tumor when gross total resection can be
achieved. Preoperative embolization is recommended by
most authors to reduce intraoperative blood loss [31]. In the
last decade, endoscopic resections have evolved, providing
reduction of complications and intraoperative bleeding and
thus an alternative to open surgery for early to intermediate
stage angiofibromas [30]. Complications in advanced-stage
angiofibromas after surgery include intraoperative blood
loss requiring transfusions, neuralgia, hearing loss, and
ophthalmoplegia [32]. Surgical contraindications include
unresectable intracranial involvement.
38 Skull Base Tumors
After primary resection of extracranial angiofibromas,
cure rates of nearly 100 % can be achieved compared with
results in patients with intracranial lesions where the cure
rates are approximately 70 %.
In case of incomplete resection, or in advanced-stage
lesions, a combination of surgery followed by radiotherapy
is indicated due to the high recurrence rate in these patients.
Advanced-stage disease with cranial base involvement and
intracranial extension often allows only subtotal resection of
the tumor.
External beam irradiation has been shown to be a useful
adjunct to therapy in patients with unresectable recurrent dis-
ease. Gamma Knife and linac-based radiosurgery with a
dose of 20 Gy to the tumor margin (55 % isodose line) is an
effective way to deliver high-dose radiation to incompletely
resected angiofibromas [32] as they represent slow-growing
and late-responding tissues. Therefore, a radiobiological
advantage to radiosurgery may be given. Radiosurgery is
regarded as a reasonable strategy in small-volume and local-
ized angiofibromas.
For larger angiofibromas, fractionated conformal radiation
therapy with total doses of 36–46 Gy is also effective and
may reduce the risk of late effects such as cranial nerve defi-
cits, bone and soft tissue necrosis. Another treatment tech-
nique described in the literature is the use of intensity-modulated
radiation therapy (IMRT) in three cases [33]. The applied
tumor dose varied from 34 to 45 Gy. In all three cases, a
reduction of tumor size occurred without significant toxicity.
Especially in children, inhibition of facial bone growth and
second malignancy are severe possible side effects and must
be considered in treatment decisions [34–36].
Esthesioneuroblastoma
Disease Pathophysiology
Esthesioneuroblastomas are rare tumors originating from the
olfactory epithelium of the upper nasal cavity [36]. The sex
distribution of esthesioneuroblastomas is uniform. The olfac-
tory nerves perforate the groove in the ethmoid bone in the
cribriform plate and continue into the subarachnoid spaces.
Therefore, a high incidence of intracranial extension results.
This highly dedifferentiated tumor occurs in all periods of
life with a bimodal peak at the second and sixth decades.
The two most common clinical signs of esthesioneuroblastoma
constitute unilateral nasal obstruction and epistaxis. Other
clinical symptoms include headache, swelling of the cheek,
blurred vision, and dental pain. Esthesioneuroblastoma can
metastasize to regional lymph nodes, primarily of the neck
[37] lung, or bones. According to the WHO classification
system, the terms olfactory neuroblastoma and olfactory
neurogenic tumors are used. The Kadish staging classifica-
tion is shown in Table 38.3.
487
Table 38.3 Staging of esthesioneuroblastoma according to Kadish et al.
Stage Characteristic
A Confined to the nasal cavity
B Confined to the nasal cavity and one or more
paranasal sinuses
C Extending beyond the nasal cavity or paranasal
sinuses, including involvement of the orbit,
base of skull or intracranial cavity, cervical
lymph nodes or distant metastatic sides
From Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma.
A clinical analysis of 17 cases. Cancer. 1976; 37(3): 1571–6; used with
permission
Rationale for Treatment and Alternatives
Because of the rarity of esthesioneuroblastoma and its wide
variety of clinical behavior, there is no definitive consensus
regarding the optimal treatment. For small, low-grade tumors
confined to the ethmoids, surgery alone appears to be an
adequate method. Patients with locally advanced disease or
high-grade tumors should receive aggressive treatment with
combined modalities such as surgery, radiation therapy, and
chemotherapy [38]. Most authors recommend en bloc resec-
tion, combined with radiation therapy [39, 40]. Local failure
rates of 44 % in low-grade and 60 % in high-grade tumors
and metastatic rates of 25 % in low-grade and 47 % in high-
grade tumors are described [41]. A significantly lower recur-
rence rate with overall 5- and 10-year survival rates of 81 and
54.5 % in patients with response to neoadjuvant radiotherapy
combined with chemotherapy has been reported [42]. At
recurrence, either surgical and/or radiosurgical retreatment
can lead to long lasting remissions in 42 % of patients [43,
44]. Thus close follow-up is recommended.
Radiosurgery for Esthesioneuroblastoma
Very few studies report on radiosurgical treatment in the pri-
mary situation; the limiting factors are usually the radiosen-
sitivity of cranial nerves as discussed in Table 38.1.
Walch et al. [45] reported on three patients with olfactory
neuroblastoma treated with a combination of endoscopic sur-
gery and Gamma Knife. Stereotactic radiosurgery was per-
formed within the first 3 months of surgery. The maximum
diameter of the tumors was approximately 24.3 mm and the
marginal dose to the tumor varied from 16 to 34 Gy; 1–5 iso-
centers were used. Radiation-induced side effects were nasal
discharge and crusts. One patient developed bilateral frontal
chronic sinusitis, and in a second, endoscopic operation was
necessary.
An Austrian group described the combined treatment
of endoscopic surgery and radiosurgery for olfactory
neuroblastoma [46]. Median marginal doses ranged from
15 to 34 Gy at a marginal isodose between 45 and 85 %.
488
The maximum tumor volume treated with radiosurgery was
approximately 20 cm3. The median follow-up period was 58
months. Observed radiosurgical side effects were mild and
transient, such as cephalea and dizziness. No changes in
mental status were observed. No new pathology of the optic
pathway was described during follow-up.
IMRT is recommended for larger and more complex-
shaped Esthesioneuroblastoma [40]. However also here, the
required conventionally fractionated doses of 50–60 Gy
(postoperatively) or 65–70 Gy required for inoperable cases,
the challenge remains similar [47, 48].
Craniopharyngioma
Disease Pathophysiology
Craniopharyngiomas are benign tumors located at the base of
the skull next to the pituitary gland. Differentiation
between craniopharyngioma and pituitary can therefore
sometimes be difficult on CT or magnetic resonance (MR)
scans. Approximately 5–10 % of primary brain tumors are
craniopharyngiomas. They typically occur in childhood as
well as in the sixth to eighth decades [29]. Histopathologically,
craniopharyngiomas are benign tumors arising from squa-
mous cell remnants of the Rathke pouch during embryo-
genesis at the junction of the pituitary stalk and pituitary.
Craniopharyngiomas present as a suprasellar lesion, fre-
quently partially calcified and usually including an intrasellar
component. These tumors are often composed of solid and
cholesterol-rich cystic components. Cystic or solid compo-
nents of this tumor extension may occur laterally into the
middle or into the posterior cranial fossa. Symptoms relate to
compression effects of the tumor due to its vicinity to pitu-
itary gland, chiasm, optic nerves, and hypothalamic region.
Locally, these tumors can produce signs and symptoms of
increased intracranial pressure such as headache, drowsiness,
or vomiting at the time of diagnosis and are due to hydro-
cephalus by obstruction of the foramen Monro by tumor parts
Table 38.4 Review of the literature for radiosurgery of craniopharyngioma
Author N Median follow-up (range)
Chung et al. [64] 31 33 months (5–69)b
Mokry [65] 23 23 months (6–57)
Ulfarsson et al. [67] 21 42 months (6–348)b
Kobayashi et al. [68] 98 66 months (6–148)
Iwata [62] 44 40 (12–92)
a
Crude local control rates
b
Median values
c
Given in maximum dose
R.A.J. Sweeney and M. Guckenberger
within the third ventricle in 55–85 % of the patients [49].
Compression of the pituitary and hypothalamic region can
produce antidiuretic hormone and growth hormone deficiency
or obesity in children. Diabetes insipidus is present in approx-
imately 10 % of the patients. Visual field defects and decreased
vision due to compression of the optic chiasm and optic path-
ways are the initial symptoms in approximately 40–60 % of
these patients [50, 51] (Table 38.4).
Rationale for Treatment and Alternatives
The main treatment modality for craniopharyngiomas is
surgery. Microsurgery allows complete tumor removal in
49–100 % of the patients with low morbidity and operative
mortality [52–54]. After radical resection, 10-year
progression-free survival rates between 60 and 93 % are
reported [55, 56]. Treatment modalities include complete
resection of the tumor with radiation therapy at the time of
recurrence or subtotal resection followed by radiotherapy.
The probability of complete tumor resection decreases
with increasing tumor volume. Because of the proximity to
critical normal structures and the relatively high associa-
tion of radical surgery with visual loss and impaired hor-
mone function requiring replacement therapy, many
authors recommend less radical surgery (partial resection,
biopsy, and aspiration of cystic contents) followed by radi-
ation therapy or radiosurgery. With this strategy, local con-
trol rates of 70–83 % after 10 years are reported [57, 58]
and assumed to be similar to complete surgical resection of
the tumor [59]. Treatment-related toxicities after subtotal
resection followed by radiotherapy include impairment of
hormone function. Impairment of vision is reported for
less than 10 % of all patients treated with the combination
of subtotal resection and irradiation compared with up to
20 % after complete tumor resection [60]. Other side
effects such as radionecrosis, radiation-induced malignan-
cies, vascular morbidity, and cognitive decline occur less
frequently [60, 61].
Mean peripheral
dose (range) Local control (%)a Morbidity
12.2 Gy (9.5–16) 87.2 Visual field deficit (1 patient)
10.8 Gy (8–15) 78.2 None
30 Gy (20–50)c 36.4 Visual field deficit (8 patients)
11.5 Gy (NA) 79.5 Visual/endocrine (6 %)
13–25 Gy (1–5 85 Hypopituitarism (1 patient)
fractions)
38 Skull Base Tumors
The major goal of radiotherapy treatment strategies is
sparing of critical normal structures. Radiosurgery as well as
intracavitary irradiation with stereotactically applied β[beta]-
emitting radioisotopes maximize normal tissue sparing. The
cystic nature of craniopharyngioma has led to trials of intra-
cystic applications of β[beta]-emitting radioisotopes such as
yttrium-90 or phosphorus-32. The use of radiosurgery has
been reported in patients with minimal residual or recurrent
disease. However, for patients with larger target volumes,
tumors immediately abutting the optic apparatus and multi-
ple cystic configured lesions, fractionated stereotactic radio-
therapy should be preferred as excellent local control with
minimal morbidity can be realized [62, 63].
Treatment Planning and Results
for Radiosurgery
The target volume for craniopharyngiomas is narrowly
defined to the tumor volume, including solid and cystic com-
ponents. In cases with cyst aspiration or subtotal resection, it
is important to cover the complete cyst wall. This technique
can be used for selected patients with smaller tumors (<2 cm)
not abutting critical structures such as the chiasm and the
brain stem. Median doses to the margin of the tumor range
from 9 to 16 Gy. Chung et al. recommend a margin dose of
12 Gy to induce satisfactory tumor response [64]. The main
restriction with radiosurgery treatment is the tolerance dose
of the neighboring visual pathway. The dose to the optic
nerves and the chiasm should be kept below 8 Gy with
single-dose techniques to avoid damage to these structures.
Stereotactic radiosurgery has been used to treat small resid-
ual or recurrent tumors after surgical intervention.
Mokry et al. [65] treated 23 patients with Gamma Knife
radiosurgery for craniopharyngioma and found no relevant
morbidity. Ten patients had additional therapy with intracys-
tic bleomycin before radiosurgery. Tumor progression was
observed in 5 of 23 patients. They conclude that the best
results might be obtained in monocystic tumors amenable to
stereotactic drainage and intracystic bleomycin treatment.
The Cologne group of Kickingrieder et al. summarizes their
results on 53 patients with cystic craniopharyngiomas treated
with stereotactically applied colloidal β-emitting radioactive
sources. They concede few but notable severe side effects
(hemiparesis and third nerve palsy) as well as suboptimal
progression-free survival (79.4 ± 6.1, 72.4 ± 6.8, and
45.6 ± 8.7 % at 12, 24, and 60 months, respectively) [66].
After an average follow-up of 36 months, Chung et al.
reported a tumor control rate of 87 % for 31 patients treated
with Gamma Knife radiosurgery and a prescribed dose to
the tumor margin from 9.5 to 16 Gy [64]. One patient devel-
oped a mildly restricted visual field. None of the patients
showed additional endocrinologic impairment or neurologic
489
deterioration related to radiosurgery. In a Swedish study,
21 patients were treated with Gamma Knife radiosurgery.
They found a statistically significant difference between
tumor progression and applied dose; a higher progression
rate was found in patients treated with less than 6 Gy to the
margin than in patients treated with a dose higher than 6 Gy.
Four of these patients developed pituitary dysfunction [67].
In the literature, parenchymal injuries of the brain or second
malignancies caused by radiotherapy are estimated to be
less than 1–2 % [68].
Chordomas, Chondromas,
and Chondrosarcomas
Disease Pathophysiology
Chondromas are rare benign tumors arising at the base of the
skull, especially in the area close to the pituitary gland. It is
a very-slow-growing tumor and might be present for a long
time before causing any symptoms. Chondromas are com-
posed of cartilage formed by the meninges and is usually
attached to the dura mater. Surgical intervention might be the
treatment of primary choice because of their usually well-
defined margins.
Chordomas are relatively rare, slow-growing, primary
bone tumors arising from embryonic remnants of the noto-
chord (chorda dorsalis) at the two extreme ends of the verte-
bral axis. They are most often diagnosed in the second or
third decade of life, more common in males (2:1) and com-
prise less than 1 % of intracranial tumors [69, 70]. Twenty
five to forty percent of chordomas occur in the spheno-
occipital or skull base region. The clivus is the most common
site. Chordomas are locally more aggressive with a poorer
outcome compared with chondrosarcomas.
Chondrosarcomas are malignant tumors composed of
cartilage-producing cells encountered in the skull base. Two
histologic variants of chordoma have been described. The
first is chondroid chordoma, a typical chordoma that also
contains areas resembling low-grade hyaline chondrosar-
coma. The second variant is dedifferentiated chordoma,
which contains areas of typical chordoma mixed with com-
ponents that resemble high-grade or poorly differentiated
spindle cell sarcoma. Chondrosarcomas rarely metastasize,
are slow-growing but often invade local structures. Prognostic
factors that most influence choice of treatment are location,
local tumor extension, and surgical resectability.
Approximately 0.1 % of all intracranial tumors are chon-
drosarcomas. This locally invasive tumor is a malignant vari-
ant of a benign chondroma arising from bone and is composed
of cartilage.
Chondrosarcomas are mostly located in the sphenoid
bone or clivus. Chondrosarcomas are also more common in
490 R.A.J. Sweeney and M. Guckenberger

Table 38.5 Radiosurgical literature on chordoma and chondrosarcoma

Median
Median follow-up peripheral dose
Author N (range) in Gy (range) Local control* (%) Morbidity Comments
Krishnan et al. [107] 4.8 years (0.8–11.4) 15 (10–20)
Chordoma 25 32‡ 34 % (all with
combined EBRT)
Chondrosarcoma 4 100
Feigl et al. [82] 17 months (6–36)† 17 (14–18)†
Chordoma 3 33 Cranial nerve deficits,
headaches, diplopia
Chondrosarcoma 10 100
Pamir et al. [89] 23.3 months (NA)† NA 29 NA
Chordoma 7
Chang et al. [108]§ 4 years (1–9)† 19.4 (18–24)†
Chordoma 10 80‡ None
Hauptman et al. [85] 5 4.5 years 15.5 (to 90 % 60 Cranial neuropathy,
isodose line) visual deficits
Koga et al. [84] 14 65 months (12–167) 15 (10–20) Local relapse in all cases
of Radiosurgery after
fractionated xRT, Marginal
doses of >16 Gy crucial
Chordoma 10 40.5 (12–167) months 13.7 (10–20) 15 1 transient visual
deficit
Chondrosarcoma 4 20 (45–145) months 15.5 (12–20) 100 1 transient visual
deficit
Martin et al. [109] 7.7 years (2–17) 16.5 (10–25)
Chordoma 18 88 months 62.9‡ 1 transient effect
Chondrosarcoma 10 88 months 80‡
Hasegawa et al. [110] 59 months (1–172) 14 (9–20) 80‡ 1 worsening of facial Under 20 mL volume sig.
numbness better LC, at least 15 Gy
marginal dose required
Chordoma 30 0.72
Chondrosarcoma 7

males than in females (1.5:1). They can be classified into
three grades (I–III). Lower-grade tumors are less aggressive
and act clinically similar to chordomas. Historically, skull
base chordoma and chondrosarcoma were often pooled
together in reported series due to the rarity of these tumors;
however, recently published studies have shown important
differences with respect to diagnosis, treatment, and progno-
sis, strongly suggesting a more aggressive therapy for chor-
domas than chondrosarcomas [71] (Table 38.5).
Rationale for Treatment and Alternatives
Treatment of choice is total surgical resection, if feasible,
followed by radiation therapy. The best results in the treat-
ment of chordomas have been obtained by complete surgi-
cal resection followed by high doses of proton irradiation
[72]. Complete resection of these tumors at the skull base is
challenging and associated with higher rates of morbidity
and mortality. Furthermore, it is difficult to treat skull base
chordomas and chondrosarcomas with radiotherapy alone
because of the large tumor size, the extent of infiltrated tis-
sues, and because of dose limitations imposed by the sensi-
tivity of adjacent critical normal tissues such as the brain
stem and cranial nerves [73]. Frequently used fractionated
doses are 55–66 Gy. A clear dose-response relationship with
improved outcomes after doses exceeding 60 Gy have been
shown in chordomas [74]. Similar effects have been shown
with radiosurgery with better results after marginal doses
>15 Gy [73]. Because of the slow proliferative nature of
chordomas, high linear energy transfer may be useful. To
yield good results with respect to local tumor control, high-
dose radiation therapy with photons combined with proton
beam boost [75, 76] or particle therapy alone [77, 78], are
reported. Heavily charged particles such as protons or car-
bon ions may be superior because of their finite range in
tissues. This radiation technique offers an excellent chance
of cure with acceptable radiation-induced toxicity. However,
38 Skull Base Tumors
IMRT has also shown its effectiveness [79], so that the final
verdict may ultimately require long-term results from a ran-
domized trial.
Radiosurgery for Chordomas
and Chondrosarcomas
There is a strong argument for radiosurgical treatment of
chordomas and chondrosarcomas to reduce the incidence of
brain or bone necrosis in smaller circumscribed post-surgical
tumor-remnants. In literature, lesions with a diameter of less
than 30 mm were treated with 17–20 Gy to the tumor margin
[73, 80, 81].
Kondziolka et al. [73] reported on four patients with chor-
doma and two patients with chondrosarcoma treated with
radiosurgery. All tumors were less than 30 mm in diameter
and were treated with 20 Gy to the tumor margin. During a
mean follow-up of 22 months (range, 8–36 months), no in-
field progression was seen. Three patients showed improve-
ment of preexisting neurologic deficits. The other three
patients remained in stable neurologic condition. Serial fol-
low-up imaging studies showed tumor volume reduction in
two patients, whereas the other four patients showed stable
tumor size. One patient showed tumor progression outside
the irradiated tumor volume. In the study of Feigl et al., 13
patients with chordoma and chondrosarcoma were treated
with Gamma Knife radiosurgery after maximal tumor resec-
tion [82]. The mean treated tumor volume was 9.7 cm3 (range
1.4–20.3 cm3). The mean treatment dose was 17 Gy and the
mean marginal isodose was 52 %. After a mean follow-up of
17 months, only one recurrence of disease was seen at the
margin of the radiation field. Pamir et al. reported on 26 skull
base chordomas with a mean follow-up period of 48.5 months
receiving multimodality treatment with various combina-
tions of conventional surgery, skull base surgical techniques,
and Gamma Knife surgery [83]. The mean follow-up after
Gamma Knife treatment was 23.3 months. They recommend
Gamma Knife radiosurgery immediately after initial surgical
intervention if the tumor volume is less than 30 cm3. This
suggested treatment algorithm of Pamir and colleagues is
shown in Fig. 38.1.
Interesting results were published by the Tokyo group by
Koga et al. [84] on ten chordoma and four chondrosarcoma
patients with tumor volumes at radiosurgery ranging from
3.4 to 55.5 cm3. Four chordoma patients received radiosur-
gery with lower marginal doses (12 Gy) after 60 Gy fraction-
ated radiotherapy. All four patients recurred locally. One
chondrosarcoma patient receiving 12 Gy marginal dose
recurred locally. Five-year PFS rates for patients with higher
and lower marginal doses were 80 % and 14 % respectively
(p = 0.0005). The authors conclude that a marginal dose of at
least 16 Gy is required for local control.
491
Chordomas
Skull base approaches
Surgical intervention
No residual tumors Residual tumors
Follow-up <30 CC >30 CC
Radiosurgery as Radiosurgery Consider
soon as recurrence Re-operation
detected
Fig. 38.1 Radiosurgical management algorithm for skull base chordomas
according to Pamir et al. [83]. Should re-operation not be possible,
high-dose particle beam therapy or IMRT should be recommended
Glomus Jugulare Tumors/Chemodectoma/
Paraganglioma
Disease Pathophysiology
Glomus jugulare tumors are rare, radiosensitive tumors of
the skull base/neck regions, slow-growing, hypervascular,
and histologically benign. They comprise 0.6 % of all tumors
and are closely associated with the sympathetic system, aris-
ing from the paraganglia of the chemoreceptor system. Thus,
chemodectoma and paraganglioma are frequently used syn-
onyms. Due of their tendency to invade and compress adja-
cent tissues, local problems can evolve.
Typical clinical symptoms are gradual hearing loss, uni-
lateral pulsatile tinnitus, or imbalance.
Familial as well as multilocal/bilateral occurrence is pos-
sible and should be excluded by MRI of the skull base and
neck (Fig. 38.2).
These tumors can show metabolic activity on PET/SPECT
which may change disease management [85]. Malignant
transformation rates are rare (2–5 %) with metastatic spread
to lung, liver, and bone [86, 87]. Because of their slow
growth, up to 10 years of follow-up is necessary to establish
a cure rate for these lesions [88].
Rationale for Treatment and Alternatives
The treatment options for glomus jugulare tumors include sur-
gery, radiosurgery, radiotherapy, and endovascular occlusion
of feeding vessels either in combination or alone [89–91].
492 R.A.J. Sweeney and M. Guckenberger

Fig. 38.2 This right sided incidental jugular glomus tumor was sided glomus tumor at the level of the carotid bifurcation.
detected on 99mTc-octreotide SPECT imaging (bottom in fusion with Retrospectively, it is quite obvious in MRI
MRI) after being missed on both CT (top) and MRI (middle) for a left

Embolization alone does not prevent further tumor progression are based on the patients’ comorbidities. Surgical resection of
[92]. Surgical resection is the only treatment option that glomus jugulare tumors carries a high complication rate,
can offer immediate and complete tumor elimination. due to their high vascularity and the involvement of critical
Contraindications to surgical intervention of skull base tumors vascular and neuronal structures, which included stroke,
38 Skull Base Tumors 493

cranial nerve injury with 8–40 %, and an overall mortality rate
of 5–13 % [93]. Compared with radiosurgery, fractionated ste-
reotactic radiotherapy may reduce the risk of radiation-induced
side effects providing additional radiobiologic sparing and
should be recommended for larger tumors or those, which
cannot be precisely defined by imaging.
Patient Selection for Radiosurgery
and Treatment Planning Details
For radiosurgical techniques, the prescribed dose to the
tumor margin ranges from 12 to 25 Gy with typical doses
greater than 20 Gy for small- to medium-sized tumors but
lower doses to larger tumors due to an increased risk of
radiation-induced side effects [82, 83, 94]. Median tumor
volumes of glomus tumors should be less than 10 cm3
because of the possible increased risk of radiation-induced
cranial nerve deficits due to the radiosensitivity of cranial
nerves. On the other hand and in analogy to excellent control
rates after only 45–50 Gy in fractionated radiotherapy [95]
12 Gy single fraction or 25 in 5 Gy fractions [96] likely suf-
fice, especially in critical locations.
Review of the Literature
For well-defined and noninfiltrating glomus jugulare tumors,
stereotactic radiotherapy should be particularly beneficial.
They usually present in a small size due to their proximity to
cranial nerves whose dysfunctions often herald the presence
of the tumor. The steep dose gradient achievable with radio-
surgery minimizes the irradiation dose to surrounding nor-
mal tissue. Whereas diagnostic imaging techniques have
been much improved within recent years, they cannot reli-
ably separate tumor from adjacent cranial nerve when target-
ing radiosurgery treatment. Because of the close proximity
of glomus tumors to cranial nerves, permanent cranial nerve
deficits are possible side effects of radiosurgery. Most pub-
lished studies reported only transient dizziness or occasional
hearing loss (Table 38.6).
Jordan et al. [82] reported on eight patients treated with
Gamma Knife radiosurgery between 1990 and 1998. The
mean tumor volume of these patients was 9.8 cm3 (range,
17.3–4.3 cm3). The mean applied marginal dose was 16.3 Gy
(range, 12–20 Gy). None of these patients developed delayed
cranial neuropathy or tumor progression during a mean fol-
low-up of 27 months.
Lim et al. [94] reported on ten patients treated with
radiosurgery, whereas four patients were treated with pri-
mary radiosurgery due to several comorbidities. The other
five had prior surgeries for their tumor. Tumor size ranged
from 1.2 to 3.6 cm at the largest diameter with an average
of 2.4 cm. Six patients were treated with a frame-based
linac system and four with the CyberKnife. Prescribed
dose to the 80 % isodose ranged from 16 to 25 Gy to the
tumor margin. After a median follow-up of 21.5 months,
nine patients had no change of tumor size, whereas one
patient showed tumor regression. Nine patients had stable
neurologic symptoms and only one patient experienced
transient ipsilateral tongue weakness and hearing loss
(Fig.38.3).

Table 38.6 Side effects of radiosurgery

Median peripheral
Author N Median follow-up (range) dose (range) Local controla Morbidity Comments
Jordan et al. [82] 8 27 months (9.7–102)b 16.3 Gy (12–20)b 1 Acute vertigo (1 patient)
Foote et al. [89] 25 37 months (11–118) 15 Gy (12–18) 1 Late vertigo (1 patient) 8 decreased in size
Eustacchio et al. 19 7 years (1.5–10) 14 Gy (12–20) 0.95 None
[111]
Maarouf et al. [83] 12 4 years (0.8–9) 15 Gy (11–20) 1 Moderate facial palsy (1 8 decreased in size
patient)
Liscak et al. [88] 52 24 months (4–70) 16.5 Gy (10–30) 1 Tinnitus (2 patients) Tumor size
decreased in 40 %
Gottfried et al. 142 39.4 monthsb 0.98 8.5 % morbidity
c
[112]
Pollock et al. [113] 42 44 (6–149 months) 14.9b( 0.98 15 % new deficits (4× hearing
loss, 2× vocal cord paralysis,
temporary imbalance/vertigo ×1
Hurmuz et al. [96] 14 39 months (7–60) 25 (18–30) (in 1 None Tumor regression
1–5 fractions) in 6
a
Crude local control rates
b
Mean values
c
Literature review
494 R.A.J. Sweeney and M. Guckenberger

Fig. 38.3 Treatment plan of a patient presenting with hearing deficit, vertigo and vocal cord paresis. MR imaging showed a left sided glomus
tumor treated radiosurgically with 17 Gy marginal dose (70 % isodose). After 24 months the tumor has shrunk, no new toxicity (courtesy of Dr.
A. Muacevic, CyberKnife Centre Munich)

After an observation period of up to 6.7 years, Saringer
and co-workers [90] reported on 13 patients with glomus
tumors treated with Gamma Knife radiosurgery. Three of
these patients showed tumor size reduction, whereas ten had
stable tumor volume. Clinical symptoms remained
unchanged in six, and six patients showed an improvement
of clinical symptoms. One patient failed the follow-up. Two
patients developed transient cranial nerve complications
(worsening of preexisting swallowing disorders and tempo-
rary facial nerve palsy 1 and 12 months after radiosurgery,
respectively).
The Mayo Clinic experiences were published by Foote
et al. in 2002 [97]. They described treatment outcome for a
total of 25 patients and long-term results for a cohort of 9
patients with a median largest diameter of 3.3 cm. No acute
neurologic toxicity was identified in all 25 patients. Only one
patient experienced clinically significant vertigo 8.5 months
after treatment. They observed no new or progressive neu-
ropathy of cranial nerves V–XII.
Recently, even clearer evidence for radiosurgery’s role
has been published in the form of a meta-analysis of 869
patients with glomus tumors. Subtotal resection (STR), gross
total resection (GTR), STR + postoperative radiosurgery and
radiosurgery alone were compared in terms of local control
and cranial neuropathy. Local control after radiosurgery was
significantly (p < 0.01) higher than the other groups. The
GTR patient group had higher rates of deficits than those
who underwent SRS alone. The authors concluded that
higher rates of morbidity are not associated with improved
local control rates, compared to radiosurgery [98].
38 Skull Base Tumors
Conclusion
It can be generalized in the base of skull region as well, that
when radiosurgery is limited to lesions that are 3 cm or less,
dose fall-off is sharp and only a small amount of normal
brain tissue receives a high radiation dose. At larger volumes,
the radiation fall-off into the surrounding normal tissue is not
as steep and the risk of delayed radiation-induced side effects
increases. Still, many patients with skull base tumors larger
than 30 mm can undergo radiosurgery safely because these
tumors are often in contact with the brain for only a portion
of their surface, and therefore, radiation fall-off occurs in the
bone, the sinuses, or the infratemporal or cervical regions.
For larger lesions and those located next to the optic path-
way, fractionated radiation therapy should be recommended
due to its radiobiological advantages.
However, in order to maximize radiosurgical benefits and
minimize its dangers, all highly precise radiation techniques
must be preceded by the integration of optimal imaging (see
Chap. 2) into the treatment planning process. This is espe-
cially challenging and critical in the base of skull region.
Whether chordomas and chondrosarcomas are better
treated with particles such as protons and/or ions is awaiting
clarification, ideally in the form of randomized studies.
Radiosurgery should be the considered treatment of choice
for smaller and well-defined glomus tumors due to minimal
morbidity compared to surgery as well as shorter treatment
times and better normal tissue sparing compared to fraction-
ated radiotherapy.
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 Skull Base Tumors: Viewpoint—Surgery
Richard F. Schmidt, Smruti K. Patel, Robert W. Jyung,
Jean Anderson Eloy, and James K. Liu
Introduction
Tumors of the skull base pose unique challenges to the
neurosurgeon. These tumors tend to extend throughout intra-
cranial and extracranial compartments and may invade or
compress surrounding neurovascular structures, causing sig-
nificant neurological deficits and making complete surgical
resection difficult. However, new technologies and advances
in surgical techniques have made many of these tumors more
surgically accessible, increasing the extent of tumor resec-
tion and offering the potential for a surgical cure. As a result
of developments in frameless stereotactic image guidance,
electrophysiological monitoring, modern microneurosurgi-
cal skull base techniques, and neuroendoscopy, neurosur-
geons now have the ability to access and remove a number of
these lesions with minimal manipulation and damage to sur-
rounding neurovascular structures, ultimately leading to
significant improvements in patient outcomes [1].
The primary goal of surgical intervention in symptomatic
patients with skull base tumors is decompression of neuro-
vascular structures. Many patients often present with sig-
nificant neurological deficits as a result of tumor compression
R.F. Schmidt, M.D. • S.K. Patel, M.D.
Department of Neurological Surgery, Rutgers New Jersey
Medical School, Newark, NJ, USA
R.W. Jyung, M.D.
Department of Otolaryngology-Head and Neck Surgery, Rutgers
New Jersey Medical School, Newark, NJ, USA
J.A. Eloy, M.D.
Departments of Otolaryngology-Head and Neck Surgery and
Neurological Surgery, Center for Skull Base and Pituitary Surgery,
Rutgers New Jersey Medical School, Newark, NJ, USA
J.K. Liu, M.D., Ph.D. (*)
Departments of Neurological Surgery and Otolaryngology-Head
and Neck Surgery, Center for Skull Base and Pituitary Surgery,
Neurological Institute of New Jersey, Rutgers New Jersey Medical
School, 90 Bergen Street, Suite 8100, Newark, NJ 07103, USA
e-mail: james.liu.md@rutgers.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_39, © Springer Science+Business Media New York 2015
39
of the cranial nerves and brain stem. Surgical resection
offers direct decompression of neurologic structures in
order to restore functionality or limit symptom progression.
However, due to the complex location and pathology of
skull base lesions, many of these tumors are treated with a
multidisciplinary approach catered toward the needs of the
individual patient. Stereotactic radiosurgery (SRS) has
evolved as a therapeutic option in many circumstances.
While the goals of surgery are tumor resection and decom-
pression of neurovascular structures, the primary goal of
SRS is tumor control. As such, this treatment can be used
either as a primary intervention for small, asymptomatic
benign tumors or as an adjuvant therapy to surgery in order
to optimize tumor control. Due to the risk of radiation-
induced complications, this treatment modality is typically
limited to treating lesions less than 30 mm, where dose fall-
offs can be steep enough to limit the effect on surrounding
structures. This is a particular concern for lesions near the
optic nerve and brainstem, as radiation can cause drastic
complications at these sensitive locations.
There is currently much controversy over the role of sur-
gery vs. radiosurgery for the primary management of a num-
ber of tumors at the skull base. Currently, the treatment
decision largely depends on a combination of factors such
as tumor location, tumor biology, involvement of adjacent
neurovascular structures, overall clinical status of the
patient, availability of the technology, and the training of the
neurosurgeon. Many benign lesions can be cured by surgical
resection. Moreover, surgical resection is favorable to
decompress larger symptomatic lesions because SRS alone
may not offer sufficient symptomatic improvement. For
malignant lesions or benign lesions with highly infiltrative
properties, surgery can offer both symptomatic palliation
and cytoreduction as part of a multimodality treatment plan.
Nevertheless, surgery and SRS are both important tools in
the armamentarium of the treatment team, and can ulti-
mately complement each other to achieve the optimal out-
come for the patient. For example, a petroclival meningioma
with cavernous sinus invasion might be best treated with a
499
500
subtotal resection to decompress the brainstem followed by
postoperative SRS for tumor control of the residual tumor in
the cavernous sinus.
This chapter will discuss the surgical considerations for
tumors of the skull base, both as an individual treatment and
as part of a multimodality treatment plan. Due to the wide
variety of pathological and anatomical considerations for
various skull base lesions, the surgical management is highly
variable across tumor types. As such, the specific surgical
considerations for a number of benign and malignant tumors
will be discussed, including trigeminal schwannomas, glo-
mus jugulare tumors, chordomas, chondrosarcomas, esthe-
sioneuroblastomas, craniopharyngiomas, and skull base
meningiomas. Since these tumors fundamentally differ on a
number of levels, discussion of their radiographic appear-
ance and pathological findings are out of the scope of this
chapter. Therefore, the discussion will focus primarily on
their clinical and anatomical presentation as well as the indi-
cations and outcomes of surgical intervention.
Surgical Considerations
While the tumors discussed in this chapter vary greatly, there
are a number of considerations that are universally applied
when addressing the surgical management of the skull base.
Primarily, the specific goals of the surgery should be dis-
cussed with the individual patient based on their age and
unique clinical presentation; there is no “one-size-fits-all”
method of treatment and the risk-to-benefit ratio of surgery
varies among individual patients. An asymptomatic, elderly
patient with multiple comorbidities presenting with a small,
benign tumor may not benefit from surgical resection because
of the relatively greater risk of morbidity associated with the
procedure and postoperative recovery. On the other hand, a
young patient with severe facial pain due to compression of
the trigeminal nerve by a large tumor would likely benefit
from surgical decompression and complete resection, if
safely possible. Furthermore, tumor adherence to surround-
ing neurovascular structures may prohibit safe complete
resection and is therefore an important consideration when
determining the extent of surgical resection. A tumor encas-
ing the basilar artery might be best managed by achieving a
subtotal resection to avoid complications of vascular com-
promise, opting for postoperative adjuvant radiation therapy
for further tumor control.
Because of the variability seen in tumor extension and
infiltration, it is also important that the surgeon be equipped
with as much information as possible both before and dur-
ing the surgery. Preoperative imaging is essential for
determining the appropriate surgical approach and minimiz-
ing the manipulation of critical structures. A typical preop-
erative work-up may include magnetic resonance imaging
R.F. Schmidt et al.
(MRI) to identify the pathology and its relationship to
important structures, computed tomography (CT) to evalu-
ate for tumor calcification or bony changes of the skull base,
and vascular imaging such as CT angiography/venography
(CTA/CTV), MR angiography/venography (MRA/MRV),
or digital subtraction angiography (DSA) to determine the
surrounding vascular anatomy and vascular supply of the
tumor and venous drainage patterns. Recently, intraopera-
tive electrophysiologic neuromonitoring and frameless ste-
reotactic navigation have also proven to be useful adjuncts.
Ultimately, the best surgical approach, extent of resection,
and use of adjuvant therapies should be thoroughly consid-
ered in the context of the individual patient’s clinical status
and surgical goals.
Trigeminal Schwannomas
Trigeminal schwannomas are relatively rare tumors,
accounting for approximately 0.07–0.5 % of all intracranial
tumors and 0.8–10 % of all intracranial schwannomas [2–6].
The emergence of microsurgical techniques and skull base
approaches has significantly improved the postoperative
outcomes for patients with these tumors. Since the late
1990s, rates of gross total resection (GTR) have consis-
tently ranged from 60 to 100 %, with the majority of large
case series reporting rates greater than 70 %. Furthermore,
recurrence rates have consistently decreased, occurring in
less than 19 % of patients who undergo surgery as a pri-
mary treatment [2–5, 7–10]. Currently, surgery remains the
standard treatment for most of these tumors, as GTR is
often curative.
Trigeminal schwannomas typically arise from the trigem-
inal nerve root, the Gasserian ganglion or one of the three
peripheral branches (V1–V3), making the clinical presenta-
tion, radiographic findings, and treatment of these tumors
highly variable [3]. They usually occur during the third or
fourth decade of life but may arise earlier in patients with
neurofibromatosis type II [4, 6]. The most common present-
ing symptom is altered facial sensation occurring in 50–91 %
of patients, which may range from pain to hypesthesias and/
or paresthesias [3–6]. It has been suggested that facial pain is
typically associated with tumors arising from the Gasserian
ganglion, whereas pain is frequently absent in tumors arising
from the nerve root [2].
For the purposes of treatment by surgical resection,
tumors are typically classified based on their location. The
most commonly used classification system was developed by
Jefferson [11], grouping tumors into four distinct classes
based on location. Type A tumors are located primarily in the
middle fossa and represent 25–55 % of cases. Type B tumors
are mainly situated in the posterior fossa, representing
11–50 % of cases. Type C tumors span both the middle and
39 Skull Base Tumors: Viewpoint—Surgery
posterior fossa, commonly referred to as “dumbbell tumors,”
and represent 14–40 % of tumors. Type D tumors are charac-
terized by extradural extension and are the least commonly
reported, comprising 6–13 % of tumors [2, 5, 11].
Recently, skull base approaches have replaced conven-
tional approaches to these tumors as a result of superior
long-term outcomes [3]. The advantages of these approaches
over conventional intradural approaches include better tumor
exposure, less brain retraction, and more complete removal
[3]. A number of approaches have been recommended for
accessing type A tumors, including frontotemporal transsyl-
vian, zygomatic infratemporal, and orbitozygomatic infra-
temporal approaches, with some studies advocating an
additional anterior petrosectomy for tumors with minimal
extension into the posterior fossa [2, 3, 5, 8, 10]. Type B
tumors are typically treated using a lateral suboccipital retro-
sigmoid approach, similar to that used for vestibular schwan-
nomas [2, 5]. Type C tumors tend to be the most difficult to
resect because they occupy both the posterior and the middle
fossa. As a result, numerous methods for accessing and
removing these tumors have been proposed, with little con-
sensus on which is most appropriate. These approaches
include a subtemporal, extradural-intradural approach with
anterior petrosectomy [7, 8], combined subtemporal presig-
moid/retromastoid approach [2], and a zygomatic middle
fossa approach, which avoids tentorial incision or anterior
petrosectomy by expanding Meckel’s cave [9]. Type D
tumors typically extend down the mandibular or maxillary
divisions of the trigeminal nerve through the foramen ovale
or foramen rotundum, respectively. These tumors usually
require more extensive approaches to access the pterygopal-
atine or infratemporal fossa. Thus, the orbitozygomatic
infratemporal and zygomatic infratemporal approaches are
most commonly used [2, 3]. An extradural subtemporal-
infratemporal approach through a preauricular-infratemporal
incision has also been proposed, as well as minimally inva-
sive endoscopic endonasal/transmaxillary approaches [5].
Tumors with cavernous sinus involvement are relatively
common and are typically treated with less aggressive resec-
tion, focusing instead on maximal preservation of vascular
structures and surrounding cranial nerves rather than com-
plete tumor resection [5].
While surgery is the treatment of choice for most of these
tumors, especially in cases of large tumors or those causing
significant symptoms, SRS is emerging as a potential treat-
ment option for many of these lesions. It is well known that
SRS is very useful in patients with incomplete surgical resec-
tion, tumor recurrence, or those who would not be able to
tolerate prolonged surgical procedures [4, 5, 12]. Recent
studies suggest that SRS may be useful in patients who are
poor candidates for surgery, have tumor that is tightly adher-
ent to vital structures, such as the brainstem or posterior
portion of the cavernous sinus [3], or even as a primary inter-
501
vention in small- to medium-sized tumors [12–15]. However,
it has been suggested that larger tumors (≥15 cm3) are more
likely to progress despite SRS [13]. Given these results and
recommendations, surgery continues to remain the method
of choice for most tumors, especially large, symptomatic
lesions.
Glomus Jugulare Tumors
Glomus jugulare tumors are an extremely rare group of
tumors representing 0.03 % of all intracranial tumors with
an incidence of approximately 1 per 1.3 million population
[16]. These tumors arise from the neuroendocrine chief cells
of the paraganglia, which are located in the adventitia of the
dome of the jugular bulb. Typically, these tumors are char-
acterized as benign, slow growing lesions that cause com-
pression of adjacent bone, cranial nerves, and blood vessels
by local infiltration and spread. Only about 1–5 % of glomus
jugulare tumors are malignant and exhibit metastatic spread
[17]. Due to their difficult anatomic location at the skull
base, hypervascularity, and advanced stage at diagnosis,
glomus jugulare tumors pose a formidable challenge for
neurosurgeons (Fig. 39.1). However, recent advances in
neuroimaging, microsurgical skull base techniques, and
radiation therapy have enhanced and improved the manage-
ment of these tumors. Currently, multiple modalities of
treatment for glomus jugulare tumors exist, including pri-
mary modes of treatment such as microsurgical resection
via various skull base approaches and SRS or adjunctive
treatments such as preoperative vascular embolization and
conventional external beam radiotherapy.
Microsurgical resection remains the treatment of choice
for glomus jugulare tumors [18, 19]. Early attempts at surgi-
cal resection of these tumors were fraught with poor tumor
control, high rates of recurrence, and significant morbidity
and mortality. As a result, over time, several approaches for
microsurgical resection of glomus jugulare tumors have
been described, either as single or staged operations. These
approaches include mastoid-neck [20], mastoid-neck with
limited facial nerve mobilization [20], infratemporal fossa
type A and B [20–27], posterior fossa [23, 24], subtemporal-
infratemporal [25], retrosigmoid [25], extreme lateral trans-
condylar [25], posterolateral [28], transmastoid-transcervical
[22], combined infratentorial and posterior fossa [29],
petro-occipital trans-sigmoid [30], combined transmastoid
retro- and infralabyrinthine transjugular transcondylar
transtubercular high cervical [31], infralabyrinthine retrofa-
cial [32], and various combined approaches.
The primary goal of the microsurgical management of
glomus jugulare tumors is curative GTR. Recent studies
have repeatedly shown excellent rates of GTR of these
lesions and surgical control rates have consistently remained
502
Fig. 39.1 (a, b) Preoperative T1-weighted post-gadolinium MRI (a axial
view, b coronal view) demonstrating a glomus jugulare tumor in the right
jugular foramen (white arrow). An extended far lateral transjugular infra-
high in numerous studies [32–34]. Surgical control rate (also
referred to as tumor control rate) is defined as complete
tumor elimination with no evidence of residual or recurrent
disease throughout the follow-up period, including patients
who have multiple surgeries. Recently, many studies have
been published that have corroborated this evidence. A sys-
tematic review of seven microsurgery case series with a total
of 374 patients showed 88.2 % GTR of tumors during the
initial surgery and a surgical control rate of 92.1 % [17, 20,
25, 27, 29, 30, 35]. A meta-analysis by Ivan et al. [34]
showed that GTR was achieved in 351 (81 %) of 433 patients
during the initial surgery for glomus jugulare tumors with an
86 % surgical control rate. In a retrospective study by Borba
et al. [32] of 34 patients who underwent microsurgery for
glomus jugulare tumors, GTR was achieved in 91 % with a
surgical control rate of 94.2 % [32]. In a more recent litera-
R.F. Schmidt et al.
temporal fossa approach was performed with gross total resection of the
tumor. (c, d) Postoperative T1-weighted post-gadolinium MRI (c axial
view, d coronal view) shows complete resection of the tumor
ture review by Suarez et al. [33], 226 patients with glomus
jugulare tumors demonstrated a surgical control rate of
93.3 %.
Despite the relatively high success rate, postoperative
complications, such as cranial nerve deficits, are significant
causes of morbidity in patients with glomus jugulare tumors
that are treated with microsurgery. Due to their location near
the cerebellopontine angle, CN VII, VIII, and the lower cra-
nial nerves are primarily affected during these operations.
The most common postoperative presentations related to cra-
nial nerve dysfunction reported in the literature include facial
palsy, hearing loss, vocal cord paralysis resulting in hoarseness,
dysphagia, and decreased gag reflex resulting in aspiration.
In most cases, these cranial neuropathies were transient.
Thus, it is clear that cranial nerve preservation during resec-
tion of glomus jugulare tumors is a key factor in reduction of
39 Skull Base Tumors: Viewpoint—Surgery
postoperative morbidity in these patients. In addition, pre-
vention of postoperative CSF leak is another important chal-
lenge that is encountered during open microsurgical
treatment of glomus jugulare tumors. CSF leak has been
reported in more than half the cases presented in the litera-
ture [20–24, 26, 29, 32, 34, 36].
More recently, the use of Gamma Knife, linear accelera-
tor (LINAC), and CyberKnife SRS has been increasing for
both primary and secondary treatments of these tumors
largely due to the advantage of avoiding high rates of mor-
bidity. These tumors can serve as ideal candidates for treat-
ment with SRS because they are well demarcated on MRI
and rarely invade the brain, allowing a steep dose decrease at
the margin [37]. A recent meta-analysis of 19 studies describ-
ing the outcomes of patients with glomus jugulare tumors
who were treated with SRS as a primary treatment exhibited
an average tumor control rate of 97 % with minimal morbid-
ity [38]. Thus, SRS should be considered as a primary treat-
ment in patients who cannot tolerate surgery (i.e., advanced
age and/or medical comorbidities), patients who have under-
gone contralateral jugular foramen surgery, and for smaller
tumors that do not exhibit mass effect. SRS is an important
adjuvant therapy for residual or recurrent tumor that is not
amenable to surgical resection.
The method of treatment of glomus jugulare tumors must
be individualized and tailored based on the tumor size, loca-
tion, extent of intracranial extension, as well as the patient’s
overall surgical risk. Early and aggressive surgical resection
is ultimately favored for small tumors in younger patients in
order to offer the patient the best chance for preservation of
neurological function and prevention of future deterioration
given that the patient is an appropriate surgical candidate
[18, 21–23, 32, 36]. Tumors with significant intracranial
extension exhibiting mass effect or brainstem compression
and those that are malignant glomus jugulare tumors should
be removed surgically.
Chordomas
Chordomas are a rare neoplasm derived from undifferenti-
ated notochordal remnants in the axial skeleton, accounting
for 1–4 % of all bone malignancies and 17.5 % of malig-
nancies of the axial skeleton [39, 40]. Chordomas of the
skull base typically arise from the clivus (Fig. 39.2) and
have an incidence of approximately one per two million
population, representing approximately 25–39 % of all
chordomas [41–43]. While these tumors are histologically
low grade, they are highly infiltrative, associated with a
large tumor burden at diagnosis, and exhibit high rates of
recurrence, making them very difficult tumors to manage
clinically [44]. Without intervention, these tumors insidi-
503
ously progress and invade surrounding structures, ulti-
mately resulting in significant disability and death [45].
Clival chordomas typically present with cranial nerve
palsy secondary to tumor compression [44], and involvement
of the sella turcica by these tumors may also result in endo-
crinopathies [46]. Less commonly, they may present acutely
with epistaxis or intracranial hemorrhage [47, 48]. The main-
stay of treatment for skull base chordomas is surgical resec-
tion followed by postoperative adjuvant radiotherapy [49].
However, due to their proximity to critical neurovascular
structures, the balance between obtaining maximal tumor
resection and limiting significant postoperative morbidity
from extensive resection has remained a topic of significant
debate [50]. A recent meta-analysis of 23 observational stud-
ies conducted by Di Maio et al. [49] suggested that radical
resection was the most promising method of treatment for
improving the progression-free survival and overall survival
in patients with skull base chordomas. They found
progression-free survival rates of 85 % and 47 % with com-
plete resection compared to 50 % and 25 % with incomplete
resection at 5- and 10-year intervals, respectively.
Furthermore, patients treated with complete resection had
overall survival rates of 95 % at both 5 and 10 years, whereas
patients treated with incomplete resection had overall sur-
vival rates of 71 % and 53 % at 5 and 10 years, respectively.
Using a Kaplan–Meier analysis, they found a 3.83-fold
increase in the risk of recurrence and a 5.85-fold increase in
the risk of death at 5 years for patients treated with incom-
plete resection when compared to those treated with com-
plete resection.
Currently, a number of surgical approaches exist for
accessing clival chordomas depending on the size and loca-
tion of the tumor. Staged procedures using more than one
approach have also been advocated by some authors for
treatment of exceedingly complex lesions [51, 52]. In a study
of 71 patients, Sen et al. [42] described their rationale for
approaching these tumors using midline anterior approaches,
including extended subfrontal, transoral, transmaxillary,
transmandibular and more recently, endoscopic endonasal
approaches, for central extradural tumors [42]. For tumors
extending into the cavernous sinus, surrounding the internal
carotid artery, or involving the vertebrobasilar system and
the brainstem, they recommend using a lateral skull base
approach, suggesting that it allows for better control of the
vessels and better separation of the brainstem–tumor inter-
face [42]. Recently, the endoscopic endonasal approach has
become a favorable approach among many neurosurgeons
[42, 53]. The utility of this approach in treating chordomas is
largely due to the fact that these tumors are typically midline
and remain extradural, offering a low risk of CSF leak [53].
In an analysis of 37 studies including 766 patients, Komotor
et al. [53] found that the endoscopic endonasal approach
offered significant advantages over open microsurgical
504
Fig. 39.2 (a, b) Preoperative sagittal T2 (a) and T1-weighted post-
gadolinium (a) MRI demonstrating a clival chordoma with brainstem
compression. An endoscopic endonasal transclival approach was per-
approaches. These include significantly higher rates of gross
total resection (61.0 % vs. 48.1 %), fewer cranial nerve defi-
cits (1.3 % vs. 24.2 %), lower rates of meningitis (0.9 % vs.
5.9 %), less overall mortality (4.7 % vs. 21.6 %), and fewer
cases of tumor recurrence (16.9 % vs. 40.0 %). However,
their conclusions were limited by selection bias and a shorter
length of follow-up for endoscopically treated tumors.
Nevertheless, they recommend that the endoscopic endona-
sal route is at least as efficacious as existing microsurgical
techniques and suggest that it be highly considered for
patients with small midline tumors (<4 cm diameter or
<35 cm3 volume) with minimal lateral extension or carotid
artery involvement [53].
Adjuvant postoperative radiation therapy is a widely
accepted adjunct therapy for the management of residual
tumor following incomplete surgical resection, and has also
R.F. Schmidt et al.
formed resulting in near-total resection of the tumor. (c, d) Postoperative
sagittal T2 (c) and T1-weighted post-gadolinium (d) MRI shows
decompression of the brainstem and basilar artery
been suggested to have some utility in cases of gross total
resection [49, 51, 54]. Proton-beam radiotherapy is currently
the most widely accepted form of adjuvant treatment for
skull base chordomas, with studies suggesting that it pro-
vides improved progression-free survival when compared to
conventional radiotherapy [55]. However, there is a signifi-
cant dearth of data comparing proton-beam radiotherapy
with other modalities, such as SRS. Furthermore, multiple
studies have suggested that there is no difference between
the types of adjuvant radiotherapy that are offered [49, 56].
Ultimately, we recommend that all patients with skull base
chordomas receive aggressive surgical resection as the pri-
mary treatment and be considered for adjuvant postoperative
radiation therapy or SRS for residual disease, with the type
of radiotherapy left to the discretion of the treatment team
based on the available options.
39 Skull Base Tumors: Viewpoint—Surgery
Chondrosarcoma
Chondrosarcomas of the skull base account for approxi-
mately 0.15 % of all intracranial tumors and 6 % of all skull
base neoplasms [57, 58]. It is postulated that these tumors
arise de novo from chondrocytes within the endochondral
cartilage remnants of the petrous portion of the temporal
bone and areas of the petro-occipital, spheno-occipital, and
spheno-petrosal synchondroses; however, other authors sug-
gest that some of these tumors may arise as a result of the
metaplasia of mature fibroblasts [58–61]. Chondrosarcomas
tend to present in the fourth and fifth decades and are associ-
ated with Ollier’s disease, Maffucci syndrome, Paget’s dis-
ease, and osteochondromas [58]. They are typically divided
into four groups based on histological appearance, including
conventional, dedifferentiated, clear cell, and mesenchymal
subtypes. Most skull base chondrosarcomas fall under the
conventional or mesenchymal classifications, with conven-
tional subtypes being far more common. Fortunately, con-
ventional subtypes also have a better prognosis than
mesenchymal subtypes, with lower rates of both recurrence
(16 % vs. 63 %) and 5-year mortality (6 % vs. 54 %) [58, 62].
Additionally, these tumors are histologically stratified into a
three-tiered grading system. Grade 1 tumors have the least
malignant properties and lowest rates of recurrence, with
better long-term survival, while Grade 2 and Grade 3 tumors
possess progressively more malignant histological character-
istics and are associated with worse outcomes [62, 63]. It is
important to recognize these factors when determining the
appropriate treatment plan, as high-grade and non-
conventional lesions may require more aggressive treatment
to obtain adequate tumor control. Furthermore, it is impor-
tant to distinguish these tumors from chordomas, as chon-
drosarcomas are associated with a lower rate of recurrence
and better long-term survival [64–66]. This distinction can
be made by staining for markers such as epithelial membrane
antigen and cytokeratin, which will stain positive in the case
of chordoma, but negative for chondrosarcomas [52].
Chondrosarcomas tend to compress or invade surround-
ing neural structures as they progressively enlarge. Most
commonly, patients will present with diplopia and headache
secondary to tumor enlargement and compression of cranial
nerves III, IV, and VI [52, 58, 66]. Less frequently, the tumor
may also affect cranial nerves II, V, and VIII, resulting in
visual loss, trigeminal pain or numbness, and hearing loss
[52, 66]. Unfortunately, in many cases, complete surgical
resection is not attainable due to the extensive involvement
of surrounding critical structures, such as the cavernous
sinus and internal carotid engulfment [66]. Therefore,
decompression of neural structures, blood vessels, and the
brainstem by tumor debulking is typically the primary goal,
with additional resection being attempted only if the risk of
505
injury to other surrounding structures is minimal [66]. In an
analysis of tumor recurrence and outcomes of 560 patients
with cranial chondrosarcomas conducted by Bloch et al. [58,
62], they found that patients treated with GTR had similar
rates of recurrence-free survival compared with patients who
received incomplete resections followed by adjuvant radia-
tion therapy. Furthermore, they found that recurrence rates
were 44 % vs. 9 % and 5-year mortality rates were 25 % vs.
9 % for patients treated with surgery alone and those treated
with surgery followed by radiation therapy, respectively.
Ultimately, they suggest that less aggressive resections may
be appropriate in many situations in order to minimize the
potential morbidity from surgery, especially in low-grade
and conventional-type tumors.
The surgical approach to skull base chondrosarcomas var-
ies greatly depending on the location of the tumor and the
degree of involvement of surrounding structures. In patients
with large complex tumors, a staged method using multiple
surgical approaches to access various surgical corridors may
be warranted [52]. Wanebo et al. [66] illustrated a variety of
approaches determined by tumor location. For tumors of the
paraclinoid region and upper half of the clivus, they recom-
mend employing a pterional approach with the addition of an
orbitozygomatic osteotomy, as this provides a more exten-
sive basal exposure [66–68]. For tumors of the lower half of
the clivus, they advocate use of a retrosigmoid approach. If
there is widespread soft-tissue involvement or lateral exten-
sion of tumor, they elect for a multidisciplinary strategy
including the addition of transfrontal and transmaxillary
approaches. Since these tumors frequently appear in the mid-
line, numerous authors have also advocated for the use of
endoscopic endonasal approaches [69–71]. Proponents of
this approach suggest that the endoscope offers the benefits
of minimal access and wider panoramic visualization of
deep neural structures [70, 71].
It is important to note that these tumors frequently involve
the cavernous sinus and internal carotid artery, and may
extend intradurally toward the brainstem, hypothalamus, and
internal capsule [52]. Careful resection of the tumor off of
these elements is crucial in avoiding patient morbidity.
Furthermore, chondrosarcomas have been shown to spread
along the subperiosteal spaces and through the bone marrow.
Therefore, if total resection is desired, extensive bone drill-
ing should be performed along the tumor margins until
bleeding marrow is reached [52]. Ultimately, the choice of
surgical approach and extent of resection should be deter-
mined by the location of the tumor, the involvement of sur-
rounding structures, the patient’s clinical status, and the
operator’s experience and comfort with various techniques.
Radiation therapy has been shown to give a distinct
advantage when performed in combination with surgery,
regardless of the degree of resection [58, 62]. However, there
is scarce comparison between the different types of radiation
506
therapies available. Furthermore, most studies are limited in
that they include both chordomas and chondrosarcomas,
even though chondrosarcomas have been shown to be rela-
tively more susceptible to radiation treatment [52, 63, 72,
73]. Radiation therapy as a primary treatment has been
shown to be efficacious in certain situations; however, the
outcomes are inferior to those tumors treated with both sur-
gery and postoperative radiotherapy [58, 62]. As such, we
suggest that all patients with chondrosarcomas of the skull
base should be treated with surgical resection as the primary
method of treatment followed by postoperative adjuvant
radiation therapy.
Esthesioneuroblastomas
Esthesioneuroblastomas, also known as olfactory neuroblas-
tomas, are rare, malignant neoplasms of neural crest origin
that arise from the olfactory epithelium of the upper nasal
cavity and anterior skull base [74–76]. These tumors may
invade locally and spread to the paranasal sinuses, nasal cav-
ity, and other surrounding structures, typically causing nasal
obstruction and epistaxis (Fig. 39.3) [77, 78]. They may also
extend superiorly across the cribriform plate intracranially to
involve the brain or seed the cerebrospinal fluid. Metastasis
may occur via the lymphatic or hematogenous route in
17–48 % patients, and is most commonly seen in the cervical
lymph nodes and more distant sites, including the lungs,
brain, and bone [79, 80]. Due to the rarity of these tumors
and the heterogeneity of treatment modalities described in
the literature, a standardized management protocol has not
been established for esthesioneuroblastomas [80].
Craniofacial surgical resection has largely remained the
preferred method of treatment and usually requires the
removal of the cribriform plate in order to prevent perineural
extension. Surgical resection is typically followed by adju-
vant radiotherapy, and in some cases, chemotherapy in order
to achieve better long-term results [80–84]. The decision by
which the modality of therapy is chosen for treatment is
largely driven by the characteristics of the tumor and primar-
ily based on Kadish staging. According to most available
studies, Kadish A (tumors limited to the nasal cavity) and
Kadish B tumors (tumors that extend to paranasal sinuses)
are optimally treated with craniofacial resection followed by
postoperative radiotherapy for greater disease-free survival.
Postoperative radiation therapy, in patients with Kadish A
and B tumors, has shown to improve recurrence-free survival
at 5 years when compared to patients treated with surgery
alone [85]. Overall survival rates in patients treated with sur-
gical resection followed by postoperative radiation therapy
have been reported to be up to 100 % [86] and 5-year disease-
free survival rates up to 85.7 % [87]. Recent literature also
suggests that multimodality therapy with preoperative (neo-
R.F. Schmidt et al.
adjuvant) chemotherapy followed by craniofacial resection
and postoperative radiation therapy should be considered for
Kadish C (tumors with skull base or intracranial extension)
and higher-grade lesions (tumor with neck or distant metas-
tases) [88, 89].
Over the past 2 decades, various advances in skull base
techniques have been made to incorporate both endoscopic-
assisted craniofacial resection and more recently, purely
endoscopic endonasal resection of these tumors in addition
to standard craniofacial surgical resection [90]. The intro-
duction of endoscopy has transformed traditional open skull
base surgery and confers various advantages over conven-
tional craniofacial resection. These advantages include: (1)
no retraction of the frontal lobes, (2) better visualization in
difficult areas, (3) use of natural orifices (nasal corridor) to
avoid visible incisional scar, (4) reduction in recovery time,
and (5) less overall morbidity and mortality [91–95].
However, longer follow-up is necessary in order to better
assess the recurrence-free survival rates and prognosis in
patients with esthesioneuroblastoma resected via the purely
endoscopic endonasal route. In our experience, careful
patient selection is important when considering the purely
endoscopic approach. We generally reserve the endoscopic
approach for sinonasal tumors with minimal intracranial
extension, and use a combined transbasal bifrontal approach
and endoscopic endonasal approach (combined cranionasal)
for sinonasal tumors that have more extensive intracranial
involvement. Additionally, the role of SRS in management
of esthesioneuroblastomas has not been very well defined
and further studies are required with longer follow-up in
order to assess whether this treatment modality is efficacious
[86, 96–98].
Craniopharyngiomas
Craniopharyngiomas are benign, epithelial-squamous, extra-
axial tumors that arise along the path of the craniopharyngeal
duct or Rathke’s pouch, and are designated as WHO Grade 1
tumors [99, 100]. They have an overall incidence of 0.5–2
per 100,000 [101] and represent approximately 5 % of all
intracranial tumors and 5–10 % of all pediatric intracranial
tumors (Fig. 39.4) [102, 103]. These tumors typically exhibit
a bimodal distribution, with peak incidences at 5–14 years
and 50–74 years [101, 104], with childhood craniopharyn-
giomas accounting for 30–50 % of all cases [101, 105]. They
are classified into two histopathological subtypes, adamanti-
nomatous craniopharyngiomas, which are associated with a
mutation of the β-catenin gene and predominantly occur in
the first 2 decades, and papillary craniopharyngiomas, which
typically occur in adults [106]. Some authors have suggested
lower recurrence rates in those with papillary histology, but
others have reported no difference in outcome or recurrence
39 Skull Base Tumors: Viewpoint—Surgery
Fig. 39.3 (a, b) Preoperative T1-weighted post-gadolinium MRI
(a sagittal view, b coronal view) demonstrating an esthesioneuroblas-
toma with intracranial extension through the cribriform plate. An endo-
scopic endonasal transcribriform approach was performed for removal
between the two subtypes [106, 107]. Grossly, they are typi-
cally characterized as cystic, solid, and mixed, and many
tumors exhibit extensive calcification.
While these tumors are classified as benign, they can
sometimes exhibit tumor adherence to critical structures in
the parasellar region, including the optic apparatus, pituitary
stalk, pituitary gland, hypothalamus, third ventricle, anterior
cerebral artery complex, and surrounding perforating
arteries. Hypothalamic involvement is of particular concern,
as it has been shown to be significantly related to pre- and
postoperative morbidity, including behavioral disturbances,
obesity, cognitive decline, and an overall decrease in quality
of life [108–110]. Because of this, a separate classification
507
of the tumor with reconstruction of the resultant skull base defect. (c, d)
Postoperative T1-weighted MRI (c sagittal, d coronal) shows gross
total resection of the tumor. Packing is visualized in the nasal cavity
bolstering the skull base repair
system has been developed based on and the degree of
hypothalamic involvement, with Grade 0 tumors having no
involvement, Grade 1 exhibiting compression of the hypo-
thalamus, and Grade 2 involving the hypothalamus.
Furthermore, the clinical presentation of craniopharyngio-
mas varies by the anatomical location of the lesion with rela-
tion to the optic chiasm. Prechiasmatic lesions typically
involve the optic apparatus, resulting in decreased visual
acuity and visual field defects, usually presenting as bitemporal
hemianopsia in up to 49 % of cases [100, 111, 112].
Retrochiasmatic lesions commonly present with hydroceph-
alus and signs of increased intracranial pressure, including
headache, nausea, vomiting, papilledema, and horizontal
508
Fig. 39.4 (a, b) Preoperative T1-weighted post-gadolinium-enhanced
MRI (a sagittal, b coronal) demonstrating a pediatric craniopharyngi-
oma resulting in visual loss with optic compression. An endoscopic
endonasal transplanum transtuberculum approach was performed.
double vision [100, 113]. Intrasellar lesions typically present
with headache and endocrinopathies, including polyuria,
polydipsia, growth retardation, developmental disturbances
during puberty in children, hypogonadism in adults, and sig-
nificant weight gain [100, 114]. However, despite these
trends associated with anatomical location, many patients
will present with a combination of these clinical features.
Obtaining GTR has traditionally been the primary goal
of surgical management due to the relatively high rates of
recurrence. It has been shown that tumor recurrence is pres-
ent in approximately 10–30 % of cases treated by GTR and
up to 50 % in cases treated without GTR [104, 106, 109,
111, 112, 115–118]. Furthermore, recurrent tumors are
associated with worse morbidity, mortality, and decreased
long-term survival. However, this paradigm is currently
R.F. Schmidt et al.
(c, d) Postoperative T1-weighted post-gadolinium-enhanced MR
images (c sagittal, d coronal) show gross total resection of the tumor
with decompression of the optic apparatus
being put into question, especially in cases where GTR
might result in significant morbidity [109, 110]. Some
authors suggest that significant hypothalamic involvement
(i.e., Grade 2) is a strong indicator to undergo subtotal
resection followed by radiation therapy as opposed to GTR
[110, 117, 119]. Additionally, some recommend minimal
resection, such as cyst decompression followed by radiation
therapy in elderly patients with multiple comorbidities, or in
patients with stalk infiltration but an intact hypothalamic–
pituitary axis [117]. Nevertheless, a GTR should be
attempted whenever safely possible.
Initially, transcranial routes, including pterional, orbito-
zygomatic, subfrontal, transcallosal, and bifrontal
approaches, were the method of choice for accessing these
lesions [103, 104, 106, 109, 111, 112, 115, 116, 119–121].
39 Skull Base Tumors: Viewpoint—Surgery
While these approaches can expose a wide variety of ana-
tomical locations, they typically require significant brain
retraction and manipulation of neurovascular structures in
order to obtain optimal visualization and surgical resection
[117]. The extended transsphenoidal microsurgical approach,
utilizing an operative microscope through a nasal speculum,
provides a more direct route to the sellar and suprasellar
regions [103, 117, 122, 123]. Recently, endoscopic endona-
sal approach (transplanum transtuberculum) has emerged as
a viable treatment option for resection of these tumors [117,
124]. The use of an endoscope has enabled surgeons to
obtain a wider field of view, allowing minimally invasive
resection of these tumors with minimal manipulation of sur-
rounding structures. In general, studies have shown similar
rates of GTR among the different approaches, ranging from
9 to 90 % for transcranial approaches, 12–90 % for micro-
scopic transsphenoidal approaches, and 29–86 % for endo-
scopic endonasal transsphenoidal approaches [104, 106,
109, 111, 112, 115–117, 119, 120, 122, 123]. Ultimately, the
decision of which operative approach to use largely depends
on the specific goals of the patient as well as the training and
technical preference of the neurosurgeon.
As previously mentioned, radiation treatment has become
a commonly used therapy in certain cases of craniopharyn-
giomas. Rates of tumor control and mortality have been
shown to be comparable in cases where subtotal resection
with radiation therapy was chosen over GTR or when radia-
tion therapy was chosen for the treatment of recurrent tumors
[118, 125, 126]. However, studies addressing the use of SRS
are currently very limited. Currently, SRS is used for small,
solid craniopharyngiomas located 3–5 mm away from the
optic nerve or chiasm [127] or in cases of recurrent or resid-
ual tumors following subtotal or GTR [128]. In general, sur-
gical resection remains the treatment of choice for
craniopharyngiomas, with GTR being the ultimate goal
when obtainable. However, more studies are needed to com-
pare the long-term outcomes of various combinations of sur-
gical techniques and radiotherapy interventions in order to
establish the best possible course for patient care.
Skull Base Meningiomas
Skull base meningiomas are typically difficult lesions to
resect because of their location and close proximity to vital
neurovascular structures. These tumors include, but are not
limited to, orbital, optic nerve sheath, olfactory groove,
tuberculum sellae, cavernous sinus, sphenoid wing, cerebel-
lopontine angle, petroclival, and tentorial meningiomas.
The other inherent difficulty in treating these lesions is that
skull base meningiomas tend to differ in volume, shape,
location, and clinical symptomatology. Optimal manage-
ment of these tumors involves GTR with removal of the
509
invaded and hyperostotic bone and surrounding dura, if
safely possible [129, 130]. In many cases, only subtotal
resection can be achieved, and in these cases postoperative
radiosurgery or radiotherapy is often required for tumor
control [131].
Over the past 2 decades, it has been well documented that
extent of resection of skull base meningiomas correlates with
long-term tumor recurrence [132–136]. Therefore, the key
goals of the skull base meningioma treatment paradigm
include: (1) maximal resection of tumor with minimal neuro-
logical deficit, (2) preservation of functional outcome, and
(3) prevention of tumor recurrence [129]. Various approaches
of microsurgical resection have been described for skull base
meningiomas including infratemporal fossa [137], retrosig-
moid [138], and extended approaches to the jugular foramen;
the supraorbital [139], pterional [140], and orbitozygomatic
[141] approaches for tuberculum sellae meningiomas; com-
bined subtemporal-suboccipital approach, the preauricular-
subtemporal-infratemporal approach [142], the posterior
transpetrosal [143], anterior transpetrosal-transtentorial
[144], and combined supratentorial and infratentorial
approaches [145, 146] for sphenoid wing, petroclival, and
tentorial meningiomas; the transoral approach to the lower
clivus and upper cervical spine [43]; and the extreme lateral
transcondylar approach [147–149] for ventral foramen mag-
num meningiomas at the craniocervical junction. More
recently, endoscopic endonasal techniques have also been
described and reported for certain midline skull base menin-
giomas such as planum sphenoidale, olfactory groove, tuber-
culum sellae, and clival meningiomas [150–157].
Among the most challenging meningiomas to treat surgi-
cally include cavernous sinus, tuberculum sellae, and petro-
clival meningiomas. Cavernous sinus meningiomas typically
present with visual and ocular motor deficits such as ptosis,
diplopia, anisocoria, and ophthalmoplegia, in addition to tri-
geminal nerve dysfunction [158]. Cavernous sinus meningi-
omas are inherently difficult tumors to resect because of their
involvement of the cavernous sinus, internal carotid artery,
and cranial nerves III–VI. The treatment strategies for cav-
ernous sinus meningiomas have evolved over the past decade
[159–163]. In many cases, subtotal resection and decom-
pression of the cavernous sinus and optic nerve can be con-
sidered. In these instances, postoperative radiotherapy or
SRS for residual tumor may be indicated if the meningioma
displays atypical features on histology or if it is found to be
malignant [129]. Long-term outcomes of Gamma Knife SRS
for patients with small- or medium-sized cavernous sinus
tumors have shown good results with respect to progression-
free survival (90 and 75 %) and functional outcomes (93 and
91 %) at 5 and 10 years, respectively [164]. Tumor progres-
sion was more likely found to occur from margins that
remain outside of the treatment volume [164]. Furthermore,
tumors that are asymptomatic and radiographically stable
510
Fig. 39.5 (a, b) Preoperative T1-weighted post-gadolinium MRI (a
axial, b coronal) demonstrating a left petroclival meningioma with
brainstem compression. The patient underwent a combined petrosal
over time are followed up at appropriate intervals without
intervention.
Petroclival meningiomas (Fig. 39.5) are rare and make up
only about 3–10 % of all posterior fossa meningiomas [165].
These tumors are particularly complex because of their deep
location and often intimate relationship with vessels, nerves,
and the brainstem. In addition, the natural history of these
tumors may be unpredictable and frequently involves pro-
gressive growth and neurological deterioration [166, 167].
The neurologic presentation of petroclival meningiomas var-
ies, though some of the more common symptoms include
headache, gait disturbances, cranial nerve deficits, and other
symptoms related to brainstem compression [166, 168].
R.F. Schmidt et al.
approach resulting in gross total resection of the tumor. (c, d)
Postoperative T1-weighted post-gadolinium MRI (c axial, d coronal)
shows complete removal of the tumor with brainstem decompression
Petroclival meningiomas are typically treated on a case-
specific basis and numerous aspects of management are con-
sidered, including the size and location of tumor, choice of
surgical approach, the postoperative evaluation of results, and
treatment of recurrence [129, 138, 144, 145, 169–171]. For
smaller tumors in symptomatic patients, GTR, if feasible,
should be the goal of surgery. On the other hand, small and
asymptomatic meningiomas, particularly in elderly patients,
may be observed and followed up with serial neurological
exams and imaging. Larger petroclival meningiomas may
require combined surgical approaches to allow adequate
tumor exposure and debulking [145, 146, 171]. In cases
involving large or giant petroclival meningiomas, it is impor-
39 Skull Base Tumors: Viewpoint—Surgery
tant to consider the patient’s postoperative quality of life
[135]. In some cases, settling for a subtotal resection with
decompression of adjacent structures is reasonable, with or
without postoperative radiosurgery, particularly in cases that
involve cavernous sinus invasion, pial invasion, and tumor
adherence to cranial nerves and vessels [166].
Tuberculum sellae meningiomas make up 5–10 % of all
intracranial meningiomas and pose a unique surgical chal-
lenge. They typically arise from the tuberculum sellae, chias-
matic sulcus, limbus sphenoidale, and diaphragma sellae
[172]. These tumors commonly cause displacement of the
optic chiasm and optic nerves and often have optic canal
involvement. The most common clinical manifestation of
tuberculum sellae meningiomas is progressive visual loss,
classically known as “the chiasmal syndrome,” a term first
coined by Harvey Cushing in 1930 to describe the hallmark
presentation of these lesions [173]. The ideal treatment
involves decompression of the optic apparatus by achieving
a Simpson Grade I removal (i.e., surgical GTR of the tumor,
its dural attachments, and associated hyperostotic bone)
while preserving visual function, the integrity of critical
adjacent neurovascular structures, and endocrine function
[154, 173]. In cases where tumor extends into the optic canal,
early bony decompression of the optic canal (including ante-
rior clinoidectomy, optic canal unroofing, and incising falci-
form ligament) has been advocated during the removal of
tuberculum sellae meningiomas and appears to have a strong
influence on postoperative visual recovery [154, 173–177].
This decompression involves extradural, and in some cases,
intradural removal of the anterior clinoid process as well as
the unroofing of the optic canal followed by incision of the
falciform ligament and dural sheath of the involved optic
nerve. In addition to early decompression of the optic nerve,
this particular maneuver allows exploration of the optic canal
for additional tumor since this can be a frequent site of recur-
rence [154, 173, 174, 177–179].
Classically, skull base meningiomas have been removed
through standard, transcranial approaches. However, in more
recent years, with the introduction of extended transsphenoi-
dal microsurgical approaches and expanded endoscopic
endonasal techniques, the optimal surgical approach for
these tumors has been much debated [180]. Although there is
no firm consensus as to which method is superior for removal
of these tumors, most authors agree that each surgical
approach has its own advantages and disadvantages [181].
Ultimately, the route eventually chosen depends upon the
preference of the surgeon, the precise location and size of
tumor in relation to surrounding structures, and individual
patient factors. In either scenario, the goal of oncologic
treatment remains the same: a Simpson Grade I tumor
removal, with adequate optic nerve decompression and pres-
ervation of the visual function. The major limitation for
endoscopic endonasal resection of tuberculum sellae menin-
511
giomas is dural involvement that extends laterally over the
optic canal and anterior clinoid process. The risk of CSF
leakage is also higher but has been reduced since the advent
of the pedicled nasoseptal flap reconstruction [182, 183].
More recently, SRS has been studied both as primary
treatment for skull base meningiomas that are not readily
amenable to surgery and as an adjuvant therapy in cases
where GTR was not achieved. These studies have shown
that this treatment modality provides acceptable rates of
tumor control (upwards of 85 % in most studies), while pre-
serving neurological function in many patients and avoiding
the mortality and morbidity associated with an open surgi-
cal procedure [131, 184]. Of note, neurological preservation
or improvement was more commonly observed in patients
who received Gamma Knife treatment for lesions that origi-
nated in the petroclival, parasellar, and cerebellopontine
angle locations [184]. Though the results of these studies
are certainly promising in the treatment of these tumors, the
decision-making protocol for skull base meningiomas
should always include surgery as the primary tier of man-
agement, if it can be safely achieved, given that this is the
only option that can achieve tumor reduction, decompres-
sion of compromised neural structures, and provide poten-
tial oncologic cure.
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 Skull Base Tumors:
Viewpoint—Fractionated Radiotherapy
or Stereotactic Radiotherapy
René-O. Mirimanoff and Laura Negretti
Introduction
Skull base tumors account for up to a third of all intracranial
tumors. The most common ones are represented by menin-
gioma, pituitary adenoma, acoustic nerve schwannoma, and
craniopharyngioma; less frequent types comprise chordoma
and chondrosarcoma, PGL or chemodectoma, and very occa-
sionally rare bone tumors like bone lymphoma, giant cell
tumors, and carcinoma of the skull base can be found. Some,
like the meningioma, can involve almost any part of the ante-
rior, middle, or posterior fossa, whereas others, like the PGL,
arise from well-defined anatomic structures. Surgery still
remains the cornerstone in the management of most skull
base tumors [1]. However, in spite of a better understanding
of the natural behavior and biology of these skull base tumors,
continuous progress in anesthesiology, and the refinements in
surgical techniques, a complete surgical removal is extremely
difficult in many instances or made at a price of considerable
neurologic deficits. This is why noninvasive treatments, such
as high-precision radiotherapy with intensity-modulated radi-
ation therapy (IMRT), radiosurgery (RS), stereotactic frac-
tionated radiotherapy (STRT), and particle therapy, play an
increasing role in the multidisciplinary management of most
skull base tumors. We will focus here on chordoma and chon-
drosarcoma on the one hand, and on the PGL category on the
other, with particular emphasis on their treatment by fraction-
ated external beam radiotherapy, particle therapy, and STRT.
R.-O. Mirimanoff, M.D. (*)
Radiation Oncology Department,
CHUV, University Hospital Lausanne, Lausanne, Switzerland
Clinique de La Source, Vinet Avenue 30,
1004 Lausanne, Switzerland
e-mail: rene-olivier.mirimanoff@chuv.ch
L. Negretti, M.D.
Radiation Oncology Department, CHUV, University Hospital
Lausanne, Clinica Luganese, via Moncucco 10, 6900 Lugano,
Ticino, Switzerland
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_40, © Springer Science+Business Media New York 2015
40
Chordomas and Chondrosarcomas
Chordomas: General Features
Chordomas are rare tumors: according to the SEER data, the
incidence of these tumors is around 0.08 per 100,000 with a
peak incidence between 50 and 60 years of age; they repre-
sent only 0.1–0.2 % of all primary intracranial neoplasms
[2]. Chordomas are of neuroectodermal origin and are pre-
sumed to develop from notochordal remnants (Fig. 40.1).
The discovery of a gene duplication in the transcription
factor T gene (brachyury) in familial chordoma seems to
support this hypothesis [3]. There are several histopathologic
subcategories, with or without predominance of particular
cell types. Those include the physaliferous type, the epitheli-
oid and the chondroid cell types [4].
Immunohistochemistry shows that almost all tumors stain
positively for the epithelial membrane antigen, cytokeratins,
S-100 proteins, and are negative for HMB-45 and desmin
[4]. One third of all chordomas arise from the skull base, the
remainder from the sacrum and the spine. Although they do
grow slowly, and rarely metastasize, they are quite often
lethal due to their local progression. They commonly involve
vital neural or bony structures (Fig. 40.2), thus compromis-
ing the effectiveness of surgical or radiation therapy [5].
Intracranial chordomas typically arise from the clivus and
can invade the dura, extend in any direction, for example
toward the foramen magnum, the petrous bone, the cranio-
spinal junction or compress the brain stem, or infiltrate ante-
riorly the cavernous sinus [6].
Chondrosarcomas: General Features
Chondrosarcomas are also rare tumors that can arise from
the skull base. Like chordomas, they represent 0.15 % of
all intracranial tumors [7] although many series suggest
that they are even less common than chordomas [8–10].
517
518
Fig. 40.1 Pathology slide of a chordoma
Fig. 40.2 MRI of a skull base chordoma
Most chondrosarcomas arise de novo although they can
occur in Ollier’s disease, Paget’s disease, or in osteochondro-
mas. It is thought that they originate from primitive mesen-
chymal cells or embryonal remnants of the cartilaginous
matrix of the cranium [11] (Fig. 40.3). They are sometimes
mistakenly diagnosed as chordoma, but it is quite important
to distinguish them from the latter as they have a better prog-
nosis [6, 8, 12–16]. Several subtypes have been proposed
that include the hyaline, the myxoid, and mixed hyaline-
myxoid; the mesenchymal and dedifferentiated subtypes are
less common and disclose a more aggressive behavior,
whereas the clear cell subtype is extremely rare [17, 18].
R.-O. Mirimanoff and L. Negretti
Fig. 40.3 Pathology slide of a skull base chondrosarcoma
On immunohistochemistry, almost all chondrosarcomas
stain for S-100 protein, but none for keratin and less than
10 % for epithelial membrane antigens [18]. Thus, tumor
markers are helpful adjuncts to differentiate between chor-
doma and chondrosarcoma: chordomas express cytokeratin
and epithelial membrane antigens, whereas chondrosarco-
mas lack the former and rarely stain for the latter. Like chor-
domas, chondrosarcomas tend to invade local structures.
Distant metastases are uncommon; Hassounah et al. in their
literature review found five cases of metastases out of 50
reported patients [19].
Standard Treatment of Chordomas
and Chondrosarcomas
Although they have a good number of features in common
and their overall management is relatively similar, chordoma
and chondrosarcoma of the skull base present with important
differences in histopathology, biological behavior, and out-
come [6, 18, 20, 21]. For example, in an important series of
109 patients, recurrence and death rates were much higher in
patients with chordomas than in patients with chondrosarco-
mas [6]. Two excellent papers were recently published on
chordomas [20] and chondrosarcomas [21], which review
the management and outcome of these tumors. There is no
question that surgery remains the cornerstone of treatment.
The surgeon’s goal should be, whenever possible, to carry
out an en bloc resection with a gross total removal [6, 22].
Major advances in surgical techniques and microsurgery in
particular have allowed neurosurgeons to perform more mac-
roscopically complete resections, with clearly improved out-
comes [22]. However en bloc resections are rarely possible
with clival chordoma and thus a maximally safe aggressive
40 Skull Base Tumors: Viewpoint—Fractionated Radiotherapy or Stereotactic Radiotherapy
surgery with neurological preservation should be the goal
[20]. With extensive surgery, Crockard et al. have reported
5-year survival rates of 77 % and 93 %, respectively, for
chordoma and chondrosarcoma [15, 16]. Gay et al. obtained
a 67 % total or near total resection rate, and for these an 84 %
recurrence-free rate was achieved [8].
In spite of these improvements in surgery, it appears that
a genuine curative resection with clear margins is not often
realistic, and ultimately a majority of patients will recur and
die from their disease if no adjuvant radiation is adminis-
tered. For example, in a series of 13 operated patients with
chondrosarcomas from the Netherlands, only three received
postoperative photon (2) or proton (1) radiotherapy, and the
recurrence-free survival was only 43 % at 5 years [11]. In a
systematic literature review of intracranial chondrosarcoma,
Bloch et al. found that the 5-year mortality rate was 25 %
without and 9 % with postoperative radiotherapy [21].
Therefore, adjuvant, high-dose postoperative radiother-
apy has been considered and used for many years both for
chordomas and chondrosarcomas. In spite of old claims that
chondrosarcomas and chordomas are radioresistant tumors
[23], conventional external beam radiotherapy was shown to
provide useful and prolonged palliation in overt residual dis-
ease [5]. It was however suggested for a long time that these
tumors, in order to be controlled, need to receive relatively
high-dose radiotherapy and that the total dose should be
increased to 70–80 Gy [24–27]. Currently, with high-
precision external beam photon radiotherapy, the dose to the
PTV can be escalated to 65–70 Gy, with local control rates
comparable to those obtained with particle therapy [26].
Because of the presence of neighboring critical structures
like the brain stem or the temporal lobe, with older tech-
niques the total dose was limited to 50–60 Gy, which was
clearly insufficient to control even microscopic residual dis-
ease in the long term. Charged particles such as protons,
helium, or neons or carbon ions are well suited for extremely
precise localization of radiation and permit an increase of the
total dose from 15 to 35 % compared with conventional
X-rays [10]. In their experience with charged particle irradia-
tion of tumors of the skull base, Castro et al. have treated 53
chordomas and 27 chondrosarcomas, from 1977 to 1992,
with a mean dose of 65 Gray equivalent (GyE) (range, 60–85
GyE) [10]. Five-year local control was 63 % for chordomas
and 78 % for chondrosarcomas [10]. Since then, a number of
patients were treated with particle therapy, generally proton
beam therapy in the United States, France, Japan, Switzerland,
and Germany, with protocols using high doses of irradiation.
At the Massachusetts General Hospital (MGH), where
chordomas and chondrosarcomas were treated with 160 MV
proton beams, with a median dose of 69 CGE (Cobalt-Gray-
Equivalent), it was found that chordomas had a 31 % rate of
failure of which 95 % were local [24, 25]. It was also
shown that the 10-year local control was the highest with
519
chondrosarcomas, followed by male chordomas and female
chordomas, with 94 %, 65 %, and 42 % local control rates,
respectively [14]. At Loma Linda University, 58 patients
with chordomas and chondrosarcomas received proton beam
radiotherapy with a mean dose of 70 CGE, with a local con-
trol rate of 92 % for chondrosarcomas and 78 % for chordo-
mas [13]. An update of the French series at Orsay on 100
patients confirmed their previous results with a combination
of photons and proton beams (201 MV with a median dose of
67 CGE). In this report, the 2- and 4-year local control rates
were 86 % and 54 %, respectively [9]. Patients with chordo-
mas treated with proton beam therapy at Tsukuba University
received a median dose of 72 Gy with 5-year local control
and local-specific survivals of 42 % and 72 %, respectively
[27]. At the Paul Scherrer Institute, Switzerland, 64 patients
with skull base chordomas (42) and chondrosarcomas (22)
were treated with the spot-scanning-based proton radiother-
apy technique with a median dose of 75.5 Gy for chordomas
and 68.4 Gy for chondrosarcomas [28]. Actuarial 5-year
control rates were 81 % for chordomas and 94 % for chon-
drosarcomas; the 5-year freedom from high-grade toxicity
was 94 % [28]. With carbon ion radiotherapy, the experience
from Heidelberg and GSI in Darmstadt on 96 chordoma
patients disclosed a 70 % local control and 88 % survival at
5 years [29]. The same group obtained a 90 % 4-year local
control and 98 % 5-year survival in a series of 54 patients
with chondrosarcomas [30]. In the experience with proton
beam and carbon ion radiotherapy, late grade 3–4 toxicities
were generally low, given the high radiotherapy dose deliv-
ered, and were reported to be between 4.5 and 7 % [13, 25,
28–31]. In conclusion, high-precision, high-dose particle
radiotherapy is followed by an excellent local control for
chondrosarcoma and a reasonably good local control for
chordoma, with a low toxicity. Postoperative proton beam
radiotherapy is often considered now as the standard treat-
ment for these tumors. We will examine next if high-precision
and high-dose STRT can be considered as alternative treat-
ments to proton beam therapy.
Fractionated Stereotactic Radiotherapy
of Chordomas and Chondrosarcomas
Patient Selection
As previously emphasized, the standard management of
chordomas and chondrosarcomas should include a maximal
surgical resection, followed by postoperative high-precision,
high-dose radiotherapy, if one wants to maximize the chances
of local control [6, 15, 16, 20–30].
The indications for STRT are essentially the same as those
for RS (see chapter on RS), except that STRT combines the
precision of stereotactic positioning with the radiobiological
advantage of fractionation, especially in large tumors [12].
520 R.-O. Mirimanoff and L. Negretti

Fig. 40.4 Treatment plan for

STRT of a case of chordoma
(a) sagittal (b) axial

Table 40.1 Treatment outcomes, chordomas

Median
No. of prescribed 5-year local 5-year Median
Series Year patients Technique dose (Gy) control (%) survival (%) follow-up Comments
Krishnan et al. [33] 2005 25 GKRS 15 55 4.8 years EBRT also used in a
proportion of patients
Martin et al. [32] 2007 18 GKRS 16 63 63 7.7 years EBRT also used in a
proportion of patients
Hasegawa et al. [36] 2007 27 GKRS 14 72 84 6 years
Dassoulas et al. [38] 2009 15 GKRS 12.7 42 80 5.8 years LC improved to 50 %
after 2nd GKRS
Kano et al. [39] 2011 71 GKRS 15 66 74 5 years NAGKC (6 centers)
Henderson et al.[40] 2009 18 CyberKnife 35 59 82 4 years 35 Gy in 5 sessions
Debus et al. [12] 2000 37 Linac STRT 66.6 50 7682 19 months 1.8 Gy per fraction
Bugoci et al. [37] 2012 12 Linac STRT 66 38 76 3.5 years 2 Gy per fraction

Thus, in tumors larger than 30 mm in diameter, there is an
advantage of using STRT rather than RS, at least in theory. In
the series from Heidelberg, where STRT was used for chordo-
mas and chondrosarcomas of the skull base, the median target
volume was 56 cm3 (range, 17–215 cm3) for chordomas and
102 cm3 (range, 24–237 cm3) for chondrosarcomas [12]. This
is in sharp contrast with the mean or median volumes described
in the RS series, which ranged from 4.6 cm3 (range, 0.98–
10.8 cm3) to 14.6 cm3 (range, 2.9–52 cm3) [32–36].
Treatment Techniques
Planning techniques are similar to those used for any RS or
STRT of other intracranial lesions. Immobilization systems
including various stereotactic head frames (RS) or relocatable
head masks (STRT) are used for imaging studies under ste-
reotactic guidance and for treatment. All patients should
undergo high-resolution computed tomography (CT) and if
not contra-indicated magnetic resonance imaging (MRI),
with image fusion for treatment planning. In both cases, ultra-
thin slices are required. With regard to fractionated STRT, the
Heidelberg group has defined the clinical target volume
(CTV) as the visible tumor on CT and MRI and the potential
residual tumor, taking preoperative imaging into account [12].
They added a 2-mm safety margin for the planning target
volume (PTV). The median prescribed dose at isocenter was
66.6 Gy for chordomas and 64.3 Gy for chondrosarcomas,
with a median daily dose of 1.8 Gy [12]. More recently,
Boguci et al. have used image-guided intensity-modulated
fractionated STRT, with a median dose of 66.6 Gy prescribed
at the 90 % isodose, so that the dose at the isocenter was 74 Gy
[37]. Figure 40.4a, b shows an example of linac-based STRT
treatment plan at our institution (CHUV) for a 59-year-old
patient who was not operated due to important comorbidities.
The patient, with a skull base chordoma, received a total dose
of 63 at 1.8 Gy per fraction, using a micro-multileaf collima-
tor with six fixed beams from a 6-MV linear accelerator.
Treatment Outcomes
Because of the rare occurrence of chordomas and chondrosar-
comas, the published experience with either RS or STRT is
still limited. Table 40.1 summarizes some recent series with
RS and STRT for chordomas and Table 40.2 the experience
with chondrosarcomas. As can be seen, these series of Gamma
Knife radiosurgery (GKRS) and STRT have gathered a lim-
ited number of cases of chordomas [12, 32, 33, 36–40] and
very few cases of chondrosarcomas [12, 32–34, 36].
40 Skull Base Tumors: Viewpoint—Fractionated Radiotherapy or Stereotactic Radiotherapy 521

Table 40.2 Treatment outcomes, chondrosarcomas

Median
No. of prescribed 5-year local 5-year Median
Series Year patients Technique dose (Gy) control survival follow-up Comments
Krishnan et al. [33] 2005 4 GKRS 15 100 % 4.8 years
Feigl et al. [34] 2005 10 GKRS 17 100 % NA 17 months One patient had 2 GKRS
Martin et al. [32] 2007 10 GKRS 15 88 % (6 years) 88 % 7.7 years 1.8 Gy per fraction
Hasegawa et al. [36] 2007 7 GKRS 14 80 % 83 % 6 years
Debus et al. [12] 2000 8 Linac STRT 64.9 100 % 100 % 19 months

Overall, these results confirm the known differences in

outcome between chordomas and chondrosarcomas. Results
on local controls and survivals are fairly similar to those
obtained after postoperative proton beam radiotherapy. For
chordomas, the 5-year local control rates varied between 38
and 72 %, whereas for chondrosarcomas, it was between 80
and 100 %. The rather wide variations between the different
series are probably due to differences in surgical tech-
niques, tumor size, and in the patients’ populations, some
reports having included both primary treatments and treat-
ments for recurrence. The experience at the University of
Heidelberg and at the Kaiser Permanente in Los Angeles
with STRT showed encouraging local control rates, which
were comparable to those obtained with RS [12, 37].
It should also be re-emphasized that patients treated by
STRT had on average a much larger residual tumor volume
compared with those who received GKRS (vide supra). Fig. 40.5 Pathology slide of a case of paraganglioma
STRT yields the same excellent local control rates for chon-
drosarcomas as with RS, but admittedly the number of
patients was quite low [12]. Paragangliomas
Functional outcome after RS was reported in the rather
large North America Gamma Knife consortium: of 57 General Features
patients with prior neurological deficits, 17 improved, 18 PGLs are neuroendocrine tumors originating from the auto-
were unchanged, and 16 deteriorated [39]. nomic nervous system derived from neural crest cells.
Radiation-induced complications are generally moderate; Approximately 80–85 % of these tumors are located in the
however, cranial nerve dysfunction, pituitary insufficiency, and adrenal medulla and called pheochromocytomas (PCCs),
occasionally brain necroses were reported [32, 33]. Similarly, whereas 15–20 % grow in the extra-adrenal chromaffin tissue
the complication rates after STRT are quite low: from the 45 and are referred to as secreting paraganglioma (sPGLs).
patients treated with STRT in Heidelberg, only one presented These tumors are rare and occur in 2–8 per 1,000,000, with a
with symptomatic infarction of the pons [12]. peak incidence in the third to the fourth decade of life, with
an almost equal distribution between female and male
patients; familial tumors occur at an earlier age [41]. They
Conclusion are generally slow growing, highly vascular, with a high
intracellular liquid content and with frequent intratumoral
In conclusion, RS, either with GKRS or linac RS, and STRT cysts [42–45] (Fig. 40.5). Depending on their origin, PGLs
appear to be safe treatments as postoperative complement to can be divided into two groups: sympathetic and parasympa-
surgery or for recurrent chordomas and chondrosarcomas of thetic tumors. PCCs fall into the former category. Sympathetic
the base of the skull. It is thus reasonable to state that, in the PGLs can be found anywhere along the sympathetic ganglia,
absence of a nearby proton beam therapy facility, fraction- in the thorax, abdomen, and pelvis, and they tend to hyperse-
ated STRT represents a possible, safe and cheaper alternative crete catecholamines, like adrenal PCC. In contrast, para-
treatments for these skull base tumors. sympathetic PGLs are principally located in the head and
522
Fig. 40.6 MRI of a case of paraganglioma
neck region (HNPGLs) and base of the skull, and in their
majority are nonsecretory. They can be multicentric, espe-
cially in familial cases [45]. In some instances, they can
reach very large sizes and are referred to as giant tumors
[45]. One quarter of PGLs are malignant, defined by the
presence of chromaffin tissue in sites where it is normally
absent, such as lymph nodes, bone, liver, and lung [41].
Unfortunately, there are currently no consistent methods to
differentiate benign from malignant forms, and malignancy
is revealed by distant metastases [46]. The clinical behavior
of PGLs is generally indolent with long time intervals
between the first symptom and the diagnosis [42, 45]. In case
of sPGLs, hypertension is the main symptom, which can be
continuous, intermittent, or paroxysmal. HNPGLs are char-
acterized by a mass effect or the infiltration of adjacent
anatomical structures such as the temporal bone, the middle
ear, the clivus, the jugular vein, the internal carotid artery, the
cavernous sinus, the hypoglossal canal, and cranial nerves
V–XII [43, 44, 47–52] (Fig. 40.6). A palpable neck mass, as
well as dysphagia, pain, tinnitus, or cranial nerve palsies can
also occur [52]. The several classifications take into account
tumor location, extent, and size. The Fisch classification is
one of the most commonly used [50]. The clinical behavior
of malignant PGLs may also be associated with systemic
symptoms, including fatigue, weight loss, and anorexia, or
clinical manifestations due to metastatic disease, such as
bone metastases. Metastases can occur at the outset or after
many years. Population-based studies have established that
approximately one third of patients having sporadic PGL
have a germline mutation in a known susceptibility gene
[53–56]. Ten known susceptibility genes for PGL have been
identified to date: three genes for three distinct cancer sus-
ceptibility syndromes, VHL for von Hippel–Lindau disease,
R.-O. Mirimanoff and L. Negretti
NF1 for Neurofibromatosis Type 1, and RET for Multiple
Endocrine Neoplasia Type 2 (MEN2); others comprise the
succinate dehydrogenase (SDH) complex subunit genes
(SDHA, SDHB, SDHC, SDHD), the SDH complex cofac-
tors (SDHAF2), and two newly recognized susceptibility
genes, TMEM127 and MAX [57]. SDHB mutations are usu-
ally linked to a higher morbidity and mortality than muta-
tions in the other SDH genes [58]. A recent meta-analysis of
studies concerning SDHB-mutated patients has emphasized
that 31 % of their tumors were malignant [59]. Notably,
VHL- and SDH-mutated PGLs are associated with angio-
genesis, hypoxia, and reduced oxidative response [60] while
the group containing RET- and NF1-mutated tumors is
linked to an abnormal activation of kinase-signaling path-
ways, such as RAS/RAF/MAPK and PI3K/AKT/mTOR [61,
62]. Also TMEM127- and MAX-mutated tumors have been
associated with the activation of mTOR-signaling pathway
[63, 64]. The recommended screening test for initial evalua-
tion of PGLs is the measurement of plasma-free metaneph-
rines or urine-deconjugated differential metanephrines [65].
Metanephrines have a higher sensitivity, ranging around
98–99 %, in comparison to plasma or urine catecholamines
and vanilmandelic acid [66, 67]. The biochemical phenotype
does not allow to differentiate malignant from benign PGLs.
However, the presence of predominantly noradrenaline-
producing PGLs and high levels of plasma dopamine or its
metabolite methoxytyramine may suggest malignancy [66, 68].
Plasma chromogranin A (CgA), which is a protein stored and
cosecreted with catecholamines, is frequently increased in
functioning and non-functioning PGLs [69]. CgA shows a
sensitivity of 83–89 %, and very high plasma levels of CgA
are generally related to malignancy [66]. Computed tomog-
raphy (CT) and magnetic resonance (MRI) are major tools
for the first imaging approach in patients with PGLs. MRI
shows a good accuracy, with a sensitivity of 90–100 % and
specificity of 50–100 %, especially for the detection of extra-
adrenal disease [70]. Ultrasound is used for the detection of
HNPGLs, whereas for other disease sites its role is limited
[70, 71]. Concerning functional imaging, 131I- or 123I-
metaiodobenzylguanidine (MIBG) scintigraphy has been used
as the first-line nuclear medicine technique but 123I-MIBG is
superior to 131I-MIBG, with a sensitivity of 83–100 % and a
specificity of 95–100 % [70]. Regarding PET imaging, soma-
tostatin analogues labelled with gallium-68 can be used. This
tracer seems to be superior to 18F-labelled fluorodeoxyglu-
cose (18F-FDG) in identifying malignant sPGLs [72].
Standard Treatment for Paragangliomas
The treatment of choice of PGL is a matter of controversy.
Surgery has an important role but it is by far not the only option.
With recent imaging tools, innovative surgical techniques, and
40 Skull Base Tumors: Viewpoint—Fractionated Radiotherapy or Stereotactic Radiotherapy
cranial nerve monitoring, results have improved regarding the
possibility of complete removal, and immediate complications
have decreased. However, like for chordomas and chondrosar-
comas of the skull base, a genuine total resection without
sacrifice of cranial nerves is rarely possible. Therefore, postop-
erative cranial nerve damage can be quite substantial, with
potential impairment of nerves VII and IX–XII [45, 48, 49].
For example, in one series, preoperative deficit of cranial nerves
X–XII was between 20 and 30 % and postoperative deficits
increased to 25–50 %, although facial function recovery was
observed in 95 % of patients [49]. The rate of complete surgical
removal is quite variable and is claimed to be between 40 and
96 % [48, 49]. In general, data regarding resection rates and the
actual occurrence of complications are difficult to interpret due
to the heterogeneity and limited size of most series. There are
only few data on local control and long-term survival after sur-
gery. Some surgeons have claimed that in their hands, the
recurrence rate was quite low. Nora et al. have reported on 59
carotid body tumors, of which only 3 (6 %) presented with a
recurrence after surgery, and only one developed metastatic
disease [73]. Pareschi et al. in their series of 37 glomus jugulare
tumors, of which 96 % had a complete resection, found no
relapse, but the mean follow-up was only 4.9 years [48].
Amongst 28 patients with the so-called complex glomus jugu-
lare tumors, Al-Mefty and Teixeira were able to perform a
complete resection in 24 patients and observed altogether two
recurrences [45]. However, in other studies, local control was
much lower, with 70–100 % recurrence rates after surgery alone
[74, 75]. Because these tumors tend to recur after many years,
the actual failure rates are underestimated, especially with short
follow-ups. In addition many patients are lost to follow-up [45,
48]. Long-term mortality due to recurrence after surgery is not
so trivial and was reported to be between 5 and 13 % [76, 77].
Like for chordoma and chondrosarcoma, some authors have
claimed that PGLs are radioresistant and that radiotherapy was
associated with long-term complications [45]. These assertions
were based on old studies in which ancient orthovoltage tech-
niques were used. Indeed, with very conformal linac-based
techniques, fractionated external beam radiotherapy represents
an excellent alternative, or sometimes a complementary treat-
ment to surgery. Cole et al. have treated 32 tumors of the glo-
mus jugulare or glomus vagale with megavoltage units with
doses of 45 Gy in 5 weeks [78]. Their very long-term results
have yielded a local control rate of 94 % at 10 years [78].
Konefal et al. have treated 26 patients with 45–50 Gy; amongst
these, 15 of 16 glomus tympanicum and four of six glomus
jugulare tumors achieved a long-term control, with a mean
follow-up period of 10.5 years [79]. In a large series, 80 PGLs
of the temporal bone, carotid body, or glomus vagale were
treated by radiotherapy alone (72) or postoperatively (8) [80].
Local control was 94 % and only 5 local recurrences were
observed between 2.6 and 18.8 years, of which two could be
salvaged by surgery [80]. Other groups could obtain good local
523
controls with exclusive or postoperative radiotherapy [74, 75].
Powell et al. have treated 46 patients with glomus jugulare or
glomus tympanicum tumors with doses between 45 and 50 Gy
and a 75 % actuarial control was achieved at 25 years [75].
Notably, in these radiotherapy series, between 18 and 30 %
were previously, and sometimes heavily pretreated by surgery.
Contrarily to older reports, complication rates were low with
the most recent radiotherapy techniques [78–80]. Previously, it
was thought that these tumors were “radioresistant” because
after irradiation, they shrink but rarely disappear completely on
follow-up [78]. Therefore, local control after radiotherapy
should be defined as the absence of clinical and radiological
progression. Springate et al. have reviewed the outcome of
PGL after various treatments [81]. They noted that local con-
trol after surgery, surgery combined with radiotherapy, or
radiotherapy alone was 86 %, 90 %, and 92 %, respectively.
In the same review, treatment-related morbidity after surgical
excision was frequent, whereas late complications were rare
after radiotherapy [81]. This was more recently confirmed by
Huy et al. who compared in a retrospective and comparative
analysis radiotherapy and surgery in 88 cases of jugular PGLs,
in terms of function and tumor control [82]. Forty-seven
patients with type C or D jugular PGLs underwent surgery after
endovascular embolization between 1984 and 1998, and were
followed up on average during 66 months. Forty-one patients
with type C jugular PGLs were treated by external beam con-
formal radiotherapy between 1998 and 2003 with a total mean
dose of 45 Gy (range, 44–50 Gy); the mean follow-up was 50
months [82]. This study demonstrated that with radiotherapy, a
96 % local control was achieved, whereas with surgery it was
86 % [82]. After surgery, postoperative complications included
dysphagia, aspiration, and facial paralysis. Patients treated by
radiotherapy developed only minor sequelae. In a British retro-
spective study, 21 patients with PGL of the head and neck
region received fractionated external beam radiotherapy with a
median dose of 50 Gy in 30 fractions [83]. With a median fol-
low-up of 55 months, a 92 % 5-year local control rate was
observed [83]. Another retrospective study, with a median
follow-up of 9 years, demonstrated that treatment of PGL by
external beam radiotherapy yielded a 5-year local control rate
of 96 % and a 10- and 15-year local control rate of 90 % [84].
Fractionated Stereotactic Radiotherapy
of Paraganglioma
Patient Selection
Since external beam radiotherapy is an effective alternative
to surgery, newer, high-precision, high-dose radiotherapy
techniques such as STRS represent a logical further option.
With STRS, a smaller volume of normal tissue exposed to
the effect of radiation can be expected [47]. The criteria for
patient selection for RS or STRS for PGL are comparable to
524 R.-O. Mirimanoff and L. Negretti

Table 40.3 Treatment outcomes, paraganglioma

Median
No. of marginal Local Median
Series Year patients Technique dose (Gy) control Survival (%) follow-up Neurologic status
Eustacchio et al. [43] 1999 13 GKRS 13.5 PR 4/10 11/13 46 months Improved in 5/13
SD 6/10 Unchanged in 5/13
Stroke in 1/13
Liscak et al. [42] 1999 66 GKRS 16.6 PR 15/47 NS 24 months Improved in 15/52
SD 28/47 Unchanged in 34/52
Worsened in 3/52
Jordan et al. [86] 2000 8 GKRS 16.3 PR 4/7 NS 27 months Improved in 4/8
NC 3/7 Unchanged in 3/8
Worsened in 1/8
Foote et al. [47] 2002 25 GKRS 15 PR 8/25 80 % 5 years 37 months Improved in 15/25
Unchanged in
NC 17/25 10/25
Feigenberg et al. [85] 2002 5 Linac RS 15 PR or SD 3/5 100 % 27 months NS
PRO 2/5
Zabel et al. [44] 2004 22 Linac STRT 57.6 PR 7/22 89.5 % 5 and 10 5.7 years Improved in 13/22
years
Feigl et al. [87] 2006 12 GKRS 17 SD 13/22 100 % 33 months Unchanged in 7/22
Ganz et al. [88] 2009 14 GKRS 13.6 PRO 2/22 100 % 28 months Worsened in 2/22
Genç et al. [89] 2010 18 GKRS 15.6 90 % LC 5 and 17/18 41.5 months 1 hearing loss
10 years
Lee et al. [90] 2011 14 GKRS 13.7 100 % 100 % 40 months Improved in 12/14
Lieberson et al. [92] 2012 41 Linac STRT 20 100 % 100 % 4.8 years Improved in 10/18
94 % Unchanged in 7/18
100 % Worsened in 1/18
93 % cranial nerve
preservation
1 persistent vertigo

those used for external beam radiotherapy. RS and STRT can
be used either as primary treatment, at progression after one
or multiple surgeries, after embolization, postoperatively, or
even after previous external beam radiotherapy [42–44, 47,
85]. The indications for STRT are essentially the same as
those for RS, except that STRT combines the precision of
stereotactic positioning with the radiobiological advantage
of fractionation, especially in large tumors [12, 44]. In the
Heidelberg experience with STRT for PGL, the median tar-
get volume was 71.8 cm3 (range, 10.5–212 cm3) [44], which
is in sharp contrast with the median volumes described in the
RS series, which ranged from 5.7 cm to 10.8 cm3 (range 0.5–
27 cm3) [42, 43, 47, 85, 86].
Treatment Techniques
Pretreatment imaging includes high-resolution CT, MRI, and
preferably both and wherever needed angiography [43, 47].
For treatment planning, CT and MRI fusion are required,
especially with linac-based RS/STRT. In both cases, ultra-
thin slices are required. Head frames (RS) or relocatable
head masks (STRT) are used for imaging under stereotactic
guidance and treatment. For STRT, the Heidelberg group
defined the CTV as the macroscopic tumor on MRI plus a
10-mm margin along the involved vessels [44]. They added a
2-mm safety margin for the PTV. The median total dose was
57.6 Gy at a median daily dose of 1.8 Gy [44].
Treatment Outcomes
Because of the rare occurrence of PGL, the published experi-
ence with either RS or STRT is still rather limited. Table 40.3
[42, 43, 47, 85, 86] summarizes the available data with RS
and STRT. Altogether, each RS studies have gathered a lim-
ited number of cases mainly by GKRS [42, 43, 47, 86–90]
and less by linac-based RS [85] (Table 40.3). The results dis-
closed a good to excellent local control, especially in the
most recent series. Overall, response rates included 41 %
of partial responses, 57 % of stable lesions, and only 3 % of
progressions. When reported, 5-year actuarial local control
rates varied between 90 and 100 %. The neurological status
was improved in 40 %, stable in 55 %, and worse in 5 % of
cases. Information on long-term survivals is more limited,
but it appears that when described, the 5-year overall sur-
vival was between 80 and 100 %. Chen et al. have conducted
a systematic review evaluating GKRS for PGLs: their review
40 Skull Base Tumors: Viewpoint—Fractionated Radiotherapy or Stereotactic Radiotherapy
which included also their own cases consisted in a pooled
analysis from 11 selected studies and confirmed the excellent
(90.5 %) success rate after GKRS treatment [91]. The
Heidelberg series of STRT for PGL also discloses encourag-
ing results, with a 32 % rate of partial response, 59 % of
stable disease, and 9 % of progression [44]. The apparently
slightly worse rate of progression is likely to be due on one
hand to the longer follow-up than that of the RS series and on
the other hand to tumors with much larger volumes (vide
supra). The neurologic improvement was also quite good,
with 59 % of patients who improved, 32 % who remained
stable, and 9 % who deteriorated [44]. Altogether, the
Heidelberg data are the most reliable in terms of length of
follow-up and adequate actuarial reporting of local control
and survival. The experience at Stanford on 41 lesions in 36
patients confirms also that STRT results in an excellent
100 % local control with very few complications [92]. As far
as complications of RS are concerned, it is difficult to distin-
guish between neurologic worsening due to treatment and
due to recurrence. However, the rate of reported complica-
tions appears to be low. Eustacchio et al. had no single
case of complications in their 13 cases [43]. In the multi-
institutional report of Liscak et al., three cases of neurologic
deficits out of 52 patients are described, 2 of which were
permanent: facial nerve impairment and deafness in one case
and facial nerve impairment and vertigo in another [42]. Two
further cases of inner ear inflammatory complications are
also noted [42]. From the Mayo Clinic experience, only one
case of temporary vertigo is described [47]. Again, this low
rate of complications should be interpreted with caution as
the average median follow-up of the RS studies is altogether
not very long. Out of the 22 patients who benefited from
STRT, 3 experienced temporary xerostomia and 2 temporary
taste impairment, 4 had middle-ear effusion, but none of
these had more than a grade 2 CTC reaction, and all recuper-
ated; no late adverse reactions from STRT were observed at
follow-up [44].
Conclusion
In conclusion, fractionated external beam radiotherapy, RS,
and STRT appear to be safe and efficient therapeutic modali-
ties in the primary treatment or at progression for PGL. Yet
available follow-ups remain limited for most RS series. With
regard to STRT, the results also appear to be quite good, with
longer time of evaluation, knowing also that on average,
tumors were larger. External beam radiotherapy, RS, and
STRT deserve continuous experience, but it is reasonable to
state that they represent possible and safe alternative treat-
ments for these skull base tumors.
525
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 Head and Neck Tumors
Daniel T.T. Chua
Introduction
The technique of stereotactic radiosurgery has proved to be
effective in the treatment of a variety of intracranial tumors,
both benign and malignant, and abnormal conditions such as
vascular malformations. Because of the proximity and the
frequent involvement of the base of the skull, head and neck
tumors as a group have also been explored as targets for
extracranial radiosurgery. Gamma Knife and gantry-based
linear accelerator have been used to treat head and neck can-
cers using either a rigid or relocatable frame. Gamma Knife
however has a more limited role for treating lesions below
skull base. Advances in radiation delivery and image-guided
radiotherapy have lead to the development of new techniques
and systems capable of performing stereotactic radiotherapy
with improved dose conformity and comparable precision.
CyberKnife (Accuray Incorporated, Sunnyvale, CA, USA) is
a frameless robotic radiosurgery system that uses image-
guided radiotherapy from a lightweight 6-MV linear accel-
erator mounted on a robotic arm. The system can deliver
isocentric or non-isocentric beams from 120 different direc-
tions with six degrees of freedom. Real-time image guidance
system is used to ensure accurate localization and tracking of
target. Because malignant head and neck tumors are usually
highly aggressive and infiltrative, radiosurgery alone is sel-
dom appropriate as the primary treatment modality for newly
diagnosed disease. Radiosurgery, however, may offer signifi-
cant benefits when used as a salvage treatment for recurrent
disease or as a boost treatment after conventional radiother-
apy. Among all the head and neck cancers, nasopharyngeal
carcinoma (NPC) has attracted more attention with regard to
the application of radiosurgery due to its unique location
near the skull base, pattern of growth and invasion, relative
D.T.T. Chua, M.D., F.R.C.R., F.H.K.C.R. (*)
Department of Radiotherapy, Hong Kong Sanatorium & Hospital,
Happy Valley, Hong Kong
e-mail: danielchua@hksh.com
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_41, © Springer Science+Business Media New York 2015
41
radiosensitivity, and high incidence observed in some countries.
In this chapter, the clinical results of using radiosurgery in
the management of head and neck tumors are reviewed and
discussed, with emphasis on the management of NPC.
Nasopharyngeal Carcinoma
Local Control After Radiotherapy
Radiotherapy is the mainstay of treatment for all stages of
NPC without distant metastases. The largest series on treat-
ment outcome of NPC was reported by Lee et al. based on
5,037 patients treated at a single institution during the period
1976–1985 [1]. The 10-year local control and survival rates
were 61 % and 43 %, respectively. In the past decade,
advances in both imaging and radiotherapy techniques have
had significant impact on the management of NPC. As a
result, the outlook of patients with NPC treated in recent
years, even for those presenting with a more advanced stage,
is likely to have improved significantly. This is supported by
a recent report on the outcome of patients with newly diag-
nosed NPC treated in the modern era. In that report, based on
the results of 2,687 patients treated at all public oncology
centers in Hong Kong during the period 1996–2000, the
observed 5-year local control and survival rates were 85 %
and 75 %, respectively [2]. The 5-year local control rates for
T1–2 and T3–4 diseases were 88 % and 79 %, respectively.
These patients were mostly treated by radiotherapy alone,
and only 23 % had additional chemotherapy. The results
showed significant improvement when compared with those
reported in old series. Despite the improved results, about
11.7 % of patients still developed local failures, and 8.2 %
had isolated local failures without regional or distant failures.
In order to further improve local tumor control, combined
chemoradiotherapy has been used in advanced-stage disease,
which showed improvement in local control compared with
radiotherapy alone [3–6]. Another way to improve local
control is by escalating the dose delivered to primary tumor
529
530
based on the established dose–volume–control relationships
in NPC [7, 8]. For early-stage disease, dose escalation can be
achieved by brachytherapy using intracavitary intubation.
For advanced-stage disease, dose escalation is best deliv-
ered by either conformal or stereotactic radiotherapy.
Conventional Salvage Treatment Options
for Local Failures and Selection Criteria
Conventional Salvage Treatment Options
Aggressive salvage treatment should be considered and
offered to patients with local failures of NPC whenever pos-
sible because a significant proportion of them can still
achieve long-term survival after successful treatment. Many
salvage treatments are available, and the choice of method
depends on several factors including extent of disease, site
of involvement of disease, any synchronous nodal relapse,
cumulative radiation dose already received by the patient,
the patient’s general condition and preference, and expertise
available. In general, salvage treatments for NPC can be
classified into three types: surgery using different approaches
such as maxillary swing or transmandibular resection;
brachytherapy using intracavitary intubation, mold applica-
tion, or gold grain implantation; and external reirradiation
using various techniques including stereotactic radiosurgery
and radiation.
Patient Selection Criteria for Conventional
Salvage Treatment
A team approach involving both radiation oncologist and
head and neck surgeon is recommended in formulating a
treatment plan for local failures of NPC. All patients should
be restaged by physical examination, nasopharyngoscopy
and biopsy, and computed tomography (CT) and/or magnetic
resonance imaging (MRI) of nasopharynx and neck. Patients
with disease confined to nasopharynx (rT1) are suitable can-
didates for either surgery or brachytherapy. For brachyther-
apy, patients with unilateral small-volume disease are best
treated by gold grain implantation, whereas those with more
diffuse or bilateral disease should be treated by intracavitary
intubation. Surgery should be considered in patients with
bulky disease, especially those already receiving a high
cumulative radiation dose to nasopharynx. Patients with lim-
ited extension to nasal fossa, parapharyngeal space, and oro-
pharynx (rT2) may also be surgical candidates although most
would require external reirradiation. For patients with skull
base involvement (rT3) or intracranial extension of disease
(rT4), external reirradiation is usually the only option avail-
able, although reirradiation with curative intent is often
difficult due to the large numbers of critical structures in the
vicinity of the target that were already irradiated to a high
dose during primary radiotherapy.
D.T.T. Chua
Results of Conventional Salvage Treatments
In salvaging local failures of NPC, a better outcome was
usually observed in patients treated for persistent disease
after primary radiotherapy then recurrent disease. Brachy-
therapy in the form of intracavitary intubation or gold grain
implantation can be employed in salvaging early-stage
local failure. Our institution has been using gold grain
implantation as salvage treatment for NPC since 1986, and
the reported 5-year local control rates were 87 %, 63 %,
and 23 % for persistent disease, first recurrence, and second
recurrence, respectively [9]. Using high-dose-rate intracav-
itary intubation, Leung et al. reported an excellent 5-year
local relapse-free survival rate of 85 % in 87 NPC patients
with persistent local disease after radiotherapy [10]. The
same group also reported a lower control rate when intra-
cavitary brachytherapy alone was used in salvaging local
recurrence in a small group of patients (n = 8), with a 3-year
local relapse-free survival rate of 42 %. Surgical resection
of persistent or recurrent NPC has also been attempted
using various approaches, with reported control rates of
31–52 % [11–14], but is not commonly practiced because
of limited experience in most centers. For patients requiring
external reirradiation usually due to extensive disease not
amenable to brachytherapy or surgery, treatment results
remained poor especially in advanced T stage. The reported
5-year survival rates after external reirradiation ranged
from 7.6 to 36 % with the use of conventional two-
dimensional treatment planning and radiotherapy [15–17]
and 12.4 % in a mixed cohort of patients treated either with
conventional two-dimensional radiotherapy or three-
dimensional conformal radiotherapy [18]. A high incidence
of late complication was commonly observed after external
reirradiation, the majority being neurologic damage and
soft tissue fibrosis. In our experience, patients with rT1–2
NPC treated by conventional two-dimensional external
reirradiation alone had a 5-year survival rate of about 57 %,
but late neuroendocrine complications were common [17].
The combination of intracavitary brachytherapy and exter-
nal radiotherapy has also been employed for recurrent NPC
with the advantage of sparing more normal tissues while
achieving a high total dose to the target. In one series by
Lee et al., combined intracavitary brachytherapy and
external radiotherapy yielded a superior 5-year local con-
trol rate of 45 % compared with 32 % by external radio-
therapy and 29 % by brachytherapy [19]. The outcome of
patients with local failures of NPC may improve with the
use of intensity-modulated radiation treatment, which can
achieve better dose distribution while sparing dose-limiting
critical structures [20]. Using intensity-modulated radiation
treatment for high-dose (68–70 Gy) reirradiation of NPC,
Lu et al. reported 100 % locoregional control rate in
49 patients, although the longest follow-up was only about
1 year [21].
41 Head and Neck Tumors
Fig. 41.1 (a) Baseline CT of a patient with recurrent T1 nasopharyn-
geal carcinoma showing mass at left lateral wall of nasopharynx
(arrow). (b) Planning CT showing isodose distribution of target cov-
Radiosurgery for Local Failures of NPC:
The Queen Mary Hospital Experience
(Case Study 41.1 and Case Study 41.2)
Case Study 41.1
A 75-year-old man was diagnosed with T1N0 NPC in
1985. He underwent external radiotherapy with a dose
of 61 Gy delivered in 26 fractions using a fraction dose
of 2.5–3 Gy. The biological equivalent dose to 2 Gy
(using α/β (alpha/beta) of 10) was 65 Gy. He was inci-
dentally found to have local recurrence in 2000, after a
long latency period of 15 years. Assessment showed
a small tumor involving the left lateral wall of the naso-
pharynx, and biopsy showed undifferentiated carci-
noma, hence rT1 disease (Fig. 41.1a). Biopsies from
posterior and right lateral walls were negative. Surgery
was offered but refused by the patient, and the site of
lesion was considered not suitable for brachytherapy
because of involvement of the cushion. Stereotactic
radiosurgery using a single isocenter with 27.5-mm
collimator was performed, with a dose of 12.5 Gy deliv-
ered to 80 % isodose line (Fig. 41.1b). In this patient,
both imaging and endoscopy showed that tumor was
lateralized and confined to the lateral wall; hence, only
part of the nasopharynx was treated. Follow-up CT scan
performed at 3 and 12 months after radiosurgery showed
complete resolution of tumor (Fig. 41.1c). Endoscopy
and biopsy after radiosurgery were also negative. The
patient has now been followed up for more than 4 years
with no evidence of relapse or major complications.
Patient Population
Between March 1996 and February 2005, 48 patients
received radiosurgery as a salvage treatment for local
failures of NPC at Queen Mary Hospital, Hong Kong.
531
ered by single isocenter. The prescribed dose to target periphery was
12.5 Gy. (c) Follow-up CT taken 12 months after radiosurgery showing
complete resolution of tumor
Case Study 41.2
A 45-year-old man was diagnosed with T3N0 NPC in
1997. He received a course of external radiotherapy
with a dose of 68 Gy in 34 fractions followed by a
booster dose of 10 Gy in four fractions to the right
parapharyngeal space. He was found to have local
recurrence involving the right side of the nasophar-
ynx extending to the nasal fossa about 1 year after
treatment (Fig. 41.2a). Biopsies from the nasal fossa
and the right posterior wall both showed undifferenti-
ated carcinoma, but biopsies from the left side of the
nasopharynx were negative. The recurrent stage was
rT2N0, which was not suitable for brachytherapy or
surgery. The patient was treated with stereotactic
radiosurgery using two isocenters with collimator
sizes of 25 and 27.5 mm. Because of the larger bulk
of tumor, a higher dose of 14 Gy was delivered to
80 % isodose line (Fig. 41.2b). Endoscopy and biop-
sies after radiosurgery showed no evidence of resid-
ual disease. Follow-up CT was performed at 6 months
after treatment, which showed complete resolution of
tumor (Fig. 41.2c). He was found to have asymptom-
atic right temporal lobe necrosis 15 months after
radiosurgery. The complication was thought to be
related more to the first course of radiotherapy, which
delivered a high dose to the right temporal lobe to
ensure adequate coverage of tumor extent. He was
later found to have lung metastases and died of
uncontrolled systemic disease 24 months after
radiosurgery.
All patients had previously received radical radiotherapy for
undifferentiated type of NPC with or without concurrent/
adjuvant chemotherapy. Although the disease in some
patients that relapsed after a long latency period may actu-
ally represent a second primary in the nasopharynx, most
532
Fig. 41.2 (a) Baseline CT of a patient with recurrent T2 nasopharyn-
geal carcinoma showing mass lesion at right side of nasopharynx
extending to nasal fossa. (b) Planning CT showing isodose distribution
patients with local failures had residual tumor after prior
treatment. We arbitrarily classified these residual tumors into
persistent and recurrent disease based on the time interval
from primary radiotherapy: persistent disease was defined as
local failure diagnosed within 6 months of completion of pri-
mary radiotherapy, and recurrent disease was defined as that
occurring beyond 6 months. Using these definitions, half of
the patients were treated for persistent disease and the other
half for recurrent disease. None of these patients received
additional treatment after radiosurgery unless progression or
further failure was documented. Table 41.1 summarizes patient
characteristics of the whole group treated by radiosurgery:
those with persistent disease and those with recurrent disease.
Prior to radiosurgery, all patients were restaged by physi-
cal examination, nasopharyngoscopy and biopsy, and CT of
nasopharynx and neck. Patients with disease confined to
nasopharynx or with limited extension to nasal fossa,
parapharyngeal space, and oropharynx were first evaluated
jointly by a surgeon and a radiation oncologist for brachy-
therapy or surgery, and radiosurgery was offered only to
those patients whose disease was deemed not amenable
to these salvage treatments. At our institution, brachytherapy
for persistent or recurrent NPC was usually performed using
gold grain implantation. This technique was applicable only
to patients with a well-defined and relatively small-volume
tumor confined to the nasopharynx. Patients with extensive
mucosal recurrence involving a large area were not suitable for
gold grain implantation. In addition, patients with relapse at
the cushion near the opening of eustachian tube were also
not suitable for the procedure because gold grain could not
be directly implanted into the relatively thin mucosa overly-
ing the cartilaginous cushion. In general, patients with small-
volume mucosal tumor were usually treated by gold grain
implantation, with surgery reserved for those with more
D.T.T. Chua
of target covered by two isocenters. The prescribed dose to target
periphery was 14 Gy. (c) Follow-up CT taken 6 months after radiosur-
gery showing complete resolution of tumor
bulky tumor or those with relapse at the cushion. Patients
with disease amenable to surgery or brachytherapy who
refused these treatments or were considered to be medically
contraindicated for these procedures were also offered
radiosurgery.
Target Localization
Tumor extent was assessed by imaging and endoscopic
examination before radiosurgery. For imaging study, axial
contrast CT with a slice thickness of 2.5–3 mm was per-
formed in all patients, supplemented by axial contrast MRI
with a slice thickness of 3 mm in 73 % of patients. PET-CT
was not performed in this patient group for target localiza-
tion, although we are currently also evaluating its role in
salvaging local failures of NPC. Target volume was defined
as any abnormal soft tissue mass and/or contrast-enhancing
areas as shown in axial imaging plus a margin of about
2–3 mm. Endoscopic examination was always performed
irrespective of imaging findings to assess the mucosal extent
of tumor, including any spread to nasal cavity or oropharynx.
In our experience, endoscopic examination is the most reli-
able means to access the mucosal extent of disease and
should not be omitted even when imaging showed that only
part of the nasopharynx was involved. During endoscopy,
multiple biopsies were taken from both sides of the naso-
pharynx to assess the macroscopic as well as microscopic
extent of tumor. In patients just completing primary radio-
therapy, biopsies were routinely taken from bilateral roofs,
lateral walls, and posterior walls. In patients with tumor
apparently localized to one part of the nasopharyngeal
mucosa, mapping of tumor extent was performed by taking
multiple biopsies from grossly uninvolved mucosa surround-
ing the tumor. The results of mapping were then used to
guide the extent of target coverage for radiosurgery.
41 Head and Neck Tumors 533

Table 41.1 Characteristics of patients treated with radiosurgery for local failures of nasopharyngeal carcinoma at Queen
Mary Hospital, Hong Kong
Persistent disease (n = 24) Recurrent disease (n = 24) All (n = 48)
Gender
Male (n) 17 18 35
Female (n) 7 6 13
Age
<50 (n) 14 14 28
≥50 (n) 10 10 20
Median (years) 45 47 46
Range (years) 32–86 35–84 32–86
rT classification
rT1 (n) 18 9 27
rT2 (n) 2 4 6
rT3 (n) 4 7 11
rT4 (n) 0 4 4
Prior local failures
Yes (n) 0 9 9
No (n) 24 15 39
Previous salvage Rx
Surgery (n) 0 4 4
ERT (n) 0 7 7
Radiosurgery (n) 0 1 1
Cumulative ERT dose
65–68 Gy (n) 22 16 38
70–76 Gy (n) 2 1 3
125–130 Gy (n) 0 7 7
Interval from end of first ERT
≤6 months (n) 24 0 24
>6 months to 1 year (n) 0 4 4
>1–2 years (n) 0 3 3
>2–3 years (n) 0 5 5
>3 years (n) 0 12 12
Median (months) 4 36 8
Range (months) 3–6 9–197 3–197
ERT external radiotherapy

Radiosurgery Planning and Treatment
Radiosurgery was performed using the commercial XKnife
system (Radionics, Burlington, MA) to deliver multiple
non-coplanar arcs of photon to the target with a modified
6-MV linear accelerator (Clinac 600C; Varian, Milpitas,
CA). Head immobilization and target localization were per-
formed with the Brown–Roberts–Wells head frame and
stereotaxic system (Radionics). The head frame was ancho-
red by placing two anterior head pins to the forehead and
two to the occiput.
The head frame was not placed in a strict horizontal posi-
tion but with the posterior side tilted downward to ensure that
the localizer ring would include the whole nasopharynx.
Using this approach, it was possible to treat the entire naso-
pharynx and adjacent soft tissues, although special attention
should be given to those with disease extending down to
the junction of the oropharynx. Although some investigators
adopted the approach of anchoring the head ring anteriorly to
the zygomas to ensure complete coverage of the nasopharynx,
we did not find this to be necessary for most patients. The
target volume was localized as described above. For rT1
tumor, target confined to one side of nasopharynx was usually
covered using one isocenter, whereas target involving both
sides was covered using one or two isocenters. For rT2–4
tumors, target was usually covered by one or two isocenters.
We found it seldom necessary to use more than two isocenters.
The target volume was treated using 3–5 arcs of beams with a
degree of 90–210°. The following dose limits were set to the
critical structures: 5 Gy to brain stem, 4 Gy to optic appara-
tus, and 5 Gy to temporal lobes. An additional dose limit of
8 Gy to internal carotid artery was later set to reduce the risk
of hemorrhage. Most patients received a dose of 12.5 Gy
delivered to the 80 % isodose line. Table 41.2 summarizes the
radiosurgery treatment.
534 D.T.T. Chua

Table 41.2 Summary of radiosurgery treatment parameters of patients treated at Queen Mary Hospital, Hong Kong
Parameters Persistent disease Recurrent disease All
Number of isocenters
One (n) 20 19 39
Two (n) 4 4 8
Three (n) 0 1 1
Size of collimator
≤20 mm (n) 4 1 5
>20–30 mm (n) 19 16 35
>30 mm (n) 1 7 8
Median (mm) 25 30 25
Range (mm) 12.5–35 15–37.5 12.5–37.5
Target volume
<10 cm3 (n) 23 15 38
≥10 cm3 (n) 1 9 10
Median (cm3) 4.0 5.7 4.6
Range (cm3) 1.3–14.5 2.7–30.7 1.3–30.7
Prescribed dose to 80 % isodose line
<12 Gy (n) 3 5 8
12–13 Gy (n) 17 13 30
>13 Gy (n) 4 6 10
Median (Gy) 12.5 12.5 12.5
Range (Gy) 11.1–18 8–14 8–18
Dose to isocenter
<15 Gy (n) 4 5 9
15–16 Gy (n) 16 13 29
>16 Gy (n) 4 6 10
Median (Gy) 15.6 15.6 15.6
Range (Gy) 13.9–22.5 10–17.5 10–22.5

Tumor Control After Radiosurgery
Thirty-seven (77 %) patients achieved complete regression
of tumor after radiosurgery. All patients (100 %) treated for
persistent disease achieved complete regression of disease
compared with 13 (54 %) patients for recurrent disease.
Local failure after radiosurgery occurred in 22 (46 %)
patients, regional failure in 5 (10 %) patients, and distant
metastasis in 7 (15 %) patients. For those patients who failed
locally after radiosurgery, two received brachytherapy with
intubation and both were salvaged, four had nasopharyngec-
tomy and three were salvaged, and five had external radio-
therapy and two were salvaged. One patient with local failure
outside the radiosurgery-treated volume was salvaged by
second radiosurgery. Three-year local relapse-free and over-
all survival rates for all patients were 52 % and 66 %, respec-
tively. Patients treated for persistent disease had better
outcome than those treated for recurrent disease: 3-year local
relapse-free survival rate was 76 % in the former and 29 % in
the latter (Fig. 41.3), and the corresponding 3-year overall
survival rates were 81 and 54 % (Fig. 41.4). Patients with
advanced T classification at the time of relapse had a poorer
control rate after radiosurgery: 3-year local relapse-free
survival rates were 69 % for rT1 disease, 40 % for rT2–3
disease, and 0 % for rT4 disease (Fig. 41.5). Patients with
bulky tumor also had a poorer control rate after radiosurgery:
3-year local relapse-free survival rate was 61 % for target
volume <10 cm3 compared with 20 % for target volume
≥10 cm3 (Fig. 41.6).
Complications
Radiosurgery was well tolerated, and we did not observe any
acute complications. In assessing late effects after treatment,
it was not possible to attribute the cause of complication to
radiosurgery or external radiotherapy. Some patients also
received another course of external radiotherapy either before
or after radiosurgery, and they would expect to have a
relatively high incidence of late complications even without
radiosurgery. Table 41.3 summarizes the late complications
observed in our patients, which included all observed compli-
cations (other than xerostomia) irrespective of whether they
were thought to be mainly caused by radiosurgery or not.
Overall, 31 % of patients developed one or more late compli-
cations. The percentage decreased to 24 % if patients with two
courses of radiotherapy before radiosurgery were excluded,
41 Head and Neck Tumors 535

1.0 1.0

Local Relapse-free Survival Probability

Local Relapse-free Survival Probability

0.9 0.9
Persistent disease 0.8
0.8

0.7 0.7

0.6 0.6 rT1

0.5 0.5

0.4 0.4

Recurrent disease 0.3 rT2-3

0.3
0.2
0.2
rT4
p = 0.0004 0.1
0.1 p = 0.0042
0.0
0.0
0 12 24 36 48 60 72 84 96 108 120
0 12 24 36 48 60 72 84 96 108 120
Months after Radiosurgery Months after Radiosurgery

Fig. 41.3 Comparison of local relapse-free survival curves in patients Fig. 41.5 Comparison of local relapse-free survival curves according
with persistent and recurrent nasopharyngeal carcinoma treated by to recurrent T classification after stereotactic radiosurgery for local fail-
stereotactic radiosurgery at Queen Mary Hospital ures of nasopharyngeal carcinoma at Queen Mary Hospital

1.0 1.0
Local relapse-free survival probability

0.9 0.9

0.8 0.8
Overall Survival Probability

Persistent disease
0.7 0.7

0.6 0.6

0.5 0.5 Tumor volume < 10 cc

0.4 0.4

0.3 Recurrent disease 0.3

0.2 0.2 Tumor volume > or = 10 cc
0.1 p = 0.035 0.1 p = 0.0041
0.0 0.0
0 12 24 36 48 60 72 84 96 108 120 0 12 24 36 48 60 72 84 96 108 120
Months after Radiosurgery Months after radiosurgery

Fig. 41.4 Comparison of overall survival curves in patients with per- Fig. 41.6 Comparison of local relapse-free survival curves according
sistent and recurrent nasopharyngeal carcinoma treated by stereotactic to tumor volume after stereotactic radiosurgery for local failures of
radiosurgery at Queen Mary Hospital nasopharyngeal carcinoma at Queen Mary Hospital

Table 41.3 Late complications after radiosurgery for locally recurrent nasopharyngeal carcinoma at Queen Mary Hospital, Hong Kong
Complication One course of ERT (n = 36) Two courses of ERT (n = 12) One to two courses of ERT (n = 48)
Cranial neuropathy 2 5 7
Temporal lobe necrosis 4 3 7
Hypopituitarism 1 1 2
Carotid artery aneurysm 1 1 2
Trismus 0 1 1
None 29 4 33
ERT external beam radiotherapy, n number of patients
536
and it further decreased to 19 % if those with a second course
of radiotherapy before or after radiosurgery were excluded.
Patients with more advanced tumor tend to have a higher risk
of developing late complications. The percentages of patients
who developed late complications were 19 % in rT1 disease,
33 % in rT2 disease, 46 % in rT3 disease, and 75 % in rT4
disease. Common late complications observed were cranial
neuropathy and temporal lobe necrosis, both occurring in
about 15 % of patients. Two patients developed severe epi-
staxis, and both were found to have internal carotid artery
aneurysm located at cavernous sinus and retropharyngeal
space. Stenting was performed in both patients, which suc-
cessfully controlled the bleeding, and there were no treatment-
related deaths.
Radiosurgery Treatment Results for Local
Failures of NPC in Other Series
Radiosurgery Alone
Firlik et al. first reported the use of Gamma Knife radiosur-
gery in a patient with recurrent NPC and noted complete
regression of tumor after delivering a dose of 20 Gy to 50 %
isodose line [22]. Miller et al. reported another three patients
with NPC that were also treated by Gamma Knife: one
patient was noted to have symptomatic improvement before
disease progression, and one patient had not responded
to the treatment [23]. Buatti et al. treated three patients
with recurrent NPC by Linac radiosurgery using a dose of
12.5 Gy to 80 % isodose line [24]. Two patients also received
reirradiation, one before and the other after radiosurgery.
Of these two patients, one remained disease-free 1 year after
treatment, whereas the other had local recurrence 6 months
after treatment. The third patient received radiosurgery
alone for recurrent disease and had neurologic deterioration
of uncertain etiology 6 months after the treatment. Kocher
et al. treated five patients with recurrent NPC at the skull
base using radiosurgery with a dose of 15–24 Gy [25].
Only one patient’s tumor was controlled after treatment.
Three patients developed late complications, including two
with fatal internal carotid artery hemorrhage. Cmelak et al.
reported using Linac radiosurgery in treating 12 recurrent
NPC lesions in nine patients [26]. The dose delivered ranged
from 15 to 20 Gy with a median of 18 Gy. With a median
follow-up of 17 months, the crude local control was 53 %
(7/12), and only one patient developed radiation-induced
cranial neuropathy.
Radiosurgery as a Boost After External
Reirradiation
Chen et al. reported the outcome of 11 patients with rT3–4
NPC after conformal radiotherapy and Linac radiosurgery
[27]. The radiosurgery dose ranged from 10 to 19 Gy with a
D.T.T. Chua
median of 14 Gy. Significant regression of tumor was noted
in five patients and limited regression in another three. Chang
et al. reported 15 patients with locally recurrent NPC who
received external reirradiation followed by radiosurgery
using a dose ranging from 8 to 15 Gy [18] and noted a 3-year
survival rate of 52 %. Pai et al. reported 36 patients with
recurrent NPC also treated with external reirradiation fol-
lowed by radiosurgery boost [28]. The radiosurgery dose to
target periphery ranged from 8 to 20 Gy with a median
of 12 Gy. A 3-year local control rate of 58 % was achieved.
In these reports, it is uncertain whether radiosurgery was
used to boost the entire or partial tumor volume, with the
intention to further escalate the total dose or to selectively
boost the volume that was underdosed during external
reirradiation.
Fractionated Stereotactic Radiation
Fractionated stereotactic radiation instead of radiosurgery
has also been employed as a salvage treatment for locally
recurrent NPC. Mitsuhashi et al. treated three patients with
rT1 NPC using stereotactic radiation at a dose of 50–64 Gy,
and all three patients achieved complete response and
remained free of local disease at 4–61 months [29]. The
report by Mitsuhashi et al. also included another patient with
mucoepidermoid carcinoma of the nasopharynx treated by
stereotactic radiation after previous two courses of external
radiotherapy, but the treatment was complicated by rupture
of the internal carotid artery resulting in patient death. Using
hypofractionated stereotactic radiation at a dose of 24 Gy in
2–4 fractions, Orecchia et al. reported a less satisfactory out-
come in 13 patients with locally recurrent NPC, with a 3-year
survival rate of 31 % [30]. Ahn et al. treated 12 patients with
recurrent NPC by stereotactic radiation using a median dose
of 54 Gy and reported a 2-year local control rate of 92 %
[31]. Yau et al. also reported improved local control with
fractionated stereotactic radiation using a median dose of
15 Gy at 6–8 Gy per fractions in patients with persistent local
disease of NPC when compared with brachytherapy of 20 Gy
[32]. Xiao et al. treated 50 patients with persistent or recur-
rent NPC with a dose ranging from 14 to 35 Gy using a frac-
tion dose of 5–15 Gy [33]. Of the 31 evaluable patients with
persistent disease, 94 % had complete response with a 1-year
disease-free survival rate of 47 %. Eighteen patients, most of
them with rT3–4 tumor, were treated for recurrent disease.
The complete response rate was 56 % and 1-year disease-
free survival rate was 47 %. In Xiao’s series, however, 16 %
of patients treated by fractionated radiation developed fatal
hemorrhage, probably due to the relatively high cumulative
dose delivered and large fractional dose used in some
patients. The largest series of fractionated stereotactic radia-
tion in salvaging local failures was reported by Wu et al. who
treated 90 patients with local failure of NPC following external
beam radiotherapy [34]. Thirty-four patients had persistent
41 Head and Neck Tumors
disease and received stereotactic radiotherapy using a
Linac-based gantry system with a median dose of 18 Gy in
three fractions. Fifty-six patients had recurrent disease and
they received a median of 48 Gy in six fractions. Three-year
local failure-free rates in those treated for persistent and
recurrent disease were 89.4 % and 75.1 %, respectively. The
corresponding 3-year survival rates were 80.7 % and 45.9 %,
respectively. Late complications occurred in 18.9 % of pati-
ents, including two fatal hemorrhages. Multivariate analysis
showed that recurrent disease and large tumor volume were
independent factors that predicted poor survival. In order to
study the relative efficacy of single versus fractionated
stereotactic radiation in salvaging local failures of NPC, we
conducted a matched-cohort study using our own series and
that of Wu et al. [35]. Forty-eight pairs of patients matched
for failure type, recurrent T stage, and tumor volume were
selected for comparison. Patients received a median dose of
12.5 Gy in single fraction or 34 Gy in 2–6 fractions. Local
control rate at 3 years was better in those treated by multiple
(83 %) than single fraction (51 %). Incidence of severe late
complications was higher with single (33 %) than multiple
(21 %) fractions, including brain necrosis (16 % versus 12 %)
and bleeding (5 % versus 2 %). The differences reflect the
better outcome as a result of a higher dose that can be safely
delivered using fractionated stereotactic radiation.
Radiosurgery as a Boost Treatment After
Radiotherapy for Newly Diagnosed NPC
Radiosurgery has also been employed as a planned boost
treatment after radiotherapy for newly diagnosed NPC. The
treatment is similar in principle to the use of intracavitary
intubation or parapharyngeal boost commonly given after
conventional two-dimensional radiotherapy. Cmelak et al.
treated 11 patients using radiosurgery boost with a median
dose of 12 Gy (7–16 Gy) after a dose of 64.8–70 Gy was
delivered by external radiotherapy [26]. The reported control
rate was 91 % without any major late complications.
Investigators at Stanford University employed single fraction
of radiosurgery as boost treatment using Linac-based gantry
system following standard course of chemoradiotherapy in
patients with NPC and reported an excellent local control.
Tate et al. first reported 23 patients treated with a median
radiosurgery boost dose of 12 Gy (7–15 Gy) after external
radiotherapy; the latter delivered a dose of 64.8–70 Gy to the
primary [36]. All patients had their local tumors controlled
after the treatment although 35 % subsequently developed
regional or distant failures. Le et al. then reported a follow-
up series of 45 patients treated with the same median dose,
and the local control rate was 100 % at 31 months [37]. Late
complications however occurred in 17.8 % of patients and
537
included cranial neuropathy in four, radiological temporal
lobe necrosis in three, and retinopathy in one. In a subse-
quent follow-up report that included 33 patients treated
by Linac-based gantry system and 49 patients treated by
CyberKnife system, excellent local control was again noted
[38]. The 5-year local relapse-free rate was 98 %. Late
complications occurred in 18 % of patients and included
radiological temporal lobe necrosis in ten, retinopathy in
three, and carotid aneurysm in one. The high incidence of
brain necrosis in their series was related to the high number
of patients who received boost treatment for T4 tumors with
intracranial extension, illustrating the higher risk of com-
plication and importance of dose conformity in treating this
group of patients. In these series, radiosurgery was deliv-
ered after treatment using a radical dose of external radio-
therapy with the aim of improving local control by dose
escalation. Ahn et al. used stereotactic radiotherapy instead
as a boost treatment, with a dose ranging from 8 to 40 Gy
[31]. The dose delivered by external radiotherapy ranged
from 36 to 61.2 Gy. The reported 4-year local control and
survival rates were 89 % and 75 %, respectively. One patient
developed mucosal necrosis after the treatment. The
approach by Ahn et al. was to reduce the dose delivered
by conventional radiotherapy and substitute it by stereotac-
tic radiotherapy thereby reducing the incidence of late
complications.
Prognostic Scoring System for Prediction
of Treatment Outcome After Radiosurgery
for NPC
To better define patient group with local failures of NPC that
may benefit from radiosurgery, we have designed a prognos-
tic scoring system based on five adverse factors including
age >45, time interval >6 months from primary radiotherapy,
recurrent T4 disease, prior local failure, and tumor volume of
10 cc or above [39]. Prognostic score was calculated using a
formula based on the presence or absence of these factors
with a differential weighting: score = 0.22 × age (0,1) + 0.27 x
time interval >6 months (0,1) + 0.05 × rT4 disease
(0,1) + 0.28 × tumor volume ≥10 cc (0,1) + prior local recur-
rence (0,1). Patients were then classified as good (score: 0),
intermediate (score: >0–0.5), or poor (score: >0.5) prognostic
group according to the scores. The 5-year local failure-free
rates in patients with good, intermediate, and poor prognos-
tic groups after radiosurgery were 100 %, 42.5 %, and 9.6 %,
respectively. The corresponding 5-year overall survival rates
were 100 %, 5.1 %, and 0 %, respectively. The prognostic
scoring system was subsequently validated using published
reports that contained sufficient clinical information for esti-
mation of the prognostic scores [40].
538 D.T.T. Chua

Table 41.4 Summary of reported treatment outcomes after stereotactic radiosurgery/radiotherapy for local failures of NPC
Local control and Late complications
Authors No. of patients rT classification Treatment SRS/SRT dose survival rates crude rate: all (fatal)
Chua et al. 48 rT1–2: 69 % SRS 8–18 Gy LC: 52 % (3 years) 31 % (0 %)
(current report)
rT3–4: 31 % OS: 66 % (3 years)
Cmelak et al [26] 9 Not reported SRS 15–20 Gy LC: 58 % (crude) 11 % (0 %)
Kocher et al. [25] 5 rT3–4: 100 % SRS 15–24 Gy LC: 20 % (crude) 60 % (40 %)
Pai et al. [28] 36 rT1–2: 64 % ER + SRS 8–20 Gy LC: 58 % (3 years) 22 % (0 %)
rT3–4: 36 % OS: 54 % (3 years)
Chang et al. [18] 15 rT1–2: 67 % ER + SRS 8–15 Gy 52 % (3-year survival) Not separately reported
rT3–4: 33 %
Chen et al. [27] 11 rT3–4: 100 % ER + SRS 10–19 Gy LC: 45 % (crude) Not reported
OS: 37 % (2 years)
Xiao et al. [33] 50 rT1–2: 38 % SRT 14–35 Gy CR: 76 % 34 % (16 %)
rT3–4: 62 % OS:
P 78 % (2 years)
R 42 % (2 years)
Wu et al. [34] 90 rT1–2: 57 % SRT P: 10–24 Gy LC: 89 % (3 years) 19 % (2 %)
Orecchia et al. [30] 13 rT3–4: 43 % SRT R: 20–49 Gy OS: 81 % (3 years) 0 % (0 %)
rT1–2: 23 % 24 Gy LC: 75 % (3 years)
OS: 46 % (3 years)
LC:31 % (crude)
rT3–4: 77 % OS: 31 % (3 years)
Ahn et al. [31] 12 Not reported SRT 45–65 Gy LC: 92 % (2 years) Not reported (8 %)
OS: 60 % (2 years)
SRS stereotactic radiosurgery, SRT stereotactic radiotherapy, ER external beam reirradiation, LC local control, OS overall survival, CR complete
response, P persistent disease, R recurrent disease

Summary and Recommendations or radiosurgery, which may lead to underestimation of

Table 41.4 summarizes the outcome after radiosurgery for
local failures of NPC as reported in different series. Based on
these results, there is strong evidence indicating that radio-
surgery is an effective salvage treatment for local failures of
NPC. There is, however, no data comparing the relative effi-
cacy and complication risks of radiosurgery with other sal-
vage options for NPC. In practice, selection of treatment
modalities depends mainly on extent of disease and expertise
available. For rT1–2 disease, treatment outcome after radio-
surgery appears to be comparable with that of brachytherapy
and surgery. For rT3–4 disease, radiosurgery also seems to
yield similar results with conventional two-dimensional reir-
radiation. The advent of three-dimensional conformal radio-
therapy and intensity-modulated radiation treatment appears
to improve the outcome of recurrent NPC, particularly in
those with more advanced tumor. Hence, patients with rT3–4
disease should be treated by external beam reirradiation
using these new techniques with radiosurgery reserved as a
boost treatment or for further recurrence. In assessing late
complications after radiosurgery, it was always difficult if not
impossible to attribute them to either external radiotherapy
complication risks of radiosurgery. Although most series
reported a relatively low risk of late complications, hemor-
rhage remains the most severe form of complication after
radiosurgery with a possible fatal outcome. Although hemor-
rhage could also occur as a complication of tumor progres-
sion, most cases that developed after radiosurgery were
probably due to radiation damage to the carotid artery as a
result of high cumulative dose. The complication is probably
not related to rapid shrinkage of tumor as suggested by
Kocher et al. [25], because hemorrhage is rare after chemo-
therapy and brachytherapy, both of which can induce rapid
tumor shrinkage. To minimize the risk of hemorrhage, it is
advised to use single fraction radiosurgery only in the
absence of direct tumor encasement of carotid artery; other-
wise the patient should be treated by stereotactic or fraction-
ated radiotherapy using a small fraction dose. A proposed
decision tree for salvaging local failures of NPC is outlined
in Fig. 41.7. The role of radiosurgery as a boost treatment
after radical radiotherapy in newly diagnosed NPC is more
difficult to define, although its impact is likely to be
small with the advent of modern conformal radiotherapy,
chemotherapy, and intensity-modulated radiation therapy.
41 Head and Neck Tumors
Yes
Tumor confined Unilateral
to nasopharynx? involvement?
No
rT3/4 disease? Yes
(skull base or Persistent
intracranial disease?
invasion)
No
No
Encasement of Yes
carotid artery or
tumor volume?
10 cc? SRS
No
Fig. 41.7 A proposed decision tree for salvaging local failure of nasopharyngeal carcinoma. SRS stereotactic radiosurgery, SRT stereotactic radio-
therapy, IMRT intensity-modulated radiation therapy
Other Head and Neck Tumors
Radiosurgery has been employed in the treatment of head
and neck tumors other than NPC. A wide range of tumors,
both benign and malignant, has been treated using either ste-
reotactic radiosurgery or radiotherapy. Most treated cases
were recurrent tumors after prior surgery and/or radiother-
apy. The more commonly treated histologic type includes
squamous cell carcinoma, adenoid cystic carcinoma, and
chordoma. Most lesions were located at the skull base, mak-
ing them ideal targets for radiosurgery. For lesions located
below the skull base, fixation and immobilization are not as
rigid as for intracranial target, which should be taken into
consideration during localization of target and adjacent criti-
cal structures. The use of image-guided radiotherapy and
system capable of delivering radiation with high-dose con-
formity such as CyberKnife may be more suitable and is
increasingly being used in treating head and neck cancers.
Stereotactic Radiotherapy as Primary
Treatment for Newly Diagnosed Tumors
Use of stereotactic radiotherapy as primary treatment of
newly diagnosed head and neck tumors was reported in a
small series by Siddiqui et al. [41]. Eleven lesions in ten
patients were treated by stereotactic radiation using a Linac
gantry-based system (BrainLab, Inc., Heimstetten, Germany).
Rationale for using stereotactic radiation as primary treat-
ment included comorbidities that precluded patients from
receiving surgery or conventional radiation and patient
539
Yes Brachytherapy (gold grain implantation
or intracavitary intubation) or SRS or
nasopharyngectomy
No
SRS
Yes Yes
Encasement of SRT or IMRT
carotid artery
or tumor
volume? SRS
10 cc? No
SRT or IMRT
refusal for conventional treatments. Six patients were treated
for squamous cell carcinoma of the head and neck, two for
basal cell carcinoma, one for bilateral paragangliomas, and
one for Hurtle cell carcinoma of thyroid. Two lesions were
treated with single fraction of 18 Gy, whereas the remaining
lesions received 30–48 Gy in 5–6 fractions. Complete
response rate was 64 %. The 1- and 2-year local control rates
were 83.3 % and 66.7 %, respectively. Median overall sur-
vival was 28.7 months. The only severe late complication
was observed in the patient treated for paraganglioma who
developed severe and persistent facial pain following
treatment.
Stereotactic Radiotherapy as Salvage
Treatment for Recurrent Tumors
Stereotactic Radiation Delivered by Gamma
Knife or Linac-Based Gantry System
Cmelak et al. [26] treated 36 recurrent head and neck tumors
in 29 patients by radiosurgery using a median dose of 20 Gy
(range: 7–35 Gy). Fifteen patients were treated for squamous
cell carcinoma, six for adenocarcinoma, four for malignant
meningioma, three for adenoid cystic carcinoma, and three
for melanoma. Local control rate was 72 % but late compli-
cations including CSF leakage, trismus, and cranial neuropa-
thy occurred in four patients after treatment. Miller et al. [23]
treated 32 new or recurrent head and neck tumors in 29
patients using radiosurgery with or without external radio-
therapy. Twelve patients were treated for adenoid cystic
carcinoma, eight for squamous cell carcinoma, and eight for
chordoma. The dose delivered by radiosurgery was in the
540
range of 12–20 Gy (median, 15 Gy). Local control rates were
83 % for adenoid cystic carcinoma and 100 % for chordoma.
Late complications occurred in four patients and included
memory loss, hypopituitarism, CSF leakage, brain edema,
and optic neuropathy. Kocher et al. [25] treated four patients
with recurrent sarcoma using radiosurgery and achieved
good tumor control in three. They also treated three patients
with recurrent squamous cell or adenoid cystic carcinoma
but achieved local control in only one patient. The radiosur-
gery dose used was in the range of 9–20 Gy. One patient
developed brain necrosis and cranial neuropathy after radio-
surgery. Ryu et al. [42] treated five patients with recurrent
squamous cell or mucoepidermoid carcinoma by radiosur-
gery with a dose of 12–18 Gy and achieved complete
response in two patients. They also treated five recurrent
tumors (squamous cell, adenoid cystic, and basal cell carci-
noma) and three metastatic cervical nodes by stereotactic
radiotherapy using a dose ranging from 30 to 36 Gy in six
fractions and noted three complete responses in the former
group and one in the latter group. Elshaikh et al. [43] treated
12 patients with recurrent chemodectoma (seven with first
recurrence after surgery and five with second recurrence
after surgery) using Gamma Knife radiosurgery at a dose of
13–16 Gy and achieved 83 % control rate without any major
late complications. Using stereotactic radiotherapy, Ahn
et al. [31] treated three patients with steroid refractory orbital
pseudotumor using a dose of 20 Gy in ten fractions and noted
good response in all patients. Siddiqui et al. treated 29 lesions
in 21 patients with recurrent head and neck tumors using a
Linac gantry-based system [41]. Ten lesions received single
fraction of 16–18 Gy, and 19 lesions received 30–48 Gy in
6–8 fractions. The 1- and 2-year local control rates were
60.6 % and 40.4 %, respectively. Median overall survival
was 6.7 months. Three patients developed fistula, and one
patient developed mucosal ulceration and dysphagia after
treatment
Stereotactic Radiation Delivered
by CyberKnife System
Kawaguchi et al. [44] treated 22 patients with advanced,
recurrent head and neck tumor using CyberKnife. Eight
patients had synchronous regional nodal metastases. All
patients had prior radical radiotherapy. Marginal radiosur-
gery doses were 29–42 Gy delivered in 2–5 fractions. All
patients also received oral chemotherapy using S-1 after
radiosurgery. At a median follow-up of 24 months, 9 patients
(64.3 %) without regional metastases remained in complete
remission as compared with only one patient (12.5 %) in
those with regional metastases. Actuarial survival rates at
2 years for patients with and without regional nodal metasta-
ses were 12.5 % and 78.6 %, respectively. Kodani et al. [45]
treated 21 patients with recurrent head and neck squamous
D.T.T. Chua
cell carcinomas by CyberKnife system using a median dose
of 30 Gy in 3–8 fractions. The authors reported an overall
survival rate of 50 % at 2 years, but 28.6 % of patients
developed severe late complications including two deaths
due to massive hemorrhage in the pharynx. Roh et al. [46]
treated 44 sites of recurrent head and neck tumors in 36
patients using CyberKnife with a median dose of 30 Gy
(range: 18–40 Gy) in 3–5 fractions to the 65–85 % isodose
line and reported a 42.9 % complete response rate. One- and
2-year local recurrence-free survival rates were 61 % and
52.2 %, respectively. The corresponding overall survival
rates were 52.1 % and 30.9 %, respectively. Late complica-
tions were observed in three patients (8.6 %) including one
soft tissue necrosis, one mandibular bone necrosis, and one
skull base necrosis. One patient died due to late complica-
tions. Voynov et al. [47] at the University of Pittsburg treated
22 patients with recurrent head and neck tumors by
CyberKnife using a median radiosurgery dose of 24 Gy
with various fractionation schemes. The reported 2-year
local control rate was 26 % and overall survival rate was
22 %. They did not observe any significant late complica-
tions initially after a median follow-up of 19 months. Based
on an expanded cohort from the same institution, Rwigema
et al. later [48] reported the outcome in 96 patients with
locally recurrent head and neck tumors treated by Cyber
Knife or Trilogy system and observed a higher locoregional
control rate with the use of higher radiotherapy dose espe-
cially in patients with large tumor volume. The 1-, 2-, and
3-year locoregional control rates for patients who received
doses of 40–50 Gy were 69.4 %, 57.8 %, and 41.1 %,
respectively. The corresponding rates for patients who
received doses of 15–36 Gy were 51.9, 31.7, and 15.9 %.
The 1- and 2-year overall survival rates were 58.9 % and
28.4 %, respectively. Grade 3 late complications occurred in
three patients including two with dysphagia and one with
soft tissue fibrosis. There were no grade 4 or 5 complica-
tions, and no relationship between rates of complications
and prescribed doses was found. Unger et al. [49] at
Georgetown University reported the outcome of 65 patients
with recurrent head and neck tumors treated by CyberKnife
with a median dose of 30 Gy in 2–5 fractions. The cohort
included patients treated for radical (58 %) or palliative
(42 %, those with distant metastases) intent. About half
of the patients also received concurrent chemotherapy.
Complete responses were achieved in 54 % of patients, with
a 2-year locoregional rate of 30 % and overall survival rate
of 41 %. Multivariate analysis showed that higher total
dose, prior surgical resection, and nasopharynx site were
associated with better locoregional control. Severe late radi-
ation complications occurred in 11 % of patients including
two arterial bleeding requiring embolization and one
treatment-related death.
41 Head and Neck Tumors
Summary and Recommendations
Because of the heterogeneous nature of the patient population
treated in these series, it is not possible to conclude the efficacy
and indication of radiosurgery for specific type and site of head
and neck tumors. Most series treated patients with recurrent
squamous cell carcinoma of oropharynx and hypopharynx and
reported satisfactory local control rate. Experiences gathered
from treatment of NPC may also be relevant and applicable to
radiosurgery treatment of other head and neck tumors. Currently
it seems reasonable to recommend stereotactic radiosurgery or
radiotherapy as salvage treatment in patients with recurrent
head and neck tumors not amenable to further surgery if the site
and extent of the lesions are a suitable target of radiosurgery.
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 Head and Neck Tumors:
Viewpoint—Surgery
Scharukh Jalisi
Introduction
Seventy-five thousand new cases of head and neck cancer are
reported in the United States each year. Incidence is rising in
thyroid (up 52 %), bone (43 %), soft tissues (20 %), salivary
(20 %), tongue (16 %), tonsil (12 %), and nose (12 %).
Incidence is falling in lip (down 58 %), hypopharynx (35 %),
cervical esophagus (32 %), oropharyngeal mucosa (26 %),
and larynx (26 %). There were 30,000 deaths from head and
neck cancer in 2001 [1]. The most common risk factors are
alcohol and tobacco, but more recently there is interest and
detection of human papillomavirus (most commonly HPV
16) as an etiologic factor, particularly in the nonsmoker.
The National Comprehensive Cancer Network® (NCCN®),
a not-for-profit alliance of 21 of the world’s leading cancer
centers was formed and helps produce guidelines to treat can-
cers by different subsites. The treatment for head and neck
cancer has been either surgery or radiation for early stage
disease and a combined modality treatment (chemotherapy,
radiation, and surgery) for advanced disease cancer.
Treatment Options
There has been an increase in the utilization of nonsurgical
therapies for head and neck cancer since the publication of
the Veterans Affairs Laryngeal Study Group results in 1991
[2–9]. This study showed that 66 % of patients could preserve
their larynx without changing their survival if undergoing
nonsurgical therapy versus total laryngectomy. The only other
randomized trial in head and neck cancer treatment compar-
ing surgery to nonsurgical treatment is by Lefebvre et al. [10].
S. Jalisi, M.D., M.A., F.A.C.S. (*)
Division of Head and Neck Surgical Oncology and Skull Base
Surgery, Department of Otolaryngology and Neurological
Sciences, Boston Medical Center, Boston University School
of Medicine, Boston, MA, USA
e-mail: scharukh.jalisi@bmc.org
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_42, © Springer Science+Business Media New York 2015
42
In this article the authors randomized patients with T2–T4
piriform sinus cancer to either total laryngectomy with partial
pharyngectomy and neck dissection or to three doses of
induction chemotherapy, followed by concomitant chemora-
diation in responders (nonresponders were placed in surgical
arm). This study showed no difference in local, regional, and
5-year disease-free survival between the two groups.
Unfortunately this study excluded any advanced case requir-
ing plastic surgery repair and did not have any data on func-
tionality of the larynx.
Since then multiple articles have been published compar-
ing the efficacy of radiation with or without chemotherapy
and have supplanted the induction chemotherapy paradigm
set by the VA laryngeal study with concomitant chemoradia-
tion therapy (CRT) protocols. The Radiation Therapy
Oncology Group trial (RTOG) 9111 was instrumental in
demonstrating improved survival with concurrent CRT [11].
The problem again has been that this randomized trial did
not have a surgical arm. Similarly it seems that nonsurgical
trials are being extrapolated onto treating head and neck can-
cers without adequate comparisons to the gold standard sur-
gery. In the example of larynx cancer, the National Cancer
Data Base (NCDB) demonstrates a decrease in survival in
recent years that parallels the observed trend of increasing
use of nonoperative treatment and is not due to an increased
incidence of advanced-stage disease [4, 6].
Despite advances in surgery and CRT, local/regional
recurrence rates were around 30 %, distant metastases devel-
oped in 25 %, and 5-year survival was around 40 %.
Furthermore, in the presence of high-risk features such as
extracapsular extension, positive surgical margins, and oth-
ers, recurrence rates of up to 61 % had been observed, and
5-year survival dipped to around 30 % [11]. For this reason
the RTOG 9501 [12] trial was designed to see the effect of
adding cisplatin-based chemotherapy to postoperative radia-
tion therapy. Two hundred and thirty-one patients were ran-
domly assigned to receive radiotherapy alone (60–66 Gy in
30–33 fractions over a period of 6–6.6 weeks) and 228
patients to receive the identical treatment plus concurrent
543
544
cisplatin (100 mg per square meter of body surface area
intravenously on days 1, 22, and 43). The rate of local and
regional control was significantly higher in the combined-
therapy group than in the group given radiotherapy alone
(hazard ratio for local or regional recurrence, 0.61; 95 %
confidence interval, 0.41–0.91; P = 0.01). The estimated
2-year rate of local and regional control was 82 % in the
combined-therapy group, as compared with 72 % in the
radiotherapy group. Disease-free survival was significantly
longer in the combined-therapy group than in the radiother-
apy group (hazard ratio for disease or death, 0.78; 95 % con-
fidence interval, 0.61–0.99; P = 0.04), but overall survival
was not [13]. At the same time another study from the
European Organization for Research and Treatment of
Cancer Trial 22931 was published. In this study after under-
going surgery with curative intent, 167 patients were ran-
domly assigned to receive radiotherapy alone (66 Gy over a
period of 6 1/2 weeks) and 167 to receive the same radio-
therapy regimen combined with 100 mg of cisplatin per
square meter of body surface area on days 1, 22, and 43 of
the radiotherapy regimen. The rate of progression-free sur-
vival was significantly higher in the combined-therapy group
than in the group (47 % versus 36 %) given radiotherapy
alone (P = 0.04). The overall survival was also higher in com-
bined modality group (53 % versus 40 %) (P = 0.02). The
locoregional relapse rate was lower in combined group as
well (18 % versus 31 %) (P = 0.007) [14]. In both studies the
complication rates and toxicity rates were higher in the com-
bined modality group. The high-risk patients were consid-
ered as those with positive margins and extracapsular spread
on lymph nodes only.
The toxicities in both the abovementioned trials ranged
from mucositis, dysphagia, and ultimately gastrostomy tube
dependence [15]. In addition we see the rendering of the lar-
ynx to be nonfunctional with the patient suffering from aspi-
ration, voice changes, and ultimately requiring additional
surgery. Data suggests that complications from salvage laryn-
geal surgery after CRT have complication rate as high as
59 % with the most common complication being pharyngo-
cutaneous fistula [13]. This morbidity may require additional
surgery including free tissue transplant reconstruction.
Over the years many cancers were automatically referred
for CRT treatment, but better surgical extirpative and recon-
structive techniques are making many unresectable tumors
resectable with good quality of life and oncological control.
Evolution of Surgery
Over the years many subsites in the head and neck can be
safely operated on with minimally invasive techniques.
The last decade has seen the expansion of endoscopic skull
base resection techniques, transoral robotic surgery for
S. Jalisi
oropharyngeal cancers, and endoscopic and robotic techniques
for partial laryngectomies. The goal has been to eliminate
the cancer via targeted surgical technique and apply CRT
for the high-risk patients.
The advantage of primary surgery has been the addition
of pathological data that can help guide adjuvant therapy. For
example, if an oral cancer is removed and the neck dissected
out, we can get valuable data about perineural and lymphatic
invasion of the primary tumor, extracapsular spread of the
lymph nodes, and the number of lymph nodes. This data can
then help formulate the need or not of adjuvant radiation
therapy with or without chemotherapy. Moreover, per the
NCCN guidelines [16], radiation dose can be deintensified in
the postoperative period. For oropharyngeal cancers the rec-
ommended definitive primary radiation dose is 66–74 Gy to
the primary site and involved neck nodal stations. Uninvolved
nodal stations can receive 44–64 Gy. On the other hand once
the cancer has been primarily extirpated with neck node dis-
section, the radiation dose to the primary and involved nodes
can be reduced to 60–66 Gy. Interest in deintensification of
radiotherapy is gaining momentum due to the detrimental
impact on swallowing and hence quality of life with increas-
ing radiation dose. A recent article [17] noted that a dose of
>50 Gy to the base of the tongue and a mean dose of >51 Gy
to the superior pharyngeal constrictor, middle pharyngeal
constrictor, and inferior pharyngeal constrictor all correctly
identified penetration and aspiration of fluids at 6 months
post treatment. Mean dose to the glottic/supraglottic larynx
of >48 Gy, maximum dose to the upper esophageal sphincter
of >60 Gy, and mean dose to the esophagus of >17 Gy
also correctly identified penetration and aspiration of fluids
at 6 months. Higher doses of radiation resulted in higher
dysfunction.
Human papillomavirus (HPV) type 16 has been demon-
strated as a cause of oropharyngeal cancer that confers a good
prognosis on the patient. In a study comparing accelerated
fraction versus standard fraction radiation therapy for stage
3 and 4 oropharyngeal cancer (RTOG 0129), it was demon-
strated that 3-year overall survival in HPV-positive patients
was 82.4 % versus 57.1 % in HPV-negative patients [18].
This study has helped define HPV-positive cancers as a
different entity. The new dilemma that head and neck oncol-
ogists now face is whether there can be deintensification of
treatment for these favorable cancers.
Transoral robotic surgery (TORS), transoral laser surgery,
and endoscopic laser surgery have enabled the management
of oral cavity, oropharynx, and larynx surgery via minimally
invasive techniques that allow for faster return to swallowing
without traditional neck incisions. Currently there are studies
under way to consider the impact of TORS on HPV-positive
cancers. TORS is considered as a treatment deintensification
modality for oropharyngeal cancers that allows for targeted
therapy of cancer and along with convention neck nodal
42 Head and Neck Tumors: Viewpoint—Surgery
surgery may in the future obviate the need for adjuvant CRT
in appropriately selected patients in the future.
Endoscopic skull base techniques have similarly enabled
us to remove skull base tumors without the need for cranioto-
mies. Local vascularized reconstruction techniques that can
be accomplished endoscopically have allowed for excellent
watertight closure of the skull base [19].
Furthermore, there has been development of accountable
care organizations (ACO) to link provider reimbursements to
quality metrics and reduce overall total cost of care. ACOs
aim to place a higher degree of financial responsibility on the
providers, with hopes of improving care management and
limiting unnecessary expenditures [20]. There is also a trend
towards discussion of “regionalization” of cancer care that
may result in better outcomes for patients treated in high vol-
ume hospitals [21–23].
Stereotactic Radiosurgery
Stereotactic radiosurgery (SRS) has not been shown to be of
benefit as a primary treatment modality for any head and
neck cancer. Additionally therapy options for locoregional
recurrences in previously irradiated head and neck patients
are limited. Salvage surgery if clinically feasible is the stan-
dard treatment for recurrences [24, 25], but with extensive
locoregional spread, surgery alone is not sufficient. Those
patients who are considered inoperable often receive pallia-
tive chemotherapy with low response rates ranging from 10
to 40 % [26, 27]. Salama et al. [28] reported the long-term
outcome of concurrent treatment with chemotherapy and re-
irradiation of patients suffering from recurrent or second pri-
mary squamous cell carcinoma of the head and neck
(SCCHN). One hundred and fifteen patients were treated
with locoregional control, and free of distant metastasis rate
at 3 years was 51 % and 61 %, respectively. Re-treatment
was highly toxic with 19 toxic events, five of them due to
carotid hemorrhages. The authors came to the conclusion
that re-irradiation of recurrent head and neck cancer should
be limited to clinical trials.
As conventional reradiation therapy has high toxicity,
SRS in the re-irradiation of head and neck cancer patients
has been pursued in the last few years [29].
Voynov et al. reviewed 22 patients re-treated with SRS in
recurrent previously irradiated SCCHN [30]. Using the
CyberKnife, patients were irradiated with a median single
fraction dose of 5 Gy for a median of five fractions.
Re-treatment with SRS was considered to be safe as no grade
4 or 5 toxicities or late toxicities occurred. Local control rate
was 26 % at 2 years, with a 22 % 2-year survival. In 2009 an
analysis was published by Roh et al. of 36 patients with recur-
rent head and neck cancer who had received a full-dose radia-
tion of 66–70.2 Gy in the first radiation therapy (RT) course.
545
They were then re-irradiated with CyberKnife radiosurgery
(SRS) with three fractions of 10 or 13 Gy. The authors
changed to a fractionation schedule of five fractions of 5 or
8 Gy [31]. Fifteen patients (42.9 %) showed complete
tumor regression and 13 (37.1 %) partial regression with
median local control rates and overall survival rates after 1
year of 61 % and 52.1 %, respectively. Late adverse events
were observed in three patients: two grade 4 and one grade
5 toxicity.
Unger et al. reported on SRS re-irradiation in 65 head and
neck cancer patients [32]. Initial median RT dose was 67 Gy
(32–120 Gy) and median treatment interval between initial
course and SRS 26 months. Treatment sites were oropharynx
(n = 13), hypopharynx (n = 8), nasopharynx (n = 7), paranasal
sinus (n = 7), neck (n = 7), and others (n = 23). Patients were
treated with SRS re-irradiation either definitively (n = 38) or
with palliative intent due to metastatic or untreated local
disease (n = 27). Nine patients had complete macroscopic
resection before SRS, and 33 patients were treated with
simultaneous chemoradiotherapy. Most patients were treated
with 5 × 6 Gy (2–5 × 4–12 Gy), but dose and fractionation
were individualized by the treating physician, and total dose
was commonly reduced after complete macroscopic resec-
tion. For 56 patients evaluable for response, complete, par-
tial, and no response were observed in 30 patients (54 %), 15
patients (27 %), and 11 patients (20 %), respectively. Median
overall survival was 12 months. The overall survival (OS)
rate was 41 % for definitively treated patients and the locore-
gional control rate 30 % in these patients. The authors
reported that nasopharynx, surgical resection, and higher
total dose were significantly correlated with improved
locoregional control while nonsquamous histology and sur-
gical resection with improved OS. One patient died of
unspecified causes 2 weeks after re-irradiation, considered
treatment related. Grade 4 late toxicities were observed in six
patients (9 %) including soft tissue necrosis, arterial bleed-
ing, fistula formation, and severe dysphagia. No association
of higher SRS dose or higher cumulative dose with severe
late complications was seen, though the outcome was not
significant due to the small number of cases.
To increase efficacy of SRS re-irradiation, Heron et al.
investigated combinations of SRS with cetuximab [33].
Thirty-five patients were treated with SRS re-irradiation
alone or with additional weekly cetuximab during SRS,
respectively. Toxicities were comparable in both patient
cohorts, and an overall survival benefit was seen for the
cetuximab arm.
Vargo et al. recently reported on SRS in recurrent, non-
squamous cell cancers of the head and neck [34]. Thirty-four
patients were re-irradiated with a median SRS dose of 40 Gy
in five fractions. The toxicity and quality of life were fol-
lowed prospectively with a median follow-up of 10 months.
The authors found promising local control rates of 77 % and
546
59 % after 6 months and 12 months, respectively. For tumors
<25 mL they reported a significant improvement of local
control compared to larger tumors (>25 mL). Acute and late
grade 3 toxicities occurred in 15 % and 6 % of the patients,
respectively, and no grade 4 or 5 toxicities were observed.
In conclusion, SRS in the re-irradiation for head and neck
tumors has demonstrated to be a promising salvage therapy
modality with encouraging local control rates and justifiable
toxicities. Severe late adverse events (grade 4–5 toxicities)
have been reported in some studies but are less frequent than
in patients re-treated with conventional techniques. Very
high single fraction doses of 10–13 Gy or higher should be
avoided. There have been no studies comparing SRS to con-
ventional IMRT re-irradiation for salvage therapy.
Conclusion
Surgery is an integral part of the treatment of head and neck
cancers and is still the gold standard treatment. Over the
years several studies have demonstrated the superiority of
concurrent CRT to radiation therapy alone, but there is a
dearth of randomized controlled trials comparing the effi-
cacy of CRT to surgery. Newer surgical modalities enable us
to provide targeted therapies with excellent functional and
cosmetic outcomes. There is a growing understanding of the
impact of radiation dose on swallowing outcomes, and there
is a new focus on treatment deintensification especially in
HPV-positive patients. SRS is currently useful in the setting
of re-irradiation amongst inoperable patients with recurrent
head and neck cancer.
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 Head and Neck Tumors:
Viewpoint—Fractionated Radiation
Therapy and Chemotherapy
Michael Rutenberg and Mohan Suntharalingam
Introduction
Squamous cell carcinomas of the head and neck (HNSCC)
represent approximately 5 % of cancers diagnosed in the
United States each year. More than 40,000 patients will be
diagnosed this year, and worldwide this number will exceed
500,000 [1]. Although patients presenting with early-stage
disease are highly curable with either radiation therapy or
surgery alone, those with locally advanced disease have his-
torically had poorer prognoses and limited treatment options.
While most of these cancers remain clinically limited to the
head and neck region, locally advanced tumors present sig-
nificant therapeutic challenges. They are often characterized
by invasion into surrounding anatomic structures such as
muscle, bone, nerves, or blood vessels and may present with
clinically detectable lymph node metastases. Surgical resec-
tion with adjuvant radiotherapy offers a chance of cure for
some patients; however, this can come at a significant cost in
terms of function and cosmesis [2, 3]. Patients with advanced
head and neck cancers tend to have poor long-term survival
and a significant number ultimately die of locoregional dis-
ease progression.
The management of patients diagnosed with locally
advanced squamous cell carcinomas of the head and neck has
undergone a major paradigm shift during the past several
decades. The standard of monotherapy using either surgery or
radiation has been replaced by a multidisciplinary and com-
bined modality approach [4–6]. For many patients with
locally advanced disease, the use of systemic therapy and
radiation offers the opportunity for cure while achieving
organ preservation. In recent decades, progress has been made
in understanding optimal radiotherapy delivery schedules,
defining effective chemotherapy combinations, improving
M. Rutenberg • M. Suntharalingam (*)
Department of Radiation Oncology, University of Maryland,
22 South Greene Street, Baltimore, MD 21201, USA
e-mail: msuntha@unm.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_43, © Springer Science+Business Media New York 2015
43
risk stratification, and incorporating novel biologic targeted
therapies into treatment regimens [4–8]. As we continue to
improve disease control and organ preservation, there is
increasing emphasis on reducing treatment-related morbidity
and improving patient quality of life.
Locoregional Control and Overall Survival
The link between locoregional control and its effect on
overall survival has long been appreciated in head and neck
cancers. Historically, the overall survival of patients with
locally advanced disease has largely been determined by the
ability to achieve local control. Radiosensitizing systemic
chemotherapy has been delivered with definitive doses
of radiotherapy to improve the outcomes for these patients.
The integration of chemotherapy into the overall treatment
scheme has helped improve locoregional control and
increased overall survival rates, while achieving organ pres-
ervation and maintaining organ function. A review of the
concurrent chemotherapy and radiation literature reveals a
consistent improvement in local control associated with com-
bined modality therapy for patients presenting with advanced
disease when compared to radiotherapy alone [6, 9–12]. While
these findings are encouraging, a critical review reveals room
for improvement. Efforts to improve locoregional control
with reduced toxicity provide the rationale for ongoing
clinical trials.
Despite the fact that combination chemotherapy and radi-
ation trials have been conducted for the past 4 decades, the
absolute survival benefit associated with combined modality
therapy was historically poorly defined. In order to better
define the potential advantage of cytotoxic therapy, four
large meta-analyses were performed comparing chemother-
apy (delivered as neoadjuvant, concurrent, or adjuvant) plus
local therapy vs. local therapy alone [11, 13–15]. The primary
end point of these studies was overall survival.
These four reports included three studies that were literature
based [11, 13, 14] and one that used individual patient data [15].
549
550
The total number of cases included in each analysis ranged
from 4,292 (from 28 trials) to as high as 10,741 (63 trials). The
median follow-up for all patients ranged from 2 to 6.8 years.
Importantly, all four meta-analyses reached similar conclusions
despite significant differences in the databases analyzed.
The results from all of the studies confirmed a small, but
reproducible survival benefit in favor of the addition of che-
motherapy. The magnitude of this benefit ranged from an
absolute survival advantage of 2.8–6.5 %. The original meta-
analysis by Pignon et al. was recently updated to include 87
trials and 16,485 patients. With updated data, they observed
a hazard ratio for death of 0.88 and a 5-year absolute survival
benefit of 4.5 % with the addition of chemotherapy to locore-
gional treatment over locoregional treatment alone [12].
Each of these meta-analyses noted the largest contribution of
systemic therapy to overall survival came with the concomi-
tant use of chemotherapy with locoregional treatment
[12–15].
Combined Chemotherapy and Radiation
The VA Larynx trial, originally published in 1991, was a
landmark study demonstrating equivalent survival between
larynx preserving induction chemotherapy (cisplatin and
5FU) followed by radiotherapy (66–76 Gy) vs. laryngec-
tomy with postoperative radiotherapy (50 Gy) for laryngeal
cancers [16]. A subsequent EORTC study evaluated patients
with hypopharynx cancers and similarly showed effective
organ preservation using chemotherapy followed by radio-
therapy compared to total laryngectomy and adjuvant
radiotherapy, with no difference between arms in progres-
sion-free survival (PFS) or overall survival [17]. The 5-year
functional intact larynx rate in the EORTC study was 35 %
in the chemotherapy and radiation arm. Following these
trials, the Radiation Therapy Oncology Group (RTOG) con-
ducted a phase III randomized trial evaluating the optimal
sequencing of chemotherapy and radiation in organ preserv-
ing treatment for locally advanced head and neck cancers.
RTOG 91–11 evaluated sequential chemotherapy and radio-
therapy vs. concurrent chemoradiotherapy vs. radiation alone
in patients with stage III/IV laryngeal cancer [6]. The induc-
tion chemotherapy arm consisted of cisplatin (100 mg/m2)
and 5-fluorouracil (1,000 mg/m2) followed by 70 Gy. The
concurrent arm included cisplatin (100 mg/m2) delivered
days 1, 22, and 43 of RT (70 Gy). The radiation-only arm
received 70 Gy in 2 Gy/fraction. With a primary end point of
2-year larynx preservation rate, this trial convincingly dem-
onstrated a benefit to concurrent chemoradiation compared
to sequential chemotherapy with radiation or radiation alone,
with 2-year locoregional control rates of 80 %, 64 %, and
56 %, respectively (p = 0.004), and larynx preservation rates
M. Rutenberg and M. Suntharalingam
of 84 %, 72 %, and 67 %, respectively (p < 0.01). In a recent
update of this trial with 10-year follow-up, these data con-
tinue to show a benefit for concurrent chemoradiotherapy
in locoregional control and larynx preservation, but no differ-
ence in laryngectomy-free survival or overall survival [18].
In 2004, the French Head and Neck Oncology and
Radiotherapy Group published the results of GORTEC
94–01, a phase III trial comparing radiotherapy alone to con-
current chemoradiation (carboplatin and fluorouracil) for
stage III or IV oropharyngeal carcinomas [19]. They showed
a statistically significant benefit for 5-year disease-specific
survival and locoregional control and a strong trend towards
improvement in overall survival with concomitant chemora-
diotherapy [19].
Perhaps no other head and neck subsite has made more
progress with the addition of chemotherapy to radiotherapy
than carcinomas involving the nasopharynx. In 1998,
Al-Sarraf and colleagues published the results of Intergroup
00–99, a phase III randomized trial including patients with
stage III and IV squamous cell carcinomas of the nasophar-
ynx [10]. This trial compared standard radiation (70 Gy in 7
weeks) to concurrent chemoradiation with cisplatin (100 mg/m2)
and three cycles of adjuvant cisplatin (80 mg/m2) and fluoro-
uracil (1,000 mg/m2). The study resulted in early closure due
to demonstration of a survival benefit in the combined
chemotherapy and radiation arm at the first interim analysis.
One hundred forty-seven patients were evaluable for the pri-
mary end points of PFS and overall survival and revealed
3-year PFS of 24 % for radiotherapy alone vs. 69 % in the
chemoradiation arm (p < 0.001). The 3-year overall survival
rate was 47 % vs. 78 % (p = 0.005) in favor of combined
modality treatment [10].
This study was among the first individual randomized tri-
als to demonstrate an overall survival benefit associated with
the use of concurrent chemoradiation in any head and neck
cancer population. These results helped define the current
standard of care for patients with locally advanced squamous
cell carcinomas of the nasopharynx. Multiple institutional
trials have now documented local control rates between 80
and 90 % for these patients when combination chemotherapy
and modern radiotherapy are utilized [20–22]. Several meta-
analyses have confirmed the benefits in local control and
survival with combined chemotherapy and radiotherapy over
radiation alone [23–25]. They also indicate the largest bene-
fits in survival and local control are achieved with concurrent
chemotherapy and radiation compared to induction or adju-
vant chemotherapy. With the use of concurrent chemoradia-
tion, long-term follow-up of these patients has shown that a
majority of cancer-related deaths are a result of metastatic
disease without evidence of local recurrence. As a result,
current efforts focus on improvements in reducing metastatic
disease and treatment-related morbidity [26–28].
43 Head and Neck Tumors: Viewpoint—Fractionated Radiation Therapy and Chemotherapy
Additional support for the use of concurrent chemother-
apy and radiation as definitive treatment in head and neck
cancers comes from the previously noted meta-analysis by
Pignon et al. [12]. Eighty-seven randomized trials including
16,485 patients were evaluated and showed a significant
overall survival benefit for patients treated curatively with
concomitant chemotherapy. Concomitant chemotherapy
resulted in a hazard ratio of death of 0.81 (95 % CI, 0.78;
0.86) and an absolute survival benefit of 6.5 % at 5 years. No
statistically significant survival benefit was seen in this anal-
ysis for induction or adjuvant chemotherapy. Importantly,
the survival benefit observed for concomitant chemotherapy
was seen for all subsites analyzed, including oral cavity, oro-
pharynx, larynx, and hypopharynx [12].
Induction Chemotherapy Prior to Definitive
Radiotherapy
Recent studies comparing induction chemotherapy regimens
followed by radiotherapy have reinvigorated interest in
induction chemotherapy as a viable approach in organ pres-
ervation therapy. The TAX 323 trial randomized 358 patients
with unresectable stage III/IV, non-metastatic, SCC of the
head and neck to induction chemotherapy with either cispla-
tin and fluorouracil (PF) or docetaxel, cisplatin, and fluoro-
uracil (TPF), each followed by radiotherapy to 66–74 Gy
[29]. Median overall survival (18.8 months vs. 14.5 months,
p = 0.02) and PFS benefits (11 months vs. 8.2 months,
p = 0.007) were seen in the TPF arm compared to the PF
arm. Importantly, most treatment failures were locoregional
(>80 % in each arm).
In a trial similar to TAX 323, TAX 324 randomized 501
patients with stage III/IV head and neck cancers to three
cycles of induction chemotherapy using docetaxel, cisplatin,
and fluorouracil followed by concurrent chemoradiation
with carboplatin to doses of 70–74 Gy or induction cisplatin
and fluorouracil followed by the same course of concurrent
chemoradiation [30]. A major difference between this study
and TAX 323 was the addition of concurrent weekly carbo-
platin (AUC 1.5) with radiotherapy. Median overall survival
was significantly improved in the TPF arm compared to the
PF arm, 71 months and 30 months (p = 0.006), respectively.
PFS was 36 months in the TPF arm compared to 13 months
in the PF arm (p = 0.004). Similar to TAX 323, over 80 % of
treatment failures were locoregional [30].
GORTEC 2000–1 was a French phase III study compar-
ing larynx preservation in patients with locally advanced
squamous cell carcinoma of the larynx or hypopharynx
randomized to either induction TPF or PF followed by radio-
therapy with or without concomitant chemotherapy for
551
patients who responded to induction [31]. The TPF arm
showed a benefit over the PF arm in overall response rate
(80 % vs. 59.2 %, p = 0.002) and 3-year larynx preservation
(70.3 % vs. 57.5 %, p = 0.03). No differences between arms
were seen in the 3-year disease-free interval or overall survival.
There is much debate regarding the use of induction
chemotherapy followed by concurrent chemoradiotherapy
compared to upfront chemoradiotherapy. Proponents of
induction chemotherapy point to the high overall response
rates of induction chemotherapy and the benefit of post-
induction chemotherapy patient reevaluation for possible
risk-based treatment modifications. They also argue that
TAX 323, TAX 324, and GORTEC 2000–1 suggest potential
survival benefits when compared to concurrent chemoradio-
therapy trials.
Opponents of induction chemotherapy argue that the pub-
lished induction trials fail to compare induction chemother-
apy to the gold standard of upfront chemoradiation and
instead only show a benefit of one induction regimen over
another. Additionally, they caution that toxicity associated
with induction chemotherapy may interfere with or prevent
the delivery of chemoradiation as the curative treatment for
these patients. Notably, approximately 30 % of patients in
each arm of TAX 323 and TAX 324 did not complete their
planned radiotherapy [29, 30]. Critics of induction chemo-
therapy note that the promise of reduced distant failures has
not been convincingly shown in the induction chemotherapy
trials to date.
The DeCIDE and PARADIGM trials are two recently
completed phase III trials which compare induction
chemotherapy followed by concurrent chemoradiation with
upfront chemoradiation. The DeCIDE trial included patients
with non-metastatic HNSCC with N2/N3 disease, random-
ized to accelerated hyperfractionated radiotherapy with con-
current docetaxel, fluorouracil, and hydroxyurea or induction
chemotherapy with two cycles of TPF followed by the same
chemoradiation. The initial report with 3-year results shows
no suggestion of a difference in the primary end point
of overall survival (73 % vs. 75 %, p = 0.70) [32]. The
PARADIGM trial compared patients with locally advanced
head and neck cancers receiving radiotherapy with concur-
rent cisplatin vs. three cycles of induction TPF followed by
concurrent radiotherapy with carboplatin or docetaxel [33].
Because this study closed early due to slow accrual, it has
inadequate power to appropriately evaluate the primary end
point of survival. The data as reported fail to show a survival
benefit to induction chemotherapy. With a median follow-up
of 49 months, the 3-year overall survival and PFS were 73 %
vs. 78 % (p = 0.77) and 67 % and 73 % (p = 0.55) for the
induction chemotherapy arm and chemoradiation arms,
respectively [33].
552
Targeted Therapies as Part of a Combined
Modality Strategy
The limitations of most systemic cytotoxic agents are often
defined by the nonspecific toxicities of normal tissues.
To improve the therapeutic ratio, investigators have focused
efforts on biologic agents targeting cellular proteins.
Epidermal growth factor receptor, a member of the ErbB
family of receptor tyrosine kinases, is one of four receptors
important in cellular proliferation, differentiation, and sur-
vival [17]. The EGFR pathway controls cell-cycle events that
directly affect survival. It is estimated that 80–90 % of head
and neck carcinomas overexpress EGFR and its ligand
TGF-α [alpha] [34]. Its expression has been associated with
a poor outcome in HNSCC [34]. Anti-EGFR therapy pro-
vides a powerful target for future combined modality treat-
ment strategies.
Cetuximab is an anti-EGFR receptor that targets the
extracellular ligand binding domain. In 2006, it became
the first FDA-approved EGFR targeting agent for locally
advanced head and neck squamous cell carcinoma. This fol-
lowed from a phase III, randomized trial evaluating the addi-
tion of cetuximab to radiation for patients with squamous
cell carcinomas of the head and neck. Bonner et al. reported
a significant improvement in locoregional control (hazard
ratio 0.68, p = 0.005), progression-free survival (3-year PFS
42 % vs. 31 %, p = 0.04), and overall survival (median sur-
vival 49 months vs. 29.3 months, p = 0.03) with the addition
of cetuximab [7]. Notably, these improvements were accom-
plished without a significant increase in any grade 3 or greater
acute reactions (other than acneform rash and infusion reac-
tions). The recent update of this trial showed a continued
benefit with the addition of cetuximab to radiotherapy, with
5-year overall survival of 45.6 % in the cetuximab arm com-
pared to 36.4 % in the radiotherapy-only arm (p = 0.018) [35].
Several phase III trials are currently investigating
additional roles of cetuximab in head and neck cancers. An
overall survival benefit with the addition of cetuximab to
platinum-based chemotherapy has already been shown for
recurrent or metastatic head and neck cancers [36]. Following
from these data, combination systemic therapy and radio-
therapy are being evaluated. RTOG 05–22 is a recently com-
pleted phase III trial of accelerated radiotherapy with
concomitant cisplatin with or without cetuximab for stage
III/IV HNSCC. The initial results of this study have been
presented and show no benefit to the addition of cetuximab
to cisplatin and radiotherapy for disease-free or overall
survival [37]. RTOG 09–20 is an ongoing phase III trial ran-
domizing patients with locally advanced head and neck
cancers to postoperative radiotherapy with or without con-
current cetuximab. RTOG 10–16 is a phase III study random-
izing patients with locally advanced HPV-positive HNSCC
M. Rutenberg and M. Suntharalingam
to concurrent radiotherapy with cisplatin or cetuximab. With
the early successes of cetuximab, other EGFR targeting
agents are under investigation for treatment of head and neck
cancers, including EGFR small molecule inhibitors (e.g.,
Gefitinib, Erlotinib).
Vascular endothelial growth factor-A (VEGF) is a secreted
protein that is active in angiogenesis, largely mediated
through binding of cell surface receptor tyrosine kinases.
Increased expression of VEGF has been associated with
worse outcomes in head and neck squamous cell carcinoma
and overexpression has been observed in high numbers of
nasopharyngeal cancers. Bevacizumab is a monoclonal anti-
body that targets VEGF and blocks its signaling. Lee et al.
recently reported the results of RTOG 0615, a phase II study
combining radiotherapy with concurrent and adjuvant cispl-
atin and bevacizumab in nasopharyngeal cancer [38]. Early
results are promising for safety and efficacy.
As our understanding of tumorigenesis and tumor biology
continues to improve, new cellular proteins and pathways
will become targets of focused therapy. Small molecule
inhibitors and antibodies will undoubtedly assume increas-
ing roles in the multimodality treatment of head and neck
malignancies, with expected benefits in increased response
rates and decreased treatment morbidity.
Human Papillomavirus in Head and Neck
Squamous Cell Carcinoma: Treatment
Implications
In the late 1990s, a link between human papillomavirus
(HPV) and the development of a subset of squamous cell
carcinomas in the head and neck began to emerge [39, 40].
HPV is a sexually transmitted DNA virus with hundreds of
subtypes. Several subtypes (e.g., HPV6 and -11) are known
to cause benign papillomas or warts, while other oncogenic
subtypes (HPV16, -18, -31, -33), already implicated in the
development of cervical cancer, have been implicated in the
development of HNSCC [39, 41, 42]. Gillison et al. at Johns
Hopkins found 25 % of HNSCC contained HPV DNA, with
high-risk oncogenic subtype HPV16 accounting for 90 % of
the infections [41]. This study found an association between
HPV-infected tumors, oropharyngeal location, and poorly
differentiated cancers. HPV-positive oropharyngeal cancers
were less likely among moderate to heavy drinkers and
smokers, had lower rates of TP53 mutations, and had
improved disease-specific survival compared to HPV-
negative cancers. When patients with HPV-positive tumors
(from all head and neck subsites) were evaluated, a 59 %
reduction in risk of death compared to HPV-negative patients
was seen. A subsequent case-control study was performed
with 100 patients with newly diagnosed oropharyngeal
squamous cell carcinoma compared to 200 control patients
43 Head and Neck Tumors: Viewpoint—Fractionated Radiation Therapy and Chemotherapy
without cancer [42]. This study showed a strong association
between HPV16-positive SCC of the oropharynx and high-
risk sexual activities, including increasing numbers of
lifetime vaginal-sex and oral-sex partners, lack of condom
use, and early age at first intercourse. The authors showed
an increased risk of HPV-related oropharyngeal cancer in
patients without a history of alcohol or tobacco use and
found no evidence of an additive effect between HPV infec-
tion and alcohol/tobacco in the development of oropharyn-
geal cancer.
Several studies evaluating outcomes by HPV status have
now confirmed a favorable prognosis for HPV-related
HNSCC treated with chemotherapy and radiation compared
to HPV-negative tumors. Fakhry et al. prospectively evalu-
ated patients enrolled in ECOG 2399, a phase II trial using
induction chemotherapy followed by chemoradiation in
patients with stage III/IV laryngeal or oropharyngeal cancers
[43]. Their data showed improved overall response rates for
induction chemotherapy (82 % vs. 55 %, p = .01) and chemo-
radiation (84 % vs. 57 %, p = .007) in HPV-positive tumors
and improved 2-year survival for HPV-positive tumors com-
pared to HPV-negative (95 % vs. 62 %, p = 0.005). After
adjusting for known risk factors, patients with HPV-positive
cancers had lower risks for progression and death from any
cause compared to HPV-negative patients.
RTOG 0129 is a phase III trial comparing concurrent
chemoradiation with either standard-fractionated radiation
or accelerated-fractionated radiotherapy in stage III/IV
HNSCC [8]. In a post hoc subset analysis including more
than 300 oropharynx cancer patients stratified by HPV sta-
tus, Ang et al. showed improved 3-year overall survival
(82.4 % vs. 57.1 %), PFS (73.7 % vs. 43.4 %), and local-
regional control (86.4 % vs. 64.9 %, p < 0.001) for patients in
the HPV-positive subgroup. They found HPV status to be the
most important determinant for overall survival. This study
also established p16 upregulation in tumor cells as a clinical
surrogate for HPV-related tumors. P16 is an inhibitor of
cyclin-dependent kinases (CDK) and is responsible for slow-
ing cell-cycle progression via inhibition of CDK phosphory-
lation of pRB [8]. HPV-oncoprotein E7 activity induces p16
expression via pRB inactivation. RTOG 01–29 demonstrated
the correlation between the presence of HPV DNA and p16
expression in tumor cells. Stratification using p16 expression
was found to be consistent with HPV-based stratification for
overall survival and disease-free survival [8]. Because of its
high sensitivity, ease of analysis, wide availability, and
strong correlation with both transcriptionally active HPV
infection and patient outcomes, p16 is often used in lieu of
direct HPV evaluation in HNSCC [44].
HPV status is now a major focus in research and the clinical
management of HNSCC. Stratification schemes in clinical tri-
als have incorporated this important prognostic factor. Because
of the favorable prognosis in patients with HPV-positive
553
HNSCC, studies evaluating treatment de-intensification in an
effort to reduce treatment morbidity are underway. Conversely,
new approaches to improve the relatively poor outcomes of
HPV-negative HNSCC are ongoing.
Intensity-Modulated Radiation Therapy
The treatment of head and neck cancers presents particular
challenges in radiation delivery due to the high concentration
of critical, radiosensitive tissues in and around the treatment
fields, including the spinal cord, major and minor salivary
glands, lacrimal glands, retina, optic nerves, and the mandi-
ble. The long-term morbidity of tumoricidal doses of radia-
tion delivered to this region can be significant. Despite its
development for treatment of prostate cancer in the mid-
1990s, the benefits of intensity-modulated radiation therapy
(IMRT) were quickly appreciated in the field of head and
neck radiation oncology, which has become one of its main
beneficiaries and proponents. The benefits of IMRT in head
and neck radiotherapy include the potential for improved
tumor control with delivery of high dose radiation, while
reducing dose to nearby normal tissues with sharp dose fall-
off. An expected benefit of IMRT for head and neck cancers
is improved salivary gland sparing with decreased xerosto-
mia and improved quality of life.
Early single-institution retrospective studies using IMRT
in head and neck cancers showed good tumor control rates
and an ability to improve normal tissue sparing [20, 21, 45–
47]. The RTOG conducted a phase II, multi-institutional trial
evaluating hypofractionated IMRT for early-stage oropha-
ryngeal cancer. RTOG 02–22 included T1–2, N0–1, M0 SCC
of the oropharynx treated to 66 Gy to gross disease and
54 Gy to at-risk areas using a dose-painting technique [48].
With central quality assurance for treatment planning evalu-
ation, this study helped guide the use of IMRT for head and
neck cancers into routine use. The disease control rates and
xerostomia rates compared favorably with historical coop-
erative group studies. Importantly, RTOG 02–22 showed a
significant association between major protocol underdosing
violations and local disease recurrence [48].
RTOG 02–25 was a multi-institutional phase II pros-
pective trial evaluating the use of intensity-modulated radio-
therapy with or without chemotherapy for all stages of
nasopharyngeal cancer [26]. The results showed 2-year PFS
and overall survival rates of 72.7 % and 80.2 %, respectively.
Using IMRT, the rate of grade 2 xerostomia was 14 % and
over one-third of patients reported no xerostomia.
Several randomized studies comparing IMRT and 2D or
3D radiotherapy for HNSCC with the aim of reducing xero-
stomia have been conducted [49, 50]. The results so far have
been encouraging, with improved salivary flow rates and
reduced observer reported xerostomia using IMRT.
554
Altered Fractionation Schedules
Modifications in radiotherapy fractionation schedules allow
clinicians to take advantage of fundamental differences in
the biology between tumor cells and normal tissue, specifi-
cally differences in growth rates and genomic repair mecha-
nisms. The ultimate goal of altered fractionation is to increase
tumor control while decreasing chronic toxicity. The basis
for altered fractionation lies in the dissociation between
acute and late effects, where tumor control and acute toxicity
are increased with decreasing treatment time and increasing
total dose, and less related to fraction size. On the other hand,
late effects are related to fraction size and total dose and less
dependent on overall treatment time [51].
Hyperfractionated radiotherapy is characterized by an
increase in the total dose and the number of fractions, a
decrease in the dose per fraction, and maintenance of the
overall treatment time [51–53]. In comparison, accelerated
fractionation reduces overall treatment time, while the num-
ber of fractions, total dose, and fraction size remains rela-
tively unchanged. In either of these altered fractionation
schedules, acute toxicity is expected to increase as a result of
increased total dose (hyperfractionation) or decreased over-
all treatment time (accelerated fractionation).
Initially conceived prior to the era of combined chemo-
therapy and radiation, altered fractionation has been shown
in several large multi-institutional randomized trials to
improve local control in HNSCC when compared to conven-
tionally fractionated RT alone (DAHANCA 6&7, RTOG
90–03, EORTC 22791) [54–56]. RTOG 90–03 randomized
1,113 patients with locally advanced HNSCC to one of the
following four arms: (1) Standard-fractionated radiotherapy
(70 Gy in 2 Gy/fraction), (2) Hyperfractionated radiotherapy
(81.6 Gy in 1.2 Gy/fraction BID), (3) Accelerated split-
course fractionation (67.2 Gy in 1.6 Gy/fraction BID with a
2-week break after 38.4 Gy), or (4) Accelerated fractionation
with concomitant boost (72 Gy in 1.8 Gy/fraction qdaily to
32.4 Gy then BID with 1.8 Gy/fx qAM and 1.5 Gy/fx qPM
for the final 12 days). A recent update with a median follow-
up time of 14 years for surviving patients showed 5-year
local control rates significantly improved in the hyperfrac-
tionation arm compared to standard fractionation. At the ini-
tial publication with 2-year results, accelerated fractionation
with concomitant boost also showed a significant improve-
ment in local control over standard fractionation; however,
this was lost with longer follow-up [55]. The update also
showed a significant disease-free survival benefit to hyper-
fractionation (p = 0.046) and a strong trend towards improved
disease-free survival in the accelerated fractionation with
concomitant boost arm (p = 0.052) and the accelerated split-
course arm (p = 0.056). No statistically significant differ-
ences were seen in severe late toxicities at 5 years [57].
M. Rutenberg and M. Suntharalingam
A meta-analysis with individual patient data from 15
randomized trials including over 6,500 patients compared
conventionally fractionated radiotherapy with altered frac-
tionation (hyperfractionated and accelerated fractionation)
to determine if altered fractionation improved overall sur-
vival. The combined altered fractionation group showed a
5-year absolute survival benefit of 3.4 % compared to stan-
dard fractionation (39.7 % vs. 36.3 %, p = 0.003). When indi-
vidual altered fractionation schedules were compared to
standard fractionation, hyperfractionation showed the largest
survival benefit (8.2 % at 5 years) with accelerated fraction-
ation showing a smaller, but significant benefit (2 % at
5 years) [58].
With clear local control benefits of altered fractionation
radiotherapy over conventionally fractionated RT alone, the
opportunity for further improvements with the addition of
concurrent chemotherapy was evaluated in several trials.
Brizel and colleagues reported the results of a single-
institution randomized trial comparing hyperfractionated
radiotherapy delivered at 1.25 Gy twice daily to a total dose
of 75 Gy vs. 70 Gy plus the addition of concurrent cisplatin
(12 mg/m2/day) and 5-fluorouracil followed by two addi-
tional cycles of chemotherapy at the completion of radio-
therapy [9]. One hundred twenty-two patients with locally
advanced HNSCC were randomized. The complete response
rate was 73 % for the RT-alone group vs. 88 % for those
receiving CT + RT (p = 0.52). With a median follow-up of 41
months, locoregional control was 44 % in the radiotherapy
arm vs. 70 % with combined modality treatment (p = 0.01).
However, the improvement in local control did not translate
into a statistically significant overall survival advantage (RT
alone 34 % vs. CT + RT 55 %, p = 0.07) [9].
Jeremic et al. conducted a randomized trial comparing
hyperfractionated radiotherapy alone (77 Gy in 1.1 Gy BID)
vs. the same radiotherapy delivered in conjunction with
daily, low-dose cisplatin (6 mg/m2/day) in 130 patients with
non-metastatic, stage III/IV HNSCC [59]. With a median
follow-up of 79 months, statistically significant improve-
ments were reported in the combined modality arm for all
end points evaluated. The complete response rates were sig-
nificantly higher for the combined modality group (75 %) vs.
those receiving RT alone (45 %) (p = 0.002). Five-year overall
survival was 46 % for CT + RT vs. 25 % for the RT arm
(p = 0.041). The locoregional progression-free survival rates
were 50 % and 36 % (p = 0.041), respectively, while distant
metastasis-free survival was 86 % and 57 % (p = 0.0013).
Notably, radiation-induced toxicities were similar in both
groups (including grade III/IV xerostomia and subcutaneous
fibrosis), whereas high-grade hematologic toxicities were
more commonly seen in the combined modality group [59].
RTOG 0129 was a multi-institutional prospective random-
ized trial evaluating concurrent chemoradiotherapy using either
accelerated-fractionation radiotherapy or standard-fractionation
43 Head and Neck Tumors: Viewpoint—Fractionated Radiation Therapy and Chemotherapy
radiotherapy in 721 patients with locally advanced HNSCC
[8]. Accelerated fractionation radiotherapy consisted of 72 Gy
in 42 fractions with a concomitant boost delivered using twice-
daily radiotherapy for the final 12 days of treatment (1.8 Gy/fx
qAM and 1.5 Gy qPM). Chemotherapy consisted of cisplatin
(100 mg/m2) q3weeks during radiotherapy. With a median
follow-up of 4.8 years, there were no significant differences
between arms in severe acute toxicity, PFS, or overall
survival.
GORTEC 99–02 is a three-arm multi-institutional phase
III trial evaluating altered fractionation in non-metastatic
stage III/IV HNSCC [60]. Eight hundred forty patients were
randomized to one of the following arms: (1) conventional
chemoradiotherapy (70 Gy in 2 Gy/fraction with concurrent
carboplatin/fluorouracil), (2) accelerated radiotherapy-
chemotherapy (70 Gy in 2.3 Gy/fraction with concurrent car-
boplatin/fluorouracil), or (3) very accelerated radiotherapy
alone (64.8 Gy in 1.8 Gy/fraction twice daily). With a median
follow-up of 5.2 years, no difference in 3-year PFS was
seen for accelerated radiotherapy-chemotherapy compared
to either conventional chemoradiotherapy or very acceler-
ated radiotherapy. There was no benefit to the accelerated
radiotherapy-chemotherapy arm for 3-year locoregional con-
trol compared to conventional chemoradiotherapy. However,
the very accelerated radiotherapy arm had significantly
worse 3-year locoregional control and PFS compared to con-
ventional chemoradiotherapy (50.1 % vs. 58.3 %, p = 0.045,
and 32.2 % vs. 37.6 %, p = 0.041, respectively). Very accelerated
radiotherapy also had significantly worse grade 3–4 toxicity
compared to both chemoradiation arms [60].
With the results of RTOG 0129 and GORTEC 99–02
showing no benefits for altered-fractionation radiotherapy
when combined with chemotherapy, the enthusiasm for this
approach has dwindled. Concurrent chemotherapy with stan-
dard fraction radiotherapy remains the standard of care for
organ preserving treatment for locally advanced HNSCC.
Concurrent chemotherapy and external beam radiother-
apy have had a dramatic impact in improving local control
and in many circumstances survival for patients with locally
advanced squamous cell carcinomas of the head and neck.
Table 43.1 details the outcomes of multiple phase III trials
that have documented these benefits over radiotherapy alone.
Reirradiation for Locoregional Recurrence
The prognosis for patients with locally recurrent HNSCC is
dismal, with 50–60 % of patients dying as a direct con-
sequence of local failure and disease progression [61].
Historically, these patients were managed with systemic ther-
apy alone, with documented overall response rates between
20 and 40 % and median survivals of 5–8 months [62, 63].
Against this backdrop, investigators began examining the
555
potential of delivering second courses of radiotherapy
with concurrent chemotherapy (Table 43.2). Reirradiation
with concurrent chemotherapy for locoregionally recurrent
HNSCC has been evaluated as definitive treatment and for
postoperative therapy.
Spencer and colleagues from the University of Alabama
at Birmingham published the results of their phase I/II trial
of reirradiation with concurrent chemotherapy in unresect-
able locoregionally recurrent HNSCC [64]. They showed the
ability to safely deliver 60 Gy (delivered at 1.5 Gy BID) to
previously irradiated tissues with concurrent 5-fluorouracil
and hydroxyurea. All therapy was delivered on a week-on,
week-off schedule. The response rate of 74 % was encourag-
ing and median survival and 2-year overall survival was
10.5 months and 20 %, respectively. Importantly, this was
one of the first series to accurately define the risks associated
with reirradiation, with 4 of 35 patients developing severe
late toxicities (two radiation myelitis, two esophageal stric-
tures) [64]. Their results led to a multi-institutional phase II
trial through the RTOG. RTOG 96–10 enrolled 86 patients
with unresectable recurrent or second primaries within a pre-
viously irradiated field. Patients received concurrent chemo-
radiation to 60 Gy in 1.5 Gy BID with concurrent 5-FU and
hydroxyurea delivered on a week-on, week-off schedule
[65]. The final report of RTOG 96–10 showed 2- and 5-year
survival of 15.2 % and 3.8 %, respectively. Acute grade 4
and 5 toxicities occurred in 17.7 % and 7.6 %, respectively.
Late grade 4 and 5 toxicities occurred in 19.4 % and 3.0 %,
respectively [66]. RTOG 99–11, a multi-institutional phase
II trial, further evaluated the safety and efficacy of concur-
rent chemotherapy and reirradiation (see Table 43.2). This
study treated patients with recurrent HNSCC after prior
radiotherapy with chemoradiotherapy with cisplatin and
paclitaxel using accelerated radiotherapy to a total dose of
60 Gy in 1.5 Gy BID (4–6 h between fractions). They docu-
mented 2-year progression-free and overall survival rates of
16 % and 26 %, respectively [61].
Reirradiation with concurrent chemotherapy has also been
evaluated by multiple investigators in the postoperative setting
for in-field recurrence or second primary HNSCC [67–70].
A prospective, randomized trial showed significantly improved
locoregional control and disease-free survival for patients
treated with postoperative chemotherapy and reirradiation vs.
observation [67]. Long-term survival is achievable in this
patient population; however, treatment toxicity rates in these
studies were not trivial.
Reirradiation of head and neck malignancies requires
special consideration for treatment planning and delivery in
order to maximize tumor killing and minimize treatment-
related morbidity. Tumor location, extent of recurrence, prior
radiation details, and time interval between radiation courses
are important factors. Because local normal tissues have
received prior high dose radiotherapy (often approaching
 556

Table 43.1 Local control and survival with concurrent chemotherapy and radiation
Author Site Total dose Dose per fraction Chemo LC/*LRC DFS/PFS OS
Brizel et al. [1] OC, OP, HYP, LAR, PNS 70 Gy w/chemo 1.25 Gy BID Cisplatin, 5-FU weeks 1,6 *3 years 70 % 5 years 61 % 3 years 55 %
75 GyGy w/o chemo (2 chemo cycles post-CRT)
Jeremic et al. [2] OC, OP, NP, HYP, LAR 77 Gy 1.1 Gy BID Daily bolus cisplatin *5 years 50 % 5 years 46 % 5 years 46 %
Al-Sarraf et al. [3] OC, OP, HYP, NP, 66–73.8 Gy 1.8–2 Gy daily Cisplatin q3weeks 4 years 43 % 4 years 34 %
mSinus, LAR
Aldelstein et al. [4] OC, OP, LAR, HYP 66–72 Gy 1.8–2 Gy daily Cisplatin, 5-FU q3weeks 5 years 77 % 5 years 50 %
Wendt et al. [5] OC, OP, HYP, LAR 70.2 Gy 1.8 Gy BID (with 2 breaks) Cisplatin, 5-FU, leucovorin *3 years 36 % 3 years 48 %
q3weeks
Forastiere et al. (RTOG LAR 70 Gy 2 Gy daily Cisplatin q3weeks 5 years 71 % 5 years 38 % 5 years 55 %
91–11) [6, 7] 10 years 69 % 10 years 22 % 10 years 28 %
Denis et al. (GORTEC) [8] OP 70 Gy 2 Gy daily Carboplatin, 5-FU q3weeks 5 years 48 % 5 years 27 % 5 years 22 %
5-FU 5-fluorouracil, OC oral cavity, OP oropharynx, HYP hypopharynx, LAR larynx, PNS paranasal sinus, mSinus maxillary sinus, BID twice daily, CRT chemoradiotherapy, LC local control,
LRC locoregional control, DFS disease-free survival, PFS progression-free survival, OS overall survival
M. Rutenberg and M. Suntharalingam
Table 43.2 Definitive reirradiation with concurrent chemotherapy for locoregional recurrence
Author Total dose Dose per fraction Chemo Tx delivery Grade 4/5 toxicity LC DFS/PFS OS
Haraf et al. (U. Chicago) [9] Median 50 Gy 1.8–2 Gy qdaily HU, 5-FU CRT given on 11 % Grade 5 5 years 20 % 5 years 14 % 5 years 15 %
or 1.5 Gy BID alternate weeks
Spencer et al. 40–60 Gy 2 Gy daily or HU, 5-FU CRT given on none 2 years 20 %
(UAB) [10] 1.2 Gy BID alternate weeks
RTOG 96–10 [11, 12] 60 Gy 1.5 Gy BID HU, 5-FU CRT given on 18 % Grade 4 1 year 62 % 2 years 15 %
alternate weeks 8 % Grade 5 5 years 4 %
RTOG 99–11 [13] 60 Gy 1.5 Gy BID Cisplatin, paclitaxel CRT given on 23 % Grade 4 (acute) 2 years 16 % 2 years 26 %
alternate weeks 7 % Grade 5
DeCrevoisier et al. (Gustave- 60–65 Gy 2 Gy qdaily or RT alone or various Variable 25 % Grade 4 2 years 11 % 2 years 21 %
Roussy) [14] 1.5 Gy BID chemo 3 % Grade 5 5 years 9 %
Sulman et al. (MDACC) [15] 60–70 Gy 2 Gy qdaily 66 % with cisplatin- Variable 32 % Grade 4 2 years 58 % 2 years 54 %
based chemo 0 % Grade 5
43 Head and Neck Tumors: Viewpoint—Fractionated Radiation Therapy and Chemotherapy

5-FU 5-fluorouracil, BID twice daily, HU hydroxyurea, CRT chemoradiotherapy

557
558
maximum tolerable doses), there is considerable risk for
severe morbidity and possible mortality. Furthermore,
because these cancers have recurred after a prior full course
of radiotherapy, the recurrent tumor cells may be more
radioresistant, requiring treatment intensification. Altered
fractionation schemes are often employed to lower the risk of
severe late toxicity while allowing treatment intensification.
A related consideration is the time interval between reirra-
diation and the initial radiotherapy. With a longer interval,
normal tissues have increased capacity for recovery from the
initial radiotherapy course. Most studies have required an
interval of at least 6 months from the completion of the initial
radiotherapy to the start of reirradiation [61, 65, 67, 68].
This time interval is also prognostic for survival [71].
Another important consideration for head and neck reirradia-
tion is target volume delineation. With an increased risk of
treatment-related morbidity, there is an emphasis on reduc-
ing treatment volumes and minimizing elective target treat-
ment. Generally, planning treatment volumes have included
gross disease with a limited expansion or only high-risk
areas for postoperative reirradiation [65, 67, 68, 72]. Because
of the emphasis on treatment volume reduction, stereotactic
treatment can be particularly well suited for head and
neck reirradiation. The accurate target delineation, effective
patient immobilization, and rapid dose falloff that character-
ize stereotactic treatment enable tumor treatment with mini-
mal normal tissue coverage. Indeed, stereotactic approaches
for head and neck reirradiation have historically treated only
areas of gross tumor volume [73, 74]. Recent reports using
stereotactic body radiotherapy (SBRT) for reirradiation have
used variable expansions from gross tumor, ranging from 0
to 10 mm [75, 76]. Studies are currently underway to define
optimal target coverage when utilizing stereotactic reirradia-
tion for HNSCC [77]. Another feature of stereotactic treat-
ment conducive to head and neck reirradiation is the large
fraction sizes, which provides a means of treatment intensifi-
cation to effectively treat recurrent cancer clonogens that are
radioresistant after a prior course of standard fraction
radiotherapy.
Stereotactic Therapy in Head and Neck
Cancers
The use of stereotactic radiotherapy for head and neck cancers
originated with the treatment of base of skull and nasopha-
ryngeal cancers [73, 78–81]. In the era preceding combined
chemoradiation, the local failure rate for nasopharyngeal
squamous cell carcinomas approximated 30 %. With consid-
erable morbidity associated with progression in this area,
attempts at local control for nasopharyngeal SCC included
reirradiation with external beam radiotherapy, brachytherapy,
stereotactic radiosurgery (SRS), and combinations thereof.
M. Rutenberg and M. Suntharalingam
Recurrent nasopharyngeal squamous cell carcinoma became
the first HNSCC managed with SRS. Early studies using
either Gamma Knife or Linac-based SRS reirradiation for
recurrent disease showed good response and local control
rates with acceptable toxicity [73, 74, 81, 82]. These experi-
ences have now been expanded, with many institutions repor-
ting outcomes for salvage stereotactic radiosurgery for
recurrent nasopharyngeal cancer. With the increased availabil-
ity of SBRT, this approach has become widely used for naso-
pharyngeal recurrences and is being applied more broadly for
other sites of inoperable recurrent HNSCC [83–85].
Subsites of the head and neck are attractive for the use of
SRS/SBRT for reirradiation for several reasons. The dense
concentration and radiosensitivity of tissues and organs and
their impact on patient quality of life make precision treat-
ment and minimization of treatment of normal tissue impera-
tive. Additionally, this area has little or no respiratory-related
movement, minimizing motion-based uncertainties (although
swallowing related motion may require consideration).
Additionally, the shortened course of SRS/SBRT is ideal for
recurrent head and neck cancer patients who are frequently
debilitated with poor performance status, precluding exten-
ded treatment courses and systemic therapy.
Ryu et al. published a series from Henry Ford Hospital
including 13 patients with recurrent head and neck carcino-
mas (62 % squamous cell carcinoma) treated with either
single-dose or fractionated stereotactic radiotherapy (FSRT)
to various head and neck sites [83]. SRS doses ranged from
12–18 Gy (five patients) and FSRT was treated with
30–36 Gy in five or six fractions delivered twice weekly
(eight patients). Dose was prescribed to the 90 % isodose
line covering the entire gross tumor volume. Objective
responses were seen in 70 % of patients (46 % complete
response). A follow-up report from the same group included
21 patients treated for recurrent head and neck malignancies
using SRS (13–18 Gy) or SBRT (36–48 Gy in 5–8 fractions)
[84]. This study showed an overall response rate of 69 %
(31 % complete response). All treated patients treated in the
oropharynx or larynx experienced RTOG grades 1 and 2
mucositis and esophagitis. Five percent (one patient) and
19 % of patients treated with reirradiation experienced
RTOG grade 3 (swallowing difficulty) and grade 4 toxicities
(1 dysphagia and ulceration, 2 mucocutaneous fistulas, 1
mucocutaneous fistula and mandibular radionecrosis),
respectively. One-year tumor control was 60.6 % with a
median survival of 6.7 months [84].
Roh and colleagues published their experience using
CyberKnife-based SBRT on 36 patients with recurrent head
and neck cancers with prior irradiation [85]. Median doses of
30 Gy (range 18–40 Gy) in 3–5 fractions were delivered to
the 65–85 % isodose line on consecutive days. Their plan-
ning target volumes (PTV) consisted of gross tumor volume
(GTV) with a 2–3 mm expansion. With a median follow-up
43 Head and Neck Tumors: Viewpoint—Fractionated Radiation Therapy and Chemotherapy 559

Table 43.3 SRS/SBRT reirradiation for head and neck cancers

Median dose Number of Dose per Fractionation Grade 3+ Grade 5 Median PFS Median OS
Author, institution Pt. No. (range) fractions fraction (Gy) schedule toxicity toxicity (months) (months)
Cengiz et al. [16] 46 30 Gy (18–35) 1–5 5–18 qdaily 30 % 16 % 10.5 12
Kodani et al. [17] 21 30 Gy (19.2–45) 3–7 qdaily 29 % 10 %
Roh et al. [18] 36 30 Gy (18–40) 3–5 5–13 qdaily 44 % 3% 16.2
Unger et al. [19]a 65 30 Gy (21–35) 2–5 4–12 qdaily 11 %c 1.5 % 5.7 12
Siddiqui et al. [20]b 44 1–8 6–18 QOD 16 % 0 6.7e
Vargo et al. [21]d 34 40 Gy (17–50) 1–5 6–20 QOD 21 % (G3 only) 0 11
Comet et al. [22] 40 36 Gy 6 6 QOD 10 % (G3 only) 0 8.8 13.6
5-FU 5-fluorouracil, QOD every other day
a
Includes metastatic and postoperative patients
b
Includes patients with primary and metastatic disease
c
Includes only grade 4/5
e
Recurrent, non-metastatic disease only
d
Includes patients with recurrent disease with metastases

time of 17.3 months, the overall response rate was 80 %
(42.9 % complete response) and local recurrence-free sur-
vival was 52.1 % and 30.9 % at 1 and 2 years, respectively.
Thirty-six percent (13 patients) experienced RTOG grade 3
acute toxicity (mucositis, nausea, dermatitis), 8 % experi-
enced RTOG grade 4 late toxicity (one bone necrosis, two
soft tissue necrosis), and one patient died of treatment-
related causes with soft-tissue and skull base necrosis [85].
Unger et al. published a series of 56 patients with unre-
sectable, recurrent HNSCC treated at Georgetown University
with SBRT reirradiation [75]. Planning target volumes
included gross disease with a 2–10 mm expansion and stan-
dard dosing of 30 Gy in five fractions. Notably, many patients
in this series received concurrent systemic therapy with
cetuximab or carboplatin. They observed an 81 % overall
response rate (54 % complete response). Two-year locore-
gional control and overall survival were 31 % and 40 %,
respectively. Median PFS was 5.7 months. Eleven percent
(6 patients) experienced grade 4 treatment-related toxicity
and one patient suffered a treatment-related death two weeks
after completion [75].
A phase I dose escalation trial conducted at the University
of Pittsburgh enrolled twenty-five patients who received
SBRT reirradiation for unresectable, locally recurrent
HNSCC after previous irradiation [86]. Reirradiation was
delivered to the 80 % isodose line with at least 90 % gross
tumor coverage with a five-fraction course over two weeks.
Patients started at the lowest-dose tier of 25 Gy in 5 Gy/
fraction and increased until the top-tier dose of 44 Gy was
reached. No dose limiting toxicities occurred. Four patients
experienced acute grade 1/2 toxicities. No grade 3–5 toxici-
ties were reported [86].
Table 43.3 shows a selection of single-institution reports
utilizing SBRT for head and neck reirradiation.
Investigations of optimal dose fractionation, treatment
volumes, and use of systemic therapy with SRS/SBRT for
head and neck malignancies are ongoing and more detail on
this subject is provided in the preceding main chapter.
As stereotactic treatment for reirradiation of recurrent head
and neck cancers becomes more widespread, it is important
to rigorously adhere to the basic principles that guide all
SRS/SBRT treatments, including effective patient positioning/
immobilization, high quality imaging for disease evaluation
and treatment planning, highly conformal treatment plan-
ning, and accurate target localization. The same features of
head and neck malignancies that make it attractive for SRS/
SBRT can be sources of increased patient morbidity and
mortality.
Conclusion
Patients presenting with locally advanced head and neck
cancers represent one of the most challenging patient groups
in oncology. In recent decades, multimodality therapy, often
employing combined chemotherapy and radiation, has become
the standard of care.
Our current treatment standards for head and neck
cancers result from advances in tumor and radiation biol-
ogy, drug discovery and development, imaging technolo-
gies, advances in radiation planning and delivery, and
multidisciplinary collaboration. This has enabled the use of
stereotactic radiation therapy to become an effective tool in
the management of these malignancies. As we continue to
refine these treatments, the use of stereotactic radiation for
head and neck cancers will broaden. However, it is impera-
tive that we proceed cautiously with the delivery of high
doses per fraction to our targets. The proximity and sensi-
tivity of the surrounding normal structures must be appreci-
ated when tumors are delineated and dose constraints are
defined. Patient safety must be central to our evaluation of
these technologies as we move forward. Ultimately, this
will lead to improved local control, overall survival, and
patient quality of life.
560
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1493–500.
 Spinal Tumors and Radiosurgery
Evangelia Katsoulakis, Ilya Laufer, and Yoshiya Yamada
Benign Tumors
Unlike with malignant tumors, where radiation had a long-
established role, radiation as a primary treatment modality
for benign tumors is debatable because of the long life expec-
tancies of patients that are afflicted with these tumors. Late
radiation toxicity can take many years to manifest and the
possibility of radiation-induced myelopathy must be thor-
oughly considered when designing treatment management.
Our discussion for benign tumors is limited to vascular mal-
formations, namely, hemangioblastomas and arteriovenous
malformations (AVMs).
Hemangioblastomas
Hemangioblastomas represent a group of benign, highly vas-
cular tumors that are typically pial-based. While the majority
of hemangioblastomas (~80 %) occur sporadically, they are
often associated with an inherited syndrome, von Hipple–
Lindau (VHL) disease [1]. Historically, the standard of care
for hemangioblastomas is complete microsurgical removal.
Surgical resection, however, may aggravate underlying neu-
rological symptoms or incite new ones [2]. Additionally,
many patients are also poor surgical candidates or have inop-
erable lesions, and radiosurgery provides an attractive treat-
ment option.
In one of the largest retrospective series reported by Moss
et al., 82 hemangioblastomas involving either the spine or
cranium in 28 patients underwent stereotactic radiosurgery
(SRS). The majority of patients (89.2 %) had VHL and 93 %
E. Katsoulakis, M.D. • Y. Yamada, M.D., F.R.C.P.C. (*)
Department of Radiation Oncology, Memorial Sloan Kettering
Cancer Center, 1275 York Avenue, New York, NY 10065, USA
e-mail: ekatsoulakis@gmail.com; yamadaj@mskcc.org
I. Laufer
Department of Neurosurgery, Memorial Sloan Kettering
Cancer Center, 1275 York Avenue, New York, NY 10065, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_44, © Springer Science+Business Media New York 2015
44
underwent prior resection (mean number of resections, 2.9).
There was a total of 16 spinal lesions treated to a dose of
21 Gy (range, 20–25 GY) in 1–3 fractions (median, 2.0 frac-
tions) with a median follow-up of 33.5 months (range, 6–73
months). The mean radiation dose to the periphery of tumor
was 23.4 Gy (range, 12–40 Gy) and the mean tumor volume
was 1.8 cm (range, 0.058–65.4 cm3). Of the tumors that
exhibited neurologic symptoms, 88 % showed improvement
or complete resolution. The actuarial radiographic local con-
trol rates for the spinal lesions at 36 months and 60 months
were 92 % and 92 %, respectively [3]. Moreover, none of the
patients treated with spinal SRS developed neurologic toxic-
ity secondary to radiation [3].
In another series by Selch et al. [4], consisting solely of
spinal lesions, 20 tumors in 9 patients (5 of which had VHL)
were treated with image-guided radiosurgery to a dose of
12 Gy in a single fraction. With a median follow-up of 51
months (range, 14–86 months), the 4-year local control rate
for the entire cohort was 90 %. It has been surmised that solid
or mural nodular components of hemangioblastomas tend to
respond much more favorably to radiosurgery than cystic
components. Indeed, in this series, solid tumor control rates
were reportedly higher than cystic with a 4-year control rate
of 95 %. While the single-fraction 12 Gy dose was lower than
other reported series, local control rates were excellent. None
of the patients developed neurotoxicity or myelopathy.
Daly et al. [5] reported on the highest maximum radiosur-
gical doses ever delivered to the spinal cord in their series of
25 spinal hemangioblastomas from 18 patients. Seventeen
tumors were treated to a median dose of 20 Gy (range,
18–30 Gy) in a single fraction. The remainder of the lesions
were treated to 18–25 Gy in 2–3 fractions. Thirty percent had
prior surgical resection. With a median follow-up of
33.7 months (range, 6.6–84.0 months), the 3-year actuarial
local control was 86 %. There was one late grade 2 neuro-
logic toxicity, which manifested as a unilateral foot drop.
The 3-year rate of grade 2 or more toxicity was 4 %. While it
is difficult to discern the etiology of declining neurologic sta-
tus, and whether the cause is disease progression or radiation
563
564
toxicity, patients received the highest radiosurgical dose ever
reported to the spine.
Even though data continues to accumulate regarding the
efficacy of radiosurgery for hemangioblastomas, appropriate
spinal cord dose constraints are poorly defined in the radio-
surgical literature and warrant further discussion and longer
follow-up in the setting of benign disease. In the series by
Daly et al. [5], patients received a median spinal cord Dmax of
22.7 Gy (range, 17.8–30.9 Gy) in a single fraction, while the
multiple-fraction group had a median single-fraction biolog-
ically equivalent dose (SFBED) spinal cord Dmax of 14.1 Gy3
(range, 12.3–19.4 Gy3). The majority of treatments (59 %)
in the single-fraction group exceeded that of the Radiation
Therapy Oncology Group (RTOG) spinal radiosurgery pro-
tocol 0631. While toxicity was limited in the study, prospec-
tive studies with longer follow-up and larger patient numbers
are required prior to drawing definitive conclusions with
respect to spinal cord tolerance. In addition, hemangioblas-
tomas are known to have a long time to progression and
exhibit quiescent phases that could partially account for the
excellent control rates. In a study of cranial hemangioblasto-
mas treated with radiosurgery, median time to tumor pro-
gression was 5.9 years [2]. While radiosurgery is clearly
efficacious for the treatment of spinal hemangioblastomas,
much longer follow-up is necessary to definitively conclude
its equivalence to microsurgery.
Arteriovenous Malformation
Radiosurgery has long been acknowledged as a noteworthy
alternative to microsurgical resection and embolization for
cerebral AVMs. Over 5000 patients have been successfully
treated with high-dose radiation since the inception of SRS
in the 1970s with obliteration rates of 80–85 % over a 2- to
3-year period for lesions less than 2.5 cm. In a recent series
by Kano et al., 996 patients with grade 1 and 2 cerebral
AVMs with a median tumor volume of 2.3 cm treated to a
Table 44.1 Spine radiosurgery for benign tumors
Total dose
Patients (range)/No. of
Author (lesions) Histology fractions (range)
Moss et al. [3] 16 (16) Hemangioblastoma 21 Gy (20–
25 Gy)/2 (1–3)
Selch et al. [4] 9 (20) Hemangioblastoma 12 Gy/1
Daly et al. [5] 25 (18) Hemangioblastoma 20 Gy (18–30)/1
18–25 Gy/(2–3)
Sinclair et al. [7] 15 AVM, type II 20.5 Gy
(15–25)/3 (2–5)
Long term follow-up in this patient population indicates excellent local control with minimal toxicity
E. Katsoulakis et al.
median dose of 22 Gy (range, 15–27 Gy) had a 10-year total
obliteration rate of 93 % determined by angiography or MR
[6]. Smaller target volumes, smaller target maximum diam-
eter, and larger dose correlated with greater rates of
obliteration. The cumulative rates of AVM hemorrhage after
SRS at 5 and 10 years were 5.0 % and 6.1 %, respectively.
The corresponding rates of annual bleeding were 0.3 % and
0.2 % for years 1–5 and 5–10, respectively. There are fewer
reports in the literature, however, for spinal AVMs.
The mainstay of therapy for type I and IV spinal AVMs,
which represent dural and perimedullary arteriovenous fistu-
las, is microsurgical resection. Type II and III AVMs, how-
ever, are located within the parenchyma of the spinal cord
and it is these lesions that are best suited for radiosurgery.
Whereas type II spinal AVMs consist of a compact intramed-
ullary nidus, type III spinal AVMs are composed of a diffuse
intramedullary nidus and often contain a paraspinal component.
Both types are not amenable to surgery. Sinclair et al. [7]
reported on the largest experience with spinal cord AVMs
treated with radiosurgery in which 15 patients with intra-
medullary spinal cord AVMs (mean target volume, 2.36 mL;
range, 0.79–5.23 mL) were treated to a dose of 20.5 Gy
(range, 15–25 Gy) in 3 sessions (range, 2–5 sessions). All
patients were followed with magnetic resonance imaging
(mean follow-up of 27.9 months; range, 3–59 months),
which revealed a reduction in the AVM volume. Only five
patients, however, underwent angiography as part of their
follow-up. Of these patients, only 1 had complete obliteration
on angiography. There were no instances of rebleeding after
radiosurgery. Clinically, patient outcomes were improved or
remained stable in 92.3 %. The authors have updated this
series in abstract form and have successfully treated over 24
patients in total with similar results. Table 44.1 provides a
summary of IG-IMRT for benign tumors. The optimal dose
and long-term durability of radiosurgery for spinal AVMs
have yet to be determined. These reports suggest that radio-
surgery will play an integral role in the management of
spinal AVMs with an intramedullary nidus.
Spinal cord Follow-up
dose (months) Local control Myelopathy
NR 33.5 92 % 0%
Dmax 12 Gy 51 90 % 0%
and
V10 = 10 %
Dmax 22.7 Gy 33.7 86 % 4 % grade ≥2
Dmax 14.1 Gy
NR 27.9 All patients had 0%
radiographic
reduction of nidus
44 Spinal Tumors and Radiosurgery
Malignant Tumors
Primary Tumors
Chordomas
Although quite rare, chordomas are the most common primary
malignant tumor of the spine. Standard of care for these
tumors is en bloc resection with wide margins. In the setting
of an incomplete or intralesional resection, which often
arises in the presence of epidural disease, adjuvant radiation
to a total dose of at least 65 Gy is indicated [8–10]. In a
report by Terezakis et al., seven chordomas were treated with
postoperative image-guided conventionally fractionated
radiation therapy to a median dose of 6,600 cGy (range,
5,396–7,080 cGy) in 180–200 cGy per fraction. The median
planning target volume was 164 cm3 (range, 29–1,116 cm3).
With a median follow-up of 17.4 months (range, 2.1–
47.3 months), one patient developed in-field recurrence.
There were no patients who experienced myelopathy.
Proton radiation therapy is an established treatment option
for the treatment for sacral chordomas, and outcomes corre-
late with dose. In a study by Park et al. [11], 27 patients with
sacral chordomas (16 primary and 11 recurrent), most of
whom underwent surgical resection (78 %), received photon/
proton radiation, and were followed for a mean of 8.8 years.
The mean dose for primary tumors was 71 Gy (E) in 36 frac-
tions versus 77 Gy (E) in 41 fractions for recurrent tumor.
The mean diameter for primary tumors was 8.6 cm (range,
2.8–19.3 cm) versus 5.7 cm (range, 2.7–9 cm) for recurrent
tumors. Local control rates for surgery and radiation were
12/14 (86 %) for primary versus 1/7 (14 %) for recurrent
chordomas. Among patients receiving definitive radiation,
doses of 73 Gy (E) or more resulted in greater rates of local
control [11]. The authors recommend 77.4 Gy (E) to areas of
gross residual disease or unresected chordomas. Dose esca-
lation resulted in high rates of local control. Proton radiation
facilities are not readily accessible; however, this prompted
photon dose escalation with modern image-guided tech-
niques, enabling hypofractionation.
In the study by Jiang et al. [12], both intracranial and
extracranial chordomas were treated to a dose of 32.5 Gy
(range, 18–50 Gy) in 1–5 fractions. The average tumor vol-
ume was 16.1 cm3 (range, 2.4–45.9 cm3). With a reasonable
follow-up of 34 months (range, 2–131 months), overall
tumor control for the whole cohort was achieved in 11 of 20
patients (55 %). Eight of those patients had a reduction in
tumor size. Moreover, patients with spinal chordomas (seven
in total) had improved symptoms and higher tumor control
than intracranial lesions, 71 % versus 46 %. One patient with
no evidence of disease radiographically had collapsed at L3
and required surgical decompression.
565
Henderson et al. reported on a series of 24 lesions, the
majority of which (61 %) involved the spine or sacrum. The
median tumor volume was 128 mL (range, 12.0–457.3 mL) to
a median dose of 35 Gy (range, 24.0–40.0 Gy) in 5 fractions.
Median follow-up was 46 months (range, 7–65 months) and
actuarial 5-year local control was 59.1 %. Toxicity profiles
were similar to those reported in other series, and no patients
experienced grade 3 or 4 neurologic complications [13].
The authors currently employ image-guided high-dose
radiosurgery neoadjuvantly prior to surgical resection. In
cases where gross total resection is achievable, a neoadju-
vant approach may facilitate intralesional resection. The
neoadjuvant approach was inspired by a case report in which
a patient with spinal chordoma underwent definitive single-
fraction, high-dose, image-guided radiation to the tumor.
Unfortunately, 4 months after treatment the patient under-
went L3 corpectomy due to symptoms of mechanical insta-
bility [14], which revealed near-complete necrosis of the
resected chordoma. Results of our institutional experience
with the neoadjuvant approach will be published shortly.
Spinal Metastases
The prevalence of spinal metastases in North America is
over 100,000 patients each year. Over 40 % of cancer patients
will develop metastatic disease in the spine, the bulk of
which is extradural. Highly effective and durable palliation
is clinically significant, especially in the context of longer
life expectancies secondary to improved systemic agents
[15]. Conventionally fractionated radiation therapy has been
an integral component of the treatment paradigm for spinal
metastases; one or two open fields are used to deliver the
radiation dose bound by spinal cord tolerance [16]. The evo-
lution of image-guided technology and breakthroughs in
treatment planning has revolutionized the management of
spinal metastases [17–19]. In situations where the tumor is in
close proximity to the spinal cord, safe dose escalation is
possible via steep dose gradients. While these techniques
have been used in the primary-irradiation, postoperative set-
ting, as well as re-irradiation, the optimal dose, patient-
selection, and delivery method has yet to be defined.
Primary Irradiation: Single Fraction
The ideal fractionation schema for palliation of bone
metastases has been studied extensively [14, 20]. One of
the most eminent trials, RTOG 9714, randomized patients
to 8 Gy × 1 versus 3 Gy × 10. The single-fraction, low-dose
arm resulted in higher rates of retreatment with radiation,
18 % versus 9 % [20]. In a contrasting meta-analysis of
566
over 3,260 patients, clinical outcome was unchanged with
single-fraction, low-dose (median, 8 Gy) versus fractionated
radiation (median, 4 Gy × 5) [14]. Palliation of pain, however,
favored single-fraction, low-dose radiation. The recently
updated meta-analysis now includes over 5,000 patients and
findings show no significant difference in pain relief [21].
Particularly for spinal metastases, long-term outcomes of
conventional fractionation or single-fraction, low-dose radi-
ation for the treatment of spinal metastases have been
reported in a prospective study by Nagoya University.
Approximately 101 patients with spinal tumors received
40 Gy in 20 fractions, were followed for more than 24
months (11 months for dying patients and 53 months for sur-
vivors), and reported 67 % pain relief [22]. Similarly, in a
randomized study by Maranzano et al., metastatic cord com-
pression received 8 Gy × 2 over one well versus a split course
of 5 Gy × 3 plus 3 Gy × 5. At 33 months follow-up, pain relief
was similar for short- versus long-course patients, 56 % and
59 %, respectively [23]. In general, the mean pain relief
expected from conventional fractionated radiation is 70 %
(range, 56–100 %).
Radiographic local control rates are similar to pain relief
with conventionally fractionated radiation, about 77 %. One
of the most critical prognosticators of recurrence is tumor
histology. Favorable or radiosensitive histologies include
breast cancer, prostate cancer, lymphomas, seminomas, and
myelomas. Unfavorable or radioresistant tumors include
sarcomas, melanomas, renal cell carcinomas, gastrointestinal
cancers, and non-small cell lung cancer [24]. In the afore-
mentioned study by Maranzano, radiosensitive histologies
had significantly improved median survival and duration of
neurologic motor improvement with spine radiation, 10
versus 3 months (p = 0.001) and 11 versus 3 months
(p = 0.001), respectively [23]. Additionally, for the long-
term survivors of the Nagoya study, durable response at 53
months was greater in the radiosensitive tumors (30 % ver-
sus 10 %) [22].
Successful outcomes for spinal metastases should be dif-
ferentiated from osseous metastases and should include close
radiographic follow-up. Single-fraction, high-dose image-
guided intensity-modulated radiation therapy (IG-IMRT) is
proved to be highly effective in both pain and radiographic
control, irrespective of tumor histology. Pain improvement
is approximately 85 % and often immediate, occurring
within days of treatment [19, 24]. In general, pain usually
decreases within weeks of treatment. Long-term radio-
graphic tumor-control rates are excellent at 90 % [25–27].
Moreover, radioresistant tumor histologies that respond
poorly to conventionally fractionated radiation such as renal
cell carcinoma or melanoma are potentially cured locally
with single-fraction, high-dose IG-IMRT.
Gerszten et al. reported on a mixed population of 500
patients with spinal metastases. In approximately 65 patients,
E. Katsoulakis et al.
single-fraction, high-dose IG-IMRT was the primary
treatment modality. The mean tumor dose was 20 Gy
(range, 12–25 Gy), while mean follow-up was 21 months
(range, 3–53 months). Long-term control and pain improve-
ment was excellent at 90 % and 86 %, respectively. There
were no cases of myelopathy [28].
In a larger series of 93 patients with 103 spinal metastases
treated with radiation as the primary treatment modality,
Yamada et al. reported excellent overall radiographic local
control of 90 % [29]. In this series, patients received single-
fraction, high-dose IG-IMRT of 18–24 Gy (median, 24 Gy).
An example of isodose distribution for high-dose IG-IMRT
is shown in Fig. 44.1. The median follow-up was 15 months
and all patients underwent close surveillance with magnetic
resonance imaging at each scheduled follow-up visit to
assess local control. The 2-year estimated cumulative inci-
dence of local failure with death as a competing risk was
7.5 %, with median time to failure of 9 months. Tumor his-
tology did not predict for local control on multivariate analy-
sis, while radiation dose was the only significant predictor.
The local control rates for low-dose (18–23 Gy, mean
20.8 Gy) versus high-dose (24 Gy) radiation were 80 % and
95 %, respectively (p = 0.03). In all cases, death was due to
systemic disease progression rather than local failure. The
median time to death after treatment was 10 months (range,
1–39 months), while median overall survival was 15 months.
At the time of death, all but one patient had no evidence of
local failure.
Due to the observed dose response, the planned dose dis-
tributions were retrospectively reviewed [30]. Dosing param-
eters, including Dmin and D95, were examined for patients
experiencing local failure and compared with the whole
cohort. The median Dmin (10.8 Gy) for patients experiencing
local failure was significantly lower than those patients expe-
riencing local control (Dmin, 15.7 Gy). Moreover, when Dmin
was <15 Gy, local failure rates were 16 %. However, when
Dmin was >15 Gy, no failures were observed in any histology.
It would appear that underdosing to even a small subvolume
of treatment target is clinically significant.
Adjuvant Postoperative: Single Fraction
If the spinal cord is compromised by tumor, such as with
high-grade epidural compression or spinal instability,
decompressive surgery is the standard of care, resulting in
improved neurologic and functional outcomes [30]. Residual
tumor at the dural margin is at risk for recurrence; thus, the
majority of metastatic spinal tumors require adjuvant radia-
tion for microscopic or gross disease. High-dose, single-
fraction IG-IMRT has demonstrated superior outcomes
compared with conventionally fractionated adjuvant radia-
tion for radioresistant histologies. Postsurgical intervention,
44 Spinal Tumors and Radiosurgery 567

Fig. 44.1 Forty-eight-year-old man with radioresistant liposarcoma space. (b) Dose volume histogram reflecting the dosimetric advantages
and single metastasis at T12 treated with 2,400 cGy in a single fraction. of image-guided intensity-modulated radiation therapy and limited
Computed tomography myelogram is used to define the true cord. dose to the true cord
(a) Isodose distribution revealing a high-dose gradient in the epidural

the tumor environment is hypoxic as well as radioresistant skin dose is negligible due to steep dose gradients, IG-IMRT
and the 1-year local control rate is dismal at 20–30 % [31]. may be given early in the postoperative period.
Additionally, treatment is often delayed, with conventional In a small series of 18 patients which included highly radio-
radiation secondary to wound healing. Conversely, since sensitive histologies such as multiple myeloma, postoperative
568
single-fraction IG-IMRT was delivered with a mean dose of
11.4 Gy (range, 6–16 Gy). The results were outstanding, with
92 % of patients having stable or improved neurologic symp-
toms at a median follow-up of 7 months [32].
In another series by Moulding et al., 21 patients received
adjuvant postoperative high-dose, single-fraction IG-IMRT
to a higher median dose of 24 Gy (range, 18–24 Gy) [33].
In this series, the overwhelming majority of patients (95 %)
had radioresistant histologies. Patients were grouped into
high- and low-dose IG-IMRT groups of 24 Gy and 18 or
21 Gy, respectively. The overall local control for the entire
cohort was 81 % at a median follow-up of 310 days. When
stratified by dose group, the high-dose IG-IMRT group had a
lower 1-year estimated local failure risk than the low-dose
IG-IMRT group, 6.3 % versus 20 %. Overall survival was
not significantly different among high-dose versus low-dose
IG-IMRT.
Adjuvant IG-IMRT after surgical decompression and
instrumentation is highly effective in ensuring local control
and sustaining neurologic recovery, especially for radioresis-
tant histologies.
Salvage Reirradiation Dose
and Hypofractionation
Tumor recurrence or progression after conventional radio-
therapy at the original site is common, on the order of
50–80 % at 2 years [22]. Furthermore, recurrences after a
previous course of conventional radiation are more likely to
be radioresistant since they ultimately failed radiation and
thus require robust radiation doses for successful salvage.
Reirradiation with conventional means is limited by spinal
cord tolerance and the concern for radiation-induced myelop-
athy. In instances where additional conventional radiation or
surgery is not appropriate, IG-IMRT is a successful option.
The effectiveness of IG-IMRT has been reported in many
retrospective series with small patient numbers [34–37]. The
largest series was reported by Memorial Sloan-Kettering
Cancer Center, which examined 94 patients who underwent
reirradiation for true in-field recurrences [38]. IG-IMRT was
delivered using 4–6 Gy per fraction and a total dose of
20–30 Gy. The 1-year radiographic control was 66 %. In a
prospective phase 1–2 trial by M.D. Anderson Cancer Center,
63 previously irradiated paraspinal metastases received
6–9 Gy per fraction to a total of 27 or 30 Gy with a 76 %
radiographic control rate at 1 year [39, 40]. The University of
Pittsburgh conducted one of the largest prospective trials of
spinal metastases [28]. Over 500 mixed lesions were
included, 68.8 % of whom received prior conventional radia-
tion. The patients were salvaged with high-dose single frac-
tion radiation therapy to 12.5–25 Gy and long-term
radiographic control rates were excellent at 88 %.
E. Katsoulakis et al.
Just as in the definitive setting, a robust tumor ablative
dose is critical. In the MSKCC series, the salvage reirradia-
tion dose was either 20 Gy (five 4 Gy fractions) or 30 Gy
(five 6 Gy fractions). The salvage dose was the only signifi-
cant predictor of radiographic local failure (p = 0.04). The
incidence of radiographic local failure rates for 20 Gy and
30 Gy was 45 % and 26 %, respectively. Moreover, the BED
for the high-dose 30 Gy and low-dose 20 Gy fractionations
are equivalent to 48 Gy10 and 28 Gy10, respectively. The 1.7-
fold BED increase correlated with a 1.7-fold decrease
in local failure rate at 1 year. Dose, however, did not impact
survival; the median survival for the entire cohort was
13.6 months. Radiosensitive histology and time to reirradia-
tion were both associated with improved survival. Salvage
reirradiation was highly effective in palliating pain or neuro-
logic symptoms, with 85 % of symptomatic patients report-
ing no progression and 77 % experiencing mild or significant
pain relief.
The reirradiation prospective trial by Garg et al. reported
similar results [40]. The freedom from neurologic deteriora-
tion at 1 and 3 years was 92 % and 81 %, respectively. While
not all 63 lesions were true in-field recurrences, the majority
(85 %) received 27 Gy in 3 fractions. In this series, tumor
progression was not associated with tumor histology. Overall
survival correlated with prior radiation therapy dose received;
prior dose ≥35 Gy had a median survival of 33 months,
whereas prior dose <35 Gy had a median survival of 21
moths (p = 0.01). The correlation with prior radiation therapy
dose and survival, however, was most likely associated with
whether radiation was initially given with a curative or a pal-
liative intent.
In the study by Gerszten et al., 344 patients received sal-
vage reirradiation with a single fraction of 12–25 Gy [28].
Prior radiation was either with 3 Gy × 10 fractions or
2.5 Gy × 14 fractions. While long-term pain control was
excellent (86 %) and independent of histology, radiographic
control was 88 % and varied with histology. For instance,
radiosensitive breast carcinoma experienced 100 % local
control, whereas local control for radioresistant melanomas
was 75 %. The relationship between dose and local control
was not reported. While the optimal dose and fractionation
of salvage reirradiation with IG-IMRT has yet to be defined,
safe delivery of high-dose radiation is feasible and provides
excellent rates of local control and symptom management.
Table 44.2 provides a summary of salvage IG-IMRT after
prior treatment with radiation or surgery.
Brachy P32 Plaques
While reirradiation using image-guided techniques is highly
effective at tumor ablation and limiting dose to the cord,
there are instances in which tumor extends into the spinal
44 Spinal Tumors and Radiosurgery 569

Table 44.2 Spine radiosurgery as salvage for malignant tumors

Total dose (range)/
Patients No. of fractions Spinal cord Follow-up Local control
Authors (lesions) Prior treatment (range) dose (months) ( %) Myelopathy
Damast et al. [38] 94 (97) Radiation 20 Gy/5 Dmax 10 Gy 12.1 55 0%
30 Gy/5 Dmax 14 Gy 74
Garg et al. [40] 59 (63) Radiation 30 Gy/5 Dmean 10 Gy 17.6 76 3.3 % ≥grade 3
27 Gy/3 Dmean 9 Gy
Gerszten [28] 344 (344) Radiation 20 Gy NR 21 88 0%
(12–25.9 Gy)/1
Rock et al. [32] 18 (18) Surgery 11.4 Gy mean NR 7 94 NR
(6–16 Gy)/1
Moulding et al. [33] 21 (21) Surgery 24 Gy/1 Dmax 14 Gy 10.2 93.80 0%
18–22 Gy/1 81
In the setting of prior treatment with surgery or radiation, spinal cord sparing IG-IMRT provides good local control. Local control outcomes are
dose-dependent, with high-dose single-fraction treatment resulting in the highest reported rates

canal and impinges on the dura. Delivering a robust dose to

the dural margin, which is likely to harbor microscopic
tumor involvement, with IG-IMRT alone can be challenging.
Brachytherapy has been used to circumvent spinal cord radi-
ation tolerance while delivering high doses to the dural mar-
gin. Many radioactive sources have been used including
Iodine 125, Ytrium 90, Iridium 92, and P32.
DeLaney et al. reported on their experience with three
plaque designs in the treatment of eight patients with para-
vertebral or vertebral tumors abutting the dura treated with a
combination of conventional radiation (median dose, 54 Gy;
range, 16.2–70.2 Gy), tumor resection, and intraoperative
brachytherapy to the dura. The authors support the use of
rigid Ytrium 90 plaque for radiation safety and delivered
7.5–15 Gy at the dural surface. The results were promising.
At a median follow-up of 24 months (range, 10–34), 6 of the
8 patients were locally controlled [41].
In the largest recent spine brachytherapy series to date,
Folkert et al. [42] reported on 25 patients who received
prior conventional radiation and later developed recurrent
primary and progressive metastatic disease requiring surgi-
cal intervention due to dural involvement with an intraop-
erative flexible brachytherapy plaque. P32 plaque was
prescribed as 10 Gy at 1 mm depth, resulting in a dural sur-
face dose of 2,550 cGy and a maximum cord dose of
160 cGy. The majority of patients, 15 of 25 (60 %), received
additional high-dose IG-IMRT (median dose, 2,700 cGy;
range, 1,800–3,000 cGy). With a median follow-up of
7.3 months (range, 2.6–23.3 months), local control was
82.4 % and time to failure was 3.2 months. There were no
intraoperative or postoperative complications secondary to
radiotherapy. While longer follow-up is warranted, the
future of brachytherapy in the management of spinal tumors
appears bright.
Conclusions
Image-guided radiosurgery continues to widen the therapeutic
window for disease involving the spine. Spine radiosurgery is
proof of the principle that the accurate delivery of tumoricidal
doses of radiation is feasible with the judicious use of image-
guided technology and highly conformal treatment planning.
Additionally, patients tolerate very high-dose radiation when
image-guided techniques and brachytherapy are utilized to min-
imize the volume of normal spinal cord tissue that is irradiated.
Conflict of Interest Yoshiya Yamada is a member of the Speakers
Bureau of the Institute for Medical Education and has served as a con-
sultant for Varian Medical Systems.
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 Spinal Tumors: Viewpoint—Surgery
Faiz U. Ahmad, Gabriel Zada, and Michael Y. Wang
Introduction
The majority of spine tumors encountered by clinicians are
metastatic, accounting for approximately 70 % of all spine
tumors [1]. Each year, an estimated 18,000 patients will be
diagnosed with metastatic spine disease [2, 3]. Metastatic
lesions most frequently originate from primary tumors in the
breast, lung, and prostate. Less frequently encountered neo-
plasms of the spine and spinal cord include primary lesions
such as meningiomas, schwannomas, osseous tumors of the
spine, ependymomas, and gliomas. At the time of death,
approximately 70–90 % of all terminal cancer patients have
evidence of metastatic disease on postmortem examination
[4–6], with the spinal column being the most common site
for bony metastases [7]. Furthermore, it is likely that the
observed incidence of metastatic spine disease will continue
to increase over the next several decades, as diagnostic capa-
bilities improve [8, 9].
In the current era, a number of treatment modalities are
available for treating spinal tumors, including medical ther-
apy, chemotherapy, surgery, radiation therapy, and radiosur-
gery. Quite frequently, combinations of these therapies are
utilized to maximize clinical benefits and outcomes. Despite
the benefit of minimal invasiveness inherent to radiation
therapy or radiosurgery, there are numerous situations in
F.U. Ahmad, M.D., M.Ch.
Department of Neurosurgery, Emory University,
80, Jesse Hill Dr SE, Atlanta, GA 30303, USA
e-mail: drfaizns@gmail.com
G. Zada, M.D.
Department of Neurosurgery, Keck School of Medicine,
University of Southern California, 1520 San Pablo Street,
Suite 3800, Los Angeles, CA 90033, USA
M.Y. Wang, M.D., F.A.C.S. (*)
Department of Neurosurgery, Miller School of Medicine,
University of Miami, 1095 NW 14Tr, Lois Pope Center,
2nd floor, Miami, FL 33136, USA
e-mail: Mwang2@med.miami.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_45, © Springer Science+Business Media New York 2015
45
which surgery remains the optimal treatment for patients with
spinal tumors [10–14]. Although surgery has not been widely
accepted as a primary treatment for metastatic spine disease
in the past, a shift in this ideology is currently underway,
with many physicians advocating more aggressive surgical
resection of metastatic spine lesions [3, 11, 15]. Recent
series have demonstrated that surgery can increase the over-
all quality of life by reducing pain and maintaining neuro-
logic function as well as prolong survival in particular
patients with metastatic spine disease [10, 12, 15–17].
Careful patient selection is the key to maximizing the poten-
tial benefits of surgical intervention. This chapter will
describe the current role of surgery in the treatment of spinal
tumors and the specific factors that make surgery the pre-
ferred treatment in a given situation.
Tumor Location
Tumors of the spine are frequently characterized according
to their location with respect to the spinal canal, meninges,
and spinal cord. The overwhelming majority (95 %) of spine
metastases are extradural, while the remaining are intradural
extramedullary (4 %) and intramedullary (0.5 %) [18].
Furthermore, metastases are most commonly found in the
posterior half of the vertebral body, usually at the junction of
the vertebral body and pedicles due to the increased blood
supply to this area [19, 20]. They are infrequently confined to
the posterior spinal elements (i.e., lamina and spinous pro-
cess). The thoracic spine, with its numerous segments and a
narrower canal diameter relative to the spinal cord [21], is
the most common spinal region to present with neural com-
pression secondary to spinal metastases (70 % of patients),
followed by the lumbar spine (20 %) and cervical spine
(10 %) [10, 22, 23]. The thoracolumbar junction and the T4
vertebral body, in particular, are the most common spinal
levels to present with metastases [22, 23]. Unfortunately spi-
nal metastases are located in multiple, noncontiguous levels
in 10–38 % of cases at the time of presentation [24–26].
571
572
Multiple surgical staging systems have been devised in
the past to assist in surgical planning based on anatomical
criteria. The surgical considerations based on spinal level
and relationship to the spinal cord will be discussed later in
this chapter.
Deciding on a Treatment Modality
Following a diagnosis of metastatic spine disease, a decision
of surgery, radiation, medical treatment, and/or palliative
care must be made. The patient’s expected survival time is a
crucial factor to consider in cancer patients, as many may be
terminal patients in which surgery may not provide an over-
all quality of life benefit. As with any type of surgery, the
age, performance status, and comorbidities of the patient
must be taken into account when considering operative man-
agement for metastatic spine disease. Comorbidities such as
coagulopathy, anemia, malnutrition, liver disease, and renal
disease are frequently encountered in cancer patients and
may complicate the surgery or postoperative course. The pri-
mary tumor type should be also factored into this decision, as
some primary tumors (such as renal and thyroid cancer) may
require preoperative embolization [8].
Radiation therapy was considered the mainstay of treat-
ment for metastatic spinal disease for several years, and sur-
gery was considered to add little value or even deemed
detrimental for these patients [27, 28]. This was primarily
because posterior laminectomy (the primary surgical option
used by neurosurgeons to treat cord compression) did not
address the compression (which is usually anterior to the spi-
nal cord) directly and often led to increased spinal instability
by removing the stable/intact posterior elements in the pres-
ence of an already diseased/weak anterior column. Therefore
multiple older studies in the past failed to demonstrate a
functional or survival benefit in patients undergoing surgery
and irradiation as compared with radiation therapy alone
[16, 24, 29, 30]. Over the past decade, however, surgical
decompression of the spinal canal has regained favor because
of more contemporary series utilizing modern circumferen-
tial surgical approaches for decompression and stabilization.
Many series have demonstrated greater than 90 % mainte-
nance in ambulatory status and pain improvement following
decompression [13, 17, 31, 32].
Perhaps the most convincing evidence came from a recent
study by Patchell et al. This prospective, multi-institutional
study randomized patients with metastatic spinal cord com-
pression to surgical decompression plus radiotherapy or
radiotherapy alone. In the surgical decompression group,
42 out of 50 (84 %) of patients were able to walk following
surgery, compared with 29 of 51 patients (57 %) in the radio-
therapy group (p = 0.01). The number of nonambulatory
patients who specifically regained the ability to walk following
F.U. Ahmad et al.
surgery was also significantly higher in the surgery group
(62 % versus 19 %, p = 0.01). Finally, patients treated with
surgery retained the ability to walk for much longer than did
patients in the radiotherapy group (mean 122 versus 13 days,
p = 0.001). The study was terminated prematurely secondary
to an overwhelmingly beneficial outcome observed in the
surgical group at interim analysis [33].
Furthermore, a recent meta-analysis by Klimo and col-
leagues, reviewing 24 surgical series (999 patients) and 4
large irradiation series (543 patients), demonstrated ambula-
tory success rates in 85 % of surgical patients compared
with 64 % of radiation patients. Surgical patients in this
study were 1.3 times as likely to remain ambulatory after
surgery and twice as likely to regain ambulation when lost
preoperatively (rescue procedure) [34]. Thus, in general,
results from recent series of patients undergoing surgical
intervention for metastatic spinal disease have been promising.
Several series have also reported that greater than 90 %
of patients have benefited from surgery in terms of pain
relief as well as maintaining ambulatory status [11, 13, 15].
Furthermore, survival benefits have been reported with
extensive resections in patients with solitary bone lesions or
oligometastatic disease, with some 5-year survival rates
being greater than 15 % [15, 35]. Despite recent data sup-
porting surgical decompression as a primary treatment for
spinal metastases, radiation therapy remains a primary treat-
ment option, particularly for radiosensitive tumors such as
breast, lymphoma, multiple myeloma, small cell lung cancer,
seminoma, neuroblastoma, and Ewing sarcoma. In addition,
limited anticipated patient survival time, inability to tolerate
a surgical procedure, greater than 24–48 h of total neuro-
logical deficit, or multilevel/diffuse spinal involvement
remain factors favoring radiation therapy [36].
Guidelines for Surgical Decision Making
In the past, various scoring systems have been developed to
guide physicians in evaluating the surgical potential of a
given patient based on multiple patient and tumor criteria
(see Table 45.1) [37–40]. The complexity of these algorithms
is indicative of how many factors must be taken into consid-
eration for a given scenario. Such frameworks for decision
making offer useful guidelines to assist physicians with sur-
gical decision making, but cannot encompass the entire spec-
trum of individual factors that must be considered for each
patient situation.
Goals of Therapy
In deciding on the optimal treatment for a patient, the goal of
therapy remains a key factor. Goals for surgery in patients
45 Spinal Tumors: Viewpoint—Surgery
Table 45.1 Classification algorithms in surgical decision making for spinal metastases
Study Criteria
Harrington et al. (1986) [37] Five categories:
1. No neurologic dysfunction
2. Involvement of bone without collapse or
instability
3. Neurologic dysfunction without bony
destruction
4. Vertebral collapse with secondary
mechanical pain
5. Vertebral collapse or instability with major
neurological deficits
Tokuhashi et al. (1990) [38] 0–2 points for each of the following categories:
1. Primary tumor type
2. Neurological grade of the lesion
3. Physical condition of the patient
4. Number of lesions
5. Presence of visceral lesions
6. Spinal sites
Tomita et al. (2001) [39] Based on three categories:
1. Grade of malignancy:
– Slow growth, 1 point
– Moderate growth, 2 points
– Rapid growth, 4 points
2. Visceral metastases
– No metastasis, 0 points
– Treatable, 2 points
– Untreatable, 4 points
3. Bone metastases
– Solitary/isolated, 1 point
– Multiple, 2 points
Fourney et al. (2005) [40] “MAPS” assessment:
1. Method of resection
2. Anatomy of spinal disease
3. Patient fitness level
4. Stabilization
with spinal tumors include: (1) neural decompression, (2)
biomechanical stabilization, (3) curative resection, (4) con-
trol of intractable pain, and (5) diagnosis.
Neural Decompression
The most important indication for surgery remains neural
decompression. Ambulatory status is a key prognostic marker
for terminal patients with spinal disease [26]. Nonambulatory
cancer patients have a mean survival time of only 45 days,
due to multiple causes [13]. Maintaining neurologic function
in patients with spinal metastases may therefore prolong sur-
vival time in addition to improving quality of life.
Patients with rapidly progressive or far-advanced paraple-
gia, especially for less than 24–48 h, require emergent surgi-
cal intervention [8]. In patients with complete spinal cord
dysfunction for greater than 24 h or those with bowel/bladder
573
Recommendations
Based on category:
(1) and (2): nonoperative management
(3): left to judgment of surgeon
(4) and (5): surgery indicated
Based on total points (0–12):
≤5: nonoperative management
6–8: left to judgment of surgeon
≥9: surgery indicated
Based on total points (2–10):
≤3: wide/marginal excision (long-term local control)
4–5: marginal/intralesional excision (middle-term control)
6–7: surgery for short term palliation
≥8: nonoperative supportive care
Considerations by category:
1. En bloc spondylectomy, piecemeal excision, palliative
decompression
2. Tumor level, location, staging
3. Comorbidities, irradiation, patient age
4. Anterior, posterior, combined
dysfunction, however, surgery offers less hope for improvement
and radiotherapy is usually the mainstay of treatment [36].
Patients with progressive neurologic deterioration that is
refractory to radiation therapy should also be considered for
surgical decompression [36]. Cord compression caused by
bone or disk fragments in the spinal canal that may result
from pathological fractures should also undergo primary
surgical decompression instead of radiation therapy [41].
Recent prospective randomized trials of surgical decompres-
sion plus radiotherapy versus radiotherapy alone showed a
quality of life benefit in the surgical arm that was statistically
significant as well as a trend towards an increase in survival
benefit in the surgical arm [42, 43]. These data represent high
quality evidence favoring surgical decompression over tradi-
tional conservative radiotherapy in patients with spinal meta-
static disease.
574
Stabilization
Maintaining spinal stability is another indication for surgical
intervention in patients with metastatic spinal disease. Stability
has been defined by Panjabi et al. as allowing the degree of
motion that prevents pain, neurological deficit, and abnormal
spinal angulation [44]. Spinal instability in patients with
metastases can result from related pathologic fractures, surgi-
cal intervention, or diffuse changes in bone density and
strength. Instability has been correlated with the following
findings in patients with spine tumors: two-column injury,
vertebral body collapse greater than 50 %, kyphosis greater than
20–30°, or involvement of the same column in greater than two
levels [40, 45, 46]. Following most cases of surgical decom-
pression, especially in cancer patients, instrumentation is
required to provide stability. In non-terminal patients, postop-
erative stability is ideally achieved via a solid bone fusion fol-
lowing resection. In cancer patients, however, a bony fusion
may not be a realistic goal due to multiple potentially compli-
cating factors. Solid bony fusion may be prevented by shorter
patient survival times, anemia, malnutrition, or frequent
requirements for further chemotherapy, steroids, and radiation
therapy. Although the ability to study spinal fusion in cancer
patients has been compromised by decreased follow-up times,
one study studying fusion rates in 25 patients undergoing ante-
rior decompression and interbody fusion with bone struts fol-
lowed by irradiation reported a relatively low pseudoarthrosis
rate of 16 % at 1 year following surgery [47].
Several options are currently available for spinal instru-
mentation in cancer patients. Rigid spinal fixation systems
are often used to provide spinal stability [13, 48]. With ante-
rior approaches, constructs are often created to replace the
resected vertebral body. Cortical endplate bone integrity
must be preserved in order to stabilize anteriorly, however,
and loss of integrity may necessitate a posterior fusion or
even a combined anterior–posterior approach in cases of sig-
nificant instability [8]. In posterior approaches, 2–3 levels of
construct are generally used above and below the deficit
[13, 48]. Polymethylmethacrylate (PMMA) is frequently used
for reconstruction in conjunction with mechanical instru-
mentation if the estimated patient survival time is estimated
to be less than 6 months. PMMA may be inserted inside of a
titanium cage or chest tube and can provide immediate sta-
bility [48, 49]. It has been shown to be a safe option for
patients requiring subsequent radiation therapy [50] and is an
inexpensive, relatively easy to use, and safe alternative to
bony fusion [51].
Curative Resection and Local Control
While a curative surgical resection of spinal metastases was
not considered a reasonable goal in patients with metastatic
spinal disease for many years, recent series have demon-
strated that survival times can be significantly prolonged in
particular patients who have undergone surgical intervention
F.U. Ahmad et al.
[15, 52]. In fact, surgery is the only treatment that has demon-
strated a potential for cure of spinal metastases, as opposed to
local control of tumor available with radiation therapy [35].
Procedures such as en bloc spondylectomy and vertebrec-
tomy have become key developments in the ability to aggres-
sively treat and even potentially cure localized metastatic
spinal disease. Patients with bony metastases as opposed to
visceral metastases, and those who present following a long
disease-free interval, are considered to have a low tumor bur-
den and may be optimal candidates for curative resection
[15, 35, 39, 52, 53]. Such patients may benefit from more
aggressive surgical management in terms of pain control and
quality of life and should be treated with the intent to cure
[35, 52]. The potential for a curative resection also depends
on the source of the primary tumor. For instance, tumors of
renal origin should be treated with the intent to cure [54].
Furthermore, local malignancies such as chordomas, sarco-
mas, chondrosarcomas, Pancoast tumors, giant cell tumors,
and osteoblastomas should also be considered for curative en
bloc resection [13].
Pain Control
Pain from metastatic lesions can be a result of inflammation
and mechanical forces, as well as direct nerve compression
or damage [31]. Radicular symptoms have been reported in
up to 90 % of patients with lumbar epidural cord compres-
sion, 79 % of patients with cervical disease, and 55 % of
patients with thoracic metastases [24]. Corticosteroids and
opioids are the primary medications available for pain man-
agement secondary to cord or root compression. Radiation
therapy remains the primary intervention reserved for
patients with terminal disease who are experiencing signifi-
cant pain. However, the beneficial effects of irradiation in
relieving pain may take up to 2 weeks and may not provide
adequate pain relief [55]. In cases where pain is refractory to
radiation therapy, surgery remains a viable option. Many sur-
gical procedures offer a significant benefit in pain relief, with
recent series reporting pain relief success rates of greater
than 90 % [10, 15, 56]. Percutaneous vertebroplasty and
kyphoplasty are minimally invasive procedures that have
been shown to improve pain in patients who may not be can-
didates for more aggressive decompressive surgery. Several
series demonstrate both short- and long-term pain relief rates
of 85–100 % associated with percutaneous vertebroplasty
and kyphoplasty [57–60].
Diagnosis
Since the advent of minimally invasive techniques for tumor
biopsy of the spine, such as CT-guided and fluoroscopic-
guided biopsy, diagnosis is usually no longer a primary indi-
cation for surgical intervention. One study reported that a
tissue diagnosis was possible in 86 % of patients using
CT-guided biopsy [61].
45 Spinal Tumors: Viewpoint—Surgery
Timing of Combined Therapy
In spite of having recent Class I evidence showing the benefit
of surgery in the primary treatment for spinal metastases, radi-
ation therapy remains the primary modality for treatment at
many medical institutions. Following a radiologic diagnosis
of spinal metastases, many patients are directly referred for
radiation therapy without a surgeon seeing the patient [62].
The results of this are twofold. First, opting for radiation as a
primary measure may not provide the same survival benefit
for the patient as a wide marginal or radical excision could
potentially provide. Second, patients who fail radiotherapy
and ultimately require surgical decompression have signifi-
cantly higher chances of developing wound infections, espe-
cially in cases where irradiation was administered within 1
week prior to surgery [62]. One series of 85 patients undergo-
ing posterior decompression with or without instrumentation
determined that patients with prior irradiation had a 32 %
chance of developing wound infections, compared with a
12 % chance in the de novo surgery group. Multiple other
studies have demonstrated similar results [34, 35, 43, 62, 63].
For these reasons, many surgeons currently advocate consid-
ering de novo surgery as the primary intervention for symp-
tomatic metastatic spinal disease and have emphasized the
spine surgeon’s involvement in the decision to irradiate patients.
Deciding on a Surgical Approach
Once surgery has been decided upon, choosing the correct
surgical approach is a key factor in providing the ideal degree
of exposure for resection and subsequent stabilization. This
decision is based on the anatomical location of the spinal
metastases, the degree of surgical intervention a patient is
able to tolerate, and the ability of the surgeon to perform a
particular procedure safely. The Weinstein, Boriani, and
Biagini staging system can be used to help guide surgeons in
choosing an approach for surgical decompression based on
the anatomical location of the tumor in regards to proximity
to the dura as well as anterior to posterior localization [64].
This system maps tumors based on 12 radiating zones in a
clockwise fashion, as well as five concentric layers. It can
assist in deciding on a type of excisional procedure, includ-
ing en bloc spondylectomy, vertebrectomy, sagittal resec-
tion, and posterior arch resection.
Decompressive Posterior Laminectomy
In the past, the primary surgical procedure utilized by neuro-
surgeons to relieve compression secondary to spinal metasta-
ses was the posterior laminectomy. This procedure was
initially favorable because it could be performed by the
majority of neurosurgeons within relatively fast time frames.
For several reasons, however, this procedure fell out of favor
575
for the primary treatment of spinal metastases. Class I evidence
from a case-control study comparing decompressive lami-
nectomy plus radiation therapy with radiation therapy alone
did not show a significant functional benefit in ambulatory
status following surgical intervention [30]. Class II and III
evidence also failed to demonstrate significant functional
benefits or improvement in pain [16, 24, 29, 65]. The inability
of posterior procedures to provide adequate decompression
in any cases has been largely attributed to the majority of
metastatic lesions being located anterior to the thecal sac.
Retraction of the thecal sac would thus be necessary to com-
plete a gross total resection from a posterior approach in the
majority of patients with metastases. In addition, the risk of
spinal instability is especially concerning following laminec-
tomy in cancer patients with preexisting disease in the ante-
rior and middle spinal columns [10, 32]. Decompressive
laminectomy is now primarily reserved for metastatic lesions
located within the posterior spinal elements or in cases where
patients cannot tolerate a more complex circumferential
approach. In contrast, posterior laminectomies remain the
procedure of choice for the majority of intradural extramed-
ullary and intramedullary primary (nonmetastatic) lesions.
Some surgeons maintain that even patients with ventrally
located neoplasms can be adequately and safely decom-
pressed with posterior laminectomy if internal fixation is used
in conjunction. This practice has been reported to realign the
spine as well as distract the vertebral bodies out of the spinal
canal [66]. This procedure remains a useful option in patients
who are unable to undergo more extensive anterior approaches
or for patients with multilevel disease [67].
Newer Approaches for Spinal Cord
Decompression
Multiple studies have been published describing the efficacy
of various circumferential approaches for pain relief and pres-
ervation or improvement of neurologic function [10–12, 15,
32, 45, 68–70]. Overall, the proportion of ambulatory patients
who retained ambulatory function postoperatively (defined as
the “success” of such a procedure) has ranged between 72 and
98 %, but has been reported as lower when looking at only
posterior approaches [71]. The proportions of nonambulatory
patients who regained ambulatory status postoperatively
(defined as a “rescue” procedure) have been less consistent,
ranging between 0 and 94 % in these series [71]. Finally,
surgical morbidity rates for circumferential decompressions
have ranged between 7 and 65 %, and mortality rates have
ranged between 0 and 31 % [71]. The majority of series report
mortality rates of less than 10 %.
Approaches to the spine can be broadly classified as ante-
rior or posterior. Anterior approaches include traditional ante-
rior cervical approaches, transthoracic, and transperitoneal
approaches. Posterior approaches include traditional laminec-
tomy and posterolateral approaches such as transpedicular,
576
costotransversectomy, and lateral extracavitary (LECA)
approaches. All of these approaches require subsequent
reconstruction and stabilization.
Anterior Approaches
In general, an anterior approach is preferable for achieving
adequate decompression in patients who are able to tolerate
such an approach because spinal metastases tend to localize
to the anterior spinal column. In general, series of anterior
procedures demonstrate superior rates of neurologic function
and survival times than do posterior procedures [10, 13, 66].
In addition to decompression, reconstruction of the vertebral
body following resection is also facilitated by an anterior
approach.
In the cervical spine, reconstruction following an exten-
sive resection is accomplished using bone autograft or
allograft, PMMA, or one of many titanium cages or spacers
[72]. Stabilization is then usually achieved by way of ante-
rior instrumentation, with plating being the most common
technique in the cervical spine. In the thoracic spine, a trans-
thoracic approach can be utilized for anterior decompression
and subsequent instrumentation. The side of approach is
based on the symmetry of disease, but the left side is often
preferable in order to avoid the liver and to more easily iden-
tify the aorta. Rib resection, lung deflation, and chest tube
insertion are hallmarks of this procedure at the thoracic level
[41]. An anterior approach at the thoracolumbar junction
(T11–L1) can be done via a thoracoabdominal approach. At
this level, a portion of the diaphragm requires mobilization
in order to achieve adequate exposure. At the lumbar level,
dissection via the retroperitoneum is required, usually along
the transversalis fascia. The psoas muscles and aorta are
mobilized to provide exposure to the lumbar vertebrae [41].
Posterolateral Approaches
Lesions located in the posterior spinal elements should be
approached in this fashion. Patients who may not be able to
tolerate a more extensive anterior approach, or those with
multilevel disease, may benefit from posterior decompres-
sion with stabilization. Finally, particular regional nuances
may contribute to the decision to approach posteriorly. The
disadvantages of a posterior approach include limited ante-
rior exposure with limited tumor resection and higher rates
of wound complications [48].
The cervicothoracic junction (C7–T4) marks a transition
zone from the mobile, lordotic cervical spine to a rigid,
kyphotic thoracic spine. The hardware failure rates with sur-
gical decompression and subsequent instrumentation in this
region are comparatively high, with two series reporting sta-
bilization failure rates of 36 % [73, 74]. Le et al. advocate a
posterior/posterolateral approach to the cervicothoracic
junction because of lower incidences of hardware failure.
F.U. Ahmad et al.
The transpedicular approach can be used for disease in
the dorsal and anterior elements of the vertebrae. The advan-
tages of using this approach over an anterior approach
include early identification of the spinal canal, ability to
resect tumor in the posterior elements, and the ability to pro-
vide long segment fixation [69, 75].
A costotransversectomy allows resection of the lamina,
facet, transverse process, pedicle, rib head, and some of the
vertebral body to provide adequate exposure. Advantages of
this procedure include avoidance of a thoracotomy in patients
who may not be able to tolerate one, access to multilevel or
discontinuous spine disease, and the ability to perform both
anterior and posterior fixation. Disadvantages with this pro-
cedure include a possibly limited or indirect exposure, pos-
sible entry into the lung space requiring chest tube placement,
and possible injury to the nerve roots or dura resulting in a
CSF fistula.
The LECA approach can be used for spinal decompres-
sion and fixation in the thoracolumbar spine (T4–L3) and
provides good lateral exposure to the vertebral column with-
out violation of the pleural or abdominal space or mobiliza-
tion of the diaphragm [76]. Like the costotransversectomy,
both anterior and posterior fixations are possible with the
LECA. It is commonly used in patients requiring near com-
plete resection of 1–3 vertebral bodies. Reconstruction of the
vertebral body is then performed followed by posterior with
or without anterior fixation [76].
Combined Anterior and Posterior Approaches
While providing the benefit of excellent exposure to the rele-
vant elements of the spinal canal, anterior decompression also
carries the potential drawback of decreased spinal stability.
Several series report using anterior decompression with sub-
sequent posterior instrumentation to further stabilize the spi-
nal column [12, 32]. Particular indications for this combination
approach include involvement of metastatic disease in all
three spinal columns, significant instability, marked kyphosis,
involvement of more than one vertebral body, junctional
site involvement, and prior laminectomy [12, 32]. One study
including 110 patients undergoing spinal decompression
determined that approximately half (48 %) of all patients
undergoing decompressive surgery required a combined ante-
rior–posterior approach for added stability [12].
En Bloc Spondylectomy
In recent years, aggressive surgical resection of spinal metas-
tases has made curative resection of spinal metastatic lesions
a possible outcome. As mentioned, patients with solitary
bone metastases or oligometastatic disease can be treated
with intent to cure if the patient is a surgical candidate for an
45 Spinal Tumors: Viewpoint—Surgery
aggressive surgical procedure. Patient selection is especially
crucial when evaluating patients for an en bloc spondylec-
tomy, as this procedure tends to be long and complex with
relatively significant blood loss and a frequent requirement
for an open thoracotomy, significant reconstruction and sac-
rifice of neural and/or vascular structures [35]. Surgical plan-
ning in terms of approach and degree of resection has been
greatly emphasized, with some surgeons favoring the use of
a staging system such as the Boriani/Weinstein system in
planning this type of procedure.
Results from recent series of en bloc resections show
promising results. One such study reported a mortality rate of
less than 1 %, a morbidity rate of less than 10 %, and a mean
survival time of greater than 3 years with 48 % of patients
showing neurological improvement [35]. Pain improved
following surgery in 95 % of patients following surgery,
with 76 % achieving total pain control. Another recent series
of patients undergoing en bloc spondylectomy demonstrated
morbidity and mortality rates less than 1 % [15].
Once an en bloc spondylectomy or vertebrectomy has
been performed, vertebral body replacement or reconstruc-
tion is necessary to provide stabilization. There have been
many materials and implants used to replace the vertebral
body following vertebrectomy that have been described in
the literature, including allograft, bone cement, ceramic,
ceramic/glass, carbon fiber, and titanium spacers or cages
[77]. Recently, expandable cages have been developed for
replacing the vertebral body and disks. Such cages may offer
a benefit because they can be placed through smaller access
site and expanded in situ to restore anterior column height.
Percutaneous Vertebroplasty and Kyphoplasty
Vertebroplasty is a relatively noninvasive surgical procedure
that has been increasingly utilized in recent years to treat
pain and instability in vertebral body collapse by injecting
cement into the vertebral bodies through a posterior approach.
The procedure is often used for patients with severe, local-
ized mechanical back pain without epidural involvement
who may not be able to tolerate more aggressive procedures
[78]. Kyphoplasty is a related procedure in which an inflat-
able balloon is used initially to restore the loss of vertebral
height and create a cavity for subsequent injection of cement.
Because vertebroplasty and kyphoplasty are relatively
quick percutaneous procedures, they can be used in cancer
patients with limited survival time and poor surgical poten-
tial [78]. It has been shown that vertebroplasty can be used
prior to the initiation of radiation therapy, without compro-
mising its efficacy [50]. Many series have advocated this
combination of vertebroplasty to confer stability followed by
radiation therapy for its tumoricidal effects [58, 59, 79].
These procedures should not be used in patients with gross
spinal instability, cord compression, or epidural extension
that are able to undergo surgical intervention. Further contra-
indications for these procedures include vertebral collapse to
577
less than one-third of its original height, coagulopathies,
inability to lie prone, and inability to perform an emergent
decompressive surgery if necessary [58, 59, 79].
Vertebroplasty has been shown to provide its benefit by
restoring strength and stiffness to the spine and preventing
micro-motion [80, 81]. Additionally, PMMA has been shown
to destroy nerve endings that cause pain associated with
micromotion [58, 79, 82]. It has also been postulated that
PMMA may also provide an antitumor effect secondary to
thermal effects, cytotoxicity, and ischemia that prevents
tumor reinvasion [58, 82]. A biopsy can be done during the
same procedure prior to the injection of the filling agent.
In a series of 101 patients, Deramond reported an improve-
ment in pain and quality of life in 80 % of patients [58, 82].
Patients following vertebroplasty have experienced short-
term (within 48 h) and long-term pain relief (at 3 months
postoperatively) rates of 85–97 % and 89–100 %, respec-
tively [57, 59]. At 6 months following vertebroplasty, pain
relief was still reported by 76 % of patients, the majority of
which developed either new metastases or epidural involve-
ment of metastases [82].
Despite its many benefits and a low degree of invasive-
ness, vertebroplasty is not without complications. The over-
all complication rate has been reported as approximately
10 %, with the majority being short-term complications and
only 1.7 % resulting in long-term complications [58].
Leakage of PMMA has been reported to occur in approxi-
mately 70–75 % of cases. In the majority this does not pres-
ent a clinical problem [58, 78]. However significant clinical
risks are increased with posterior cortical wall destruction or
epidural involvement. The major clinical risk of this proce-
dure is radiculopathy secondary to PMMA leakage into the
neuroforamen or back pain caused by a local inflammatory
reaction to PMMA [58, 81].
In summary, vertebroplasty and kyphoplasty are mini-
mally invasive procedures that may be performed for selected
patients with metastatic spine disease in order to provide fast
pain relief and improved spinal stability. It is often the proce-
dure of choice as a palliating measure for patients with lim-
ited survival or those who are otherwise unable to tolerate
surgical intervention.
Conclusion and Considerations
In summary, surgical management remains a viable and
increasingly efficacious option for the management of spinal
tumors. The primary goals for surgery are neural decompres-
sion, spinal stabilization, curative resection, and pain man-
agement. Curative resection of solitary or localized metastatic
disease is now a potential goal with aggressive surgical meth-
ods. Careful patient selection is the key factor for maximizing
the potential benefits and avoiding the associated risks of
any treatment modality, be it surgery or radiotherapy.
578 F.U. Ahmad et al.

Case 45.1
A 54-year-old female developed 1 week of progressive lower extremity weakness and attendant bowel and bladder
dysfunction. She was wheelchair-bound at the time of presentation, and a CT scan showed a pathologic fracture at T7
(Fig. 45.1a). Her past medical history was significant for invasive ductal carcinoma treated 10 years prior and in remission.
An MRI demonstrated this to be consistent with a metastatic lesion with a soft tissue component compressing upon the
spinal cord (Fig. 45.1b), and SPECT studies showed no evidence of other lesions (Fig. 45.1c). The patient underwent
an urgent T7 corpectomy via a transthoracic approach. The vertebral body was replaced by a PEEK vertebrectomy
spacer packed with rib autograft and supplemental plating was utilized (Fig. 45.1d, e). She went on to have a complete
neurologic recovery, ambulating without assistance 5 days after surgery.

Fig. 45.1 (a–e) Plain CT scan showing a pathologic fracture at T7 (a). MRI thoracic spine T2WI revealed the cord compression (b), and
SPECT studies showed no evidence of other lesions (c). The patient underwent an urgent T7 corpectomy via a transthoracic approach. The
vertebral body was replaced by a PEEK vertebrectomy spacer packed with rib autograft and supplemental plating was utilized. Postoperative
plain X-ray lateral (d) and AP view (e) showing the instrumentation
45 Spinal Tumors: Viewpoint—Surgery 579

Case 45.2
A 54-year-old male with prostate cancer presented with worsening upper back pain, progressive inability to walk, and
signs of myelopathy for 10 days prior to presentation to the emergency room. He was found to have multiple spinal
lesions but only the lesion at T3 was causing spinal cord compression. MRI demonstrated diffusely abnormal signal
intensity in T3 body with extension to right pedicle and lamina and epidural enhancement with spinal cord compres-
sion (Fig. 45.2a–c). There was no signal change in the spinal cord itself. CT scan demonstrated multiple lytic and
blastic lesions in the thoracic spine with loss of height of T3 body and epidural breakthrough of soft tissue mass into
the spinal canal (Fig. 45.2d). He underwent T3 vertebrectomy with reconstruction of anterior spinal column with a
carbon fiber cage, along with supplemental posterior fusion from T2–T6 without complications (Fig. 45.2e).
Postoperatively his motor strength returned to normal and he was discharged home after a brief stay at the rehab center.
He subsequently underwent spinal radiation and hormonal therapy and was doing well 1 year after the surgery.

Fig. 45.2 (a–e) MRI demonstrating a diffusely abnormal signal intensity in T3 body with extension to right pedicle and lamina and epi-
dural enhancement with spinal cord compression on axial (a) and sagittal (b–d) images. There was no signal change in the spinal cord
itself. CT scan demonstrated multiple lytic and blastic lesions in the thoracic spine with loss of height of T3 body and epidural break-
through of soft tissue mass into the spinal canal (e). The patient underwent T3 vertebrectomy with reconstruction of anterior spinal column
with a carbon fiber cage, along with supplemental posterior fusion from T2–T6, as shown on postoperative AP X-ray (f)
580
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 Spinal Metastases: Viewpoint—
Fractionated Radiation Therapy
Quynh-nhu Nguyen, Almon S. Shiu, and Eric L. Chang
Introduction
Approximately 40 % of all cancer patients will develop
metastatic spinal disease [1]. Some patients may be satisfacto-
rily treated with conventional radiotherapy for palliation of
pain and neurologic symptoms arising from spinal metastases.
For other patients, a conventional dose of 30–45 Gy may be
inadequate to achieve durable control. Furthermore, reirradia-
tion of the spine with conventional means is rarely an option.
The American Society for Therapeutic Radiology and
Oncology (ASTRO) has described a new field of stereotactic
body radiation therapy (SBRT) in conjunction with the
American College of Radiology (ACR). SBRT is a “newly
emerging radiotherapy treatment method to deliver a high
dose of radiation to the target, utilizing either a single dose or
small number of fractions with a high degree of precision
within the body. The ability to deliver a single or a few frac-
tions of high-dose ionizing radiation with high targeting accu-
racy and rapid dose falloff gradients encompassing tumors
within a patient provides the basis for the development of
SBRT [2].” This perspective explores the respective merits of
single-dose and hypofractionated SBRT to the spine.
Fractionated Versus Single-Session SBRT
SBRT to spinal tumors has the potential to expand on treat-
ment options currently available. Potential indications for
SBRT to the spine include primary treatment for a single or
oligometastases in the spine, postoperative treatment, or sal-
vage treatment after surgery or previous irradiation. SBRT
has advantages, such as the ability to give higher doses to the
Q. Nguyen, M.D. • A.S. Shiu, Ph.D. • E.L. Chang, M.D. (*)
Department of Radiation Oncology, Keck School of Medicine
of USC, USC Norris Cancer Hospital, 1441 Eastlake Avenue,
Los Angeles, CA 90033, USA
e-mail: eric.chang@med.usc.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_46, © Springer Science+Business Media New York 2015
46
spinal tumor while minimizing dose to the spinal cord.
Before SBRT to the spine can be considered a viable treat-
ment, clinical safety, which is predicated upon accurate and
precise treatment, should be demonstrated.
While there is some ability to adjust or compensate for
positional setup errors after hypofractionated SBRT, no such
remedy exists to make corrections after single-session
SBRT. This statement has profound implications for new
investigators choosing between fractionated and single-
session SBRT. Thus, at the inception of our SBRT program
at The University of Texas M. D. Anderson Cancer Center
(MDACC), we conservatively chose hypofractionated
SBRT. Our conservative philosophy recognizes the reality
that a learning curve exists with any new procedure that must
be climbed by the entire treatment team while meeting the
simultaneous requirement of safety. Single-fraction SBRT
should be deferred until the entire team has sufficient confi-
dence in the entire procedure. The treatment plans represent-
ing SBRT to a typical T10 vertebral body target volume
prescribed to 18 Gy in 1 fraction, 27 Gy in 3 fractions, and
30 Gy in 5 fractions while limiting the spinal cord to 8 Gy,
9 Gy, and 10 Gy, respectively, are shown in Fig. 46.1.
The long-term patient-reported outcomes data collected
prospectively for hypofractionated SBRT at MDACC was
reported by Wang et al. [3] on 149 patients with mechani-
cally stable spinal metastases. Fractionated SBRT was found
to be effective therapy for tumor control and symptomatic
improvement. Patients received a total dose of 27–30 Gy,
delivered in 3 fractions. With a median follow-up of
15.9 months, the progression-free survival after SBRT was
80.5 % at 1 year and 72.4 % at 2 years. The number of
patients reporting no pain from bone metastases increased
from 26 to 54 % 6 months after SBRT. In addition, there was
a statistically significant reduction in multiple symptoms
including disturbed sleep, drowsiness, sadness, fatigue, dis-
tress, lack of appetite, nausea, and difficulty remembering.
On the other hand, single-fraction SBRT has the advan-
tage of convenience to the patient and treatment team and
is thus attractive, if and only if it can be delivered safely.
583
584
Fig. 46.1 Comparison of treatment plans for 1-, 3-, and 5-fraction
SBRT
The spinal cord tolerance may be better defined for single-
fraction SBRT based on extrapolation of data from radiosur-
gery to the optic chiasm of approximately 8 Gy making it
easier to achieve complete target volume coverage. This can
be appreciated by examining dose-volume histograms from
treatment plans representing 30 Gy in 5 fractions, 27 Gy in 3
fractions, and 18 Gy in 1 fraction (Fig. 46.2). Furthermore,
single-fraction SBRT follows the successful paradigm estab-
lished in the arena of intracranial radiosurgery and may lead
to superior local control. Single-fraction SBRT may be pref-
erable for single tumors that are small in volume and ana-
tomically favorable in terms of greater distance from the
spinal cord. Fractionated SBRT may be preferable for spinal
tumors with paraspinal components spanning multiple verte-
bral body levels or with large prevertebral components juxta-
posed to small bowel, because the biological dose to
surrounding normal tissues can be minimized to a greater
degree. For tumors surrounding the spinal cord, involving
the epidural space, or causing compression of the thecal sac,
Q. Nguyen et al.
it may be prudent to request that the neurosurgeon resects the
disease in close proximity to the spinal cord so that a more
favorable anatomic configuration can be obtained for
SBRT. A comparison of modalities including single-fraction
and hypofractionated SBRT, conventional radiotherapy, and
surgery is shown in Fig. 46.1.
Published Clinical Results
At selected centers, SBRT programs are becoming more
mature, and there is recognition of the importance of cre-
dentialing system that is being put into place at many cen-
ters. Therefore, the opportunity to collect larger experiences
or long-term clinical data is now happening. Bilsky et al.
from Memorial Sloan Kettering reported on their initial
clinical experience in treating 16 paraspinal tumors with
intensity-modulated stereotactic radiotherapy. Metastatic
tumors received a dose of 20 Gy in 4–5 fractions while lim-
iting the spinal cord to a maximum dose of 6 Gy. Of the 15
patients who underwent radiographic follow-up, 13 demon-
strated either no interval growth or a reduction in tumor size
in a median follow-up period of 12 months (range, 2–23
months) [4]. Our group at The University of Texas MD
Anderson Cancer Center (MDACC) reported on 15 consec-
utive patients with metastatic spinal disease who underwent
75 treatments involving 90 isocenter setups on a phase I
clinical trial involving intensity-modulated, computed
tomography (CT) image-guided SBRT. Patients uniformly
received 30 Gy in 5 fractions while the spinal cord was con-
strained to a maximum dose of 10 Gy [5]. The procedure
was technically feasible to perform in all patients, and no
neurologic toxicity was observed in any patient with a
median follow-up time of 9 months (range, 6–16 months).
Because SBRT for spinal metastases is usually given in the
context of palliation and avoiding spinal cord damage is
paramount, we initially chose to prescribe a hypofraction-
ated dose of 30 Gy in 5 fractions on alternating days to
allow for sufficient sublethal damage repair while conserva-
tively limiting the spinal cord dose to 10 Gy. It is important
to note that treatment planning programs approximate doses
to critical structures and are limited by the accuracy of beam
data taken by ion chamber measurements, which is affected
by the size or volume of the ion chamber, and whether leak-
age between the leaves used in multileaf collimators and
leaf shape are taken into account. Recognizing that treat-
ment plans may over- or underestimate the actual doses
delivered, it is prudent to conservatively limit doses to the
spinal cord. A dose of 10 Gy in 5 fractions is considered
clinically insignificant. The biologic equivalence (BED2Gy)
of 30 Gy in 5 fractions is 40 Gy for early responding tissues
assuming an α/β of 10 Gy and 54–64 Gy assuming an α/β of
1.5–3 Gy for the spinal cord. With the increased confidence
46 Spinal Metastases: Viewpoint—Fractionated Radiation Therapy
Fig. 46.2 Single-fraction dose delivering 18 Gy to nonrenal cell spinal metastases (a) axial and (b) sagittal
of our safety and setup data demonstrating consistent daily
patient setups within 1 mm of isocenter [5], we have pro-
ceeded to shorten our treatments to a total dose of 27 Gy in
3 fractions on alternating days to allow for sufficient repair
while limiting the spinal cord dose to 10 Gy.
Garg et al. reported the MDACC experience in delivering
single-fraction SBRT to the spine in a prospective phase I/II
study for previously unirradiated patients with sufficient
585
space between disease and spinal cord. There were 63 non-
cervical spinal metastases treated with single-fraction SBRT,
all tumors received >16 Gy. Patients were stratified according
to histology (renal versus nonrenal). For nonrenal spinal
metastasis the mean GTV was prescribed 18 Gy, and for renal
spinal metastasis the mean GTV received 24 Gy. For paraspi-
nal tumors, nonrenal histology tumors were prescribed
18 Gy to the GTV and 24 Gy to the GTV for renal tumors.
586 Q. Nguyen et al.

Table 46.1 Comparison of various spinal metastasis treatments

Single-fraction SBRT
Safety Unforgiving. No
possibility for correction
after delivery of treatment;
spinal cord tolerance
extrapolated from optic
chiasm; may be less
appropriate in previously
irradiated patients
Efficacy Theoretically may have
greater ability than
hypofractionated SBRT to
overcome radioresistance
especially for renal cell
carcinoma, melanoma, and
sarcoma by getting over
shoulder of survival curve
Convenience Ultimate in convenience to
patient and treatment
team, must be balanced
against potential risks
Cost-effectiveness May be less costly than
fractionated SBRT from a
resource standpoint, and
therefore more cost-
effective if efficacy is
proved to be equivalent
Hypofractionated SBRT Conventional radiotherapy Surgery
Some compensation possible if 30 Gy in 10 fractions has Usual potential risks of
initial setup error made; spinal track record of safety in surgery including wound
cord tolerance for treating a large number of infection, bleeding,
hypofractionated radiotherapy patients worldwide damage to nerves, and
ill-defined; good approach for spinal cord
setting up new programs during
learning curve; may be safer for
previously irradiated patients
Needs to be prospectively Mainstay for palliation of Rapid resolution of
compared with single-fraction spinal metastases; limited neurologic symptoms
SBRT and conventional by spinal cord tolerance due to spinal cord
radiotherapy so dose may be compression or pain
inadequate; reirradiation caused by mechanical
usually not possible instability
Greater expenditure of resources Can start immediately, Postoperative recovery
required for labor-intensive easy to give, widely time, wound healing,
procedure; may be required during available rehabilitation time to
learning curve or for previously achieve ambulation
irradiated patients near cord
tolerance
More costly due to multiple Cost-effective and Costly but definite
iterations of the same procedure; appropriate for majority indications for spinal
however, this cost may need to be of diffuse spinal cord compression and
incurred initially by new programs metastases involving salvaging previously
to ensure patient safety until track multiple levels irradiated metastases
record for safety established

100
The 18-month actuarial rate of local tumor control for all T10GTV
patients was 88 %, and specifically for patients treated post- 1RX
Normalized volume (%)

80
operatively with SBRT, the local tumor control was 100 %. 3RX
Cord
The 18-month actuarial rate of freedom from neurologic 60 5RX
deterioration was 82 % [6] (Fig. 46.3).
There are also several publications documenting experi- 40 1RX
ence with single-fraction SBRT. Ryu et al. reported on pat- 3RX
terns of failure for 49 patients with 61 spinal metastases who 20
5RX
underwent single-dose radiosurgery (10–16 Gy) at Henry
Ford Hospital. Follow-up ranged from 6 to 24 months. 0
Complete and partial pain relief was achieved in 85 % of the 0 1000 2000 3000 4000
lesions treated, with relapse of pain at the treated site was Dose (cGy)
7 %, and there was progressive metastasis in the immediate
Fig. 46.3 Comparison of dose-volume histograms for 1-, 3-, and
adjacent spine in 5 % [7]. Benzil et al. treated 31 patients 5-fraction SBRT
who had 35 tumors with stereotactic radiosurgery to the
spine using the Novalis unit at New York Medical College.
Twenty-six tumors were spinal metastases and 9 were pri- Two patients experienced transient radiculitis, and one patient
mary tumors of the spine. In general, metastases not previ- had permanent neurologic deterioration due to pathologically
ously treated with radiation received 25 Gy in 10 fractions of confirmed radiation necrosis. The authors concluded that a bio-
external-beam radiation followed by a 6- to 8-Gy single- logical equivalent dose >60 Gy was associated with an
fraction boost. increased risk of radiculitis [8]. Gerszten et al. from the
Patients previously irradiated with 30 Gy using conven- University of Pittsburgh treated 115 consecutive patients with
tional radiation were treated with 10 Gy in 2 fractions. Rapid single-fraction radiosurgery using CyberKnife (45 cervical, 30
and significant pain relief was noted after treatment in 32 of thoracic, 36 lumbar, and 14 sacral). There were 17 benign and
34 treated tumors within 72 h and up to 3 months later. 108 metastatic tumors. Tumor volume ranged from 0.3 cm3 to
46 Spinal Metastases: Viewpoint—Fractionated Radiation Therapy
232 cm3 and tumor dose was 12–20 Gy prescribed to the 80 %
isodose line (mean, 14 Gy). No acute radiation toxicity or new
neurologic deficits occurred during the follow-up period
(range, 9–30 months; median, 18 months), and axial and radic-
ular pain improved in 74 of 79 patients who were symptomatic
before treatment. The authors concluded that the CyberKnife
system was found to be feasible, safe, and effective [9].
DeSalles et al. from the University of California Los Angeles
using the Novalis system treated 14 patients with 11 metasta-
ses, 2 neurofibromas, and 1 meningioma. Twelve patients
underwent previous conventional irradiation. A mean dose of
12 Gy (range, 8–21 Gy) was prescribed. With a mean follow-
up of 6.1 months (range, 1–16 months), no complications were
seen, and seven patients experienced significant pain relief.
Seven of 22 lesions that were treated progressed [10].
Spinal SBRT continues to emerge as an effective thera-
peutic approach for spinal metastases. However, treatment
planning and delivery remain individualized to specific
radiosurgery centers. The group at MDACC has developed a
generalizable class solution approach for spinal SBRT to
provide optimal target coverage, reduce integral dose, and
maximize planning efficiency. This is of particular impor-
tance for treatment planners who do not have experience
with spinal SBRT planning. The class solution technique
generated plans that maintained target coverage and
improved conformality while reducing normal tissue integral
dose for planners who had no prior experience with spinal
SBRT. The class solution technique reduced treatment plan-
ning time by 30–60 % and MUs required by 20 % indepen-
dent of prior planning experience [11].
Although this collective body of preliminary data is
encouraging, it should be cautioned that because the field is
young, long-term complications are under investigation. It is
currently unknown to what extent high doses of radiation
will affect vertebral stability [12]. Vertebral compression
fractures after spinal SBRT have been reported at two centers
at Memorial Sloan Kettering and MDACC [13, 14] with
rates ranging from 20 to 39 %. It also remains to be defined
what is the threshold of spinal cord tolerance with hypofrac-
tionated or single-dose schedule of irradiation in the setting
of primary or reirradiation.
Conclusion
Reports of the relative safety of fractionated and single-
fraction SBRT to the spine have been published from several
institutions. Larger experiences with long-term follow-up
data are supporting the relative safety of high-dose SBRT to
spinal tumors, although cases of spinal cord myelopathies
are being reported. In addition, well-designed prospective
clinical investigations are needed to help address important
clinical issues such as optimal dose and fractionation,
587
integration of SBRT with systemic therapy, determination of
spinal cord tolerance, and long-term sequelae of high doses
of irradiation to the spine.
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1. Klimo P, Schmidt MH. Surgical management of spinal metastases.
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Timmerman R, Ryu S, Hevezi JM, Welsh J, Mehta M, Larson DA,
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Allen PK, Azeem SS, Brown PD, Sharp HJ, Weksberg DC, Cleeland
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Weinberg JS, Mathews LA, Brown BW, Maor MH, Cox JD. Phase
I clinical evaluation of near-simultaneous computed tomographic
image-guided stereotactic body radiotherapy for spinal metastases.
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6. Garg AK, Shiu AS, Yang J, Wang XS, Allen P, Brown BW,
Grossman P, Frija EK, McAleer MF, Azeem S, Brown PD, Rhines
LD, Chang EL. Phase 1/2 trial of single-session stereotactic body
radiotherapy for previously unirradiated spinal metastasis. Cancer.
2012;118(20):5069–77.
7. Ryu S, Rock J, Rosenblum M, Kim JH. Patterns of failure after
single-dose radiosurgery for spinal metastases. J Neurosurg. 2004;
101 Suppl 3:402–5.
8. Benzil DL, Saboori M, Mogilner AY, Rocchio R, Moorthy
CR. Safety and efficacy of stereotactic radiosurgery for tumors of
the spine. J Neurosurg. 2004;101 Suppl 3:413–8.
9. Gerszten PC, Ozhasoglu C, Burton SA, Vogel WJ, Atkins BA,
Kalnicki S, Welch WC. CyberKnife frameless stereotactic radiosur-
gery for spinal lesions: clinical experience in 125 cases.
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10. De Salles AA, Pedroso AG, Medin P, Agazaryan N, Solberg T,
Cabatan-Awang C, Espinosa DM, Ford J, Selch MT. Spinal lesions
treated with Novalis shaped beam intensity-modulated radiosur-
gery and stereotactic radiotherapy. J Neurosurg. 2004;101 Suppl
3:435–40.
11. Weksberg DC, Palmer MB, Vu KN, Rebueno NC, Sharp HJ, Luo D,
Yang JN, Shiu AS, Rhines LD, McAleer MF, Brown PD, Chang
EL. Generalizable class solutions for treatment planning of spinal
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12. Rock JP, Ryu S, Yin FF, Schreiber F, Abdulhak M. The evolving
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 Arteriovenous Malformation
Radiosurgery
Bruce E. Pollock
Introduction
Intracranial arteriovenous malformations (AVM) are con-
gential lesions arising from abnormal blood vessel formation
[1–3]. Whereas normal embryogenesis results in the differ-
entiation of primordial vascular channels into mature arter-
ies, veins, and capillaries, patients with AVMs develop direct
arteriovenous shunts without the appropriate intervening
vascular beds. Recent large, prospective population-based
studies have determined the incidence of newly diagnosed
AVM patients to range from 1.12 to 1.34 per 100,000 person-
years [4, 5]. The majority of patients become symptomatic in
the second through fourth decades of life with the most com-
mon presentation being intracranial hemorrhage (ICH).
Patients may also have seizures or headaches, and the num-
ber of incidentally discovered intracranial AVMs continues
to rise as more patients undergo magnetic resonance imaging
(MRI) of the head. Traditionally, the estimated annual risk of
ICH from AVMs has ranged from 2 to 4 % [5–12] with a
combined annual morbidity and mortality of approximately
1 % [11]. Because most AVM patients are diagnosed at a
point when their life expectancy is long, the cumulative hem-
orrhage risk is substantial. For example, a 30-year old person
carries approximately a 75 % lifetime chance of ICH. Factors
associated with an increased risk of bleeding include prior
hemorrhage [9, 10, 12, 13], increasing age [14, 15], single or
deep draining veins [12, 13], associated arterial aneurysm
[16], and a diffuse AVM nidus [12]. Pediatric patients [17],
and patients with AVMs located in the basal ganglia, thala-
mus, brain stem, or cerebellum [12, 18], and patients with
small AVMs [19] are more likely to present after a hemor-
rhage. It remains uncertain whether these patients actually
B.E. Pollock, M.D. (*)
Department of Neurological Surgery and Radiation Oncology,
Mayo Foundation, 200 First Street SW, Rochester,
MN 55905, USA
e-mail: pollock.bruce@mayo.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_47, © Springer Science+Business Media New York 2015
47
carry an increased annual hemorrhage risk or whether they
are just unlikely to develop other symptoms (seizures or
headaches) that would permit the diagnosis.
AVM Management
The management options for patients diagnosed with intra-
cranial AVMs include observation, surgical resection, and
stereotactic radiosurgery (SRS) (Fig. 47.1). Embolization of
AVMs as primary treatment has recently been utilized [20, 21],
but is more often performed in conjunction with either surgi-
cal resection or SRS. Conventional fractionated radiation
therapy has been utilized in the past but results in a low AVM
cure rate [22]. Patients who present after a large ICH require
surgical evacuation to remove the mass effect associated
with the hematoma. In some instances, surgery is performed
before the patient has undergone cerebral angiography to
delineate the AVM morphology. Once the blood clot has
been removed and abnormal vessels discovered, most neuro-
surgeons recommend stopping surgery and performing angi-
ography to determine a definitive plan for the residual nidus.
After a recent hemorrhage, surgical resection is the preferred
treatment for patients with accessible AVMs even if they do
not require immediate clot evacuation. The benefit of surgi-
cal resection compared to radiosurgery is the immediate
elimination of future hemorrhage risk. The Spetzler–Martin
grading system is the most frequently utilized scale to pre-
dict outcomes after the surgical excision of cerebral AVMs
[23]. This grading scale is based on AVM size, AVM loca-
tion, and the pattern of venous drainage, and has been shown
to predict patient outcomes after AVM resection in a number
of large AVM series [24–29].
As an alternative to surgical resection, SRS has been
shown to be a safe and effective method to manage patients
with cerebral AVMs. In 1972, Dr. Ladislau Steiner and col-
leagues from the Karolinska Institute recognized that single
fraction, high-dose irradiation caused the progressive oblit-
eration of AVMs and subsequent cure from the risk of later
589
590
Fig. 47.1 Treatment algorithm
for intracranial AVMs
hemorrhage [30]. In fact, because AVMs could be visualized
through angiography before the development of axial imag-
ing, AVMs were a common indication treated in the early
radiosurgical series of Leksell. From 1968 until 1982, 204 of
the first 762 patients (27 %) having Gamma Knife radiosur-
gery had AVMs [31]. Concurrent with the work of Leksell
and Steiner, Kjellberg and Fabrikant were using heavy
charged particles instead of photons to irradiate AVMs
[32, 33], and other centers soon developed modified linear
accelerators (LINAC) to perform AVM radiosurgery [34–36].
Similar to the Swedish experience, these innovators noted
that focused radiation techniques could obliterate a high per-
centage of irradiated AVMs.
Observation is also a recognized management strategy for
AVM patients especially if the AVM has not previously bled.
The decision to treat an AVM is simply a comparison of the
estimated risk of intervention to the calculated risk if the
malformation is left untreated. If the risk of treatment is per-
ceived to be less than the lifetime risk based on the natural
history of untreated AVMs, then treatment is recommended.
Prior to advent of modern imaging, improved microsurgical
techniques, and SRS, the majority of AVMs were not treated
directly, and patients discovered to have AVMs were treated
for their seizure disorder or headaches. Yet, once it was rec-
ognized that selected AVM patients could undergo treatment
directed at the AVM with acceptable morbidity, the trend
shifted so that surgical excision or radiosurgery was recom-
mended for the majority of patients [37]. Despite technologi-
cal advances, it is recognized that the risk of treatment for
patients with large AVMs is not insignificant, and observa-
tion of Spetzler–Martin Grade IV and V AVMs is generally
recommended unless the patient has hemorrhaged or is suf-
fering from a progressive neurologic deficit [38].
B.E. Pollock
Recently a number of factors have led some investigators
to reexamine observation for patients discovered to have
unruptured brain AVMs [39]. First, the annual rate of bleed-
ing for patients with unruptured brain AVMs may be as low
as 1 % [40, 41]. Second, the morbidity associated with AVM
bleeding may be less than previously thought [42, 43]. A
review of 119 AVM patients found that 47 % of patients suf-
fered no disability related to their first ICH and an additional
37 % of patients remained independent in their activities of
daily living [42]. Third, neurologic deficits after surgical
resection of AVMs may be greater than previously described.
Hartmann et al. reported outcomes for 124 AVM patients fol-
lowed prospectively after surgical resection [44]. At last
follow-up, 38 % of patients had new postoperative neuro-
logic deficits. Six percent of patients were disabled after sur-
gery. Factors related to a decline in neurologic function were
female gender, AVM size, and deep venous drainage.
Likewise, Lawton et al. found that patients with unruptured
AVMs were 2.3 times more likely to experience a decline in
their modified Rankin Score (MRS) compared to patients
with ruptured AVMs [45]. A randomized trial of unruptured
brain arteriovenous malformations (ARUBA) was designed
to compare the risk of observation versus prophylactic inter-
vention for patients diagnosed with unruptured BAVM [46].
The primary endpoints of the ARUBA trial are the composite
risk of death or stroke and risk of death or clinical impair-
ment, defined as a MRS ≥ 2. Although the design of ARUBA
has been criticized for a number of reasons including the
intended follow-up period after randomization (planned,
5–10 years) [47], it was funded by the National Institute of
Neurological Disorders (U01 NS051483) and began enroll-
ing patients in April 2007 at cerebrovascular centers around
the world.
47 Arteriovenous Malformation Radiosurgery
AVM Radiosurgery
Patient Selection
Proper patient selection is essential for successful AVM
radiosurgery. Once it has been determined that intervention
is preferred over observation, several factors must be consid-
ered when considering radiosurgery for AVM patients. Most
importantly, has the patient bled, and if so, how recently?
Patients with a recent ICH and a surgically accessible AVM
typically are best managed with surgical resection. However,
patients with a recent hemorrhage and a surgically inacces-
sible AVM are generally good candidates for radiosurgery
assuming that the AVM is not too large. Also, patients with a
hemorrhage months or years earlier can certainly be consid-
ered for radiosurgery because they have passed the time
when a re-hemorrhage is most likely to occur. In this situa-
tion, a comparison of the chance of AVM elimination with-
out new deficits risk between surgical resection and
radiosurgery should be undertaken. Standardized scales such
as the Spetzler–Martin Grade [23] and the radiosurgery-
based arteriovenous malformation score (RBAS) [48, 49]
should be used to estimate the efficacy of surgical resection
and radiosurgery, respectively, for individual AVM patients.
Of course, the success of any intervention must take into
account the physician’s experience with a particular group of
patients, rather relying on published reports from experi-
enced centers.
Other considerations regarding treatment choice include
the presence or absence of associated aneurysms, history of
seizures, and need for pretreatment embolization. Aneurysms
on feeding vessels of AVMs are likely caused by the stress on
the arterial walls due to increased blood flow to the AVM.
Patients with associated aneurysms and surgically accessible
AVMs can often have both operated in a single procedure,
thereby immediately removing the hemorrhage risk. Patients
with associated aneurysms and surgically inaccessible AVMs
can be considered for pre-radiosurgical surgical clipping or
endovascular treatment of their aneurysm, with radiosurgery
performed during a separate later procedure. Conversely, if
the associated aneurysm is small, radiosurgery alone is gen-
erally sufficient because the aneurysm will likely either sta-
bilize or regress as the blood flow to the AVM decreases after
radiosurgery.
Another consideration when discussing surgical resection
or radiosurgery for AVM patients is a history of seizures.
Approximately 15–20 % of AVM patients will present with
a seizure [50, 51]. However, few patients will have medically
resistant epilepsy, and the use of standardized scales to deter-
mine seizure frequency is uncommon in AVM papers.
Piepgras et al. studied seizure outcomes after AVM surgery
[51]. Preoperative seizure burden was defined as less or more
591
than four seizures prior to treatment. In the “low-seizure
group” with a follow-up longer than 2 years, 93 % were
seizure-free, 2 % improved but continued to have seizures,
and 5 % had worsening of their seizures. In patients with
more than four seizures preoperatively, seizure freedom
measured at 2 years of follow-up or longer was achieved in
76 % of patients, 21 % were improved, and 3 % remained
unchanged. Overall, 83 % of patients remained seizure-free
at last follow-up in this study. Likewise, Han et al. reviewed
440 patients undergoing resection of supratentorial AVM
[50]. Preoperative seizures were associated with prior AVM
hemorrhage, male sex, and frontotemporal lesion location.
At a mean follow-up of 21 months, 96 % of patients had a
modified Engel class I outcome (seizure-free, 80 %; one
postoperative seizure, 16 %). We retrospectively reviewed 65
AVM patients with one or more seizures having SRS at our
center between 1990 and 1998 [52]. Twenty-six patients
(51 %) were seizure-free (aura-free) after radiosurgery at
3-year follow-up; 40 patients (78 %) had an excellent out-
come (non-disabling simple partial seizures only) at 3-year
follow-up. Factors associated with seizure-free or excellent
outcomes include a low seizure frequency score (<4) before
radiosurgery, smaller AVM volume, and smaller AVM diam-
eter. Twenty-three patients had intractable partial epilepsy
prior to treatment. Twelve (52 %) of 23 and 11 of 18 (61 %)
patients with medically intractable partial epilepsy had
excellent outcomes at years 1 and 3, respectively. Yang et al.
analyzed 161 consecutive patients having SRS for unrup-
tured AVM (mean follow-up, 90 months) [53]. Sixty-six of
86 patients (77 %) were seizure-free after SRS. In this series,
AVM obliteration correlated with a seizure-free outcome
after SRS (97 % versus 31 %). Although the number of
patients who are seizure-free appears higher in most studies
after AVM resection, selection bias in these anecdotal series
prevents any conclusion as to which approach correlates
with improved seizure outcomes.
Technique
The goal of SRS is to accurately deliver a high dose of radia-
tion to an imaging-defined target. Although the definition of
SRS has been modified to include treatment in 1–5 fractions,
the majority of patients with intracranial AVMs treated with
SRS are treated in a single fraction. Thus, placement of a
stereotactic headframe is generally performed to ensure rigid
fixation and minimize patient movement during imaging and
radiation delivery. Headframe placement for adults is per-
formed under local anesthesia supplemented by a low dose
of benzodiazepine. Patients less than 16 years typically
require general anesthesia for radiosurgery. Once the stereo-
tactic headframe has been placed, most patients undergo a
post-gadolinium MRI and biplanar cerebral angiography.
592
Reliance on angiography alone for radiosurgical dose plan-
ning increases the chance of treating too much adjacent nor-
mal brain tissue due to the often irregular shape of AVMs
[54]. In addition, for AVMs located in the posterior fossa and
lateral temporal regions, the chance of not including a por-
tion of the nidus in the prescription isodose volume (PIV) is
greater secondary to the difficulty in visualizing the AVM
clearly on angiography. Over the past 15 years, we have
become increasingly confident in performing AVM SRS
without a stereotactic angiogram and now perform approxi-
mately 20 % of our cases based on MRI alone. Patients with
small, compact, hemispheric AVMs with simple venous
drainage are ideal candidates for using MRI alone for dose
planning. Nonetheless, we continue to insist that patients
have a complete diagnostic angiogram, including appropri-
ate external carotid injections, before any decision is made
about the feasibility of SRS and to determine if the patient
has any associated aneurysms.
The goal of SRS planning is to create a conformal dose
plan that precisely covers the three-dimensional shape of the
nidus. Feeding arteries and draining veins are not included in
the dose plan if possible. Inclusion of these vessels will
increase the volume covered, which may decrease the radia-
tion dose prescribed. Dose prescription must take into
account two conflicting considerations: the chance of oblit-
eration versus the chance of radiation-related complications.
Increasing radiation dose directly correlates with the chance
of obliteration. Assuming that the radiation is well targeted,
the chance of AVM cure is approximately 70 %, 80 %, and
90 % for radiation doses of 16, 18, and 20 Gy, respectively
[55, 56]. However, the likelihood of radiation-related com-
plications after AVM radiosurgery increases at higher radia-
tion doses and larger AVM volumes. Early dose prescription
generally followed either Kjellberg’s 3 % isodose line [32] or
Flickinger’s integrated logistic formula [57] to predict the
probability of radiation-related complications. More recent
studies have correlated the chance of radiation-related com-
plications after AVM radiosurgery relates to some measure
of the radiation dose to the surrounding tissue [58, 59].
Patients with AVMs in the thalamus, basal ganglia, and
brainstem are more likely to develop neurologic deficits sec-
ondary to imaging changes noted on MRI [58].
After the dose plan is reviewed by all members of the
radiosurgical team and found to be acceptable, the patient
undergoes radiation delivery. Following radiation delivery,
the patient is typically discharged home the day of the proce-
dure. Immediate complications are rare. Some patients com-
plain of pin site discomfort, neck pain, or headache, but
these are usually temporary and can be managed with over-
the-counter medications. Follow-up after radiosurgery
typically consists of clinical examination and MRI at yearly
intervals for the first 5 years after SRS. If MRI suggests that
the AVM has gone on to complete obliteration, then follow-
up angiography is recommended to confirm cure [60, 61].
B.E. Pollock
Patients with residual AVM on follow-up angiography are
evaluated for observation, repeat SRS, or surgical resection
based on their age, clinical condition, and the AVM response
from the first radiosurgical procedure.
Obliteration After Radiosurgery
The primary goal of AVM radiosurgery is complete nidus
obliteration to eliminate a patient’s risk of future hemorrhage.
Lindquist and Steiner in 1988 defined AVM obliteration as
follows: “we have considered a result satisfactory only when
the arteriogram has shown a normal circulation time, com-
plete absence of pathological vessels in the former nidus of
the malformation, and the disappearance or normalization of
draining veins from the area” [62]. Generally, AVM oblitera-
tion occurs between 1 and 5 years after radiosurgery.
Sequential histopathological changes after AVM radiosurgery
include early damage to the endothelial cells, followed by
progressive thickening of the intimal layer secondary to pro-
liferation of smooth muscle cells which produce an extracel-
lular matrix containing Type IV collagen, then cellular
degeneration and hyaline transformation [63]. The effect of
high-dose single fraction radiation has been studied in cell
cultures taken from patients undergoing AVM resection [64].
Within 5 days after irradiation, the proliferation index
decreased and remained decreased over the observation
period. Other notable findings were immunohistochemical
evidence of apoptosis and transformation of fibroblastic cells
into activated myofibroblasts. Histologic and electron micro-
scopic studies of seven AVMs resected after bleeding 10–52
months after radiosurgery revealed spindle cell proliferation
in the connective tissue stroma and in the subendothelial
region of irradiated vessels [65]. It was concluded that the
characteristics of the spindle cells were similar to myofibro-
blasts noted during wound healing, and these cells likely con-
tributed to the occlusive process and final obliteration of
AVMs after radiosurgery.
The most important factor associated with obliteration
after AVM radiosurgery is the margin dose delivered to the
nidus [55, 56, 66–69]. A number of models have been devel-
oped to predict the chance of AVM cure after SRS. Karlsson
et al. reported the K index as a method to predict obliteration
after AVM radiosurgery [56]. Based on 945 AVM patients
having radiosurgery from 1970 until 1990, they found a log-
arithmic relationship between minimum dose and AVM
obliteration increasing to a maximum of 87 %. A higher
average dose also shortened the latency to AVM obliteration.
The correlation of obliteration rate to the product minimum
dose (AVM volume)1/3 was termed the K index. The oblitera-
tion rate increased linearly with the K index up to a value of
approximately 27, and for higher K values, the obliteration
rate had a constant value of approximately 80 %. For the
group of patients receiving an AVM margin dose of at least
47 Arteriovenous Malformation Radiosurgery
25 Gy (n = 273), the obliteration rate at 2 years was 80 %. If
obliterations that occurred beyond 2 years are included, the
obliteration rate increased to 85 %. Schwartz et al. developed
the obliteration prediction index (OPI) as a method to predict
success or failure for individual AVM patients [70].
Analyzing a total of 426 patients having either Gamma Knife
or LINAC-based SRS, a relationship was noted between the
calculated OPI (AVM margin dose, Gy/lesion diameter, cm)
and AVM obliteration. Although both the K index and the
OPI correlate with AVM elimination, neither takes into
account the likelihood of producing radiation-related com-
plications for a given radiation dose.
Perhaps more instructive than studies analyzing factors
relating to AVM obliteration has been a number of papers
that have reviewed patients with incompletely obliterated
AVMs after SRS [71–73]. The most common reasons for
incomplete nidus obliteration are targeting errors, recanali-
zation of a portion of the AVM that was previously emboli-
zed, reexpansion of nidus after hemorrhage, and low radiation
dose. These studies have demonstrated the need for complete
nidus coverage at the time of SRS. The routine use of CT or
MRI in conjunction with angiography has been the most
important change to reduce the chance of “missing” a por-
tion of the AVM with the PIV [54]. It is also critical that all
possible feeding arteries are injected at the time of SRS,
including the external carotid arteries for peripherally located
AVMs. Certainly part of the problem in AVM SRS is defin-
ing the nidus accurately. Buis et al. had six independent cli-
nicians contour the nidus of AVM patients based off digital
subtraction angiography (DSA) [74]. They noted significant
interobserver variation when outlining the nidus and con-
cluded that this may contribute to failure in some AVM
radiosurgical cases. Yu et al. compared dose plans based on a
combination of angiography and MRI to those derived from
MRI alone [75]. They concluded that MRI-based dose plan-
ning without angiography should be limited to patients with
smaller AVMs and compact niduses. A study from the
University of Florida has suggested that AVM morphology is
an important factor associated with obliteration [76].
Specifically, they noted patients with a diffuse nidus struc-
ture and associated neovascularity were at a higher risk of
incomplete nidus obliteration when compared to patients
with compact AVMs. High-flow AVMs have also been noted
to have a lower rate of obliteration compared to low-flow
lesions. In a study of 139 patients, patients with angioarchi-
tectural features consistent with high-flow achieved had a
complete obliteration rate less than 40 % [77].
Post-radiosurgical Hemorrhage
The primary drawback of AVM SRS when compared to surgi-
cal resection is that the patient remains at risk for hemorrhage
until the AVM has gone onto complete obliteration (Fig. 47.2).
593
Fig. 47.2 Neuroimaging studies of a 26-year-old woman with an inci-
dentally discovered left basal ganglia AVM. Lateral (Left, a) and
anterior-posterior (Middle, b) left internal carotid angiograms showing
AVM on the day of SRS. (Right, c) Computed tomography performed 6
months after SRS showing both intraparenchymal and intraventricular
hemorrhage
The issue of AVM bleeding during this latency interval has
been extensively studied. Early papers on AVM radiosurgery
suggested that the risk of bleeding initially increased before
AVM obliteration occurred [35, 78]. Colombo et al. reported
180 patients having LINAC-based AVM radiosurgery [35].
Twenty-seven patients with large AVMs underwent partial
treatment; the mean follow-up in this series was 43 months.
Fifteen patients bled after radiosurgery. In totally irradiated
cases, the bleeding risk decreased from 4.8 % in the first 6
months after SRS to 0 % starting from 1 year after SRS. Patients
with partially irradiated AVMs had bleeding 4–10 % over the
first 2 years, then no bleeding thereafter. A review of 65
patients with Spetzler–Martin Grade I–II AVMs found that
five patients (8 %) sustained an ICH after radiosurgery [78].
Although the annual hemorrhage rate was 3.7 % over the
latency interval, all the observed hemorrhages occurred within
the first 8 months after the procedure. Despite these early
papers suggesting an increased risk of bleeding after radiosur-
gery, larger and more detailed analysis of this question has
confirmed that the risk of bleeding is either unchanged or
decreased following AVM SRS [79–83]. Maruyama et al. per-
formed a retrospective observational study of 500 AVM
patients having radiosurgery [83]. Comparing the risk of
bleeding before and after radiosurgery, they found a 54 %
reduction in the bleeding risk during the latency interval. The
risk reduction was greatest among patients who presented
with a hemorrhage. Likewise, Karlsson et al. analyzed the
594
Fig. 47.3 Long-TR MRI of a 10-year-old boy who presented with
headaches. (Left, a) MRI before SRS showing the right-sided AVM
involving the sensorimotor cortex. (Middle, b) MRI 9 months after
large AVM experience at the Karolinska Institute and found
that some measure of protection occurred as early as 6 months
after radiosurgery for patients receiving an AVM margin dose
of 25 Gy [82]. The presence of nidal or associated aneurysms
has also been associated with an increased risk of ICH after
AVM radiosurgery [80, 81]. Following angiographic oblitera-
tion, the chance of hemorrhage is markedly reduced, but cases
of ICH after nidus elimination have been reported [84, 85].
Risk factors for postobliteration bleeding include young age
and persistent enhancement of the irradiated nidus.
Radiation-Related Complications
Advances in imaging and radiosurgical devices have signifi-
cantly improved patient outcomes after SRS. Nonetheless,
the tissue adjacent to a radiosurgical target does receive a
dose of radiation. Assuming that the dose plan conforms to
the three-dimensional shape of the target, the major factors
that determine the amount of radiation delivered to nearby
structures are the PIV and the prescribed radiation dose. As
the PIV increases, the fall off of radiation becomes less steep,
resulting in more radiation to the adjacent brain. It is this
general principle that typically limits the size of intracranial
radiosurgical targets to 3 cm or less in average diameter.
Recognition of the relationship between the overall radiation
exposure and the chance of radiation-related complications
has resulted in studies correlating imaging changes on MRI
to measures of radiation such as the 12 Gy volume (V12)
[58] and the mean dose received by 20 cm3 surrounding the
maximum radiation point (Dmean20) [59]. Areas of
increased signal on long-TR MRI are noted in approximately
30–50 % of AVM patients after SRS. The chance of develop-
ing these imaging changes increases at larger V12 or
Dmean20. Levegrun et al. studied the correlation of radiation-
B.E. Pollock
showing the nidus to be smaller and adjacent edema. The patient con-
tinued to have headaches, but was neurologically intact. (Right, c) MRI
26 months after SRS showing near-complete resolution of the edema
induced imaging changes and dose distribution parameters
in 73 patients having AVM radiosurgery [86]. The AVM tar-
get volume correlated significantly with the development of
edema and breakdown of the blood–brain barrier. They con-
cluded that each measure studied (including V12 and
Dmean20) yielded similar results, and no parameter was
favored over the others. Yet, although such imaging changes
are frequently noted within the first year after AVM radiosur-
gery, most are temporary and the majority of patients remain
asymptomatic (Fig. 47.3). It is believed that many “radiation-
related” imaging changes noted after AVM SRS are related
to alterations in the regional blood flow in the brain adjacent
to the AVM as the nidus obliterates and blood is being
directed into vasculature that has lost the capability for auto-
regulation. Early closure of draining veins before occlusion
of the nidus may also be a factor that contributes to the devel-
opment of edema after SRS (Fig. 47.4) [87, 88]. Patients
with AVMs in the thalamus, basal ganglia, and brainstem are
more likely to develop neurologic deficits secondary to
imaging changes noted on MRI [58, 67, 68, 89].
Although most imaging changes detected on MRI after
AVM SRS are temporary and resolve by 2 years, a small per-
centage of patients will continue to demonstrate imaging
changes consistent with radiation necrosis (Fig. 47.5). MRI
findings consistent with radiation necrosis include persistent
enhancement at the irradiated site beyond 2 years with associ-
ated edema and mass effect. Again, the chance that a patient
will have symptoms related to radiation necrosis relates pri-
marily to the location of the AVM. In addition to radiation
necrosis, other late complications have been noted after AVM
radiosurgery including diffuse white matter changes [90], cyst
formation [91–93] (Fig. 47.6), and stenosis of major intracra-
nial vessels [94]. The most devastating complication after any
radiation-based procedure is a radiation-induced neoplasm.
To date, only a few cases of radiation-induced tumors have
47 Arteriovenous Malformation Radiosurgery
Fig. 47.4 MRI of a 49-year-old woman with an incidentally discov-
ered left frontal AVM. (Left, a) Long-TR image before SRS. Eighteen
months after SRS the patient suffered a generalized seizure. Long-TR
Fig. 47.5 Post-gadolinium (left) and long-TR (right) MRI performed 3
years after SRS of a left sylvian fissure AVM demonstrating persistent
enhancement and edema consistent with radiation necrosis
been reported after AVM radiosurgery [95]. Although the
actual incidence of this complication will not be known for
years, it is estimated that the risk of a radiation-induced tumor
after radiosurgery will be significantly less than fractionated
radiation therapy [96].
Repeat AVM Radiosurgery
Patients with residual nidus after AVM radiosurgery remain at
risk for ICH. A number of studies have analyzed the results of
repeat AVM radiosurgery [72, 97–99]. Karlsson et al.
reviewed 112 patients and tested whether models developed
after one radiosurgery also predicted obliteration and compli-
cation rates after repeat AVM radiosurgery [97]. Sixty-two
of 101 patients with angiographic follow-up had complete
595
(Middle, b) and T1-weighted without gadolinium (Right, c) MRI at that
time showed the nidus to be decreased in size with adjacent edema.
Note acute thrombus within nidus and the draining veins
Fig. 47.6 MRI of a 35-year-old woman who underwent LINAC-based
SRS 7 years earlier for an incidentally discovered left frontal AVM. The
patient developed increasing headaches, seizures, and syncope. (Top,
left, a, and right, b) Post-gadolinium and long-TR images showing cyst
formation, edema, and mass effect. Angiography revealed complete
obliteration. (Bottom, left, a, and right, b) Post-gadolinium and long-
TR images 2 months after surgical resection of the obliterated AVM
showing resolution of edema and mass effect
obliteration (predicted number of obliterations, 65). Fourteen
patients (13 %) had radiation-related complications after a
second radiosurgical procedure. They concluded that the
obliteration rate after repeat radiosurgery is similar to pri-
mary procedures, but the complication rate increases with the
overall amount of radiation given. Two recent studies from
596
the University of Florida [99] and the University of Pittsburgh
[72] confirmed that complete obliteration is achieved in
approximately 70 % of patients after repeat SRS. Patients
with smaller volume AVMs at the time of repeat SRS had
higher rates of obliteration in both of these series. Kano et al.
found that the incidence of radiation-related complications
increased from 5 % after initial SRS to 10 % after repeat SRS
[72], whereas Stahl et al. noted no change in the risk of radi-
ation-related complications between the first and second pro-
cedures [99]. Overall, repeat SRS should be considered a safe
and effective option for patients with incomplete AVM oblit-
eration after their initial radiosurgical procedure.
Radiosurgery of Large AVMs
Although AVM obliteration is significantly related to higher
radiation doses, dose prescription must also take into account
the likelihood of radiation-related complications. Studies on
the dose–volume relationship of AVM post-radiosurgical
radiation-related complications have demonstrated a high
morbidity for large AVMs [58, 59, 86]. Miyawaki et al.
reported that following linear accelerator-based radiosurgery
of AVMs greater than 14 cm3 receiving 16 Gy or more, the
incidence of post-radiosurgical abnormalities on long-TR
MRI was 72 % [100]. The incidence of radiation necrosis for
these patients was 22 %. Consequently, single-fraction SRS
is generally performed only for patients with AVMs of an
average diameter of 3 cm or less (approximately 14 cm3).
Alternative strategies that utilize radiation in the manage-
ment of large AVMs include embolization followed by SRS,
fractionated radiation techniques, and staged-volume SRS.
Planned embolization and SRS has been used for many years
to manage patients with large AVMs as an alternative to sur-
gical resection for these difficult lesions [101–104]. As
opposed to embolization prior to resection where flow reduc-
tion is the goal, the goal of pre-radiosurgical embolization is
permanent volume reduction. Gobin et al. published the
results in 96 patients undergoing acrylate embolization fol-
lowed by radiosurgery [102]. Complete AVM obliteration
was documented in 53 of 90 evaluable patients (59 %).
Sixteen patients (13 %) had complications from the emboli-
zation procedures, and two patients died of intracerebral
hemorrhages prior to having radiosurgery. Recanalization of
the AVM was seen in 14 % of patients. Blackburn et al.
described the management of 21 patients with large AVMs
(>3cm) using combined embolization and SRS from 1994 to
2006 [101]. Eight complications occurred in 43 embolization
procedures (24 %). The majority of complications were tem-
porary and no patient had a permanent major neurologic defi-
cit. Following SRS, 16 of 19 patients (84 %) had obliteration
confirmed by either angiography (n = 13), MR angiography
(n = 2), or CT angiography (n = 1). They concluded that
endovascular therapy followed by SRS was an effective and
B.E. Pollock
safe method to treat large AVMs not amenable to standard
surgical or SRS treatment.
Conventional fractionated radiation therapy has been
used to treat patients with large AVMs [22, 105]. Redekop
et al. reported 15 patients with inoperable AVMs ranging
from 1.5 to 6.5 cm in diameter who underwent conventional
radiation therapy between 1955 and 1985 [105]. Fourteen of
15 patients received a total radiation dose of 40 Gy or more
in 15–28 fractions. At a mean follow-up of 8.1 years, the
annual hemorrhage rate was 3.3 %, and later angiography
confirmed AVM obliteration in 2 of 12 patients (17 %).
Karlsson et al. reviewed the outcomes of 28 AVM patients
undergoing fractionated radiation therapy between 1980 and
1985 [22]. The median volume treated was 78 cm3. Using a
fractionation scheme of 42 Gy in 12 fractions, only two
patients (8 %) demonstrated angiographic cure. The annual
hemorrhage rate after radiation therapy was 6 %. Although
the information on low dose fractionation for AVM patients
is limited, it appears that little protection is provided against
future bleeding after this technique.
More recently, a number of centers have examined the
efficacy of hypofractionated radiation schedules using higher
radiation doses per fraction to treat patients with intracranial
AVMs [106–109]. Lindvall et al. used several fractionation
schemes (generally 30–35 Gy/five fractions) to treat 36
AVMs patients [108]. Two-year follow-up angiography
showed that 48 % of the patients were cured; angiographic
obliteration rose to 76 % on 5-year angiography. Although
the median AVM volume was only 8.5 cm3 for the entire
group, obliteration for patients with AVMs larger than 10 cm3
(n = 10) was 70 % at last follow-up. Veznedaroglu and col-
leagues from Jefferson Hospital managed 30 patients with
large AVMs from 1995 to 1998 using a combination of pre-
radiation embolization and stereotactic radiation therapy
(SRT) [109]. Patients received either 42 Gy in six fractions
(n = 7) or 30 Gy in six fractions (n = 23). Angiographic oblit-
eration was noted on 5-year follow-up angiography in 83 %
of patients in the 42 Gy group (five of six patients) compared
to only 22 % of patients in the 30 Gy group (4 of 18 patients).
However, the overall morbidity in the higher dose group was
43 % (14 % permanent deficits). Chang et al. treated 33 AVM
patients with SRT using a treatment regimen of 25–35 Gy in
four daily fractions [106]. Fifteen of the 33 patients (45 %)
had AVMs larger than 2.5 cm in diameter. The 5- and 6-year
actuarial obliteration rates were 61 % and 71 %, respectively.
One patient (3 %) developed radiation necrosis after
SRT. Hattangadi et al. reported 59 patients having planned
two-fraction stereotactic proton beam SRS from 1991 to
2009 [107]. The median AVM volume was 23 cm3; the most
common dose prescription was 16 Gy radiobiologic equiva-
lent in two fractions. At a median follow-up of 56 months,
nine patients (15 %) had total obliteration. Five patients
(9 %) had permanent complications after proton-beam ther-
apy, none of which were severe.
47 Arteriovenous Malformation Radiosurgery
Recognition of the limitations of the various management
options available to patients with large AVMs has encour-
aged some radiosurgical centers to begin staged-volume
radiosurgery for these patients [110–112]. Volume staging of
large AVMs into multiple radiosurgical sessions separated by
several months allows a higher radiation dose to be delivered
to the entire AVM volume while minimizing the radiation
exposure to the adjacent brain. We performed a dosimetric
study comparing staged-volume AVM radiosurgery and
hypothetical single-session procedures for our first ten
patients [112]. Staged-volume radiosurgery decreased the
V12 by an average of 11.1 %, and the non-AVM V12 was
reduced by an average of 27.2 %. Huang et al. reported the
outcomes for 18 patients with large AVMs (>15cm3) under-
going staged-volume SRS over a 13-year interval [110]. The
median radiation dose at each stage was 15 Gy. The 5-year
rate of complete obliteration and hemorrhage after SRS was
29 % and 31 %, respectively. One patient (6 %) had a
radiation-related neurologic deficit. Kano et al. treated 47
patients with staged-volume SRS between 1992 and 2006
[111]. The median total volume was 22.0 cm3; the median
AVM margin dose was 16 Gy. The 5-year actuarial oblitera-
tion rate was 28 %. Patients treated with doses ≥ 17 Gy had a
5-year obliteration rate of 62 %. Radiation-related complica-
tions occurred in 13 % of patients. By minimizing the radia-
tion exposure to the adjacent brain, the incidence of
radiation-related complications has been reduced after
staged-volume SRS for large AVMs compared to single-
fraction SRS [100]. More data are need on this relatively new
Fig. 47.7 Lateral cerebral angiograms of two patients with Spetzler–
Martin Grade I–II AVMs that have significantly different risks from SRS.
(Left, a) Nineteen-year-old woman with headaches and was found to
have a 1.2 cm right frontal AVM (Spetzler–Martin Grade I). The patient
underwent single-session SRS (margin dose, 25 Gy); the modified RBAS
was 0.48. (Right, b) Sixteen-year-old boy who had tonic–clonic seizure
597
technique to permit a better comparison with other available
treatment options for this difficult patient group.
Radiosurgery-Based AVM Grading System
The Spetzler–Martin grading system has become widely
accepted as an accurate method to predict patient outcomes
after surgical resection of AVMs [23]. Comprising three
components (AVM size, location, and pattern of venous
drainage), this system has been validated prospectively [25]
and by numerous cerebrovascular centers of excellence
[26–29]. Although some authors have noted discrepancies
between AVM grade and patient outcomes, especially in
regard to Grade III AVMs [24, 113, 114], the general consen-
sus supports this grading scale as practical and reliable.
Unfortunately, the Spetzler–Martin classification is insensi-
tive to changes in AVM volume for lesions less than 3 cm,
and AVMs located in the basal ganglia, thalamus, or brain-
stem are considered at equal risk for radiation-related com-
plications as AVMs located in-or-near critical cortical
locations such as the sensorimotor cortex. For example, a
1 cm diameter AVM has a volume < 1 cm3, whereas a 3 cm
diameter AVM has an approximate volume of 14 cm3. The
expected obliteration rates for these AVMs should be approx-
imately 90 % and 50 %, respectively. Yet, both would be
considered small (<3 cm) in the Spetzler–Martin system
(Fig. 47.7). Consequently, a valid instrument capable of
accurately predicting outcomes after AVM SRS is necessary
and was found to have a 4 cm left frontal AVM (Spetzler–Martin Grade
II). The patient underwent staged-volume SRS (margin dose, 15 Gy); the
modified RBAS was 2.14. From Pollock BE, Niranjan A, Kano H,
Lumsford LD, eds. Gama Knife Radiosurgery for Brain Vascular
Malformations. Prog Neurol Surg. Basel, Karger, 2013; 27:1-9; used
with permission from S. Karger AG, Basel
598
to adequately compare the expected results of microsurgery
and SRS for individual AVM patients.
Successful AVM radiosurgery results in complete nidus
obliteration without new or worsened neurologic deficits.
Karlsson et al. reported the K index as a method to predict
obliteration after AVM SRS [56]. In a similar fashion,
Schwartz et al. proposed the OPI as a means to estimate the
chance of AVM obliteration for individual patients [70].
Although both correlate with AVM obliteration after SRS,
neither takes into account the chance of radiation-related
complications. Also, the K index and OPI are based on the
radiation dosimetry used (AVM margin dose) at the time of
treatment and not on patient and AVM characteristics alone.
Therefore, our center in collaboration with the University of
Pittsburgh developed a radiosurgery-based AVM grading
system that accounts for these shortcomings and predicted
the chance of successful, single-session AVM radiosurgery
based solely on patient and AVM variables [48].
The RBAS was developed based on the multivariate anal-
ysis of 220 patients having SRS between 1987 and 1991 at
the University of Pittsburgh. The dependent variable in all
analyses was excellent patient outcomes (complete AVM
obliteration without new neurologic deficit). The grading
scale was then tested on a separate set of 136 AVM patients
treated between 1990 and 1996 at the Mayo Clinic. Overall,
121 of 220 (55 %) of the Pittsburgh patients had excellent
outcomes. Multivariate analysis found five variables related
to excellent patient outcomes: AVM volume, patient age,
AVM location, prior embolization, and number of draining
veins. Regression analysis modeling permitted removal of
two significant variables (prior embolization, number of
draining veins) and resulting in an equation to predict patient
outcomes after AVM radiosurgery. Seventy-nine of 136 Mayo
Clinic patients (58 %) had excellent outcomes. Testing of the
RBAS on the Mayo patients showed the AVM score predicted
patient outcomes after radiosurgery. All patients with an
AVM score ≤ 1.0 had an excellent outcome compared to only
39 % of patients with an AVM score > 2.0. Consequently,
despite significant differences in preoperative patient charac-
teristics and dose prescription guidelines at the two centers,
the RBAS strongly correlated with patient outcomes after
single-session radiosurgery for both patient groups. Since
that time, the RBAS has been modified using location as a
two-tiered variable (basal ganglia, thalamus or brainstem ver-
sus other) rather than a three-tiered variable [49] (Table 47.1).
In side-by-side testing with the original RBAS, the modified
RBAS performed equally well in predicting both AVM oblit-
eration without new neurologic deficits or decline in MRS
after radiosurgery (Fig. 47.8). The RBAS has been validated
by a number of centers performing not only the Gamma
Knife SRS but also LINAC-based SRS, CyberKnife SRS, as
well as proton beam SRS [89, 107, 115–124]. The RBAS per-
mits an accurate estimation of outcomes from SRS to aid in
B.E. Pollock
Table 47.1 Radiosurgery-based AVM grading system
Factor Coefficient
AVM volume (cm3) 0.1
Patient age (years) 0.02
AVM location 0.5
Cerebral hemisphere, corpus callosum, cerebellum = 0
Basal ganglia, thalamus, brainstem = 1
AVM score = (0.1) (AVM volume) + (0.02) (patient age) + (0.5)
(AVM location)
preoperative decision making between surgical and radiosur-
gical management for individual AVM patients.
Advances in endovascular techniques, microsurgical
resection, and SRS have all contributed to improving
outcomes for AVM patients. To provide the best care for
AVM patients, we should utilize every tool available to indi-
vidualize their management taking into account the patient’s
age, presentation, nidus size and morphology, AVM location,
and patient preference.
Illustrative Case
A 10-year-old boy complained of headaches that continued
to increase despite medical therapy for migraines. In addi-
tion, he developed episodes of numbness and tingling involv-
ing his left hand and arm that also were increasing in
frequency and intensity. Of note, the boy was left handed. An
MRI of his head revealed a large AVM located in the tempo-
ral, frontal, and parietal lobes with extension into the lateral
portion of the thalamus (Fig. 47.9). The AVM measured
4.5 cm × 4.2 cm × 3.5 cm. There was no evidence of either
recent or remote hemorrhage. An electroencephalogram
showed diffuse slowing in the region of the AVM, but no
distinct epileptiform activity. A cerebral angiogram showed
the AVM had arterial supply from the right anterior, middle,
and posterior cerebral arteries. The AVM had both superficial
and deep venous drainage. There were no intranidal or feed-
ing vessel aneurysms and no evidence of venous outflow
restriction. The case was reviewed at our combined cerebro-
vascular conference and the options of observation, surgical
resection, and radiosurgery were discussed. It was felt that
the AVM was becoming symptomatic, most likely from a
“steal phenomenon,” so treatment of the AVM was recom-
mended. The risk of neurologic injury from surgical resec-
tion of this Spetzler–Martin Grade IV AVM in the patient’s
dominant hemisphere was considered high, especially since
the AVM was unruptured. Due to the large size (estimated
volume, 30–35 cm3) of the AVM, the RBAS was estimated to
exceed 3.5. Therefore, radiosurgery of the entire lesion in a
single procedure was also considered a poor option. After
discussing the options of planned embolization followed by
47 Arteriovenous Malformation Radiosurgery 599

Fig. 47.8 Graph showing

percentage of AVM patients who
achieve an excellent outcome
(nidus obliteration without new
neurologic deficits) (solid line) or
decline in modified Rankin Score
(dashed line) based on the
modified RBAS. From Pollock
BE, Niranjan A, Kano H,
Lumsford LD, eds. Gama Knife
Radiosurgery for Brain Vascular
Malformations. Prog Neurol
Surg. Basel, Karger, 2013;
27:1-9; used with permission
from S. Karger AG, Basel

Fig. 47.10 Lateral (left, a) and anterior–posterior (right, b) right

carotid angiograms showing the dose plan for the first SRS covering the
medial portion of the AVM. Injection of the vertebral artery filled an
additional posterior component of the AVM not visualized on the
carotid injection, but which was included in the dose plan

Fig. 47.9 Axial post-gadolinium MRI of a 10-year-old boy with a

large right-sided AVM located in the temporal, frontal, and parietal
lobes with extension into the lateral portion of the thalamus

SRS or staged-volume SRS, the patient’s family consented

to staged-volume radiosurgery.
The procedures were performed under general anesthesia
using stereotactic MRI and angiography for dose planning.
The first SRS covered the medial portion of the AVM
(Fig. 47.10). The dose plan consisted of 11 isocenters of
radiation to cover a volume of 15.5 cm3. The margin dose
was 15 Gy and the maximum dose was 30 Gy. The patient
Fig. 47.11 Lateral (left, a) and anterior–posterior (right, b) right
returned 4 months later and underwent a second SRS to carotid angiograms showing the dose plan for the second SRS covering
cover the lateral portion of the AVM (Fig. 47.11). The dose the lateral portion of the AVM
600
Fig. 47.12 Lateral right carotid
angiogram at the time of repeat
SRS (52 months after completion
of staged-volume SRS). The
nidus has decreased in size from
>30 to <1 cm3
plan consisted of 13 isocenters of radiation to cover a volume
of 17.0 cm3. The margin dose was 15 Gy and the maximum
dose was 30 Gy. The patient had a reduction in his headaches
within several months of staged-volume SRS and remained
neurologically intact. Yearly MRI showed the AVM to be sig-
nificantly smaller but there appeared to be persistent filling
of an early draining vein. Fifty-two months after completion
of staged-volume SRS, the patient underwent a stereotactic
angiogram which confirmed near-total obliteration of the
AVM (Fig. 47.12). The AVM volume at the time of repeat
SRS was 0.8 cm3. The margin dose was 18 Gy and the maxi-
mum dose was 36 Gy. Three years after his last SRS proce-
dure the patient remains well and has completed high school.
Follow-up angiography is planned in several years to deter-
mine the obliteration status of his AVM.
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 Arteriovenous Malformations:
Viewpoint—Surgery
Eric M. Deshaies and Surasak Komonchan
Introduction
Arteriovenous malformations (AVMs) are congenital vascular
lesions comprising of direct connections between arteries and
veins without an intervening capillary network. The central
collection of intertwined vessels formed by these arterial-to-
venous shunts, called the nidus, is often embedded within the
parenchyma of the central nervous system. The etiology of
AVMs is uncertain, but current thought is that they represent
nests of abnormal regression in the fetal vasculature [1, 2].
AVMs vary in size, location, and angioarchitecture, each
central to preoperative planning. They are frequently sup-
plied by multiple arterial pedicles causing abnormally high
flow and pressure within the nidus and draining veins
(Fig. 48.1). The abnormal hemodynamic forces within the
AVM and surrounding vasculature can result in hemorrhage.
Traditionally, surgical resection has been the only treatment
for these lesions. However, with the development of mini-
mally invasive techniques including endovascular emboliza-
tion and stereotactic radiosurgery (SRS), AVM treatment
plans have become more complex and frequently require a
multimodality approach [3–7]. Occasionally, depending
upon the size, location, and natural history of the AVM, and
the patients risk-factors and medical comorbidities, the saf-
est treatment may be no treatment at all [3–5].
E.M. Deshaies, M.D. (*)
Department of Neurosurgery, SUNY Upstate Medical University,
750 East Adams Street, Syracuse, NY 13210, USA
e-mail: deshaieE@upstate.edu
S. Komonchan, M.D.
Department of Neurology, Prasat Neurological Institute,
312 Rajavithl Road, Rajthevee 10400, Thailand
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_48, © Springer Science+Business Media New York 2015
48
Natural History of Arteriovenous
Malformations
The prevalence of AVMs in the general population is less
than 1 % [8–11]. AVMs can manifest with seizures, head-
ache, cognitive deficit, pulsatile tinnitus, or other focal neu-
rological deficits. The most common presentation is
intracranial hemorrhage associated with a 50 % morbidity
and mortality [12, 13]. AVMs are the most common cause of
intracranial hemorrhage in children and young adults [13,
14]. The risk of hemorrhage in unruptured AVMs is esti-
mated to be about 2–4 % annually [9, 11, 15–22] but is
cumulative such that patients diagnosed at a younger age are
at a higher risk of bleeding during the course of their life-
time. After the initial hemorrhage, the risk of another bleed
is 18 % in the first 6 months and returns to baseline by 3–5
years [15, 20, 22].
The abnormally high flow and pressure within the AVM
contribute to the bleeding and can also result in aneurysm
development. AVM-associated aneurysms further increase
the annual bleeding risk to 41 % [12, 15, 23]. These aneu-
rysms are likely the result of abnormal shear stress on the
arterial walls creating further weakening with aneurysm for-
mation. Venous aneurysms, or varices, form in the venous
system and can bleed, particularly when the vein distal to the
varix is stenotic, further increasing the pressure within the
venous aneurysm.
Arterial aneurysms are classified by location relative to
the AVM: (1) intranidal, (2) extranidal, and (3) flow related
(Fig. 48.2). The first two types are directly associated with
the vasculature of the AVM, whereas the flow-related aneu-
rysms are located elsewhere on the circle of Willis (COW)
[24]. Intranidal aneurysms were reported in 13.6 % of AVMs,
extranidal aneurysms in 10.9 % of AVMs, with the latter
being flow-related 72 % of the time and in the COW 27 % of
the time [24]. The etiology of the AVM-associated aneu-
rysms seems related to the abnormally high-flow within the
AVM vasculature, but it is less clear how the distant ones
605
606
Fig. 48.1 (a) Digital subtraction angiography demonstrating the three
main components of an AVM: arterial feeding pedicles (small arrow),
nidus (circle), draining vein (thick arrow) into the superior sagittal
sinus. (b) Digital subtraction angiography using iFlow analysis
(Siemens, software version 20) of an AVM; arterial (red) and venous
(blue) phases. Notice that the superior sagittal sinus (SSS) is yellow
Fig. 48.2 3D digital subtraction angiogram demonstrating AVM nidus
(circle) and an extranidal AVM-associated multilobulated aneurysm
(arrow)
form. Though speculative, distant aneurysms may result
from structural wall defects that arise either from congenital
or acquired etiologies that increase the susceptibility of these
vessels to aneurysm formation.
E.M. Deshaies and S. Komonchan
rather than blue, depicting early venous drainage from the
AVM. Additionally, cortical veins not associated with the AVM are blue
(small arrows) suggesting that the AVM does not drain through these
veins. (c) Intraoperative visualization of well-demarcated flow (arrow)
between arterial (red) and venous (blue) blood in an arterialized cortical
vein associated with an AVM
Clinical Presentation and Initial Assessment
Patients with unruptured AVMs most often present with
chronic headaches or seizures, while ruptured ones present
with severe acute headache and neurological deficits [12, 21,
25]. Risk factors for AVM bleeding are often controversial
with conflicting reports in the literature. However, some of
the more accepted risk factors include prior hemorrhage,
associated aneurysm, venous varix, and venous outflow ste-
nosis, while nidus size remains controversial [15, 16, 23, 26].
In the case of patients who present with ruptured AVMs,
initial assessment can be artificially divided into two catego-
ries: hemorrhage with and without symptomatic mass effect.
Clearly, patients with AVM bleeding significant enough to
cause severe neurological deficit from mass effect should be
considered for operative intervention to evacuate hematoma
and resect the AVM. However, the extent of surgical resec-
tion in these emergent situations is often decided intraopera-
tively depending on the size and location of the lesion. For
example, the entire AVM may not be removed at the time of
clot evacuation if it is located in eloquent regions because it
could exacerbate neurological deficits. In this situation, it
would be better to evacuate clot leaving the AVM behind to
limit further neurological deficits and prevent profuse bleed-
ing intraoperatively.
In situations where there is no symptomatic mass effect,
timing of treatment becomes more complex. Some neurosur-
geons prefer to delay treatment until the clot retracts, cerebral
edema resolves, and elevated intracranial pressure subsides,
48 Arteriovenous Malformations: Viewpoint—Surgery 607

using only aggressive medical management as needed [27]. Table 48.1 Spetzler-Martin grading of AVMs [28]
Acute surgical intervention in this setting can make treat- Grading feature Points assigned
ment more precarious and potentially increase the risk of Size of nidus
dangerously elevating intracranial pressure. For example, if Small (<3 cm) 1
preoperative embolization is being considered in the acute Medium (3–6 cm) 2
phase, a second bleed, and an ischemic event or redirection Large (>6 cm) 3
of the flow in the AVM from vascular occlusion, could result Eloquence of adjacent brain
in additional edema and mass effect, forcing surgical inter- Non-eloquent 0
vention. Similarly, preoperative angiography in the setting of Eloquent 1
brain shift and edema may not allow full and accurate visu- Pattern of venous drainage
Superficial 0
alization of the AVM angioarchitecture, making complete
Deep 1
resection less likely and more difficult. Delaying interven-
tion until the hematoma, edema, and elevated intracranial
pressure resolve followed by elective noninvasive functional
Table 48.2 Spetzler-Martin grade and predicted surgical risk [28]
brain mapping and angiography will enable the neurosur-
Grade No deficit (%) Minor deficit (%) Major deficit (%)
geon to operate more safely with better outcomes than in the
1 100 0 0
acute scenario.
2 95 5 0
3 84 12 4
4 73 20 7
Imaging Modalities for Presurgical Planning 5 69 19 12

In order to appropriately choose candidates for surgical

resection, imaging modalities assessing the angioarchitec- Table 48.3 Supplementary grading system [30]
ture of the AVM, surrounding cortical eloquence, and anat- Grading feature Points assigned
omy of the white matter tracks can be helpful during Age
preoperative planning and discussions with the patient about <20 years 1
surgical risks. Not all patients with AVMs are surgical candi- 20–40 years 2
dates particularly with the advent of endovascular emboliza- >40 years 3
tion and SRS [6]. Here, we will discuss the utility of the Unruptured presentation
Spetzler-Martin grade and imaging modalities during preop- No 0
erative treatment planning. Yes 1
Diffuse
No 0
Yes 1
AVM Surgical Grading Systems

The AVM size (<3 cm, 3–6 cm, >6 cm), location (eloquent or
non-eloquent), and venous drainage pattern (deep or superfi-
cial) were found to be important AVM characteristics when
determining surgical risk and predicting postoperative neu-
rological outcomes [28]. The Spetzler-Martin grading sys-
tem (SMG) was developed using size, location, and venous
drainage patterns to assign a numeric score (1–5) with the
higher number predicting higher surgical risk with worse
neurological outcomes (Table 48.1); an SMG of 6 has been
used to imply an “unresectable” AVM. This system was vali-
dated and predicts that an SMG of “1” has a 0 % risk of defi-
cit from surgical resection, while an SMG of “5” has a 31 %
risk. The authors further divided surgical risk into “major”
and “minor” neurological deficits (Table 48.2). Though the
SMG has been very useful to many surgeons planning for
AVM resection, it does have pitfalls. For example, surgical
outcomes associated with the SMG will be different for indi-
vidual surgeons depending upon their training, technical
abilities, case volume, and experience. Additionally, interob-
server variability for the SMG was 28 %, with venous drain-
age having the least interobserver variability and nidus size
having the greatest [29].
A modification of the SMG was subsequently described
where age, rupture status, and nidus diffuseness were consid-
ered important characteristics for assessing surgical outcome.
This modification was published as the “supplementary
grading system” (SGS) developed by reviewing 300 patients
who underwent microsurgical AVM resection and determin-
ing their modified Rankin score, SMG, and SGS (Table 48.3)
[30, 31]. The predictive accuracy of the SGS for postsurgical
608
neurological deficits was higher (0.73) than the SMG (0.66).
However, the SGS is intended to be an adjunct to the SMS
and not a substitute. Therefore, the modification includes
adding the SMG and SGS scores to obtain a combined score
ranging from 0 to 10. Using this scoring system, a grade of
1–3 predicts low surgical risk, 4–6 moderate risk, and 7–10
high risk, for surgical AVM resection.
A three-tier classification system was recently described
in order to guide AVM management based on the SMG [32].
AVMs were classified into “A” through “C” based on SMG
with recommended management options according to the
classification (Table 48.4). The recommendations based
upon this classification system were Class “A” (SMG 1, 2),
surgical resection; Class “B” (SMG 3), multimodality treat-
ment; and Class “C” (SMG 4, 5), no treatment.
Imaging Studies
Various imaging modalities can be used to depict the anatomical
features of an AVM, including computed tomography angio-
graphy (CTA), magnetic resonance angiography (MRA), and
magnetic resonance venography (MRV) (Fig. 48.3).
Table 48.4 Three-tier classification of cerebral AVMs [32]
Class Spetzler-Martin grade (SMG) Treatment
A 1 and 2 Surgical resection
B 3 Multimodality
C 4 and 5 No treatment
Fig. 48.3 Coronal section of a CTA (a) and MRA (b) depicting the
three main architectural components of an AVM: arterial feeding pedi-
cles, nidus, and venous drainage. These static images make it difficult
E.M. Deshaies and S. Komonchan
However, only catheter-based digital subtraction angiography
(DSA) can demonstrate the anatomical and hemodynamic fea-
tures of the AVM. Differentiating between arterial feeding
pedicles and draining veins can be challenging on the static
imaging such as CTA and MRA (Fig. 48.3). Additionally,
clearly identifying the extent of the AVM nidus on MRA and
CTA can also be challenging at times, particularly with diffuse
lesions. Static images, however, unlike DSA, depict the brain
tissue relative to the AVM and are therefore very important for
determining the location of the AVM within the cerebral hemi-
spheres. These static imaging modalities are particularly useful
for determining AVM proximity to eloquent cortical and
subcortical areas. Newer static imaging modalities such as
functional MRI (fMRI) and diffusion tensor imaging (DTI) can
be particularly useful for preoperative planning.
Functional MRI
The emergence of FMRI in the 1990s and its continued
development enable clinicians to identify eloquent cortical
areas using real-time noninvasive mapping techniques. The
patient is presented with a series of tasks during an MRI and
the cortex can be mapped based on changes in blood flow
and oxygen delivery, making this a functional and physiolog-
ical test for detection of eloquent brain tissue. The proximity
of eloquent areas relative to the AVM can then be viewed
when planning the surgical approach and assessing surgical
risk with the patient (Fig. 48.4). The combined use of nonin-
vasive static imaging (MRA, fMRI, CTA) and minimally
to distinguish between arterial and venous structures and determining
the precise boundaries of the AVM nidus
48 Arteriovenous Malformations: Viewpoint—Surgery
invasive dynamic imaging (DSA) allows the neurosurgeon to
apply the SMG in a more precise manner when considering
potential treatment options [33]. For example, an AVM
clearly located in the eloquent cortex or deep white matter
structures would likely result in an unacceptably high surgi-
cal risk, making embolization or SRS a safer option. fMRI is
also helpful with AVM treatment planning because a small
percentage of individuals exhibit cortical rearrangement,
such that functionality is not where one would typically
expect. These functional anomalies could have important
implications for surgical planning when they are identified
ahead of time and avoid unexpected poor outcomes from
neurological deficits (Fig. 48.5).
Fig. 48.4 fMRI depicting vascular flow voids from the AVM in the left
frontal lobe anterior to the right-hand motor cortex (yellow blob)
Fig. 48.5 fMRI demonstrating cortical rearrangement in a left-handed individual who was asked to tap his right fingers. Notice bilateral cortical
involvement (red blobs) with the left cortical activity lying deep, medial to the AVM flow voids
609
Diffusion Tensor Imaging
DTI is a relatively new form of MRI technology that uses
water diffusion in the brain tissue to map the white matter
tracks (tractography) throughout the hemispheres (Fig. 48.6).
The result is a color-coded map of the white matter tracts that
can be viewed relative to the location of the AVM. White
matter tracts originating from eloquent structures passing
through the AVM nidus could be an important deterrent to
surgical resection. For example, surgical resection of an
AVM nidus adjacent to the white matter tracts connecting
Broca and Wernicke areas may result in a conductive aphasia
from disconnection of these fibers. Another example would
be an AVM in Meyer’s loop resulting in visual field deficits
after resection. In this way, DTI tractography can be an
important tool for presurgical risk assessment and may guide
the decision towards a minimally invasive therapy that is less
likely to injure critical brain structures.
Presurgical Embolization
The first reported AVM embolization was performed by Drs.
Luessenhop and Spence in 1960. They reported near-total
angiographic occlusion of an AVM using methyl methacry-
late embospheres [34]. Since that time many different mate-
rials have been developed for embolization, including
calibrated particles, silk thread, absolute ethyl alcohol
(EtOH), and polyvinyl alcohol (PVA). Liquid embolic agents
have been developed with the advantage over particles
because they form a vessel cast resulting in better occlusion
and are less likely to migrate into the venous system when
there is a high-flow fistulae.
One of the first and more commonly used embolic agents
was the liquid adhesive N-butyl-2-cyanoacrylate (NBCA,
610 E.M. Deshaies and S. Komonchan

Fig. 48.6 DTI tractography demonstrating white matter tracks sur- left parieto-occipital AVM in a patient who presented with receptive
rounding the AVM (a) with corresponding MRI (b) allowing localiza- aphasia, visual field cut, and dyslexia after hemorrhage. The arrow in
tion of the AVM relative to critical brain structures. Depicted here is a (a) points to a disruption in the white matter tracts seen as a black void

Trufil, Codman), first introduced in the 1980s for intravascu-

lar embolization. This was followed by a nonadhesive agent
called ethylene vinyl alcohol (Onyx, eV3/Covidien
Neurovascular) in the 1990s, which occludes flow by pre-
cipitating in the vessel, allowing for a more controlled injec-
tion, longer working time, and lower risk of microcatheter
retention. Each of these embolic agents has its pros and cons,
which are discussed in greater detail elsewhere in this book.
Onyx has become the more popular liquid embolic agent
because its nonadhesive properties make it easier to work
with for reasons mentioned previously. Embolization alone
does not always cure AVMs and has a more important role as
an adjunctive treatment prior to surgical resection or
SRS. Complete angiographic obliteration of AVMs after
embolization has been reported in several studies in up to
57 % of cases [35–37]. However, AVMs have been reported Fig. 48.7 Onyx glue (black) identified in an embolized arterial feeding
to hemorrhage even with angiographic evidence of complete pedicle intraoperatively
embolization, supporting the notion that nests of the AVM
may remain despite “angiographic cure” [38–40]. This post-
embolization hemorrhage may be from small nidal nests that the AVM nidus throughout the resection and increase the
can’t be visualized angiographically or from AVM recur- difficulty of resection. Therefore, prior embolization can
rence secondary to recanalization of the occluded arterial reduce the complexity of surgery resulting in improved clinical
feeding pedicles. The low cure rate with current emboliza- outcomes. Data suggest that occlusion of >75 % of the AVM
tion materials and techniques makes endovascular therapy an nidus facilitates surgical resection, while elimination of <50 %
important adjunct to surgical resection or SRS, but not a helps little during surgical resection [45]. An additional benefit
practical sole treatment. of presurgical embolization is the easy identification of the
Presurgical embolization reduces the number of arterial feeding pedicles intraoperatively guiding the neurosurgeon to
feeding pedicles to the AVM ultimately making surgery safer the nidus, particularly those parts that are covered with brain
with less blood loss and shorter anesthesia time [7, 35, 41–44]. tissue and difficult to visualize initially (Fig. 48.7).
It is particularly useful for those larger AVMs with multiple Interestingly, bipolar cauterization of the Onyx casts
arterial feeding pedicles and those with deep feeding arteries causes sparks, with seemingly no risk to the patient.
that would not be accessible until the end of resection. These Additionally, unlike n-BCA, solidified Onyx is moderately
deep-seated arteries, when not embolized, continue to feed compressible allowing placement of AVM or aneurysm clips
48 Arteriovenous Malformations: Viewpoint—Surgery
during surgery. Glue casts also act as formidable arterial
plugs after transecting the arterial feeding pedicles during
nidus resection.
When using multimodality therapy, the cumulative risk of
AVM embolization (single or staged treatment) plus the risk
of surgical resection (determined by the SMG or SGS) must
be taken into account [7]. Complications from AVM emboli-
zation include transient (11.5 %) and permanent non-
disabling (2.6 %) neurological deficits and permanent
disabling deficits or death (1.6 %) [7, 38, 43, 46, 47]. The
cumulative risk of embolization plus surgical resection must
be discussed with the patient as part of their individualized
surgical treatment plan.
Presurgical Stereotactic Radiosurgery
SRS is not often used as a presurgical adjunct to AVM resec-
tion. It generally takes 15–30 months to be effective, tempo-
rarily increases the risk of bleeding over baseline, and affords
little or no protection from hemorrhage during the first cou-
ple of years. SRS can, however, reduce the size of the AVM
and modify the structure of the arterial walls, making surgery
easier to perform [48]. SRS is particularly useful as an
adjunct to surgical resection postoperatively if residual or
inoperable AVM must be left behind. SRS can be helpful
when a patient presents with an AVM hemorrhage requiring
emergent surgical evacuation from an otherwise inoperable
lesion. In this situation, clot evacuation and brain decom-
pression can be performed leaving the inoperable AVM for
SRS at a later date once the patient recovers. A more in-
depth discussion of SRS for AVMs can be found elsewhere
in this textbook.
Surgical Considerations
Surgical success is not only dependent upon technical prow-
ess but upon perioperative medical management skills as
well. A multidisciplinary approach increases the safety of
surgical resection and likelihood of good outcome. When the
situation allows, preoperative assessment should include (1)
the patient’s primary care physician to address any comor-
bidities that would increase anesthesia and surgical risks
such as hypertension, pulmonary and cardiac disease; (2)
anesthesia assessment focusing on intraoperative blood pres-
sure control, seizure prophylaxis, anesthetic type, and blood
transfusion; (3) neuromonitoring team for cortical mapping
in situations where the AVM is in proximity to the eloquent
cortex or to help guide resection of an epileptic focus; and
(4) discussions with an intensivist about postoperative blood
pressure management, potential cerebral edema, stroke, and
611
seizures. These issues ideally are addressed ahead of time to
minimize complications and optimize surgical success and
patient outcome.
Anesthesia Considerations
AVM resection is performed via craniotomy under general
anesthesia and has the potential for large volumes of blood
loss. Therefore, preoperative preparation should include
radial artery line for stringent blood pressure control, periph-
eral or central intravenous access for crystalloid and colloid
resuscitation, and a urinary catheter for fluid output monitor-
ing [49, 50]. The patient should be cross matched for at least
two units of blood and have them available for transfusion. A
specific range of systolic blood pressure or mean arterial
pressure should be stated clearly to the anesthesiologist
along with goals for hematocrit, end-tidal pCO2, and the type
of anesthetic needed for neuromonitoring.
By this point, the decision to use intraoperative neuro-
monitoring should have been made and the specific need for
SSEP, MEP, VEP, BAER, and cortical mapping discussed
with the monitoring team [51]. This is imperative because
the type of anesthetic (gas anesthesia versus total intrave-
nous anesthesia or TIVA) can affect the neuromonitoring
signals and if not attended to properly, could render them
useless [52].
Tenets of Surgical Resection
Before draping the patient, femoral artery access should be
prepared and draped for possible intraoperative angiography
without contaminating the surgical field. Imaging studies
pertinent to the resection should be readily available for
viewing during the surgery along with neuronavigation and
multimodality image fusion.
The patient should be positioned to expose the area of
interest and allow for a wide craniotomy that encompasses
the entire nidus and exposes the arterial feeding pedicles and
draining veins. Too little bone removal could result in a pre-
carious situation where the feeding and draining vessels are
under the skull and unable to be accessed sufficiently. If neu-
ronavigation is being used, it can aid in planning the crani-
otomy incision and bone removal to ensure adequate
exposure of all major components of the AVM. Additional
room may be needed if neuromonitoring grids will be placed
for cortical mapping or simultaneous resection of an epilep-
tic focus is planned.
General principles of AVM resection are to first occlude
the arterial feeders to stop flow into the nidus followed by
resection of nidus and occlusion of the venous outflow
612
Fig. 48.8 Surgical resection of an AVM in the occipital cortex fed by
the right posterior cerebral artery. (a) The arterial feeding pedicles on
the cortical surface contain blackish-gray Onyx glue before entering the
nidus seen between the bipolar tips. (b) AVM nidus being resected from
vessels (Fig. 48.8). Resecting in this order minimizes the risk
of AVM nidus rupture and severe bleeding. Temporary AVM
or aneurysm clips can be used to test vessels when there is
uncertainty as to whether the vessel is an arterialized vein or
arterial feeders that needs to be ligated. At times it can be
difficult to distinguish between the two types of abnormal
vessels, and permanently occluding an arterialized vein early
in the resection could result in severe bleeding. AVM or
small aneurysm clips and cauterization are used to perma-
nently occlude the vessels. En passage cerebral vessels need
to be preserved to avoid ischemic stroke, and these too can
be tested with temporary aneurysm clips while watching for
changes in neuromonitoring signals.
If preoperative embolization was performed, the glue
cast can be followed to the AVM nidus. Occlusive glue
casts can be transected and left behind to ensure persis-
E.M. Deshaies and S. Komonchan
the occipital lobe is partially cauterized, and Onyx glue is seen in the
artery between the bipolar tips. (c) Partially resected AVM with clips
seen in view alongside cauterized nidus. (d) Resection cavity after
complete nidus resection
tent arterial occlusion although the surgeon may consider
adding a clip or further cauterize the vessel, depending on
its size, as an additional precaution against bleeding from
recanalization.
If bleeding becomes difficult to control during resection
of the AVM, the surgical approach should be reassessed for
the premature occlusion of a venous outflow conduit or
entrance into the nidus itself. Bleeding from the nidus is dif-
ficult to control because of the pressure from high blood flow
and the pathological vessel walls, making them less respon-
sive to cauterization. In this situation, the surgeon should
begin working peripherally, away from the actual nidus, until
a complete resection can be performed. Irrigating bipolar
cautery tips are recommended to minimize “sticking” of the
vessels to the tips resulting in tearing of the nidal vessels and
worsened bleeding.
48 Arteriovenous Malformations: Viewpoint—Surgery
Fig. 48.9 Digital subtraction angiography of the AVM fed from the posterior cerebral and superior cerebellar arteries (a) before and (b) after
surgical resection
Intraoperative Angiography
After a gross total resection of the AVM is suspected, intra-
operative angiography is recommended [53]. Small nests of
AVM nidus can remain after apparent “gross total resection”
that may be difficult to visualize in pockets of white matter
or the sulci. Intravenous fluorescein angiography can be per-
formed under the microscope if this feature is available to the
surgeon, but small rests of AVM nidus enveloped by the
brain parenchyma likely will not be seen with this technique.
Therefore, DSA is recommended instead and remains the
gold standard vascular imaging study (Fig. 48.9). In situa-
tions where intraoperative angiography is not available, post-
operative angiography can be performed at a later time. This
is not ideal, however, because if residual AVM is not identi-
fied until after surgery, re-exploration, endovascular emboli-
zation, or SRS will be required to treat the remnant.
Postsurgical Care
Postoperative evaluation should look for signs of cerebral
edema, seizures, ischemic stroke, and hemorrhage from
“normal pressure breakthrough syndrome (NPBS)” [54].
Typically these patients are observed in the intensive care
unit or a unit where detailed neurological examinations by
the nursing staff and tight blood pressure control can be per-
formed safely. NPBS can be problematic when it occurs and
613
is likely the result of the acute hemodynamic changes that
occur within the local vasculature after AVM resection.
Systolic blood pressures should be kept within low-normal
ranges (90–120 mmHg) postoperatively, monitored by an
arterial line, and antihypertensive intravenous drips and pain
control used when necessary. Antiepileptic agents should
also be continued after supratentorial AVM resection.
Postoperative angiography should be obtained at this
point if not performed in the operating room to evaluate for
residual AVM. If there is residual nidus, consider re-
exploration potentially with image guidance, endovascular
embolization, or SRS.
Conclusion
AVM treatment frequently requires multimodality therapy.
Thorough preoperative investigation with static imaging,
angiography, fMRI, and DTI will help to assess surgical risk.
Once the neurosurgeon has decided on AVM resection, pre-
operative embolization should be considered and periopera-
tive treatment discussed with members of a multidisciplinary
team who will be involved with the surgery. Neuromonitoring
capabilities for intraoperative monitoring and localization of
an epileptic focus when necessary should be available during
surgery. Postoperative care management in an ICU includes
close neurological examinations by a trained nursing staff
and monitoring for seizure activity and NPBS.
614
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 Cerebral Arteriovenous
Malformations Viewpoint:
Endovascular Therapy Perspective
M. Yashar S. Kalani, Richard W. Williamson,
Felipe C. Albuquerque, and Cameron G. McDougal
Introduction
Arteriovenous malformations are some of the most treacher-
ous lesions in medicine. Although initially postulated to be
congenital lesions, more recent data suggest that these mal-
formations undergo dynamic remodeling, and can expand or
involute [1]; rare cases of de novo formation have been
reported in the literature [2, 3]. The recent publication of the
ARUBA trial [4] has led to much confusion on the role of
intervention versus medial management of these lesions.
Although most practitioners agree that the results of the
ARUBA trial are marred by design and execution flaws, the
study serves as a reminder that careful patient selection and
the availability of a multidisciplinary team with expertise in
neurological surgery, interventional techniques, and radia-
tion therapy are cornerstones of successful treatment.
Natural History
The decision to treat any pathology rests on a solid under-
standing of the natural history of the disease, the morbidity
and mortality associated with intervention, and the expertise
of the practitioner(s) involved in the care of the patient.
Therefore any discussion on treatment of AVMs depends on
an understanding of the presentation and natural history of
these lesions in the general population.
Hemorrhage is the most common presenting symptom of
patients with AVMs, followed by seizures and focal neuro-
logical deficits, likely caused by microhemorrhage or steal
phenomena from adjacent brain [5]. Several large studies
M.Y.S. Kalani, M.D., Ph.D. • R.W. Williamson, M.D.
F.C. Albuquerque, M.D. (*) • C.G. McDougal, M.D.
Division of Neurological Surgery, Barrow Neurological Institute,
St. Joseph’s Hospital and Medical Center,
300 West Thomas Road, Phoenix, AZ 85013, USA
e-mail: Yashar.kalani@bnaneuro.net; neuropub@dignityhealth.org
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_49, © Springer Science+Business Media New York 2015
49
have attempted to shed light on the annual risk of hemor-
rhage from cerebral AVMs and suggest that the risk of hem-
orrhage from AVMs is between 2 and 4 % [6, 7]. In the event
of a hemorrhage, the risk subsequently increases to 7–17 %
for the year immediately after the hemorrhage [8]. Although
results vary greatly between series, each episode of hemor-
rhage is associated with a 10–15 % and 15–30 % risk of mor-
bidity [9, 10]. Most practitioners agree that hemorrhage and
alterations in physiology of the AVM, as manifested by new
neurological deficits or seizure, should lead to detailed
work-up and possibly intervention to eliminate the risk of
hemorrhage.
Although guidelines for treatment of AVMs are based on
expert opinion, the recently published randomized control
trial ARUBA attempted to address the role of intervention
versus medical therapy for unruptured AVMs [4]. Despite
best intentions, ARUBA had major shortcomings associated
with study design and execution. The ARUBA investigators
reviewed 1,740 patients aged 18 years or greater without a
history of hemorrhage for inclusion in the study. Of the
cohort reviewed, 726 patients fit inclusion criteria but 177
patients were treated outside the trial and 323 refused enroll-
ment; 226 were actually included in the study. The authors
do not address the reasons for a large number of patients
being treated outside the trial. A second critique of the trial
design is the lack of elaboration on what the study defined as
an “intervention group.” This group consisted of patients
treated with surgery, endovascular embolization, and radio-
therapy, but few details are provided on the techniques of
embolization and radiotherapy, use of embolysates, number
of endovascular interventions, or the fractionation regimen
or dose of radiation. Furthermore, the study followed patients
for a mean of 33 months, a time point that is certainly inad-
equate for assessing lesions that leave patients with a life-
time risk for hemorrhage. These shortcomings have resulted
in many practitioners questioning the utility of the results of
ARUBA [11, 12].
In the absence of level I evidence, one has to turn to
expert guidelines for management. Spetzler and Martin [13]
617
618
Table 49.1 The Spetzler–Martin [13] and the updated Spetzler–Ponce
grading scale [15] for cerebral arteriovenous malformations
Description Points
Size
<3 cm 1 increased risk of complications, due to the aggressive nature
3–6 cm 2 of embolization needed to completely occlude the AVM
>6 cm 3 nidus, and is rarely the strategy of choice in most centers [18,
Eloquence
Yes 1
No 0
Deep venous drainage
Yes 1
No 0
Reprinted from Spetzler RF, Martin NA. A proposed grading system for
arteriovenous malformations. J Neurosurg. 1986;65:473–83, with
permission from the American Association of Neurological Surgeons
Points are attributed to size, deep venous drainage, and eloquence of
brain involved. The sum of the points dictates the Spetzler–Martin
grade of the AVM. Experience suggests that grade I and II AVMs and
grade IV and V AVMs behave similarly and have similar morbidity and
mortality profiles. This led Spetzler and Ponce to suggest a modified
three-tier grading scheme where grades I and II (now grade A) and
grades IV and V (now grade C) lesions are combined, with grade III
lesions re-classified as grade B
introduced a simple grading scheme based on angiographic
features, size, and location of AVMs that has provided a
reproducible benchmark for assessing morbidity and mor-
tality associated with surgical intervention for AVMs
(Table 49.1) [14]. Hamilton and Spetzler [14] reported mor-
bidity and mortality rates of 1 % and 3 % for treatment of
low grade (I/II and III, respectively) AVMs. The combined
morbidity and mortality rates for treating high-grade (IV
and V) AVMs approach 50 % in the immediate posttreat-
ment period and decline to 17–22 % at follow-up. Based on
data on morbidity and mortality after treatment, current
guidelines suggest surgery for grade I and II AVMs, emboli-
zation followed by surgery for most grade III AVMs, and
observation for most grade IV and V AVMs [15]. Although
this is a great oversimplification and each patient requires
independent evaluation based on angiographic features of
the AVM, AVM location, presence of high-risk features, the
capabilities of the treating team, and patient and family
wishes, this paradigm for treatment serves as guideline for
intervention.
Endovascular Treatment
Endovascular embolization has become a pillar in the multi-
disciplinary treatment of AVMs [16, 17]. Endovascular treat-
ment can be used as a preoperative adjunct for the curative
resection of AVMs. This indication constitutes the largest use
of endovascular techniques for AVMs, and the advent of the
embolysate ethyl vinyl alcohol copolymer (EVOH) or Onyx
M.Y. Kalani et al.
(ev3, Irvine, CA) has greatly expanded the indications and
safety of this approach [18]. In rare circumstances, emboliza-
tion may be used as a curative modality for the complete
occlusion of AVMs. This strategy is associated with an
19]. A third indication for endovascular treatment is its appli-
cation as an adjunct before radiosurgery. Yet other indications
are the use of embolization for targeted treatment of high-risk
features of AVMs (such as intranidal aneurysms) or as a pal-
liative tool to minimize patient symptomatology. In general,
the indication to use embolization in the treatment strategy
should take into consideration the added risk associated with
this intervention. We adhere to the guidelines mentioned
above and rarely embolize grade I or II AVMs. Embolization
is commonly performed for grade III AVMs and is utilized as
a part of multimodality regimen for more complex lesions.
Preoperative Embolization
The goal of preoperative embolization is reduction in the
number of arterial pedicles feeding the nidus of the AVM,
especially those vascular feeders that reside deep to the nidus
and are difficult to access early in the surgical approach
(Fig. 49.1). At our center we perform embolization proce-
dures on the day prior to planned microsurgical resection.
Although the timing of embolization and surgery are contro-
versial, we are reluctant to leave the patient at risk for
hemorrhage after the hemodynamic changes induced by the
embolization. In the post-embolization period and prior to
resection, patients with complex AVMs are kept sedated with
strict blood pressure control. Others have postulated that
surgery should be performed in a delayed fashion (2–3 weeks
after embolization) to allow for normalization of hemody-
namic parameters after embolization [20, 21].
Curative Strategies
Angiographic cures have been achieved in a subset of AVMs
with embolization as a stand-alone therapy. Using
cyanoacrylate-based glues (e.g., N-butyl cyanoacrylate
[NBCA]), a complete occlusion rate of 20 % has been
reported [19]; however, the more recent introduction of ethyl
vinyl alcohol copolymer (EVOH) or Onyx has increased
total obliteration rates to as high as 51 % [18] among all
AVMs and up to 96 % for select AVMs with simple angio-
graphic features [22]. AVMs most amenable to complete
obliteration are those lesions with a small nidus, readily
visible draining vein, and few arterial pedicles. These char-
acteristics are common among grade I and II AVMs, which
49 Cerebral Arteriovenous Malformations Viewpoint: Endovascular Therapy Perspective
Fig. 49.1 Embolization as an adjunct to operative resection. This
52-year-old male presented to our clinical service after an intraventricu-
lar and parenchymal hemorrhage. (a) Axial computed tomography (CT)
demonstrates the bleed pattern. Axial (b), sagittal (c), and coronal (d)
CT angiography revealed an intraventricular AVM fed by branches of
the posterior cerebral artery (PCA) with deep venous drainage.
Anteroposterior (AP) (e) and lateral (f) right internal carotid artery
(ICA) injections demonstrate that the primary arterial feeder of the
nidus is the PCA and provides evidence of the early draining vein.
can readily be treated with surgery, with low resultant
morbidity and mortality. As such, we rarely attempt a com-
plete angiographic cure with embolization alone at our cen-
ter. Another issue of concern with curative embolization is
the question of durability of an angiographic cure with
embolysates. Experience with surgical resection suggests
that despite angiographic cure, residual blood flow is noted
at the time of surgery through embolized vessels.
619
Onyx was used to embolize a branch of the PCA feeding the nidus. AP
(g) and lateral (h) projections post-Onyx embolization reveal dimin-
ished flow to the AVM with preservation of the draining vein. The
patient underwent microsurgical resection of the AVM via a transcorti-
cal approach. AP (i) and lateral (j) ICA injections demonstrate minimal
residual nidus left apposed to the brainstem. The patient was scheduled
to receive radiosurgery to the residual nidus. Used with permission from
Barrow Neurological Institute
Pre-radiosurgery
Embolization can be selectively used in patients with deep-
seated or complex lesions being considered for radiation ther-
apy (Fig. 49.2). Embolization can shrink the AVM nidus
thereby decreasing the volume that must be targeted for ther-
apy with radiation. Despite obvious benefits of downsizing
and reducing the complexity of AVMs with embolization, the
620
Fig. 49.2 Embolization as an adjunct prior to radiotherapy. This
28-year-old male with a grade V AVM presented to our service with a
large diffuse lesion involving the internal capsule with deep venous
drainage. (a) Axial T2-weighted magnetic resonance (MR) scan reveals
the diffuse and extensive nature of the AVM nidus. The patient under-
went pre-radiosurgery embolization with Onyx. (b) T2-weighted axial
MR images 3 years after radiosurgery demonstrate a significant reduc-
Fig. 49.3 Targeted embolization of AVMs. In select cases angiographic
features of AVMs may predispose them to higher rates of hemorrhage.
High-risk features predisposing to hemorrhage include intranidal aneu-
rysms and venous outflow obstruction. (a) Anteroposterior (AP) angi-
ography of the left vertebral artery demonstrates a thalamic AVM with
multiple intranidal aneurysms fed from the left posterior cerebral artery.
embolysate may actually make targeting of lesions difficult
by causing distortion of the nidus, thereby reducing the rate
of AVM obliteration during the period of latency [23–25].
The process of embolization also creates discrete foci of
AVM with intervening embolized nidus, which can make
planning for radiosurgery more challenging [26]. Furthermore,
the possibility of recanalization of embolyzed segments leads
to uncertainty of the fidelity of the treatment. Nonetheless, for
select complex AVMs, embolization and radiosurgery may be
used as a last resort treatment option [27].
M.Y. Kalani et al.
tion in the size of the nidus. The lesion was felt to be amenable to
microsurgical resection. (c) Anteroposterior angiography with vertebral
artery injection demonstrates the size of residual nidus and pure super-
ficial drainage of the lesion. The patient underwent craniotomy with
resection of the lesion. (d) Postoperative T1-weighted axial MR scan
reveals complete resection of the lesion. Used with permission from
Barrow Neurological Institute
Given the location of this lesion in the thalamus, it was felt that the
patient would benefit from treatment of high-risk features and close
follow-up. (b) AP vertebral artery angiography demonstrates residual
nidus after targeted embolization of the high-risk features with Onyx.
Used with permission from Barrow Neurological Institute
Targeted Embolization
Targeted embolization can be used to treat angiographic fea-
tures of an AVM that may predispose it to a higher risk of
rupture. In general this strategy is used in cases when defini-
tive treatment is not possible or is too risky. Features that
increase the likelihood of rupture, so called high-risk fea-
tures, include intranidal aneurysms, outflow venous stenosis,
and the presence of a single deep draining vein (Fig. 49.3)
[28–30]. Although partial treatment of an AVM affords no
49 Cerebral Arteriovenous Malformations Viewpoint: Endovascular Therapy Perspective
Fig. 49.4 Palliative embolization of AVMs. High-grade AVMs not
amenable to multimodality therapy may present with symptoms sug-
gestive of steal. In select cases, embolization may result in improve-
ment in symptomatology and quality of life. This patient presented with
worsening intractable headaches. It was felt that her symptoms were
likely due to vascular steal. Lateral angiograms of the right external
(a) and internal (b) carotid artery demonstrate a large right occipital
protection over the natural history of the lesion, treatment of
high-risk features, such as intranidal aneurysms, decreases
the likelihood of hemorrhage [31].
Palliative Embolization
In select cases, AVMs may become symptomatic due to vas-
cular steal. In these instances, palliative embolization may
decrease steal, thereby palliating the symptoms (Fig. 49.4)
[32]. Although data in support of this paradigm are limited to
small series, in select cases palliative embolization does result
in improvement in quality of life of the patient [31, 33, 34].
Conclusions
More so than any other lesion, AVMs require an interdisciplin-
ary team with expertise in microsurgery, endovascular emboli-
zation, and radiation therapy. Despite the disappointing results
of the ARUBA trial, mainly due to flaws in study design and
execution, a preponderance of evidence suggests that carefully
selected patients gain benefit from aggressive and timely resec-
tion of AVMs. These lesions should be treated in high-volume
centers where the necessary expertise is available.
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 Radiosurgery for Cavernous
Malformations and Other Vascular
Diseases
Ajay Niranjan, Greg Bowden, John C. Flickinger,
and L. Dade Lunsford
Intracranial Cavernous Malformations
Intracranial cavernous malformations are angiographically
occult malformations of the vascular bed. These abnormal
vascular connections although usually congenital may
enlarge over time from bleeding events or even develop de
novo [1, 2]. The lesions can even occur on a familial basis
[3, 4]. Patients may be asymptomatic, although they often
present with headaches, seizures, or parenchymal hemor-
rhages. Substantial advances in the cellular and molecular
biology of the vasculogenesis, angiogenesis, and cardiovas-
cular physiology of these anomalies along with findings
from detailed clinicopathologic and clinicoradiologic retro-
spective and prospective longitudinal studies have led to a
better understanding of these vascular malformations as a
whole. However, controversy still remains regarding the
treatment options.
Pathophysiology
Cavernous malformations can be found in any part of the
brain because they can occur at any location along the vascu-
lar bed. Most (80–90 %) of the lesions are supratentorial, and
the frontal and temporal lobes are the most common sites.
The deep cerebral white matter, corticomedullary junction,
and basal ganglia are common supratentorial sites, whereas
the pons and cerebellar hemispheres are common posterior
fossa sites.
A. Niranjan, M.D., M.B.A. (*) • G. Bowden, M.D., M.Sc.
Department of Neurological Surgery, University of Pittsburgh
Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA
e-mail: niranjana@upmc.edu
J.C. Flickinger, M.D. • L.D. Lunsford, M.D.
Department of Radiation Oncology, University of Pittsburgh,
5230 Centre Avenue, Pittsburgh, PA 15213, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_50, © Springer Science+Business Media New York 2015
50
Cavernous malformations are considered to be vascular
hamartomas composed of closely approximated endothelial-
lined sinusoidal collections without significant amounts of
interspersed neural tissue. The lack of intervening neural tis-
sue distinguishes these lesions from capillary telangiecta-
sias. De novo pathogenesis may occur spontaneously or in
association with initiating events, such as biopsy, a preexist-
ing venous malformation, or perhaps following radiation
therapy. Pathologically, 9–88 % of cavernous malformations
show evidence of recent and remote hemorrhage depending
on source and bleed criteria [5]. Evidence of this is from
hemosiderin-laden macrophages, cholesterol crystals, and
hemosiderin-stained parenchymal tissues. Cavernous mal-
formations are discrete multilobulated lesions and grossly
resemble small mulberries. Clots and blood products in vari-
ous stages of evolution can be seen within these lesions.
Calcification and gliosis are also often seen. The architecture
of the component vessels consists of a single layer of endo-
thelium and varying quantities of subendothelial fibrous
stroma. Smooth muscle and elastic fibers are absent.
Re-endothelialization of the hemorrhagic cavities, growth of
new blood vessels, and proliferation of granulation tissue
may account for the apparent growth of some cavernous
malformations.
Epidemiology
Cavernous malformations represent approximately 1 % of
intracranial vascular lesions and 15 % of cerebrovascular
malformations although these numbers may be underestima-
tions [6]. In early studies of major autopsy reports, the calcu-
lated prevalence was 0.02–0.53 %. With the advent of MRI,
cavernous malformations are currently the most commonly
identified brain vascular malformations. The detection of
previously unidentified asymptomatic lesions by MRI has
recently raised the estimated overall prevalence to 0.45–0.9 %
[7–9]. Multiple lesions are seen in approximately 15–33 % of
623
624
spontaneous cases, although one series reported an incidence
as high as 50 %. Multiple lesions are more common in the
familial form, occurring in as many as 84 % of patients [4, 10].
The familial form of the disorder is inherited as an autosomal
dominant trait with variable expression. Cavernous malfor-
mations are the most common CNS vascular malformation
subtype in patients with mixed vascular lesions. Associated
developmental venous anomalies (DVAs) are present in
approximately 10–30 % of patients with cavernous malfor-
mations [11].
Molecular Basis
Although most cavernous malformations are believed to be
sporadic, many familial cases have been observed over the
last 2 decades. These cases exhibit an autosomal dominant
pattern of inheritance [12] and seem to affect the Hispanic
population in particular. Recent research has demonstrated at
least three separate genes (CCM1, CCM2, and CCM3)
related to the familial form of the disease. Although research
is still pending, the three CCM protein products appear
involved in new blood vessel stabilization. Linkage analyses
using autosomal dominant families manifesting CCMs have
identified three different causative loci on chromosomes
7q21.2 (CCM1), 7p13 (CCM2), and 3q25.2-q27 (CCM3).
Mutations in the gene Krit1 are responsible for CCM1, muta-
tions in the gene MGC4607 are responsible for CCM2, and
mutations in the gene PDCD10 were recently reported to be
responsible for CCM3. Of familial cavernous malforma-
tions, 40 % can be linked to a protein created by the mutated
CCM1 gene. This is the gene responsible for most of the
cases of familial multiple cavernous malformations in
Mexican-American families and in a number of other fami-
lies. CCM1 is responsible for creating KRIT1 protein or
Krev interaction-trapped one protein. The exact function of
KRIT1 protein is not known. If both copies of the CCM1
gene mutate, the KRIT1 protein cannot function and
cavernous malformations form [13]. CCM2 gene controls
the production of a protein named malcavernin. Of familial
cavernous malformations, 20 % can be linked to a CCM2
mutation [14–16].
Clinical Presentation
Cavernous malformations can occur at any age, but they
are most likely to become clinically apparent in patients
aged 20–40 years. Patients with cavernous malformations
may remain asymptomatic, but they most often present
with headache or neurological symptoms after a hemorrhage
or repeated hemorrhage. Because of the extruded blood
products and the fact that some malformations can enlarge
A. Niranjan et al.
slowly, the lesions may also produce seizures and a variety
of neurological findings similar to those expected of intra-
cranial tumors. Once patients become symptomatic,
40–50 % present with seizures, 20 % present with focal
neurological deficits, and 10–25 % present with hemor-
rhage. Symptoms may progress rapidly, remain stable for
years, or wax and wane. Headache is estimated to be a
symptom in as many as 25 % of patients. Acute headaches
may result from parenchymal irritation secondary to gross
or repeated extralesional hemorrhage. Chronic headaches
could be the result of mass effect in slow-growing larger
lesions as a result of multiple intralesional hemorrhages.
The clinical symptoms usually result from the location of
the lesion and, at times, their slow expansion. Infratentorial
location and previous gross hemorrhage are associated with
an increased risk of subsequent and progressive neurological
disability. Large hemorrhages can cause both obstructive and
nonobstructive hydrocephalus. Any hemorrhage found on CT
scans in a relatively young patient should be investigated
further, and cavernous malformation must be considered a
possible etiology. In the workup of a patient with a seizure
disorder, cavernous malformation must be considered as a
potential cause, especially if the patient is aged 20–40 years.
The bleeding rate is estimated to be 0.5–2.5 % per lesion-year
and 0.25–16.5 % per patient-year [11]. This risk is increased
in patients with established prior hemorrhage. A study at the
University of Pittsburgh concluded that in patients who had
at least one prior hemorrhage, the subsequent annual risk of
hemorrhage was 33.9 %. After the first bleed, annual hemor-
rhage rates in years 1–5 were 52 %, 35 %, 39 %, 24 %, and
32 %, respectively [17]. In addition, women are at a slightly
higher risk for hemorrhage, especially. However, pregnancy
does not appear to change the rate of hemorrhage events com-
pared to natural history [18, 19]. The hemorrhage is rarely
life-threatening. Hemorrhages in critical locations can have
more severe effects, and thus, they are more likely to produce
symptoms. Progressive neurological deficits are more often
associated with cavernous malformations in the infratentorial
space and with lesions that demonstrate slow enlargement
because of rebleeding episodes.
Radiologic Features
Although cavernous malformations can be diagnosed using
CT scans, MRI is the modality of choice for the long-term
follow-up of patients as well as the assessment of family
members in whom similar lesions are suspected. Cavernous
malformations can be divided in three components: the
peripheral pseudocapsule composed of gliotic hemosiderin-
laden tissue, the irregular intersecting connective tissue
septa separating the sinusoidal spaces, and the central vas-
cular area composed of slow-flowing sinusoidal spaces [20].
50 Radiosurgery for Cavernous Malformations and Other Vascular Diseases
MRI findings of parenchymal cavernous malformations
demonstrate typical, popcorn-like, well-circumscribed,
well-delineated lesions. The core is formed by multiple foci
of mixed signal intensities, which represents hemorrhage in
various stages of evolution. Acute hematoma containing
deoxyhemoglobin is isointense on T1-weighted images and
markedly hypointense on T2-weighted images. Subacute
hematoma, which contains extracellular methemoglobin,
displays hyperintensity on both T1- and T2-weighted images
because of the paramagnetic effect of the methemoglobin.
The interspersed fibrous-containing elements demonstrate
mild hypointensity on both T1- and T2-weighted images
because they contain a combination of calcification and
hemosiderin. The heterogeneous core typically is sur-
rounded completely by a low-signal-intensity hemosiderin
rim on T1-weighted images. The hypointensity of this rim
becomes more prominent on T2-weighted images because
of the magnetic susceptibility effects. Smaller cavernous
malformations may appear as focal hypointense nodules
with both T1- and T2-weighted sequences. Typically, cav-
ernous malformations are not associated with mass effect or
edema and do not demonstrate a feeding artery or draining
vein, except when associated with other vascular malfor-
mations. Cavernous malformations can be associated with
DVAs, which typically demonstrate a prominent medullary
vein with the classic caput medusae pattern of drainage.
MRI has largely replaced conventional angiography in the
diagnosis of cavernous malformations. However, when the
lesions occur in combination with other types of vascular
malformations, as they do in as many as 30 % of patients,
MRI characteristics become more complicated and less spe-
cific. In these patients, angiography can help further define
the lesions. Because of the extremely slow flow of blood
through these lesions, cerebral angiograms are often normal.
Most cavernous malformations (37–48 %) are avascular
masses on conventional angiograms. The avascular appear-
ance is the result of compression or destruction of vascular
channels by hemorrhage, thrombosis, and generalized slow
flow because of the small size of the connecting sinusoidal
vessels with the peripheral normal parenchymal vessels.
When lesions are smaller and not associated with hemato-
mas, 20–27 % of angiograms demonstrate normal findings.
Capillary blush which is not a specific finding is demon-
strated at 12–20 % [21].
Management Options
When a patient is diagnosed with a cavernous malformation,
the reason that led to the detection of the lesion must be fac-
tored into the final decision as to what, if any, treatment
should be offered. Severe complications can occur after treat-
ment of lesions in critical locations in the brain and brainstem.
625
The rate of these complications must be carefully balanced
against the natural history of the lesion itself (Table 50.1)
[2, 4, 7, 10, 11, 22–25]. It is important to ascertain the pres-
ence of DVAs, as these are composed of functional venous
channels that should not be resected or radiated because of
the risk for venous infarction. Increasingly, DVAs are identi-
fied in association with cavernous malformations [6].
In older patients or patients with low-risk lesions which
are difficult to reach surgically, observation with periodic
imaging may be appropriate. When patients present with
recurrent hemorrhage, progressive neurological deteriora-
tion, or intractable epilepsy, then treatment in the form of
surgery or radiosurgery should be considered. The manage-
ment options for a patient with a cavernous malformation
must be based on age, symptoms, hemorrhage risk, and loca-
tion, especially as it relates to surgical accessibility. Resection
clearly provides immediate advantages for accessible lesions
and complete resection is achieved in 91 % (62 % bleed
rate in partially resected lesions) [26]. However, surgery on
average has a 45 % postoperative and 15 % long-term mor-
bidity [26]. These results can be much higher when resection
of deep-seated lesions is conducted (Table 50.2) [27–33].
For younger patients with more accessible lesions, the
removal of lesions may help control epilepsy, improve neu-
rological deficits, and prevent any subsequent hemorrhage.
Radiosurgery is a minimally invasive option for patients
presenting with recurrent hemorrhages from deep-seated
cavernous malformations.
The Role of Radiosurgery
The successful management of cerebral AVMs with stereo-
tactic radiosurgery prompted the exploration of its role in the
management of cavernous malformations. The benefits of
radiosurgery for cavernous malformations are difficult to
assess because of its unclear natural history and the lack of
an imaging technique that can document a “cure.” The role
of radiosurgery in this disease is still considered controver-
sial by many physicians. However, the lack of options for
surgically inaccessible cavernous malformations has made
radiosurgery a possible alternative to conservative manage-
ment for lesions with a high risk of symptomatic bleeding
(Table 50.3) [17, 34–40].
Dose Planning Technique for Cavernous
Malformation Radiosurgery
All patients must have stereotactic magnetic resonance imag-
ing. We prefer contrast-enhanced MRI using gradient
recalled acquisitions (1-mm slice thickness) supplemented
with T2-weighted sequences. The malformation is defined as
626 A. Niranjan et al.

Table 50.1 Natural history of cavernous malformations

First author Patients FU length Lesion location Clinical presentation Annual bleeding risk Comment
Robinson 66 patients 26 months Supratentorial: 55 Seizures: 34 patients 0.7 % per lesion – HRG common in
[7] (1991) patients female and in
Deep: 4 patients Focal deficit: 30 patients infratentorial lesions
Cerebellar: 9 patients HRG: 6 patients
Brainstem: 8 patients Incidental: 9 patients
Zabramski 31 patients 2.2 years Supratentorial: 92 % Symptomatic: 61 % HRG + symptom: 6 % – Developed new
[4] (1994) Multi: 84 % Infratentorial: 8 % Incidental: 39 % HRG overall: 13 % cavernoma: 29 %
Aiba [22] 110 4.71 years Supratentorial: 65 % HRG: 62 patients Re-HRG: 22.9 % per – Younger and female
(1995) patients lesion patients had higher
Deep: 11 % Seizures: 25 patients HRG risk
Brainstem: 18 % Incidental: 23 patients
Kondziolka 122 34 months BG/thalamus: 17 % HRG = 1: 41 % Total: 2.6 % – No influence on
[23] (1995) patients location, sex, and
Multi: 20 % Brainstem: 35 % HRG > 1: 9 % No HRG: 0.6 % number on HRG risk
Seizures: 23 % Previous HRG: 4.5 %
Porter [2] 173 46 months Superficial: 109 HRG: 25.4 % 4.2 % annual rate – Significantly greater
(1997) patients patients
Multi: 17.9 % Deep: 64 patients Seizure: 35.8 % 10.6 % deep location Bleed rate for deep
Neurological deficit: 20.2 % ~37 % recovered from
Incidental: 12.1 % new deficits
Labauge 40 patients 3.2 years Supratentorial: 176 HRG: 19 patients 11 % per patient – 1/3 bleeds,
[11] (2000) symptomatic
Multi: 93 % Cerebellar: 30 Seizures: 12 patients 2.5 % per lesion – 27.5 % of patients
develop new lesions
Brainstem: 26 Focal signs: 4 patients
Kupersmith 37 patients 4.9 years – 12 midbrain HRG: 73 % 2.5 % per patient – Young patient with
[24] (2011) – 18 pons Mass effect only: 22 % 5.1 % rebleeding risk lesion of >10 mm had
– 7 medulla Asymptomatic: 5 % higher risk of HRG
Al-Holou 92 patients 3.5 years Supratentorial: 75 Acute symptoms: 17 HRG: 1.6 %/year – Brainstem location
[10] (2012) patients patients
Multi: 30 % Infratentorial: 1 Chronic symptoms: 5 Re-HRG: 8 %/year and age increased
patient patients
Incidental: 34 0.2 % if incidental bleed rate
Salmon 139 5 years Lobar: 67 % Incidental: 47 % HRG: 2.4 %/year – Risk declines over
[25] (2012) patients
Multi: 17 % Brainstem: 14 % Seizure: 25 % Re-HRG: 29.5 %/year 5 years and is higher
Cerebellum: 13 % HRG: 12 % HRG year 1: 19.8 % for women
Deep structures: 6 % Neurological deficit: HRG year 5: 5 %
15 %
HRG hemorrhage, ARE adverse radiation effect, BG basal ganglia

the region characterized by mixed signal intensity within an
outer hemosiderin ring, typified by low signal intensity.
Hematoma eccentric from the malformation is excluded
from dose planning. The prescription isodose covers the
mixed signal intensity malformation but not the low-signal-
intensity region surrounding it. Targeting within the MRI-
defined T2 signal hemosiderin rim is very important because
radiation delivered to the iron-impregnated gliotic brain sur-
rounding the CM may increase the risk of adverse radiation
effects if this area is included in prescription isodose [41].
Single or multiple isocenter dose plans are used to construct
a conformal irradiation volume that matches the malforma-
tion margin (Fig. 50.1). The 50 % or greater isodose is used
to prescribe margin dose. Associated DVAs are excluded
from dose planning (Fig. 50.2). Selection of the radiosurgery
dose is dependent upon malformation volume and brain
location. Typically, the dose is less than that used for AVMs
of similar volumes. The margin dose to the cavernous mal-
formation margin varies from 12 to 20 Gy, which is depen-
dent upon the brain volume and location. Patients usually
receive a single dose (40 mg) of methylprednisolone at the
conclusion of the radiosurgery procedure and, if pertinent,
maintain their current dose of antiepileptic medication.
Follow-up imaging studies and clinical evaluations are
requested at 6-month intervals for the first 2 years following
radiosurgery and then annually (Fig. 50.3).
50 Radiosurgery for Cavernous Malformations and Other Vascular Diseases 627

Table 50.2 Summary of reports on resection of deep-seated cavernous malformations

Immediate postoperative
First author Patients Location Presentation outcome Long-term outcome
Steinberg [27] 56 patients Brainstem: 42 HRG: Average of 2.1 16 % improved 43 % improved
(2000) Thalamus: 5 55 % stable 52 % stable
Basal ganglia: 10 29 % worse 5 % worse
No death 4 patients had
re-HRG
Mathiesen [28] 68 patients Basal ganglia: 11 Varied with location 25/29 complete Re-HRG: 4 partial
(2003) resection resections
Thalamus: 12 HRG 1 or 2: 68 patients 69 % neuro-decline 20 patients improved
Mesencephalon: 5 Only 2 (5 %) permanent (10 patients intact)
Pons: 31 4 stable, 5 worse
Medulla: 5 1 died of rebleed
Wang [29] (2003) 137 Midbrain: 29 HRG = 1: 45 patients 131/137 total resection Re-HRG: 3 partial
patients resections
Pons: 85 HRG > 1: 58 patients 72.3 % stable or improved Death: 1
Medulla: 19 HRG 3 or more: 34 27.7 % new deficits 7.8 % living
patients dependently
Cerebellar peduncle: 8 60 % annual rebleeding
Ferroli [30] 52 patients Medulla: 7 HRG = 1: 32 patients 4 repeat surgeries 19 % permanent
(2005) Pontomedullary: 3 HRG > 1: 18 patients 29 patients stable deficits
Pons: 31 No HRG: 2 patients 23 patients worse
Pontomesencephalic: 3 HRG: 3.8 % annual risk 1 death
Midbrain: 6 Re-HRG: 34.7 % annual
Hauck [31] (2009) 44 patients Pons: 25 HRG = 1: 20 patients Improved: 30 % Residual: 1
Midbrain: 11 HRG > 1: 23 patients Stable: 59 % Re-HRG: 2 patients
Medulla: 8 Worse: 11 % Revisions: 8 patients
Abla [32] (2011) 260 Pons: 112 HRG: 252 patients New deficits: 53 % Death: 3
patients Medulla: 29 New deficits: 7 patients Residual lesion: 29 New deficit: 36 %
Midbrain: 49 Re-HRG: 7.7 Improved: 45 %
Pontomedullary: 40 Died: 2 Re-HRG: 2.0 %
Pontomesencephalic: 31
Pandley [33] 176 Pons: 94 HRG = 1: 70 patients Second operation: 17 Death: 3
(2012) patients patients
20 pediatric Midbrain: 28 HRG > 1: 102 patients New deficit: 31.3 % Improved: 61.8 %
Medulla: 14 Seizure: 4 patients Improved: 19.9 Stable: 25.9 %
BG/thalamus: 43 Re-HRG: 5 patients
HRG hemorrhage, ARE adverse radiation effect, BG basal ganglia

Results of Cavernous Malformation cavernous malformations. Kondziolka et al. reported the

Radiosurgery
The results of multiple studies indicated that radiosurgery is an
option for some patients with deep-seated cavernous malfor-
mations. Kida et al. reported 20 cases of symptomatic angio-
graphically occult vascular malformations treated using
radiosurgery [42]. Among 20 lesions, 14 were located supra-
tentorially, 4 in the brainstem, and 2 in the cerebellar hemi-
spheres. The lesions were treated using 15–20 Gy at the lesion
margins. These investigators reported a significant reduction
of rebleeding risk, as well as improvement in seizure control.
Adverse effects were generally mild and well controlled by
medication. Thus, the preliminary results indicated a certain
usefulness of radiosurgery in the treatment of symptomatic
results of radiosurgery in 47 patients who harbored a hemor-
rhagic malformation in a critical intraparenchymal location
[43]. Of these, 44 patients had experienced at least two hemor-
rhages before radiosurgery. At a mean follow-up of 3.6 years
after radiosurgery, these authors reported significant reduc-
tions in the proportion of patients with hemorrhage and the
mean number of hemorrhages per patient. The annual hemor-
rhage rate in the first 2 years after radiosurgery was 8.8 %
which further decreased to 1.1 % in the 2- to 6-year interval
after radiosurgery. After radiosurgery, 12 patients (26 %) sus-
tained neurological worsening, of which eight improved on
medications, two underwent surgical resection and died, and
two had new permanent deficits. This study provided further
support for the role of radiosurgery in selected patients.
628 A. Niranjan et al.

Table 50.3 Summary of some recent Gamma Knife radiosurgical series of cavernous malformations
First author Patients/FU Location Presentation Dose/volume Outcome Morbidity
Karlsson 22 patients Cortical: 8 HRG: 16 patients Margin: 18 Gy Post-GK HRG rate: ARE: 6 patients
[34] (1998) (9–35) 8 %/year
Deep cerebral: 7 Epilepsy: 6 patients – Years 1–2: 10 % – 5 symptoms
GK 6.9 years Brainstem: 6 Prior resection: 1 – Years 3–4: 12 % Onset 16 months
patient
Cerebellum: 1 – Years 5–6: 5 %
– Years 7–8: 7 %
Hasegawa 82 patients Supratentorial: HRG: 82 patients Margin: 16.2 Gy HRG: 12.3 % first 2 ARE: 11 patients
[17] (2002) 16 (1–7 bleeds) (12–20) years
Deep: 13 HRG rate: 33.9 %/ HRG: 0.76 % years None after 1992
year 2–12
GK 4.89 years Brainstem: 52 Prior surgery: 20 Vol.: 1.85 cm3
patients (0.12–6.98)
Liu [35] 125 patients Brainstem: 49 HRG: 112 patients Margin: 12.1 Gy HRG rate: 6.5 %/year ARE: 13.1 %
(2005) (9–20)
BG/thalamus: 14 HRG >1: 45 HRG: 10.3 % first 2 Symptoms: 2.5 %
patients years
GK 5.4 years Cortical: 39 HRG rate: 29.2 %/ Vol.: 3.12 cm3 HRG: 3.3 % after
year (.032–25.9) year 2
Cerebellum: 10 Seizures: 28
patients
Kim [36] 42 patients Cortical: 21 HRG: 26.6 % Margin: 14.55 Gy Seizure cessation: Edema: 5 patients
(2005) (10–25) 75 %
Brainstem: 6 Seizures: 28.6 % – Mean of – Symptoms: 5
31.3 months patients
GK 29.6 months Basal ganglia: 5 Neurological HRG: 1 – Recovered: 5
deficit: 45.2 % patients
Liscak [37] 112 patients Brainstem: 33 HRG in 59 patients Margin: 16 Gy HRG rate: 1.6 %/year Edema: 30
(2005) (9–36) patients
Cortical: 54 Seizures in 40 Vol.: 0.9 cm3 – 2 deaths from – Symptoms: 17
patients (0.06–12.5) HRG patients
GK 48 months BG/thalamus: 17 Neurological Neurological deficits: – Recovered: 16
deficit: 51 patients 33 % improved patients
Cerebellum: 8 7 patients prior
partial resection
Nagy [38] 113 patients Brainstem: 79 HRG high risk >1: Margin: 12–15 Gy High risk <2 years: ARE: 6 symptoms
(2010) 41 patients (10–20) 15 %/year
BG/thalamus: 39 HRG low risk <1: Vol.: High risk >2 years:
54 patients 0.33–0.83 cm3 2.4 %/year
GK 48 months Neurological deficit Low risk <2 years:
high risk: 72 % 5.1 %/year
Neurological deficit Low risk >2 years:
low risk: 43 % 1.3 %/year
HRG pre GK:
30.5 %/year
Lunsford 103 patients Brainstem: 66 HRG >1: 103 Margin: 16 Gy HRG <2 years: ARE: 19 patients
[39] (2010) patients (12–20) 10.8 %/year
BG/thalamus: 27 HRG pre GK: Vol.: 1.31 cm3 HRG > 2 years: 1 %/ Symptoms: 12
32.5 %/year year patients
GK 67.8 months Deep lobar: 10 Seizures: 8 patients 75 % seizure
cessation
Lee [40] 49 patients Pons: 34 HRG >1: 49 Margin: 11 Gy HRG <2 years: ARE: 3 patients
(2012) patients (9–15) 3.33 %/year
Midbrain: 10 HRG pre GK: Vol.: 3.2 cm3 HRG > 2 years: Symptoms: 2
31.3 %/year 1.74 %/year patients
GK 40.6 months Medulla: 3 Neurological Cyst: 1 patient
deficits: 49 patients
HRG hemorrhage, Vol. volume, ARE adverse radiation effect, BG basal ganglia
50 Radiosurgery for Cavernous Malformations and Other Vascular Diseases 629

Fig. 50.1 Gamma Knife radiosurgery dose plan for cavernous malfor- struction covers the malformation but stays within the low-signal
mation of the brainstem. Fifty percent 14-Gy isodose line projected on region. An 8-Gy line is also present for perspective
axial contrast-enhanced MR images with sagittal and coronal recon-

Fig. 50.2 Gamma Knife radiosurgery dose plan for cavernous malfor- MR images with sagittal and coronal reconstruction covers the malfor-
mation of the left thalamus with a history of multiple symptomatic mation. Multiple developmental venous anomalies were noted
bleeds. Fifty percent isodose line projected on axial contrast-enhanced
630
Fig. 50.3 A 28-year-old female presented with history of two hemor-
rhagic episodes from cavernous malformation in her anterior right
pons. Axial MR gadolinium-enhanced MR (left) has shown pontine
cavernous malformation at the time of radiosurgery. A margin dose of
Pollock et al. evaluated the efficacy and safety of
radiosurgery for patients with cavernous malformations [44].
Seventeen patients underwent radiosurgery for high-surgical-
risk cavernous malformations that were located in eloquent
regions (the thalamus/basal ganglia, brainstem, and corpus
callosum). All patients had at least two documented hemor-
rhages before undergoing radiosurgery. The median margin
radiation dose was 18 Gy and the median maximum dose
was 32 Gy. The annual hemorrhage rate during the 51 months
preceding radiosurgery was 40.1 %, compared with 8.8 % in
the first 2 years following radiosurgery and 2.9 % thereafter.
These investigators reported a high (41 %) permanent
radiation-related morbidity rate with 18 Gy as margin dose.
Hasegawa et al. studied outcome of Gamma Knife radio-
surgery for 82 symptomatic patients who had imaging-
confirmed hemorrhages for which resection was believed to
be associated with high risk [17]. Most patients had multiple
hemorrhages from the brainstem or diencephalic cavernous
malformations. During an observation of 354 patient-years
prior to radiosurgery, 202 hemorrhages were observed, for an
annual hemorrhage rate of 33.9 %, excluding the first hemor-
rhage. After radiosurgery, during a total of 401 patient-years,
19 hemorrhages were identified, of which 17 occurred in the
first two posttreatment years, and only two after 2 years had
elapsed. The annual hemorrhage rate was 12.3 % per year for
the first 2 years after radiosurgery. The annual hemorrhage
rate dropped to 0.76 % per year after 2 years. Eleven patients
developed new neurological symptoms without hemorrhage
after radiosurgery (13.4 %). The symptoms were minor in six
of these patients and temporary in five. These investigators
concluded that radiosurgery conferred a reduction in the risk
of hemorrhage for high-risk cavernous malformations. This
reduction was most pronounced after 2 years [17].
A. Niranjan et al.
16 Gy was delivered to 50 % isodose line (middle). A 4-year follow-up
MRI shows regression in cavernous malformation with stable appear-
ance of the brainstem
Kim et al. evaluated the efficacy of radiosurgery in
symptomatic cavernous malformations for which the surgical
risk was thought to be unacceptable. These investigators
treated the first 11 cases with LINAC radiosurgery using
CT-based planning and the next 11 cases with GK radiosur-
gery using MR-based planning. The volume of the lesion
ranged from 0.09 to 4.8 cm3 (mean, 1.42 cm3) and the mean
marginal dose was 16.1 Gy (range, 8–24 Gy). The median
follow-up period after radiosurgery was 38.3 months. In the
group with prior hemorrhage, the bleeding rate of cavernous
malformation after radiosurgery (1.55 %/year) was lower
than that during the pre-radiosurgical period (35.5 %/year).
Six patients showed neurological deterioration following
radiosurgery; however, the neurological deficits persisted in
only two of the patients treated with LINAC. These authors
suggested a possible correlation of LINAC radiosurgery with
radiation-induced neurological deficits. The size of the
lesion decreased in 11 patients, increased in one, and did not
change in ten cases. A perilesional hyperintense signal on
T2-weighted MR images was seen in nine patients and
correlated with the treatment modality used, being more fre-
quent after LINAC radiosurgery [45]. Kim et al. evaluated
42 cavernous malformation patients treated with Gamma
Knife surgery with 14.55 Gy as mean margin dose [36]. The
mean follow-up period after radiosurgery was 29.6 months
(range, 5–93 months). The tumor decreased in size in 29
cases, was unchanged in 12, and increased in size in one. In
the seizure group, seizures were controlled without anticon-
vulsant medication in nine cases (81.8 %) after 31.3 months.
Rebleeding occurred in only one case (2.3 %). On
T2-weighted imaging, changes were seen in 11 cases
(26.2 %), and neurological deterioration was correlated with
imaging changes in three (7.1 %). These authors concluded
50 Radiosurgery for Cavernous Malformations and Other Vascular Diseases
that patients who receive a marginal dose below 15 Gy had
better outcome than those treated with higher doses [36].
Liscak et al. followed 107 patients treated with Gamma
Knife radiosurgery using an average of 16-Gy margin dose
[37]. After a median of 48 months, lesion regression was
observed in many patients. These authors reported a tran-
sient morbidity (rebleeding and edema) rate of 20.5 % and
permanent morbidity rate of 4.5 % [37].
Nagy et al. published on 113 patients with primarily
brainstem and thalamic lesions that were followed over a
mean of 48 months [38]. This group demonstrated a hemor-
rhage rate of 30.5, which is compatible with other recent
studies [40]. They separated malformations into high and
low risk based on whether they had greater than 1 bleed pre-
viously. The higher-risk group had a hemorrhage rate of
15 % for 2 years that decreased to 2.4 % after that time. The
low-risk group had 5.1 and 1.3 % risks for the first 2 years
and beyond, respectively. Adverse symptomatic outcomes
were observed in six patients. This demonstrates the hetero-
geneity of cavernous malformation activity and impact of
previous bleeds. Lundsford et al. presented a review of 103
patients with deep lesions, including 65 % within the brain-
stem [39]. Two or more bleeds were required and pre Gamma
Knife bleed rate was 32.5 %. The 67.8-month follow-up
demonstrated a 10.8 % hemorrhage rate in the first 2 years
which decreased to 1 % per year after that point.
One of the most frequent presentations of cavernomas is
seizure. The ability to control these episodes or eliminate
them is a major impetus for treatment. Baumann et al. pro-
vided information from the surgical perspective by analyzing
168 patients who underwent resection for supratentorial soli-
tary cavernous malformations with at least three prior sei-
zure episodes [46]. At 3 years 65 % of patients were seizure
free and on no medication (Engel 1); these results were
roughly in context with results seen by other sources [47].
Lunsford et al. and Kim et al. have both published from the
Gamma Knife perspective with results of 75 % of patients at
Engel 1 at 3.6 years and 31.3 months, respectively [36, 39].
These results are based on a combined 20 patients.
Radiobiological Considerations
Post-radiosurgery AVM obliteration is likely due to endothe-
lial cell proliferation leading to vessel wall hyalinization,
fibrosis, and myofibroblast-induced vessel wall contracture.
We believe that the response of cavernous malformation to
irradiation is similar. It is reasonable to expect a latency
interval of several years for hemorrhage protection as it
occurs before AVM obliteration. At present, there are no
good histologic studies of irradiated cavernous malforma-
tions in patients who were thought to be successfully man-
aged. Histologic studies of irradiated patients who later
underwent cavernous malformation resection could not draw
631
any conclusion regarding the mechanism of efficacy [48].
However, a recent case report suggests that the histopatho-
logical findings after irradiation on these lesions may be
similar to those described in arteriovenous malformations
after Gamma Knife surgery [49].
A significant number of centers have published data indi-
cating a significant decrease in the symptomatic hemorrhage
rate following stereotactic radiosurgery of cerebral cavern-
ous malformations [38, 40, 50–52]. This demonstrates that
this technique may be an effective management strategy for
patients with hemorrhagic malformations in high-risk
brain locations when administered by skilled personnel.
The patients that were selected for radiosurgery harbored
malformations with a rate after two hemorrhages of
30–32.5 % annual risk for another symptomatic event in con-
trast to a 0.6 % annual risk in those who had not had a prior
symptomatic hemorrhage [38–40]. There is a subset of
patients who seem to bleed more frequently than others [22,
23, 53]. The reduced hemorrhage rate achieved after a 2-year
latency from radiosurgery (1 %) approaches the low risk
(0.6 %) identified in many natural history studies for
nonhemorrhagic cavernous malformations. The probability
of developing post-radiosurgery imaging changes compati-
ble with ARE depends on the CM marginal dose and treat-
ment volume. The volume of tissue receiving 12 Gy or more
(the 12-Gy volume) provides predictive information about
the probability of developing such imaging changes [41]. In
addition, care must be taken to achieve a highly conformal
treatment area and use caution around the hemosiderin depo-
sition zone at the edge of the cavernous malformation.
All reports on cavernous malformation radiosurgery are
based on clinical outcome because cavernous malformation
obliteration cannot be documented using any of the available
imaging modality. Without this documentation, patients can-
not be declared as “cured” after radiosurgery. Although
patients may be encouraged by a reduction in hemorrhage
risk, they cannot be told that this risk is eliminated. Even
though radiosurgery significantly lowers the risk of hemor-
rhage, there can be complications. The complex natural his-
tory of cavernous malformations (solitary, multiple, and de
novo) makes clarity even harder to obtain. These risks and
benefits must be carefully balanced against the natural history
of untreated lesions if the use of radiosurgery is considered.
Radiosurgery for Other Vascular
Abnormalities
Dural Arteriovenous Fistulas
Dural arteriovenous fistulas (AVFs) represent approximately
10–15 % of all intracranial vascular abnormalities [54]. They
are direct connections between the meningeal arterial system
and dural venous sinuses or cortical veins. Most are thought
632
Fig. 50.4 Cerebral angiogram revealed a dural vascular malformation to
the sigmoid sinus. This malformation was treated with radiosurgery fol-
lowed by embolization. Radiosurgery dose planning was performed on
to be acquired lesions, secondary to dural venous channel
occlusion leading to recruitment of collateral blood supply.
Trauma, infection, and hypercoagulable states are risk fac-
tors for the development of dural AVFs. The majority involve
the transverse, sigmoid, and cavernous sinuses. These are
generally low-flow lesions, which present with bruits and
pulsatile tinnitus. Cavernous sinus lesions can also present
with chemosis and ophthalmoplegia and, eventually, lead to
loss of vision. Other notable locations include the superior
sagittal sinus and tentorium, and these tend to follow a more
aggressive course. Regardless of their locations, dural AVFs
can cause subarachnoid or intraparenchymal hemorrhage.
The bleeding risk is related primarily to the presence of lep-
tomeningeal venous drainage, dural sinus occlusion, and
aneurismal venous dilation [55].
Dural AVFs can be classified based on the pattern of
venous drainage and patency of dural sinus involved [56].
Type I fistulas drain in an anterograde fashion in a patent
dural sinus. Type IIa fistulas drain retrogradely in an
A. Niranjan et al.
MR images supplemented with cerebral angiograms. Gamma plan shows
dose plan projected on axial MR poster with sagittal and coronal recon-
struction. A margin dose of 20 Gy was delivered to 50 % isodose line
obstructed sinus, while type IIb fistulas drain retrogradely
into leptomeningeal veins through a venous sinus. Type
IIa + b combines the features of both previous categories.
Type III fistulas involve direct connections between menin-
geal arteries and cortical veins, without intervening dural
sinus. Type IV is the same as type III, with added variceal
dilation of the cortical veins. Type V represents a fistula
draining into perimedullary veins. The risk of bleeding
increases directly with the fistula grade for types I–IV. Type
V fistulas usually present with myelopathy.
Treatment of dural AVFs varies according to the location
and grade of the lesion. Endovascular embolization through a
transarterial or transvenous route is the mainstay of treatment
for simple, low-flow lesions involving the transverse-sigmoid
or cavernous regions, with high cure rates [57]. High-risk
lesions are usually treated with multimodality management
comprising embolization and microsurgery. Stereotactic
radiosurgery has emerged as a minimally invasive adjunct or
alternative management modality for AVFs (Fig. 50.4).
50 Radiosurgery for Cavernous Malformations and Other Vascular Diseases
Yang et al. published results out of Pittsburgh on 40
patients treated for 44 dural AVFs [58]. The average volume
was 2.0 cm3 and the median dose was 21 Gy. Three groups
were examined: Gamma Knife therapy alone, Gamma Knife
with embolization performed together, and delayed Gamma
Knife after previous embolization. The follow-up was 45
months and 28 patients with 32 dural AVFs demonstrated
obliteration. Gamma Knife alone had an obliteration rate of
67 %. When coupled with embolization, 83 % was achieved.
The delayed radiosurgery group saw results of 71 % likely
due to difficulty identifying peripheral areas treated with
embolization material. The authors came to the conclusion
that small low-flow dural AVFs could be managed with
Gamma Knife radiosurgery alone if necessary [58].
Hanakita et al. performed a retrospective analysis of 22
patients treated with Gamma Knife radiosurgery [59]. Fifty-
five percent of patients had obliteration of their dural AVF
within 5 years. The obliteration rate without cortical venous
drainage was 86 %, but only 47 % with cortical drainage. No
hemorrhages or complications were identified. They indi-
cated that Gamma Knife is a viable option in the multidisci-
plinary but should be considered carefully when cortical
venous drainage is present.
Koebbe et al. described 18 dural AVF patients managed
with Gamma Knife radiosurgery [60]. Three patients pre-
sented with intracerebral hemorrhage. Embolization was
performed in ten patients (prior to radiosurgery in nine and
after in two patients). Margin dose ranged from 15 to 30 Gy
(mean, 20 Gy). The mean nidus volume was 2.16 cm3.
Complete resolution of symptoms was seen in nine patients,
with the nine others experiencing significant symptom
reduction. Follow-up imaging demonstrated fistula oblitera-
tion in 12 patients (eight on angiography and four on MRA)
and decrease in size in three patients. Three patients did not
have follow-up imaging. No further hemorrhage was seen
after the Gamma Knife procedure. One patient experienced
transient symptomatic radiation-induced edema, and two
patients with cavernous sinus fistulas had a permanent com-
plication from embolization (facial numbness and sixth
nerve palsy). Clinical outcomes were better for patients
treated with radiosurgery alone compared to the combined
treatment.
Friedman et al. reported the outcome of 23 patients with
transverse-sigmoid fistulas treated with combined radiosur-
gery followed by transarterial embolization in most cases
[61]. Symptoms completely resolved in 87 % of patients,
with 9 % also experiencing significant relief. Out of 17
patients who had follow-up angiography, seven (41 %) were
cured, four (24 %) had more than 90 % obliteration, and six
(35 %) had more than 50 % obliteration of the fistula. No
patient had radiation-induced complication and one patient
suffered a transient embolization-related ischemic episode.
Two patients had ischemic events following diagnostic angi-
ography (transient in one case and permanent in the other).
633
Pan et al. published the results of Gamma Knife radio-
surgery as primary treatment of patients (n = 20) with
transverse-sigmoid AVFs [62]. Tinnitus and headache were
the most common symptoms. Three patients had previously
bled. Two patients had failed prior surgery and embolization.
Marginal doses ranged from 16.5 to 19 Gy. Complete oblit-
eration associated with resolution of symptoms was seen in
58 %, with an additional 16 % having near-total occlusion
after median follow-up of 19 months. Temporary hair loss
over the mastoid region was the only adverse effect of irra-
diation, seen in ten patients.
Pollock et al. managed 20 patients with cavernous sinus
fistulas using radiosurgery alone (seven patients) or fol-
lowed by embolization (13 patients) [63]. Clinical symp-
toms improved in 95 % of patients. Follow-up angiogram
was obtained for 15 patients and demonstrated total oblit-
eration in 13 and near-total in one patient. No subsequent
hemorrhage occurred. Morbidity was seen in two patients
following embolization procedures. Finally, Lewis et al.
reported the results of transarterial embolization followed
by LINAC radiosurgery (seven patients) or surgery (two
patients) in a cohort of patients with high-risk tentorial dural
AVFs [64]. Five patients had experienced prior hemorrhage.
In the radiosurgical group, dose delivered ranged from 8 to
20 Gy (mean, 15.6 Gy). Four of seven patients showed com-
plete thrombosis of the lesion 24 months after the procedure,
and the others had significant occlusion. One patient suffered
from transient radiation injury to the brainstem 14 months
after radiosurgery.
The outcome data suggests that stereotactic radiosurgery
provides significant benefit in the management of dural AVFs.
The obliteration rate is high with minimal radiation-induced
morbidity. It is a valuable addition in the multimodality man-
agement of high-risk dural AVFs and also as primary treat-
ment of low-flow dural AVFs of the transverse, sigmoid, and
cavernous regions, with or without adjunct embolization.
Radiosurgery followed by embolization appears to be a sound
strategy for patients with bothersome symptoms such as tin-
nitus. Radiosurgery should be performed first because the
whole nidus can be better defined and treated prior to emboli-
zation. It is followed by embolization, which can provide
immediate relief from acute symptoms.
Vein of Galen Malformations
Vein of Galen malformations (VGMs, also known as vein of
Galen aneurysms) are rare vascular abnormalities that are
usually found in the pediatric population. They constitute
approximately 1 % of all intracranial vascular malformations
[65]. They are direct fistulous connections between the cere-
bral arterial vasculature and the galenic venous system, often
associated with straight sinus stenosis or occlusion and per-
sistence of a falcine sinus. Clinical presentation is dependent
634
on the age at which it manifests. Neonates usually show
signs of overt high-output cardiac failure, while older patients
can present with hydrocephalus or intracranial hemorrhage.
Yasargil classified VGM into four different types based on
the arterial supply of the fistula [66]. Type I malformations
are direct anastomosis between branches of the distal poste-
rior cerebral artery or the pericallosal artery and the vein of
Galen. Type II malformations constitute connections between
thalamoperforating arteries and the vein of Galen. Type III
combines the features of types I and II. Type IV malforma-
tions are classic parenchymal AVMs with venous drainage in
the galenic system and are not true VGM.
Treatment of VGM usually consists of staged endovascu-
lar embolization, with the intent of progressively reducing
the arteriovenous shunt and avoiding complications of cere-
bral venous congestion. Neonates with cardiac decompensa-
tion need to be medically stabilized and have urgent
treatment, but elective embolization can be done for stable
patients. Microsurgery is technically demanding and is best
reserved for type I and simple type III malformations which
are not amenable to endovascular procedures [67].
There have been few reports of radiosurgical management
of VGM. Watban et al. reported three infantile cases which
were successfully obliterated by transarterial embolization
18–24 months after having failed radiosurgery [68]. Margin
doses used varied from 20 to 25 Gy. Payne et al. studied the
outcomes of Gamma Knife radiosurgery in a series of nine
patients with VGM [69]. The population consisted of eight
children (aged from 4 to 14 years) and one adult. Four
patients presented with hemorrhage, two with increased head
circumference, two with headaches, and one with hydro-
cephalus. Three patients had a Yasargil type I lesion; one, a
type II lesion; two, type III lesions; and three, type IV lesions.
Four had failed prior endovascular treatment. Three patients
required two Gamma Knife procedures. The mean marginal
dose used was 20.5 Gy (range, 15–25 Gy). Out of eight
patients who underwent follow-up cerebral angiogram, four
had complete obliteration and four showed significant oblit-
eration (50, 80, 80, and 90 %) with a follow-up ranging from
15 months to 8 years. One patient had transient symptomatic
radiation-induced edema after two Gamma Knife proce-
dures, and MRI showed evidence of edema in another patient
who remained asymptomatic. These promising results dem-
onstrate that stereotactic radiosurgery can be of benefit in the
management of stable VGM patients who can tolerate the
time interval needed for obliteration.
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 Cerebral Cavernous Malformations:
Viewpoint—Surgery
Robert L. Dodd and Gary K. Steinberg
Introduction
Cerebral cavernous malformations (CCMs), also known as
cavernous angiomas, cavernomas, or cryptic vascular mal-
formations, are rare low-flow vascular lesions [1, 2]; how-
ever, because their hemorrhage can result in significant
morbidity and mortality [3, 4], a great deal of effort has been
devoted to their detection and treatment. Although previ-
ously thought to be congenital, it is now well recognized that
most cavernous malformations are acquired [5], arising de
novo or occasionally following radiotherapy. The natural
history of cavernous malformations is only now being eluci-
dated with the widespread use of magnetic resonance imag-
ing (MRI). Preliminary reports suggest the annual risk of
clinically significant hemorrhage to be less than 1 % [1–4],
although many factors may increase this risk. In general,
results from surgical removal of accessible symptomatic cav-
ernomas are excellent, with improved control of medically
intractable seizures, restoration of neurological function, and
decreased risk of future hemorrhage. Surgically inaccessible
lesions remain a difficult clinical challenge.
Epidemiology
The prevalence of CCMs remains undetermined; however,
most reports estimate their occurrence in approximately 0.3–
0.9 % of the general population [1, 2]. These estimates are
based on autopsy results and prospective cohort studies using
MRI, which suggest cavernous malformations comprise
8–15 % of all vascular lesions [6, 7], therefore accounting for
the second most common type of vascular malformation after
R.L. Dodd, M.D., Ph.D. • G.K. Steinberg, M.D., Ph.D. (*)
Department of Neurosurgery, Stanford University School
of Medicine, 300 Pasteur Drive, Room 281, Stanford,
CA 94305, USA
e-mail: gsteinberg@stanford.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_51, © Springer Science+Business Media New York 2015
51
developmental venous anomalies (DVAs), which are often
found in association with CCMs [8, 9]. The incidence of these
lesions is approximately 0.5–0.6 per 100,000 people per year
[1, 2], in whom over 40 % are clinically symptomatic and
most of whom present with seizures. The age distribution of
patients with clinically symptomatic cavernous malforma-
tions is bell shaped, with the highest incidence between the
third and fifth decades [10]. New presentation of cavernous
malformations in infants or adults over the age of 80 years,
though documented, is rare. One-quarter of cases, however,
are estimated to occur during childhood [11–15]. Whereas a
few published reports have found slight male or female pre-
ponderance, most studies with large patient populations con-
cur that there is no difference in the sex incidence of CCMs.
Cavernous malformations are defined as an assembly of
thin-walled vascular sinusoids without intervening brain
parenchyma, lined by a single layer of endothelium, devoid of
mature vessel elements such as smooth muscle and elastin. In
contrast to other vascular lesions, cavernous malformations
rarely bleed into the subarachnoid space or into the ventricu-
lar system; more commonly, these lesions bleed into the sinu-
soidal space of the malformation itself, resulting in acute
enlargement or intraparenchymal hemorrhage. Although
these vascular malformations are low flow and undergo con-
tinual microhemorrhaging, clinically significant intralesional
hemorrhage or gross hemorrhage beyond the lesion is rare,
with an estimated risk between 0.25 and 6 % per year [3, 11,
16–20]. Hypertension, cigarette smoking, oral contraceptive,
alcohol consumption, and cocaine use are all known risk fac-
tors for intracerebral hemorrhage in general, but no study to
date has shown increased risk in patients who harbor cavern-
ous malformations. The most widely cited risk factor for
clinically significant hemorrhage, apart from family history,
is prior hemorrhage [3, 17, 19, 20]. Interestingly, while the
high frequency, rapidity, and gravity of hemorrhagic recur-
rences after the first intracranial hemorrhage have been
stressed by some, other series have shown little influence.
Several authors have found a female preponderance in bleed-
ing risk, suggesting that endocrine factors may influence
637
638
hemorrhage tendencies, particularly since some of the bleeding
episodes occurred during pregnancy [3, 9, 19]. These obser-
vations are supported by the detection of estrogen receptors in
a few cavernous malformations obtained from females [21],
as well as by speculation that hormonal fluctuations during
pregnancy increase endothelial cell proliferation in these
lesions and their propensity to hemorrhage [19].
Anatomical Distribution
Cavernous malformations can be found throughout the cen-
tral nervous system including every region of the brain,
brainstem, spinal cord, cranial nerves, and ventricles. The
cerebral hemispheres are the most frequently affected areas
(in one study 21 % frontal, 16 % parietal, 15 % temporal, and
3.5 % occipital), with most being subcortical in location
[22]. Recently, more cases of lesions in the basal ganglia,
corpus callosum, thalamus, and third ventricle have been
reported because of the interest generated by their therapeu-
tic complexity. Between 10 and 23 % of cavernous malfor-
mations are located infratentorially, where the pons is the
preferred site [21–25]. In 40–60 % of cases, multiple lesions
exist, and multiplicity should always raise the suspicion of
the familial form of the condition [26]. Multiple intracranial
cavernous malformations are sometimes associated with
similar vascular lesions in other organs, suggesting the pres-
ence of a wider and more systemic condition.
Molecular and Genetic Basis of CCMs
CCMs can occur in either a sporadic or familial form of the
disease, and while the occurrence of cavernous malforma-
tions in more than one family member was initially believed
uncommon, more recent evidence suggests as many as half
of CCM cases maybe familial in nature [27–29]. Hereditary
forms of CCM exhibit Mendelian autosomal dominant
inheritance with variable penetrance caused by loss-of-
function mutations which to date have been associated with
three genes: KRIT1 (also known as CCM1) on chromosome
7q11.2-21 [30, 31]; CCM2 (encoding the malcavernin pro-
tein), on chromosome 7p13 [30, 32]; and PDCD10 (also
known as CCM3) on chromosome 3q26.1 [10, 30, 33, 34].
In addition, discrepancies in the observed relative incidence
of mutations in these three genes between the original link-
age analysis data and the mutation screening data suggest a
potential fourth CCM locus (CCM4) [35].
The importance of CCM genes is highlighted by the
observation that at least one of the CCM genes is mutated in
most familial cavernous malformations. Over 100 different
single-gene (KRIT1) mutations have been found in CCM1-
linked families, which are believed to cause cavernous
R.L. Dodd and G.K. Steinberg
malformation induction in 40–53 % of familial cases [36–39],
with mutations in genes at CCM2 and CCM3 accounting for
15–20 % [38, 39] and 10–40 % [38, 39], respectively [10].
Interestingly, the majority of Hispanic-American patients of
Mexican descent have the same mutation in CCM1, indicating
a common ancestor [40]. Reports of cavernous malforma-
tions in familial series indicate the majority of these indi-
viduals had multiple lesions (up to 93 %), were clinically
symptomatic, and presented at a younger age.
Proteins expressed by the CCM genes have been identi-
fied histologically in neurons, astrocytes, and vascular endo-
thelium [37, 41–43]. Their primary and secondary structures
reveal ultrastructural regions that suggest binding, and
research has established that the three CCM proteins interact
with each other to form ternary complexes [44–47], which in
turn interact with other proteins [48, 49]. KRIT1 seems to be
predominantly localized in the cytoplasm although the pro-
tein has both a nuclear localization signal and a nuclear
export signal, suggesting it can be shuttled to and from the
nucleus [50]. Malcavernin also localizes to the cytoplasm,
binds KRIT1, and may inhibit its nuclear translocation
[32, 36, 51, 52]. PDCD10 binds to malcaverin and also has
structural domains that interact with the (PI3K-) PIP3-
PDPK1-Akt signaling pathway [34, 53].
The precise pathophysiologic mechanisms that explain
how an alteration in the CCM complex results in manifesta-
tions of the clinical disease remain unclear. However, animal
models and in vitro biochemical experiments, while imper-
fect, suggest that CCM gene products in concert with other
cellular machinery form ternary complexes that regulate key
steps in blood vessel formation and maintenance [54–58]. It is
postulated that the inability to compose these protein com-
plexes leads to the dysfunction in cytoskeletal processes
responsible for cell–cell adhesion, cell adhesion to the extra-
cellular matrix, and tight junction assembly important for
cell polarity [59]. This ultimately results in dysregulation of
vascular development and endothelial permeability [60, 61].
Natural History
Decisions on treatment recommendations are based to a great
extent on the estimated risk of further morbidity; therefore,
knowledge regarding the natural history of cavernous malfor-
mations is an important consideration in clinical practice.
Despite recognition of this point, our present knowledge is
incomplete because of several factors: the low frequency of
occurrence limits study population size, the relatively recent
introduction of MRI technology required for accurate diagno-
sis limits the length of clinical follow-up, the paucity of pro-
spective studies limits analysis of the natural history of
cavernous malformations, and confusion in the literature exists
on what constitutes a clinically significant hemorrhage.
51 Cerebral Cavernous Malformations: Viewpoint—Surgery
Nevertheless, several recent studies have provided some
estimates for risk of bleeding and growth [1, 4, 62, 63]. The
risk of clinically relevant hemorrhage after detection of a
cavernous malformation depends on the presenting symp-
toms as well as the location of the lesion. Preliminary reports
indicate that the frequency of clinical hemorrhage among
patients with supratentorial nonfamilial cavernous malfor-
mations who present either with incidental diagnosis or with
seizures is approximately 0.25–2 % per year [2, 3, 17, 19].
The percentage appears to be significantly higher (6.5 % per
patient per year; 1.3 % per lesion per year) in patients with
the familial form of the disease [20]. Likewise, worsening of
neurologic signs and symptoms is more frequent in the
familial group, occurring in more than 15 % per year [20].
Among patients with nonfamilial cavernomas who present
with symptomatic hemorrhage, the annual recurrent hemor-
rhage rate may be higher (about 4–5 %) in the next year than
in patients with no prior hemorrhage (0.6 %) [2]. Barker
et al. provide evidence for temporal clustering of hemor-
rhages, suggesting rebleed rates as high as 2.1 % per month
for the first 2.5 years after the initial hemorrhage before
decreasing to 1 % per month [62]. The risk of hemorrhage
may also depend somewhat on location, with some reports of
patients with deep lesions having an initial annual clinical
hemorrhage risk of 4.1 % compared with 0.4 % among those
with superficial lesions [2]. However, a recent meta-analysis
of 11 natural history studies suggests that this difference
largely reflects differences in the definition of hemorrhage
(radiographic versus clinical) [64], with deep/eloquent loca-
tions behaving more clinically aggressive without radio-
graphic changes on MRI. Younger patients may also have a
higher risk than older patients of a second hemorrhage.
Cavernous malformations are often surprisingly dynamic,
with changes in size, number, and MRI signal characteris-
tics. The size of these lesions in the literature has been
reported to vary between less than 1 mm up to more than
10 cm in diameter [23]. The mean cavernoma size in several
large series was approximately 15–19 mm, with the majority
of symptomatic lesions being greater than 1 cm in diameter
[16, 19, 23]. However, clinical symptoms are more related to
location than to size, as very small tectal cavernomas can
cause ophthalmoplegia, while giant frontal lobe lesions may
be asymptomatic. Clatterbuck et al. prospectively followed
114 lesions in 68 patients over 352.9 patient-years and dem-
onstrated that most lesions either increased or decreased in
size with less than 22 % being stable in volume [65]. Three
de novo lesions were observed during this period and may
represent the growth of very small lesions without symptom-
atic hemorrhage. In addition to changes in volume, they also
demonstrated a stereotypical progression of changes in
appearance. The mechanisms purported to cause growth and
MRI signal changes include: (1) progressive ectasia of vas-
cular channels and budding of capillaries from cavernous
639
spaces, resulting in growth of the vascular nidus; (2) recurrent
“external” microhemorrhages or red blood cell diapedesis
with thrombosis, followed by organization, fibrosis, and cal-
cification; (3) acute gross hemorrhage, resulting in acute size
increase; and (4) cyst formation “internal” hemorrhage that
ruptures septae between adjacent sinusoids. Further growth
and perifocal edema may be related to secondary microhem-
orrhages and fluid exudation from the neocapillary mem-
brane in the cyst capsule.
As our understanding of bleeding and growth rates is far
from exact, and indeed many patients who experience bleed-
ing from cavernous malformations may show good clinical
recovery, some authors have encouraged conservative treat-
ment, particularly for brainstem cavernous malformations.
Kupersmith et al. report that the majority of 23 nonsurgically
treated patients with symptomatic brainstem cavernous mal-
formations followed over a mean of almost 5 years either
improved (78 %) or remained clinically stable (17.4 %) [66].
Other larger series of similar patients however detail a much
more ominous outlook, with a 3.5 % perioperative mortality
rate, an 8 % overall mortality rate during follow-up after
surgery, and a 20 % mortality rate for nonsurgically treated
patients after 35.7 months of follow-up [21]. Such variability
demonstrates the sometimes unpredictable clinical courses
of these lesions and highlights our deficient knowledge of
how they behave.
Furthermore, survival from and successful treatment for a
cavernous malformation that has hemorrhaged may not
always provide a cure for the disease. Clinical reports have
documented the de novo formation of cavernomas for both
familial and sporadic forms of the disease [5, 20, 65]. In
patients with genetic predispositions, the new cavernoma
formation has been estimated to have an incidence of 0.2–0.4
lesions per patient-year [20, 67]. The incidence of de novo
lesions in patients without known genetic predisposition is
unclear, but multiple cavernomas have been described to
occur in one report, in 14 of 55 sporadic cases (25.4 %) [65].
Clinical Presentation
The clinical symptomatology of cavernous malformations is
highly variable, ranging from an asymptomatic incidental
finding to discovery in autopsy after fatal hemorrhage.
Typically patients come to medical attention because of sei-
zures, focal neurological deficits, or headaches, though there
have been an increasing number of patients with malforma-
tions found incidentally following imaging for other pur-
poses such as trauma. All of these symptoms are believed to
be secondary to either lesion hemorrhage or mass effect on
neural structures. In one series of 565 cases of symptomatic
cavernous malformations, 217 (38.4 %) presented with sei-
zures, 191 (33.8 %) with tumor-like symptoms, 66 (11.6 %)
640
presented with headache, and 101 (17.8 %) with overt hem-
orrhage [68]. Numerous other reports have confirmed epilep-
tic seizures constitute the most frequent clinically presenting
symptom. Between 35 and 70 % of symptomatic cavernomas
are associated with recurrent seizures, which are drug resis-
tant in 40 % of cases [69]. All seizure types including simple
seizures, complex partial seizures, and generalized seizures
[10] have been known to present in patients with supratento-
rial cavernous malformations. The pathogenesis of seizures
is debated, but most believe they are related to the presence
of iron products after red cell breakdown secondary to mul-
tiple microhemorrhages. Most patients with seizures present
with lesions in their frontal or temporal lobes. The estimated
risk of developing seizure is 1–2 % per person-year exposure
and mean age at time of first seizure is 42 ± 3.78 years [9, 11].
The second most frequent presentation is that of focal
neurological deficits, which correspond to lesion location,
and are usually produced by intralesional or perilesional
hemorrhage. They account for 35–50 % of reported cases
[14]. Vertigo, diplopia, ataxia, hemiparesis, associated sen-
sory disturbances, and changes in level of consciousness are
typical of infratentorial cavernous malformations, which,
occasionally, may even produce signs of increased intracra-
nial pressure due to obstructive hydrocephalus. Aphasia and
apraxias produced by supratentorial lesions, visual loss by
lesions within the optic nerve or chiasm, and symptoms of
trigeminal neuralgia from extra-axial cavernous malforma-
tions of the middle fossa have also been reported.
Neurological deficits may be transient, progressive, or fixed.
In rare instances cavernous malformations may simulate
multiple sclerosis due to fluctuating progressive neurological
deficits, such as repeated exacerbation of complaints and
alternating periods of remission. Cavernous malformations
have also been found in the spinal cord where they present
with an acute or subacute myelopathy.
Headache accompanies cavernous malformations in many
patients and may have prompted diagnostic evaluation
uncovering the lesion. While this is a controversial present-
ing complaint due to its nonspecific and nonlocalizing nature,
it represents a major symptom in 25–30 % of reported cases
[14]. The prevalence of asymptomatic lesions in the general
population is unknown, but recent evidence suggests it is
much higher than previously suspected. Studies among con-
secutive patients undergoing MRI have detected asymptom-
atic cavernous malformations in 14–19 % of patients [14].
Other reviews of the literature have found as many as 21 %
of patients to be without symptoms at first discovery [3, 22].
The incidence of cavernous malformations that present
with clinical hemorrhage is uncertain. This is because of
variability in hemorrhage patterns of cavernous malforma-
tions as well as variability in the literature of what defines a
clinically significant event. Some have described clinically
significant hemorrhages as those that are sizable and present
R.L. Dodd and G.K. Steinberg
with acute symptoms. The prevalence of this type of hemor-
rhage in large series ranges between 6 and 30 % of cases
[9, 11, 16, 22, 65]. The clinical presentation of hemorrhage
is acute, but usually not as dramatic as those that occur from
intracranial aneurysms or AVMs. Sudden onset headache
followed by a focal neurological deficit is typical, depending
on the location and size of the hematoma.
Diagnostic Imaging
The most sensitive and therefore the most important diagnos-
tic tool is MRI (Figs. 51.1, 51.2, and 51.3). The high sensitiv-
ity of gradient-echo sequences is particularly helpful in
detecting both acute and chronic hemorrhages that may not
be seen with conventional spin-echo techniques. Indeed the
widespread use of MRI has led to the detection of asymptom-
atic cavernous malformations, therefore increasing previous
estimates regarding the prevalence of these lesions. The MRI
appearance of cavernous malformations has been detailed by
many authors including Zabramski et al., who distinguish
four types of MR characteristics [20]. Type I lesions are
hyperintense on T1- and T2-weighted images and indicate
subacute hemorrhage. Type II lesions show a mixed-signal
intensity on T1- and T2-weighted imaging with a surround-
ing hemosiderin ring. Type III lesions are hypo- to isointense
on T1- and T2-weighted images and most probably indicate
chronic hemorrhage. Type IV lesions are poorly visualized
except on gradient-echo sequences. Histopathological corre-
lations to these MRI patterns have been confirmed. In addi-
tion to establishing the diagnosis, MRI also defines the exact
size, location, and extent of cavernous malformations as well
as provides information about multiplicity, hydrocephalus,
and the condition of the adjacent brain parenchyma.
Treatment
Given the excellent results of microsurgical resection of cav-
ernous malformations, it is generally easy to endorse the phi-
losophy of operative management for most of these lesions.
However, increasing evidence suggesting a relatively benign
natural history of some lesions has indicated the need for
reevaluation of management decisions. In particular, when
dealing with a patient harboring several lesions, a family
affected by a hereditary form of this condition, or deep-
seated lesions in the brainstem, it becomes apparent that an
aggressive approach is not always advisable. The only clear
indications for surgery are for medically intractable epilepsy,
documented recurrent hemorrhage, and progressive neuro-
logical deficit. Patients with an established diagnosis of
CCM who present without clinical hemorrhage, seizures, or
other specific symptoms are usually candidates for clinical
51 Cerebral Cavernous Malformations: Viewpoint—Surgery
Fig. 51.1 Selected (a) axial FLAIR, (b) coronal T1 postcontrast, and
(c) sagittal T1 MRI scans of a 31-year-old female medical student who
presented with four clinical hemorrhages resulting in headaches, gait
instability, and symptoms of hypothalamic dysfunction including
observation and repeat imaging. Conservative management
is also appropriate for many patients with purely incidental
lesions or malformations located deep within functional
areas that do not present to a pial or ventricular surface.
Microsurgical Treatment of Supratentorial
Lesions
Surgical resection of most cavernous malformations is
straightforward because these lesions have no major arterial
supply and do not bleed much at surgery. The most difficult
task in resection is often intraoperative localization and
choosing an appropriate surgical corridor. This has been
facilitated with the use of stereotaxic MRI computer-
guidance systems for neuronavigation, which allows plan-
ning of surgical trajectories to avoid functional cortex and
major blood vessels, as well as target localization to within
1–2 mm. The risk of open microsurgery is generally related
to lesion size, location, and proximity to critical structures. In
addition, advanced age, medical comorbidities, and poor
neurological condition are all negative prognostic factors for
a good surgical result. Several surgical series have reported
excellent results in removal of superficial lesions of both elo-
641
hypersomnolence, loss of appetite, and memory difficulties. A cavern-
ous malformation is centered in the midline involving the massa inter-
media, hypothalamus, midbrain, third ventricle, and extending to the
suprasellar cistern
quent and noneloquent areas. More than 75 % of all cavern-
ous malformations are located supratentorially [22], most of
which are located in cortical and subcortical regions that are
readily accessible with modern surgical techniques. Even
prior to MRI, surgical series have documented the successful
removal of cavernous malformations with low risk. Vaquero
et al. report successful treatment of 19 supratentorial cavern-
ous malformations located in the cerebral hemispheres from
1977 to 1987. Of the 19 patients, 17 had excellent results (no
seizures without medication) and two were classified as good
outcomes (occasional seizures with medication) [70]. There
were no poor outcomes or deaths in this cohort. Similarly,
excellent results have been documented in the post-MRI era.
McCormick reviewed his experience with removal of supra-
tentorial cavernous malformations. In 63 of 65 patients, com-
plete removal was obtained, two patients experienced
worsening of an existing deficit, a third patient developed a
new deficit, and there was only one postoperative death [71].
When performed for medically intractable epilepsy, several
published results confirm a greater than 90 % likelihood of a
seizure-free outcome with surgical extirpation of cavernous
malformations and the surrounding epileptogenic tissue [69].
The surgical approach is defined by the lesion location,
and in general the craniotomy is centered over the lesion.
642
Fig. 51.2 Selected immediately postoperative (a) axial T1, (b) coronal T1
postcontrast, and (c) sagittal T1 MRI scans demonstrate gross total resec-
tion of the cavernous malformation seen in Fig. 51.1. (d) Microsurgical
removal was performed via an interhemispheric transcallosal approach to
the third ventricle. The asterisk (*) is on the corpus callosum, through
which a small incision was made that exposed an enlarged foramen of
Monro. The laser pointer is focused on the superior aspect of the cavernous
The use of neuronavigation allows precise targeting that
minimizes the size of the craniotomy and risk to exposed
brain (Fig. 51.3). Lesions that involve the anterior corpus
callosum near the genu and cingulate gyrus can be approached
through a small frontal craniotomy. Lesions that are more
basal in the subfrontal or septal regions often require a lower
frontal craniotomy through a bicoronal incision or an inter-
hemispheric approach. Posterior parasagittal approaches are
generally used for lesions in the body of the corpus callosum,
cingulate gyrus, and midline posterior frontal, parietal, or
occipital areas (Fig. 51.4), as well as for some thalamic CMs.
Medial anterior temporal lesions involving the amygdala, the
hippocampus, or the uncus are approached through the
Sylvian fissure via a standard pterional craniotomy.
Superficial cortical lesions are often easy to identify because
of overlying cortical discoloration, whereas small subcorti-
cal lesions often require stereotaxis. Both trans-sulcal and
trans-gyral approaches can be employed depending on lesion
geometry and the location of cortical vasculature. Once iden-
tified, a well-defined gliotic plane typically allows for easy
separation of the lesion from surrounding tissue so that com-
plete lesion resection can be achieved. When surgery is indi-
R.L. Dodd and G.K. Steinberg
malformation. (e) A 3.5-cm cavernous malformation was resected piece-
meal from the third ventricle, diencephalon, and midbrain. There was
acute, subacute, and chronic hemorrhage within the malformation, which
was composed of thin-walled, fragile vascular channels. No attempt was
made to remove the surrounding hemosiderin-stained brain. Postoperatively,
the patient quickly recovered to her neurologic baseline and has continued
to improve, though some memory difficulties still remain
cated for seizures, the hemosiderin- or hematoidin-laden
gliotic tissue should be resected due to its role in seizure gen-
eration. Intraoperative electrocorticography may be helpful
for confirming the extent of abnormal electrical activity, par-
ticularly for lesions near the motor or sensory cortices. For
dominant hemisphere lesions, awake intraoperative speech
mapping may be required to preserve language function.
Microsurgical Treatment of Infratentorial
Lesions
Lesions located deep within the brain are difficult to remove
and present special challenges (Figs. 51.1, 51.2, 51.3, and
51.4), though recent series describe improved outcomes with
image-guided techniques. Approximately 10–30 % of all
intracranial cavernous malformations are located in the pos-
terior fossa [21–25], and some reports suggest these lesions
may be more frequently symptomatic [21]. Surgical removal
is indicated for symptomatic lesions located in the cerebellum
or superficially in the brainstem when eloquent parenchyma
can be spared. Several surgical approaches have been
51 Cerebral Cavernous Malformations: Viewpoint—Surgery
Fig. 51.3 (a) Sagittal T1, (b) coronal T1 postcontrast, and (c) axial T2
and (d) T1 MRI scans illustrate a 1-cm, right midpontine cavernous
malformation with subacute hemorrhage surrounded by a rim of hemo-
siderin and surrounding brainstem edema (arrow in c). Although this
lesion did not present to a pial or ventricular surface, three clinically
significant hemorrhages were observed over a 7-month period, result-
ing in diplopia, facial weakness, sensory loss, and mild hemiparesis.
Fig. 51.4 Selected 3-year postoperative (a) sagittal, (b) coronal, and (c) axial T1 MRI scans demonstrate gross total resection of the cavernous
malformation seen in Fig. 51.3
detailed in the literature including suboccipital, infratento-
rial supracerebellar, occipital transtentorial, far lateral,
transtemporal, subtemporal transtentorial, and combined
petrosal. Furthermore, much emphasis has been placed on
643
Microsurgical resection of the cavernous malformation was therefore
performed. (e) A right subtemporal approach was used as illustrated,
aided by the intraoperative surgical navigation. Brainstem functional
mapping was employed prior to making the few-millimeter incision in
the lateral surface of the pons (right upper panel, e). Postoperatively,
the patient’s hemiparesis transiently worsened, but he recovered within
1 week and currently has no focal deficits
the selection of an approach that optimizes exposure to the
lesion with minimum disruption to surrounding structures.
In general, lesions of the cerebellar vermis, medial cerebellar
hemispheres, floor of the fourth ventricle, and dorsal medulla
644
are easily approached through a standard suboccipital
approach. Lesions of the tectum and pineal region are often
best approached via infratentorial supracerebellar access.
The occipital transtentorial approach provides exposure of
the superior cerebellar peduncles and vermis, the anterior
medullary velum, posterior third ventricle, the splenium, and
the quadrigeminal plate. The far lateral approach provides
excellent exposure of the anterior and lateral medulla and
cervicomedullary junction. Transtemporal approaches allow
access to lesions in and around the internal auditory meatus
such as pontomedullary junction cavernous malformations
and can be employed in patients without serviceable hearing.
Cavernous malformations involving the anterior midbrain–
interpeduncular fossa region can be approached through a
pterional trans-sylvian, subtemporal, or orbitozygomatic
craniotomy, and occasionally lesions located in the upper
two-thirds of the brainstem require a combined petrosal
approach. CSF drainage for brain relaxation, electrophysio-
logical monitoring, and functional mapping are all important
for minimizing complications and reducing the risk of per-
manent neurological deficit.
Unlike supratentorial cavernous malformations, deep
lesions can be extremely adherent to the normal parenchyma
and are sometimes removed in a piecemeal fashion following
circumferential separation and devascularization from the
surrounding gliosis. All perforating arterial vessels must be
dissected meticulously and preserved. Furthermore, the
hemosiderin staining surrounding the malformation should
be spared from surgical removal. An association between
cavernous malformations and venous malformation has been
described and may be as high as 16 % [72], and while the
goal of surgery is complete excision of the cavernoma, inter-
ruption of a venous malformation is to be avoided because of
the risk of venous infarction. The risk of open microsurgery
for superficial cerebellar lesions is low, similar to that for
most supratentorial cavernous malformations. The risks
associated with surgical exploration of deep-brain and brain-
stem cavernous malformations is considerably higher, as dis-
cussed below.
Radiosurgical Treatment of Cavernous
Malformations
A number of groups have used stereotactic-focused radio-
surgery with heavy-charged particles (protons or helium
ions) or photons (Gamma Knife or LINAC radiosurgery) in
attempts to improve the natural history of deep, difficult-to-
resect cavernous malformations [13, 73–81]. Although there
has been no prospective randomized study, recent reports
from several groups suggest that, for certain patients,
R.L. Dodd and G.K. Steinberg
radiosurgery may decrease the risk of clinical hemorrhage,
compared with the statistically derived natural history [13, 73,
74]. Our combined Stanford University–University of
California, Berkeley, program previously treated 57 cavern-
ous malformations in the brainstem, thalamus, and basal
ganglia using Bragg peak helium ion radiosurgery (47
lesions) or LINAC radiosurgery (10 lesions), with mixed
results [74]. Eighteen patients (32 %) experienced symp-
tomatic bleeding (20 hemorrhaging episodes) after radio-
surgery. Sixteen hemorrhaging episodes occurred within 36
months after radiosurgery (9.4 % annual bleeding rate; 16
hemorrhaging episodes/171 patient-years), and 4 hemor-
rhaging episodes occurred more than 36 months after treat-
ment (1.6 % annual bleeding rate; 4 hemorrhaging
episodes/257 patient-years) (P < 0.001). The radiosurgery
group at Harvard University reported a decrease in the
annual hemorrhage rate from 17.3 % before radiosurgery to
4.5 % after a latency period of 2 years after radiosurgery
[73]. Similar symptomatic hemorrhage rates after Gamma
Knife radiosurgery for cavernous malformations were
reduced from 8.8 % during the first 2 years after radiosur-
gery to 1.1 % thereafter [13]. A more recent study of 103
patients with solitary cavernous malformations who were
treated with Gamma Knife radiosurgery at the University of
Pittsburgh with follow-up from 2 to 20 years demonstrated
a 10.8 % annual hemorrhage rate for the first 2 years after
treatment and then a 1.06 % annual bleed rate after 2 years
[82]. However, statistical modeling analysis showed that the
hemorrhage rate from untreated cavernous malformations
appeared to demonstrate temporal clustering of hemor-
rhages such that the rehemorrhage rate from untreated cav-
ernous malformations was found to be high initially (2 %
monthly rehemorrhage rate during the first 2.5 years follow-
ing hemorrhage; 14 % cumulative incidence of a second
hemorrhage during the first year) with decreases 2–3 years
after a previous hemorrhage (to less than 1 % per month)
[62]. These results therefore question whether the data from
the radiosurgical series represent protective effects of treat-
ment or simply the natural bleeding history of these lesions.
Additionally, in ten patients who underwent microsurgical
resection of their cavernous malformations 1–10 years fol-
lowing radiosurgical treatment, none of the cavernous mal-
formations were found to be thromobosed on pathological
examination [83]. Furthermore, in our series of patients
with cavernous malformations who underwent radiosur-
gery, 7 % experienced symptomatic radiation edema and
2 % experienced radiation necrosis [74] (Fig. 51.5). Other
groups have documented a 13.5 % incidence of new neuro-
logic deficits [82] and a 16 % incidence of permanent neu-
rological deficits with a 3 % mortality rate secondary to
radiation-induced complications [73].
51 Cerebral Cavernous Malformations: Viewpoint—Surgery
Fig. 51.5 (a) Axial proton-density MRI of a 35-year-old woman who
initially presented with generalized seizures shows a 1-cm vascular
malformation located in the left thalamus adjacent to the posterior limb
of the internal capsule. She was first treated with stereotactic heavy-
charged-particle Bragg peak radiosurgery. Nine months after radiosur-
gery, she experienced worsening right hemiparesis; (b) axial T2
imaging at that time demonstrated extensive radiation-induced changes
extending into the basal ganglia and thalamus. She subsequently under-
went stereotactically guided microsurgical resection via a small left
posterior parietal, interhemispheric transcallosal approach through the
pulvinar. The patient recovered extremely well and was discharged
Brainstem Cavernous Malformations
Brainstem cavernomas, though very rare, deserve special
mention because their clinical presentation, natural history,
and treatment decisions often differ from those of cavernous
malformations in other locations. Such lesions account for
9–35 % of all cavernomas and for 18–22 % of all intracranial
cavernomas [21, 23, 25]. Fifty to 70 % of these lesions occur
in the pons, 20–35 % in the midbrain, and 15–25 % in the
medulla. Symptoms vary from cranial nerve deficits, sensory
dysfunction, paresis/plegia, ataxia, dysmetria, speech diffi-
culty to headaches and decreased levels of consciousness.
The clinical presentation can often be confusing and many
patients who have experienced episodic clinical deterioration
secondary to hemorrhaging have been diagnosed with hav-
ing multiple sclerosis.
There is evidence that the natural history of brainstem
cavernous malformations differs from that of other locations,
suggesting that this subgroup has a higher propensity for
clinical bleeding. Porter et al. reported nearly all of their 100
brainstem cavernomas presented with evidence of clinically
significant hemorrhage, 56 % with multiple bleeds, and 22 %
with more than two clinical bleeds [21]. While some patients
with hemorrhage from brainstem cavernous malformations
make good recoveries without intervention, it is also clear
that multiple bleeding episodes increase the likelihood of a
645
2 days after surgery without new deficits. (c) Hematoxylin and eosin-
stained specimen from a surgically removed brainstem cavernous mal-
formation 5 years after stereotactic heavy-charged-particle radiosurgery.
Patent vascular channels (arrow) are observed. (d) Surgical specimen
from tissue adjacent to a cavernous malformation removed from another
patient with delayed radiation-induced injury 3 years after stereotactic
radiosurgery of a right parietal cavernous malformation. Histopathologic
changes consisted of thick-walled hyalinized vessels with fibrinoid
necrosis (arrow), postradiation gliosis, and reactive astrocytosis and
necrosis (arrowhead), characteristic of radiation effects
persistent deficit. Various series have demonstrated recurrent
hemorrhage rates of 5–60 % [21, 66, 84–87]. Furthermore,
when multiple bleeding episodes do occur, the time interval
between hemorrhages is increased and the mortality rate for
each hemorrhage may be as high as 20 %.
Surgical treatment of brainstem cavernous malformations
is considerably more risky than operative intervention in
other less eloquent areas of the nervous system. Difficult
access, narrow surgical corridors, and sensitivity to injury of
critical structures near these lesions present unique obsta-
cles. Despite the high risk of permanent morbidity and tech-
nical challenges of microsurgical excision, several centers
have demonstrated expertise in removing these lesions with
good outcomes. Pandey et al. reported a series of 176 patients
with 179 deep-brain cavernous malformations located in the
brainstem (n = 136), thalamus (n = 16), and basal ganglia
(n = 26), which were microsurgically resected [86].
Neuronavigation, mild hypothermia (32–33 °C), electro-
physiological monitoring, cranial nerve mapping, and use of
the CO2 laser assisted in the safe removal of these lesions.
Over a 20-year period with a mean follow-up of 3.5 years,
the overall results were excellent (mRS = 0–1) in 54 %,
good (mRS = 2) in 29 %, and poor (mRS = 3–6) in 18 %; 5 %
of patients died. Ninety-six percent of these lesions were
completely resected after a single surgery (86 %) or 2 surger-
ies (9.6 %), 88 % of the patients were either neurologically
improved or unchanged after 6 months, and only 12 % of the
646
patients were worse than their preoperative status at the last
follow-up. Of 135 patients undergoing microsurgical resec-
tion of 136 brainstem cavernous malformations in this series,
although slightly less than 1/3 of the patients were immedi-
ately worse after surgery, at long-term follow-up (>6
months), 87 % of the patients were neurologically unchanged
or improved, while 13 % had worsened. Porter et al. reported
their experience with 100 patients with brainstem cavernous
malformations, of which 86 underwent microsurgical resec-
tion. Over a 12-year period, 87 % were the same or better,
10 % were worse, and 4 % died; the long-term neurological
morbidity rate was 12 %. Bertalanffy et al. reviewed their
series of 24 brainstem cavernous malformations over a
5-year period [23]. Seventy percent had Karnofsky scores of
90 or better at follow-up, 21 % had scores of 60–70, and 4 %
had scores less than 60. Their rate of long-term morbidity
was 5.5 % and there were no deaths. Therefore, while the
risks of surgical intervention for brainstem and deep-brain
cavernous malformations are not low, the natural history of
such lesions is likely worse than that of cavernous malforma-
tions at other CNS sites, and we recommend that surgical
resection be considered for symptomatic lesions that present
to a pial or ependymal surface and in certain circumstances
even for those malformations that do not present to a pial/
ependymal surface, if they have bled repetitively and can be
exposed through a safe corridor [86].
Conclusions
Surgical resection of symptomatic cavernous malformations
provides an excellent treatment option and, when completely
excised, is curative for most lesions. When cavernous mal-
formations are removed in patients with medically refractory
epilepsy, improved seizure control is typical and many cen-
ters report high rates of “seizure-free” patients. In general,
the surgical morbidity associated with the resection of super-
ficial lesions in the cerebral and cerebellar cortices is mini-
mal, and mortality is considered unusual. Resection of
lesions in and around eloquent cortex requires electrophysi-
ological monitoring and often functional mapping, but can
be performed safely. Deep-seated cavernous malformations
in the thalamus, basal ganglia, and brainstem are associated
with higher surgical risks; however, for symptomatic lesions
that demonstrate recurrent hemorrhage and present to a pial
or ventricular surface, resection by an experienced neurosur-
geon is well reported and should be considered. The role of
radiosurgery for unresectable malformations remains uncer-
tain and at our institution was associated with significant
risks of radiation-induced injury without any significant
change in the natural history of hemorrhaging. Until better
evidence of its efficacy is established, we do not recommend
radiosurgery for treatment of cavernous malformations.
R.L. Dodd and G.K. Steinberg
Acknowledgement This work was supported in part by support from
Bernard and Ronni Lacroute, the William Randolph Hearst Foundation,
and Russell and Beth Siegelman (to GKS).
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 Trigeminal Neuralgia
Lawrence S. Chin, Seung S. Hahn, Shilpen Patel,
Thomas Mattingly, and Young Kwok
Introduction
Trigeminal neuralgia (TN) is a facial pain syndrome charac-
terized by a severe electrical, shooting pain lasting seconds
to minutes that is confined to one or more distributions of the
trigeminal nerve. More recently, the International Headache
Society has defined TN pain as the following: (a) paroxys-
mal attacks, lasting from a second to 2 min, affecting one or
more divisions of the trigeminal nerve; (b) pain that is
intense, sharp, superficial or stabbing, precipitated from trig-
ger areas or factors; (c) attacks stereotyped in the individual
patient; (d) no clinically evident neurologic deficit; and (e)
pain not attributed to another disorder [1]. The pain, typi-
cally unilateral, may be bilateral in approximately 5 % of
cases and may occur either spontaneously or be triggered by
innocuous sensations or activities such as a gust of wind,
chewing, drinking, brushing teeth, shaving, or washing the
face. Severely affected patients may lose weight from not
eating. The median age of presentation is in the sixties, and
it affects women more often than men [2]. The incidence of
trigeminal neuralgia is 4–13 per 100,000 people and approx-
imately 15,000 new cases occur in USA each year [3].
L.S. Chin, M.D., F.A.C.S., F.A.A.N.S. (*)
Department of Neurosurgery, SUNY Upstate Medical University,
750 East Adams Street, Syracuse, NY 13210, USA
e-mail: chinL@upstate.edu
S.S. Hahn
Department of Radiation Oncology, SUNY Upstate Medical
University, 750 East Adams Street, Syracuse, NY 13210, USA
S. Patel
Department of Radiation Oncology, University of Washington
Medical Center, Seattle, WA, USA
T. Mattingly
Department of Neurosurgery, University of Maryland,
Baltimore, MD, USA
Y. Kwok
Department of Radiation Oncology, University of Maryland
Medical Center, Baltimore, MD, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_52, © Springer Science+Business Media New York 2015
52
The diagnosis is based on history. Typically, the neurologic
exam is normal, unless the syndrome is secondary to another
process such as a tumor in the posterior fossa or multiple scle-
rosis. Imaging studies obtained in the workup include mag-
netic resonance imaging (MRI) to rule out structural causes,
but usually this is normal. An atypical form of TN exists and
is characterized by pain of longer duration that may be asso-
ciated with a burning sensation and facial numbness [4].
Occasionally, patients with typical TN may develop atypical
features over time. It is not unusual for TN to have periods of
remissions and exacerbations; seasonal variation is also com-
mon with winter being a particularly difficult time for most
sufferers. Patients with TN usually note a progression of their
symptoms with time: the pain becomes more intense and the
remissions more rare.
The pathophysiology of this process is somewhat contro-
versial. As a result of surgical observations in the posterior
fossa, Dandy postulated that vascular compression, usually
from a branch of the superior cerebellar artery at the trigemi-
nal root, was the primary cause of TN [5]. This idea was
advanced by Gardner, Jannetta, and others who developed
microvascular decompression (MVD) via retromastoid cra-
niectomy as a treatment [6]. It is postulated that arterial pul-
sation of the trigeminal nerve root entry zone results in
demyelination and subsequent ephaptic transmission [7].
However, not all patients with typical TN have vascular com-
pression found at MVD, and vascular compression of the
trigeminal roots has been observed in patients without TN. In
addition, patients with multiple sclerosis (MS) and brain-
stem infarcts may develop TN, indicating that TN may be
generated by central mechanisms as well [8].
Treatment Options
Patients with TN have a number of treatment options. The first
line is medical therapy. Carbamazepine (Tegretol) is the drug
of choice, but other anticonvulsants such as gabapentin
(Neurontin), phenytoin (Dilantin), oxcarbazepine (Trileptal),
649
650
Table 52.1 Results of linac-based or CyberKnife SRS in idiopathic TN
No. of Median follow-up
patients (months)
Chen et al. [11] (Kaiser Los Angeles) 32 8 78
Richards et al. [12] (Wisconsin) 28 12
Lim et al. [13] CyberKnife (Stanford) 41 11
Smith et al. [14] (UCLA) 60 23
NR not reported
lamotrigine (Lamictal), and topiramate (Topamax) can also be
effective. Baclofen (Kemstro) has also been used though it has
a different mechanism of action; it acts by inhibiting mono-
synaptic and polysynaptic spinal reflexes. In severe cases, two
or more drugs may be required. Narcotic pain medications are
typically not recommended because most trigeminal attacks
do not last for a significant duration to justify routine use of
such medications. Medication may only help in approxi-
mately 75 % of patients, and side effects such as drowsiness,
cognitive dysfunction, bone marrow suppression, and hepatic
dysfunction can be significant. In addition, patients will fre-
quently become refractory to medication over time [9].
If medical therapy fails or is not tolerated, there exist two
primary surgical therapies: MVD and ablative percutaneous
procedures. Performing an MVD requires general anesthesia
and carries a risk of stroke, infection, hemorrhage, cerebro-
spinal fluid (CSF) leak, facial numbness, weakness, and
hearing loss. For patients over the age of 70 years and for
those with surgical contraindications, MVD may not be an
ideal treatment. The percutaneous approaches (radiofre-
quency ablation, glycerol injection, and balloon compres-
sion) to the trigeminal ganglion are performed under local
anesthesia but are associated with a significant risk of tri-
geminal dysfunction. Stereotactic radiosurgery (SRS) pro-
vides an alternative treatment that is minimally invasive yet
effective and causes few side effects.
SRS was first described in 1951 by Lars Leksell as an
adaptation of his arc-centered stereotactic frame with a radia-
tion source replacing the lesioning electrode. In his initial
attempts at SRS, Leksell coupled a dental X-ray tube to his
stereotactic arc to irradiate the trigeminal ganglion [10]. After
trying several different radiation sources, he subsequently
reported the successful treatment of TN in two patients with
Gamma Knife stereotactic radiosurgery (GK-SRS) using
cobalt-60 [11]. With the development of high-resolution
MRI, the proximal portion of trigeminal nerve is usually well
identified between the pons and the Meckel’s cave, and con-
sidered to be a well-defined and safer target for SRS.
Thus, the radiosurgery target has moved toward root entry
zone of trigeminal nerve which allowed much higher radio-
surgery dose (70–90 Gy) without risking significant side
effects [12].
L.S. Chin et al.
BNI I–III Time to Median Recurrence Complication
relief (%) pain relief dose (Gy) rate (%) rate (%)
1.5 months NR NR 6
75 1 month 80 46 14
93 7 days 78 16 51
72 2.7 months 90 26 25
With recent improvements in technology and imaging,
linear accelerator (linac)-based and CyberKnife SRS for
TN have become more common. Table 52.1 compares
some of the major series reported in the literature. The
range of patients achieving good relief (Barrow
Neurological Institute [BNI] I–III) is 72–93 %. The median
time to pain relief varies from 1 week to 2.7 months. An
analysis of recurrence revealed rates that ranged from 6 to
51 % [13–16].
Ma from the University of Maryland performed a
comparative analysis of linac and GK-SRS for TN therapy.
Specifically, the dose fall-off characteristics and set-up error
tolerance of the two modalities were examined. This study
found equivalent dose fall-off properties between Gamma
Knife and linac-based SRS provided only if a sufficient num-
ber of arcs (>7) and small intra-arc error (<0.5 mm) were
satisfied for linac-based deliveries. Furthermore, because of
the large number of arcs that are required, the treatment time
for linac-based SRS compared with Gamma Knife is signifi-
cantly increased [17]. At this time, robust safety and long-
term efficacy data exist only for Gamma Knife treatment of
TN; however, the clinical experience in this disease with
other forms of radiosurgery is growing and will lead to
greater patient options.
Mechanism of GK-SRS Effect
The relationship between post-procedure numbness and effi-
cacy suggests that GK-SRS works by blocking axonal trans-
mission. As predicted by models of radiation injury, both the
time to effective pain relief and numbness are delayed,
although pain relief frequently occurs many months before
any side effects are experienced. Kondziolka et al. used a pri-
mate model to explore the effects of 80 or 100 Gy to trigemi-
nal nerves and observed a combination of axonal degeneration
and edema [18]. Necrosis was seen in nerves that received
the higher dose, and both myelinated and unmyelinated
fibers were equally affected. Why the functional improve-
ment is seen in patients before these histologic changes are
seen is unknown, but an effect of GK-SRS on ephaptic trans-
mission provides a possible mechanism.
52 Trigeminal Neuralgia
Targeting, Dose, and Dose Rate
Early SRS treatments for TN targeted the trigeminal ganglion
because the trigeminal cistern in the Meckel’s cave could be
inferred from landmarks on skull films, a practice later
refined by stereotactic cisternography. In fact, glycerol rhi-
zotomy was discovered incidentally during the use of glyc-
erol as a carrier for tantalum dust in outlining the trigeminal
cistern [19]. In 1991, Lindquist et al. reported 46 cases of
GK-SRS directed at the trigeminal ganglion with 22 patients
localized using cisternography [20]. They did not report pre-
scription doses. The results were disappointing as only 4 of
22 patients had prolonged pain relief. Rand et al. reported a
series of 12 patients treated by GK-SRS doses ranging from
57 to 74 Gy with only mild success and concluded that the
ganglion was not the appropriate target [21]. Based on these
findings and with the development of high-resolution MRI,
which made it possible to reliably target the trigeminal nerve
anywhere along its course from the pons to the Meckel’s
cave, the optimal target moved toward the trigeminal nerve
root entry zone.
In 1996, Kondziolka et al. published the results of a mul-
ticenter trial of GK-SRS that standardized the target [22].
A single 4-mm isocenter was applied to the trigeminal nerve
2–4 mm anterior to the junction of the nerve at the pons as
seen on axial and coronal MRI scans. This location has since
been confirmed effective by several large series [23]. The
20 % isocenter line typically contacts the brain stem using
this protocol, which is well tolerated at the current maximum
doses of 70–80 Gy to the isocenter. Evaluation of brain-stem
dose as well as evidence of compression was evaluated at the
University of Maryland. Doses to the brain stem ranged from
10 to 20 %, and evidence of compression was seen in 12 %
of patients. Both brain-stem dose and evidence of compres-
sion did not have any effect on treatment response, medica-
tion use, or development of facial numbness [24]. Beam
shaping is accomplished by plugging some of the 201 sources
during a treatment and can be used to accomplish a flattening
of the lower isodose curves such that the 10 % line is parallel
to the brain stem (Fig. 52.1). Theoretically, this should
decrease the risk of radiation necrosis to the brain stem.
Some centers have also tried using two isocenters to irradiate
a greater length of nerve. A randomized, prospective study
reported by Flickinger et al. found no increase in efficacy but
did show a statistically significant increase in trigeminal dys-
function [25]. Efficacy was reported to be 67.7 ± 5.1 % in
both arms, and facial numbness and mild and severe pares-
thesias developed in 19 %, 12 %, and 2 % in two isocenter
patients versus 7 %, 9 %, and 0% in one isocenter patient,
respectively. In the multivariate analysis, the length of nerve
treated was the only significant factor predicting for facial
numbness.
651
Fig. 52.1 Gamma Knife treatment plan for a patient with right trigemi-
nal neuralgia. Isodose coverage of the nerve is seen in the right upper
panel. The 20 % line touches the brain stem, and the 10 % line cuts into
it. Beam shaping is accomplished by plugging 32 beams as shown in the
left lower panel. The result, seen in the right lower panel, is a flattened
10 and 20 % isodose line such that the brain stem receives 10 % only
along the edge
In Leksell’s original 1971 paper, he described successful
treatment at maximum doses of 16.5 and 22 Gy [11]. Patients
studied in the 1996 multicenter trial received doses ranging
from 60 to 90 Gy [22]. Patients who received at least 70 Gy
fared significantly better, but no difference was seen by
increasing the dose to 90 Gy. At these doses, the edge of the
brain stem receives no more than 16 Gy, which is well
tolerated.
At the University of Maryland, MRI imaging is performed
with gadolinium-enhanced short-TR sequences (T1-weighted)
with axial volume acquisitions using 512 × 216 matrices at
1.5-mm slice intervals. Occasionally, it is difficult to visual-
ize the affected prepontine trigeminal nerve on the axial MRI
view. This was evaluated and it was found that MRI quality
did not affect treatment response, medication use, and devel-
opment of facial numbness [24]. Based on this study, it is
recommended that if the trigeminal nerve is difficult to image,
additional axial long-TR sequences (T2-weighted) or use of
the coronal and sagittal views is useful (Case 52.1). A single
4-mm isocenter shot is placed just anterior to the entry of the
trigeminal nerve into the pons with the 20 % isocenter barely
touching the pons surface. Coronal MRI scans are examined
to ensure that the 50 % line surrounds the nerve, and 90 and
99 % lines are evaluated to make sure the center of the nerve
receives the maximum dose. A customized plugging pattern
is then applied that elongates the lower isodose curves and
652
Case 52.1
This 42-year-old man with a 10-year history of well-
controlled multiple sclerosis began experiencing typi-
cal right V3 trigeminal neuralgia 4 years prior to
treatment. He had been placed on increasing doses of
Tegretol and Neurontin with decreasing effectiveness.
The increased doses of medication also worsened his
MS symptoms. He had typical lancinating pain with no
numbness that was triggered by touching the face and
talking. At the time of GK-SRS, he had T1- and
T2-weighted MRI scans done. Because the T1 scans
did not show the nerve, we used the T2 scan to target
the nerve (Fig. 52.2a, b). A 4-mm shot was used with a
plugging pattern to shape the 10 and 20 % isodose
lines. A dose of 75 Gy was delivered to the 100 % line.
One month after GK-SRS, he noticed the sudden
improvement in his pain. At 2 months after treatment,
he was weaned off both medications. He remains pain-
free for 2 years.
Fig. 52.2 MRI images from the Gamma Knife treatment of a patient
with right trigeminal neuralgia. (a) T1-weighted MRI scan that shows
the left nerve (arrow) but not the right. (b) T2-weighted MRI scan at the
same level illustrates the right nerve well (arrow)
minimizes the volume of brain stem covered by the 10 % line.
Finally, a dose of 75 Gy is delivered to the 100 % isocenter
(37.5 Gy to the 50 %).
Patients with a pacemaker or other MRI contraindications
present a dilemma. Provided the patient is not on anticoagu-
lants, computed tomography (CT) contrast cisternography is
used for localizing the trigeminal nerve (Case 52.2). In rare
circumstances, an MRI scan in patients with a pacemaker is
required. A cardiologist is present in these cases in the MRI
suite with a defibrillator, and the pacemaker is programmed
before the scan to avoid extraventricular pacing and is then
reset immediately after the MRI.
For gamma rays, dose rate is one of the principal factors
that determine the biologic consequences of a given absorbed
L.S. Chin et al.
Case 52.2
This 60-year-old man had a 5-year history of typical
trigeminal neuralgia that initially responded to glyc-
erol rhizotomy. His pain recurred and he required
treatment with Tegretol, which was becoming ineffec-
tive. One year prior to GK-SRS, he had a cardiac defi-
brillator placed for arrhythmias. A cisternogram was
performed through a C1–2 puncture. Axial CT scans
were obtained that showed the right trigeminal nerve
(Fig. 52.3). The nerve was targeted according to proto-
col with a 4-mm shot of radiation with a total dose of
75 Gy delivered to the isocenter. Three weeks after
treatment, his pain disappeared. He remains pain-free
1 year after treatment.
Fig. 52.3 CT cisternogram of a patient with right trigeminal neuralgia
and a cardiac defibrillator. CT contrast in the CSF cisterns around the
trigeminal nerve highlights it well (arrow)
dose. As the dose rate is lowered and the exposure time
extended, the biologic effect of a given dose is generally
reduced. The University of Maryland examined this effect in
a series of patients treated the year prior to a source change
(median dose rate, 162 cGy/min: range, 151 to 179 cGy/min)
compared with patients treated in the year immediately after
a source change (median dose rate, 343 cGy/min: range, 321
to 366 cGy/min) and found the difference in pain relief was
61 % compared with 83 %, respectively (p = 0.05). These
data suggest that if dose rate falls below 179 cGy/min, con-
sideration should be made for dose escalation in the treat-
ment of TN [26].
52 Trigeminal Neuralgia 653

A comparison of selected major series reported in the

Treatment Response
Assessing positive treatment responses in TN is challenging
because the symptoms are subjective. The BNI pain intensity
score combines severity of pain with medication use
(Table 52.2) [27]. Patients able to stop all medications are clas-
sified as BNI I if they have complete pain relief or BNI II if
they have occasional tolerable pain. Patients remaining on
medication are BNI III if they have good pain relief, but are
BNI IV if they are not adequately controlled. Patients receiving
no relief are classified BNI V. Most patients are BNI V before
their treatment. For comparison with other series, we consider
BNI I to III to be a good outcome. The McGill pain score is
useful in the preoperative patient assessment (Table 52.3).
Patients are asked to rate their TN pain and their worst non-TN
headache using a range from mild (I) to excruciating (V).
Table 52.2 Barrow Neurological Institute pain intensity score
I No trigeminal pain, no medications
II Occasional pain that is well tolerated, no medications
III Occasional pain that requires medication to be tolerated
IV Pain that is not adequately controlled with medication
V Severe pain without relief
Table 52.3 McGill pain assessment score
I Mild
II Discomforting
III Distressing
IV Horrible
V Excruciating
literature is shown in Table 52.4 [22, 23, 27–32]. In general,
there is good correlation between the different series.
The range of patients achieving good relief (BNI I to III) is
69–94 % with 22–76 % achieving complete pain relief on no
medications (BNI I). The median time to pain relief varies
from 2 to 4 weeks. An actuarial analysis of recurrence has
shown rates of 23 %, 33 %, and 39 % at 1, 2, and 3 years,
respectively [28]. A follow-up of the original Maryland
series (median follow-up 5.6 years) shows that recurrent pain
become more common over time. At 5 and 7 years after treat-
ment, only 34 and 22 % of patients were free of recurrence
[33]. Quality of life assessments have documented that most
patients believe their GK-SRS treatments were successful
even when the relief was temporary. The lack of side effects
appears significant in this regard, and a high proportion of
patients who fail initial GK-SRS elect for an additional
treatment.
A variety of prognostic factors have been found to corre-
late with treatment outcome. A universal finding in all forms
of surgical therapy for TN is that the patient’s initial treat-
ment is the most effective; the results with GK-SRS are no
different. Most studies find that the absence of a prior surgi-
cal treatment correlates with a better outcome [23, 28, 29,
32]. Other preoperative prognostic factors for treatment suc-
cess include a shorter duration of symptoms and a patient
description (McGill pain scale) of their TN pain as severe
and their non-TN headaches as mild [28]. The implications
of this finding are unclear. Patients with more classic TN
pain may have fewer secondary gain issues or conflicting
social issues that may impair their treatment. A prognostic
finding that has had conflicting results is the presence of

Table 52.4 Results of initial GK-SRS in idiopathic TN

Time to
No. of Median BNI I BNI I–III pain relief Recurrence Complication
patients follow-up relief (%) relief (%) (weeks) Median dose rate (%) rate (%)
Kondziolka et al. [22] 50 18 months 58 94 4 70 Gy to the 100 % 6 10
(multicenter)
Maesawa et al. [23] 220 22 months 40 69 8 80 Gy to the 100 % 13.6 7.7
(University of Pittsburgh)
Rogers et al. [27] (Barrow 54 12 months 35 89 2 35 Gy prescribed 21 9
Neurological Institute) to the 50 %
Petit et al. [28] (University 96 30 months 42 75 3 75 Gy to the 100 % 29 7.3
of Maryland)
Pollock et al. [32] (Mayo 117 26 months 58 75 3 80 Gy to the 100 % 23 37
Clinic)
Young et al. [29] (Northwest 110 19.8 months 76 88 2 70 Gy to the 100 % 34 2.7
Gamma Knife Center)
Sheehan et al. [30] 151 19 months 47 70 3.5 80 Gy to the 100 % 27 9
(University of Virginia)
Brisman et al. [31] 293 4.6 years 22 76 NR 76.8 Gy to the 24 12
(Columbia) 100 %
NR not reported
654
atypical TN symptoms. Whereas some studies indicate atyp-
ical symptoms carry an unfavorable prognosis, others have
not confirmed this [22, 23, 27–29].
A minimum treatment dose of 70 Gy appears necessary
for a good outcome, but doses of 90 Gy and above do not
appear to provide additional pain relief. The issue of dose
escalation, however, remains an open question for a number
of reasons. The possibility of a type II error in the published
clinical series may mask a small benefit from a higher pre-
scription dose. Also, the development of posttreatment facial
numbness has been shown to correlate with good results, and
because facial numbness is dependent on the dose, an
increased dose should result in an improved or more durable
outcome [27, 32]. The development of more dysesthesias
with higher doses, however, may temper the desire to use
higher doses.
Complications
The distinguishing characteristic of GK-SRS for TN is the
very low morbidity and absence of mortality. Similar to the
percutaneous ablative procedures, the primary side effect is
trigeminal dysfunction. There is no risk to any cranial nerves
other than cranial nerve V. The reported risk of posttreatment
numbness or paresthesias varies from 2.7 to 37 % (Table 52.4)
and is not bothersome for the majority. The primary risk fac-
tor for developing this complication is receiving a dose of
90 Gy. Only one case of deafferentation pain/pain due to loss
of sensory input into the central nervous system, the most
feared complication because it is so difficult to treat, has
been reported [23]. Corneal numbness, another dangerous
complication because of the potential risk of permanent
damage to the eye, has been reported in only three patients,
all treated with 90 Gy [34]. No mastication motor deficits
were seen in any study. As expected, patients who undergo a
repeat GK-SRS treatment to the same trigeminal nerve have
a higher incidence of facial numbness, but there has not been
an increase of dysesthesias or symptomatic radiation necro-
sis reported. A complication that is not reported but has been
observed in our patients is the temporary exacerbation of tri-
geminal pain in the initial month after GK-SRS. In no
patients has this become permanent.
Table 52.5 Results of repeat GK-SRS for idiopathic TN
Follow-up
N (months)
Herman [35] (University of Maryland) 18/112 28
Hasegawa et al. [36] (University of Pittsburgh) 27/387 20.4
Shetter [37] (Barrow Neurological Institute) 19/240 13.5
Pollock [38] (Mayo Clinic) 10/100 15
L.S. Chin et al.
Treatment Options for Recurrent
Trigeminal Neuralgia
Although the initial response to GK-SRS is often quite good,
the response may not be durable. As seen in patients treated
by MVD and the percutaneous procedures, recurrence rates
increase with time. Using an actuarial analysis, this recur-
rence rate for GK-SRS may be as high as 39 % by 3 years
after treatment. Petit found that absence of a prior surgical
treatment, duration of TN less than 50 months before
GK-SRS, and a BNI I response to GK-SRS correlated with
smaller risk of recurrence [28].
Most patients choose to undergo a repeat GK-SRS at first
recurrence. Data from four institutions on repeat GK-SRS
for recurrent TN are presented in Table 52.5 [35–38].
Although there are variations in technique, primarily related
to the dose given at the second treatment, the results of repeat
GK-SRS are generally quite good. The University of
Maryland reported 18 patients from a total series of 112
patients who underwent repeat GK-SRS for TN [35]. BNI I
result was seen in 45 % and BNI I–III was seen in 33 %.
Repeat GK-SRS was more effective for patients that experi-
enced a longer period of pain relief after their initial
GK-SRS. Patients that had no response to initial GK-SRS
also failed to respond to their second treatment. Only 11 %
experienced increased numbness in this experience. The
target for the second treatment is usually not different from
the initial treatment, although Hasegawa advocated placing
the second lesion just anterior to the first one to reduce the
brain-stem dose [36]. The optimum dose to be used at second
treatment has not been established. Some centers use a lower
dose at repeat treatment, whereas others have advocated
increasing the second dose to 90 Gy.
The University of Maryland recently presented data com-
paring treatment outcomes for patients treated with repeat
radiosurgery for refractory or recurrent TN with a low dose
(70–75 Gy) performed at the University of Maryland and a
high dose (90 Gy) performed at the University of Kentucky.
Similar rates of pain control were seen in both groups. The
higher dose was associated with an increased probability of
discontinuing all medications. It is worth noting though that
25 % of these patients had increased or new-onset numbness
BNI class BNI class First dose Second Trigeminal
I (%) I–III (%) (Gy) dose (Gy) dysfunction (%)
45 78 75 70 11
19 85 75 64 11
53 85 78 46.6 42
80 80 70 90 80
52 Trigeminal Neuralgia
or dysesthesias [39]. Not unexpectedly, using the higher
doses results in 80 % of patients experiencing trigeminal
dysfunction, but the percentage of patients having an excel-
lent result (BNI I) is also increased. Because there is no pre-
cedence for performing a third GK-SRS on the same nerve
until recently, the risk of radiation necrosis of the brain stem,
which is presumed to be high, is unknown. At SUNY, the
authors have recently treated a case of right-sided trigeminal
neuralgia three times over 10 years, the last one delivered a
year ago. This patient has a relatively long segment of tri-
geminal nerve between the pons and Meckel’s cave. The
single 4-mm target isocenter for the third GK-SRS was made
7.5 mm away from the pons. The treatment prescription was
70 Gy to 100 % and the maximum dose to the pons was cal-
culated to be 9.98 Gy, which was considered to be safe. The
patient experienced good pain relief after the third GK-SRS
without any side effects including no facial numbness at one
year follow-up.
The alternative to a repeat GK-SRS is either MVD or a
percutaneous procedure. Pollock et al. found that an excel-
lent outcome was seen in 75 % of patients undergoing MVD
and in 71 % undergoing glycerol rhizotomy [32]. Interestingly,
five of eight patients were observed to have a region of pre-
sumed radiation injury on the segment of the superior cere-
bellar artery that contacted the trigeminal nerve. In four of
these five cases, the patient either received a high dose
(90 Gy) or had a repeat GK-SRS treatment. Our anecdotal
experience with MVD after failed GK-SRS is that arachnoidal
adhesions do form on the trigeminal nerve and can complicate
mobilization of arterial loops. Good outcomes, however, are
still possible with MVD in this setting [40].
Secondary Trigeminal Neuralgia
Patients with secondary TN experience symptoms caused by
the compressive effects of a tumor. The two most common
tumors are meningioma and trigeminal schwannoma, but
other tumor types such as metastases, chordoma, and epider-
moids are also possible. These tumors are usually located in
the cavernous sinus, Meckel’s cave, petroclival region, or
tentorial notch. In addition to TN, patients may present with
facial numbness, weakness, diplopia, visual loss, and hemi-
paresis. Treatment with GK-SRS in these patients is both
effective at controlling tumor growth and TN symptoms.
Regis et al. reported 46 patients with tumors amenable to
GK-SRS who were treated with a multiple-shot dose plan to
a mean dose of 14 Gy (range, 8–25 Gy) [41]. Forty-five
patients were followed for a median time of 55 months.
Initially, 80 % had complete pain relief (BNI I) and 16 %
were improved. Recurrent pain was experienced by 6
(13.3 %) patients, and slight hypesthesias were seen in 2
(4.4 %). In comparison with published microsurgical series,
655
GK-SRS for secondary TN has a much lower rate of
postoperative trigeminal dysfunction (4 % versus 17–45 %),
and essentially no risk of other cranial nerve deficit or motor
weakness. In addition, patients avoid the customary compli-
cations of craniotomy and general anesthesia. The mecha-
nism of pain relief is not known because these benign tumors
do not change significantly in size after GK-SRS, and the
doses given are significantly smaller than typical doses for
idiopathic TN. Compensating for the lower doses may be the
fact that the prescription isodose lines in the tumor cases
are generally much closer to the brain stem indicating that
the brain stem at the root entry zone may receive a dose simi-
lar to patients treated by the standard 4-mm shot protocol.
These results raise the interesting hypothesis that the effec-
tiveness of GK-SRS in TN is related more to the brain-stem
dose than to the nerve dose [42]. Further studies will be
needed to clarify this issue.
Multiple Sclerosis, Post-herpetic Neuralgia,
and Atypical Facial Pain
TN is a well-recognized symptom of MS, and its manifesta-
tions are indistinguishable from classic, idiopathic TN. It
occurs in 1–2 % of patients with MS but rarely as the pre-
senting symptom. Patients with MS present at an earlier age
and frequently have bilateral pain [42]. Pharmacological
treatment of MS-TN patients is complicated by their greater
sensitivity to gait imbalance and other side effects of medica-
tions. Both MVD and percutaneous procedures have a lower
rate of effectiveness for patients with MS, but GK-SRS has
been shown to be effective in up to 80 % of MS-TN patients
[43, 44]. The treatment protocol for these patients is
unchanged with respect to dose and target. Because MS
patients comprise a small portion of the major series pub-
lished to date, their sensitivity to GK-SRS compared with
typical TN patients is unknown [28, 29]. An increase in tri-
geminal complications has not been seen [43].
The use of GK-SRS for atypical facial pain syndromes such
as post-herpetic neuralgia is controversial. Pharmacological
therapy is frequently ineffective, and MVD and percutaneous
treatments are contraindicated because they may worsen the
pain. Only nucleus caudalis dorsal root entry zone (DREZ)
lesions have been documented to show some benefit. Urgosik
reported on 16 patients who received GK-SRS and found a
successful result (excellent, very good, and good) in only 44 %
of patients. Pain relief occurred after a median interval of 1
month, and no radiation-related side effects have been observed
in these patients [45]. The University of Maryland experience
with atypical facial pain syndromes is similar. In this study,
approximately half of the patients presented with atypical TN
and half initially presented with classic TN that then pro-
gressed to atypical TN. Seventy-two percent of patients
656
reported pain relief with a median time to relief of 5.8 weeks
(range, 0–24 weeks). There was no significant difference
between those that presented with atypical pain and those that
progressed to atypical TN. Approximately 60 % of patients
were able to discontinue or decrease the use of pain medica-
tion. Bothersome numbness was reported in five (27 %)
patients. Of the patients with sustained pain relief, quality of
life improved an average of 82 %, and of the patients in whom
pain returned, quality of life improved an average of 63 %
[46]. The standard treatment protocols are used, and an
increase in complications or worsened pain has not been noted.
Conclusion
GK-SRS for TN is effective and should be considered a stan-
dard alternative to conventional surgical treatments for idio-
pathic TN. Initial results are comparable with other
treatments, but a significant recurrence rate is observed. It is,
however, an extraordinarily safe procedure particularly for
elderly patients and those wishing to avoid surgery or have
surgical contraindications.
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 Trigeminal
Neuralgia: Viewpoint—Surgery
Craig Rabb and Ahmed Cheema
Introduction
Trigeminal neuralgia is a severely debilitating disease with
annual incidence of 4.3 cases per 100,000 and accounting for
15,000 new cases diagnosed each year [1]. Its lifetime preva-
lence is estimated to be around 0.3 % [2]. It is a clinical diag-
nosis usually characterized by unilateral sharp stabbing pain
exacerbated by touch with pain-free intervals in between epi-
sodes [3]. It is well established that the majority of cases are
caused by some kind of compression at the root entry zone
[4]. The pathophysiology of trigeminal neuralgia has been
extensively studied yet poorly understood. Prior to undertak-
ing treatment, trigeminal neuralgia must be differentiated
from patients with atypical facial pain [5]. Although vascular
compression is most likely the culprit for neuralgia, other
compressive and demyelinating causes account for about
6–16 % of the cases and should be entertained during evalu-
ation including tumor, aneurysm, venous compression, and
multiple sclerosis [6–10]. Surgical options for trigeminal
neuralgia can be broadly divided into either destructive or
nondestructive. This chapter reviews these techniques fol-
lowed by a comparison with stereotactic radiosurgery (SRS).
Percutaneous Glycerol Rhizotomy
Since its inception by Håkanson in 1981 and subsequent testing
and progression by Beck and Lunsford, percutaneous retrogas-
serian glycerol rhizotomy still is used for treatment of trigemi-
nal neuralgia [11–13]. It involves identification of Meckel’s
cave and then successful injection of 0.2–0.4 mL glycerol [14].
It is a chemically destructive method of treatment.
C. Rabb, M.D. (*) • A. Cheema
Department of Neurosurgery, University of Oklahoma
College of Medicine, 1000 N. Lincoln, Suite 400,
Oklahoma City, OK 73104, USA
e-mail: craig-rabb@ouhsc.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_53, © Springer Science+Business Media New York 2015
53
Technique
The procedure is carried out under sedation as patients need
to be awake for examination during rhizotomy. The patient is
placed in the supine position and Hartel’s technique can be
used to visualize the path to foramen ovale and eventually to
Meckel’s cave. The Hartel’s technique describes three points
[15]. Point 1 is located inferiorly at mid pupil, Point 2 is
located 3 cm anteriorly to external auditory meatus along
zygoma, and Point 3 is located 2–3 cm lateral to oral com-
missure. The foramen ovale is located at the junction of
vertical axis (Point 1) and horizontal axis (Point 2). Point 3
signifies the entry point of needle. Cannulation of the fora-
men ovale is carried under local anesthesia and confirmed
with fluoroscopy, wince reflex, contraction of masseter mus-
cle, and flow of cerebrospinal fluid (CSF). Additionally, cis-
ternography can be used to confirm the location of needle in
appropriate location. Lately, frameless stereotaxy has also
been used to increase accuracy and decrease time to cannula-
tion of foramen ovale with promising results [16–18]. Once
the needle is appropriately placed in Meckel’s cave, cisternal
volume is estimated and anhydrous glycerol is injected. The
patient is kept in sitting flexed position for an hour, then
watched overnight in the hospital before being discharged.
Results
Lunsford described a series of 112 patients undergoing
percutaneous glycerol rhizotomy (PGR), with 67 % having
complete pain relief, 23 % improved requiring minimal med-
ical therapy, and 10 % having an unfavorable outcome [19].
Fujimaki et al. followed 122 patients who underwent PGR
for 38–54 months and noticed a median pain-free interval of
32 months and a recurrence rate of 72 % [20]. They also
noticed 63 % of patients having post-procedure hypesthesias,
29 % having dysesthesias, and two patients with anesthesia
dolorosa. Blomstedt et al. evaluated the complications rela-
ted to the procedure. They observed persistent debilitating
659
660
complications in 28.1 % of patients including labial herpes
(1.8 %), anesthesia dolorosa (0.8 %), dysesthesias (22.7 %),
hearing loss (1.9 %), and meningitis (1.5 %) [21]. When
compared to Gamma Knife surgery, both have good initial
outcomes; however, there were more recurrences in the PGR
group compared to Gamma Knife and a later treatment
response in the Gamma Knife group [22].
Percutaneous Radiofrequency Ablation
Radiofrequency ablation is a thermal destructive method for
treatment of trigeminal neuralgia. Its technique and results
are described below.
Technique
This procedure can be carried out under local anesthesia
with mild sedation. Access to the foramen ovale and confir-
mation are carried out as discussed in glycerol rhizotomy
section. Once the foramen ovale is cannulated, either a
straight or curved thermal-coupled or cordotomy-type elec-
trode can be used for selection of trigeminal nerve divi-
sions. Curved electrodes give the surgeon an opportunity to
selectively ablate rootlets. The nerve roots can be located
using the clivus as anatomical landmark. The maxillary
nerve is located at the clivus, the ophthalmic division is
located distally, and the mandibular is located proximal to
clivus.
Once the desired nerve branch is selected, a preliminary
lesion is produced using 70 °C for 70 s. The patient’s facial
sensation is assessed and sometimes facial flushing can be
noticed that is present in the selected rootlet.
Results
Ischia et al. in his series of 124 patients noted greater than
90 % immediate relief with only 67 % of patients having
no pain at 3.7-year follow-up [23]. They also noted that
2–3 % of patients have hypesthesia, dysesthesia, decreased
visual acuity, and masseter dysfunction following the
procedure.
Percutaneous Balloon Compression
Balloon micro-compression is a mechanical destructive
method for treatment of trigeminal neuralgia.
C. Rabb and A. Cheema
Technique
Balloon compression is carried out under general anesthesia as
there is a risk of bradycardia that should be closely monitored
and watched during the extent of procedure. An external pace-
maker is placed. The foramen ovale is cannulated as described
before. Once the foramen ovale accessed, a Fogarty balloon is
inflated with intraluminal pressures of 1,200–1,500 mmHg
and resultant tissue compression of 650–950 mmHg. The bal-
loon shows characteristic pear shape. The balloon is inflated
for 1 min and then withdrawn.
Results
Belber et al. reported improvement in 76 % of patients after
balloon compression [24]. In elderly cohort, Mizuno et al.
reported promising results with 10/16 patients benefiting
from the procedure and others having at least 50 % improve-
ment in their pain [25].
Microvascular Decompression
Microvascular decompression (MVD) has long stood the test
of time for treatment of trigeminal neuralgia in appropriately
selected patients. It is an invasive but nondestructive method
of treatment for trigeminal neuralgia focusing mainly on
decompression of trigeminal nerve. It has been extensively
studied and is considered the gold standard for comparison
with other treatments while newer methods are still being
investigated.
Technique
The procedure requires the patient to be under general anes-
thesia and appropriately positioned to have CSF diverted to
allow for maximal cerebellar retraction with minimal mechan-
ical retraction. The patient is positioned in the lateral decubitus
position with the head secured using three-point fixation with
head holder, flexed, and rotated to allow the maximal access to
the cerebellopontine angle. The ipsilateral arm is carefully
padded, and placed on an “airplane,” and is taped under mild
tension so as to move the shoulder out of the line of vision, an
access to the cerebellopontine angle (CPA). Reverse
Trendelenburg position can be used for optimal venous flow.
The entry point can be determined by drawing a line run-
ning from the inion to the zygoma, which in the retromastoid
area identifies the transverse sinus. The digastric grove is then
53 Trigeminal Neuralgia: Viewpoint—Surgery
the anatomical landmark for the sigmoid-transverse junction
[26]. In studies, it has been shown to be posteroinferior to the
asterion [27, 28]. Image guidance can be used to further
assess the junction, although we have not found this neces-
sary. A curvilinear “lazy S” incision is made and carried down
to the bone. A high-speed drill is used for making a burr hole,
to initiate exposure. Kerrison rongeurs are then used to
remove bone in an anterior-superior direction until the stereo-
typic bluish appearance of the sinus is identified, and the
transverse sigmoid junction is partially exposed. The dura is
open in a T-shaped manner inferior and posterior to the
sinuses [26]. The procedure may be carried out while continu-
ous brain stem auditory evoked potentials are being moni-
tored [29]. CSF is allowed to liberally drain during exposure.
The microscope is then brought in. Typically, the tentorial
dura above the cerebellum is used as an orientation point, and
bony and dural exposure should be continued until the under-
surface of the tentorium is readily visualizable. Then, one can
trace this anteriorly until the junction with the petrous bone
forms an unmistakable angle, which is the direct route to the
trigeminal nerve. The arachnoid of the CPA cistern is opened
using microdissection techniques, and CSF is further drained.
The cerebellum then relaxes considerably. We usually employ
extremely gentle retraction on the upper surface of the cere-
bellum until sufficient CSF has drained that it is no longer
needed. In the lateral position, once CSF is drained, gravity
becomes an excellent retractor.
The eighth nerve can be encountered en route to the
trigeminal nerve, and can be confused for the fifth nerve by
less experienced surgeons. Maintaining awareness of this is
crucial. The trigeminal nerve, once encountered, is usually
unmistakable by its characteristic location at the apex of the
tentorium/petrous junction and by its brilliant white appear-
ance. The surgeon then must use careful microdissection
to mobilize the offending vessels from the nerve. The most
common artery compressing the nerve is the superior cere-
bellar artery. One must be careful not to assume there is just
one vessel causing symptoms. Occasionally, compression
can originate from petrosal veins or the anterior-inferior cer-
ebellar artery. Veins causing compression usually require
cauterization and division [30]. Our preference for treatment
of the arteries is to mobilize them extensively, and place a
sling of Teflon around the vessel, and glue it to the tentorium
well away from the nerve using fibrin sealant. The Teflon felt
requires teasing it with Adson forceps until a thin strip
results. Only when the artery cannot be mobilized suffi-
ciently do we place a pad of Teflon felt between the artery
and nerve. The whole nerve should be examined for any
offending loops from its origin in brain stem all the way to
the Meckel’s cave [31].
661
It has been shown that isolated ophthalmic division
symptoms are most likely in cigarette-smoking older patient
population and are via caudal compression [32]. Maxillary
division symptoms are usually found in woman and usually
secondary to a venous compression [33]. Mandibular nerve
symptoms are usually caused by rostral compression from
the superior cerebellar artery [32].
The wound is copiously irrigated and any venous oozing
stopped meticulously. Bone edges are waxed and the dura is
closed watertight with 4-0 or 5-0 suture, and augmented with
fibrin sealant. Cranioplasty is performed using calcium phos-
phate cement, and scalp is closed in usual fashion. Patients
are watched in the intensive care setting overnight and usu-
ally discharged in 2–3 days.
Results
Several studies have evaluated patients undergoing MVD
years following surgery. Originally, Apfelbaum in a series of
273 patients followed for 55 months showed immediate
relief in 94 % of patients and satisfactory pain relief in 70 %
of patients on follow-up [34]. Kolluri and Heros described
similar results with 78 % pain relief in patients undergoing
MVD with a mean follow-up of 5 years [35]. Burchiel et al.
had a higher recurrence rate of 47 % in his study with major
recurrence rate of 3.5 % annually and minor recurrences of
1.5 % annually [36]. In these studies, it was noted that patient
with definitive arterial compression had lower rate of recur-
rences when compared to venous and/or bony compression.
In a larger study, Barker et al. mentioned that at 6.2 years, the
treatment success in patients undergoing MVD was 70 %
[37]. The recurrence rate after 10 years of follow-up was less
than 1 % and most of the recurrences were in the initial
2-year follow-up. Similar results were also reported by Olson
et al. in their 25-year follow-up of MVD [38]. Special atten-
tion should be paid to patients with multiple sclerosis and
trigeminal neuralgia. This subpopulation of patient has been
thought to be refractory to treatment with MVD. Resnick
et al. in their analysis showed that MVD alone is insufficient
for treatment, however should be considered on a case-by-case
basis [39–42].
McLaughlin et al. in their analysis of complication rate of
MVD in a large series have observed that in experienced
hands the complications associated with MVD are low.
Since 1990, after modifications of MVD technique under
Dr. Jannetta, the rate of cerebellar injuries is 0.45 %, CSF
leak is 1.85 %, and hearing loss is 0.8 %, based upon analysis
of 1995 patients who underwent MVD [43]. In another anal-
ysis by Kondo et al., they witnessed increasing satisfaction
662
and pain-free interval in patients undergoing surgery after
1990, where satisfaction rate grew from 92.9 to 96.7 % with
recurrence decreased from 10.2 to 6.5 % [44]. Risk stratifi-
cation for MVD has been done to predict outcomes.
Theodosopoulos et al. stratified patients undergoing MVD as
high risk based upon age less than 53 years, female sex, men
with left-sided trigeminal neuralgia and pain lasting greater
than 11 years and found that in high risk group 58 % of the
patients are pain free at 4-year follow-up compared to
80–89 % of patients in lower risk profile [45].
Discussion
Microvascular Decompression Versus
Glycerol Rhizotomy
Fergusson described a series of 45 patients who were
followed after PGR compared to MVD in 24 patients, which
showed 58 % pain free at 30 months compared to 71 %,
respectively [46]. Suwa et al. retrospectively analyzed the
pain-free interval and found 7 % recurrence in case of MVD
at 95 months compared to 49 % in PGR group at 84 months
[47]. Similar results were also seen in a retrospective study
for a 20-year follow-up that showed 50 % recurrence rate
with PGR at 2-year follow-up compared to MVD with 64 %
pain-free and lesser sensory deficits after 20 years [48, 49].
Microvascular Decompression Versus
Radiofrequency Ablation
Apfelbaum originally described comparison of percutaneous
radiofrequency ablation (PRFA) with MVD and described a
series of 103 patients followed for 36 months, with results
showing 88 % relief in PRFA group versus 96 % in MVD
with recurrence rates of 13 % and 5 %, respectively [50].
Microvascular Decompression Versus
Gamma Knife
Kondziolka et al. in their analysis for SRS have shown that
96 % of the patients initially treated with Gamma Knife have
good to excellent result at 1-year follow-up [51]. In patients
previously treated with MVD, SRS proved to be beneficial to
85.6 % of patients, further elucidating its important role in
patient population with recurrent and refractory trigeminal
neuralgia and as an adjuvant therapy [52]. Pollock et al.
showed in their analysis that when compared with SRS,
MVD offers more prolonged pain-free interval at 3-year
follow-up (72 % versus 59 %) [53]. Sheehan et al., in another
3-year follow-up study, confirmed the delayed onset of relief
C. Rabb and A. Cheema
following Gamma Knife radiosurgery (mean 24 days, range
1–180 days) and a 33 % recurrence rate at 1-year follow-up
[54]. These results stress the need for further studies however
also show that in patients suitable for MVD, surgery should
be offered, with Gamma Knife reserved for patients not ame-
nable to surgery, or those who decline open surgery.
Microvascular Decompression in Elderly
Jodicke et al. in their limited analysis of eight patients with
median age of 70 years showed that 6/8 patients were pain
free after MVD and propose consideration of MVD even in
patients older than 65 years of age if they are medically sta-
ble to undergo surgery [55]. Ogungbo et al. in a 42-patient
retrospective analysis found no differences in outcomes
in patients older than 65 years of age when compared to
younger cohort [56]. Similar results were also reported by
Ferroli et al. and Pollock et al. in their analysis [57–59].
Economical and Patient’s Perspective
of Treatment Options
Pollock and Ecker, in their prospective cost-based analysis,
showed “The cost per quality adjusted pain-free year was
$6,342, 8,174, and 8,269 for glycerol rhizotomy, microvas-
cular decompression, and SRS, respectively” [60]. This chapter
emphasizes that in older patients percutaneous methods may be
more cost-effective and in younger population MVD remains a
better surgical option when considered from an economic
standpoint of view. Zakrzewska et al. based upon questionnaire
showed that 89 % of the patients undergoing MVD were satis-
fied with the surgical outcome compared to 72 % with percuta-
neous rhizotomy [61]. The MVD group was also less dissatisfied
at 4 % compared to 20 % in percutaneous rhizotomy group.
Conclusion
There are multiple invasive and noninvasive treatments
available for trigeminal neuralgia. While percutaneous pro-
cedures offer a less invasive modality for treatment, their
long-term recurrence rates are higher when compared to the
MVD. Even in patients refractory to initial MVD, recur-
rences have been successfully treated with re-exploration
[62]. These reoperations have shown arterial (22 %), venous
(13 %), and Teflon compression (13 %) in these patients.
Percutaneous methods show promise in selected patient
populations who cannot undergo surgery due to comorbidi-
ties. SRS offers another alternative to MVD as it can be
performed in patients with significant medical comorbidi-
ties. It has a delayed onset yet usually gives good pain relief.
53 Trigeminal Neuralgia: Viewpoint—Surgery
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 Trigeminal Neuralgia:
Viewpoint—Medical Management
Neil C. Porter
Introduction
Trigeminal neuralgia is a well-recognized neuropathic pain
syndrome characterized by brief paroxysms of facial pain in
the distribution of the trigeminal nerve. The syndrome can
occur secondary to a number of medical conditions includ-
ing multiple sclerosis, basilar artery aneurysm, and brain
tumor [1]. The disorder can also be idiopathic, the latter
instance being known as Tic Delouroux. Trigeminal neural-
gia can strike persons of any age but typically affects older
individuals. Treatment options include a number of neuro-
pathic pain medications as well as neurosurgical and radio-
surgical interventions. The mainstay of treatment for most
individuals, however, remains medication.
Clinical Features
Trigeminal neuralgia is characterized by recurrent facial pain
in the distribution of the trigeminal nerve. The trigeminal
nerve is divided into three branches, V1, V2, and V3, provid-
ing sensory innervation to the forehead, cheek, and chin,
respectively. The pain of trigeminal neuralgia most fre-
quently occurs in the distribution of V2 or V3. The pain is
usually lancinating in nature, occurring as fleeting shocks.
This pain can be extremely intense, producing a great deal of
distress in sufferers. The pain is typically triggered by chew-
ing, ingesting cold foods or liquids, cold winds, or simple
tactile stimulation on the face.
N.C. Porter, M.D. (*)
Department of Neurology, University of Maryland School
of Medicine, 110 S. Paca Street, Baltimore, MD 21201, USA
e-mail: Nport001@umaryland.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_54, © Springer Science+Business Media New York 2015
54
Pathophysiology
The pathophysiology and pathogenesis of trigeminal neural-
gia are poorly understood. A number of theories abound,
however [2, 3]. Given that the condition occurs in multiple
sclerosis, some investigators have argued that demyelination
at the entry zone of the nerve root is a common feature to
both primary and secondary trigeminal neuralgia [4]. Others
have focused on structural concerns with the “vascular com-
pression theory” [5]. In this latter circumstance, the pain is
believed to be the consequence of compression on the tri-
geminal nerve by some vascular anomaly. In any event, the
major focus in treating the patient is the elimination of the
subjective pain.
Neuropathic Pain
Trigeminal neuralgia is a condition characterized by neuro-
pathic pain. Other notable conditions that also involve neuro-
pathic pain include painful diabetic neuropathy, post-herpetic
neuralgia, and complex regional pain syndrome. In contrast
to nociceptive pain, whereby the nervous system detects
some unpleasant stimulus alerting the body to potential dam-
age, in neuropathic pain the nervous system generates the
impulses that are appreciated as pain by the patient.
Neuropathic pain can be constant or intermittent in nature. It
may be characterized as burning, aching, stabbing, or shoot-
ing. The pain may occur spontaneously or, as with trigeminal
neuralgia, be elicited by tactile stimulation.
Neuropathic Pain Agents: Overview
Medications used to treat neuropathic pain can be conve-
niently organized into a number of classes including antiepi-
leptic drugs, GABA-related medications, antidepressants, and
local anesthetics or topical agents. Although not traditionally
665
666
viewed as neuropathic pain agents, narcotics are also effective
in treating neuropathic pain. Particular benefits and draw-
backs are associated with each class of agent as well as spe-
cific agents within each class. Most of the agents are well
tolerated, but cognitive side effects may limit the utility of
many of the antiepileptic drugs and antidepressants in certain
cases. For trigeminal neuralgia, the antiepileptic medications
dominate the treatment strategy followed by the GABA ago-
nists. Antidepressants have little role while narcotics provide
only adjunctive therapy. An excellent review of the literature
regarding pharmacologic treatment options is contained
within a Practice Parameter from the American Academy of
Neurology in 2008 on issues surrounding the diagnosis and
treatment of trigeminal neuralgia [6].
Antiepileptic Drugs
Carbamazepine
Carbamazepine is clearly the drug of choice for trigeminal
neuralgia. Known mostly for treatment of partial and sec-
ondarily generalized seizures, Carbamazepine is also a well-
known neuropathic pain agent. Structurally similar to the
tricyclic antidepressants, Carbamazepine’s effectiveness for
seizures and neuropathic pain is believed to occur through its
action on sodium channels. Carbamazepine acts to block
sodium channel function in a rate-related fashion. This
allows the medication to affect dysfunctioning neurons
greater than those firing normally.
Carbamazepine was first reported to be effective in treat-
ing trigeminal neuralgia in 1962 [7]. This agent was proven
efficacious in a number of randomized placebo-controlled
clinical trials [8–10]. In each trial initial response rates were
as high as 70–90 %. Long-term efficacy, however, dimin-
ished to approximately 50 %.
Carbamazepine has a relatively short half-life, necessitat-
ing a dosing schedule of 3–4 times per day. Because it auto-
induces its own metabolism, a patient cannot be loaded with
Carbamazepine. Instead, Carbamazepine must be started at a
relatively low dose and then slowly titrated upwards. The
patient should be started at 100 mg BID or TID. The dose
can be increased every 3–5 days by 200 mg total up to
200–400 mg TID. Some refractory patients may require
doses as high as 2,400 mg/day (800 mg TID).
Carbamazepine’s major advantage is its efficacy in most
patients. The medication is relatively well tolerated with
only minor side effects in the majority of patients.
Additionally, Carbamazepine is relatively inexpensive, being
available in generic form.
Unfortunately, Carbamazepine is not without its shortcom-
ings. Given its relatively short half-life, the medication requires
relatively frequent dosing that may affect compliance.
N.C. Porter
Carbamazepine is associated with a dose-related leukopenia
but in rare circumstances has been linked to irreversible
aplastic anemia (risk at 1:40,000). Additional side effects
include dizziness and hyponatremia. Drug interactions are
also problematic given that Carbamazepine affects the levels
of other medications that are metabolized by the P450
system.
In summary, Carbamazepine is the mainstay of medical
treatment for trigeminal neuralgia, with proven efficacy in
randomized clinical trials. Efficacy initially ranges from 70
to 90%, but response rates may diminish over time to 50%.
The medication must be started cautiously and titrated
relatively slowly.
Oxcarbazepine
Oxcarbazepine is a newer antiepileptic drug structurally
related to Carbamazepine. Like its structural analog,
Oxcarbazepine is a sodium channel blocker. Because of
structural modifications, however, this newer drug has a
number of theoretical and practical advantages over
Carbamazepine. Oxcarbazepine has much less effect on the
P450 system and therefore is associated with far fewer drug
interactions. Furthermore, Oxcarbazepine cannot be metabo-
lized to an epoxide derivative that is responsible for some of
the side effects seen with Carbamazepine. Obviously, though,
given its lesser track record, Oxcarbazepine is less well
established than Carbamazepine as a treatment for trigemi-
nal neuralgia.
Although Oxcarbazepine has not been proven effective
for trigeminal neuralgia in a randomized, placebo-controlled
trial, it has been shown to have similar efficacy as
Carbamazepine in two randomized trials. Response rates in
these trials approached 90% [11, 12]. Furthermore, the drug
appeared to be better tolerated than Carbamazepine.
Oxcarbazepine is typically started at 150–300 mg BID,
with the lower dosing associated with less side effects.
Typical target dosages range from 300 to 600 mg BID with
some refractory patients requiring up to 1,200 mg BID.
Oxcarbazepine appears to possess several advantages
over Carbamazepine, including better tolerability and fewer
drug interactions. One disadvantage, however, is cost.
Being a newer agent, Oxcarbazepine is significantly more
expensive than the older Carbamazepine. Additionally,
Oxcarbazepine has been associated with a number of side
effects similar to other sodium channel blockers, including
dizziness, headache, gait instability, nausea, and vomiting.
In summary, Oxcarbazepine holds great promise to poten-
tially replace Carbamazepine as the first-line treatment for
trigeminal neuralgia. Although both medications have simi-
lar efficacy, Oxcarbazepine appears to be safer and better
tolerated.
54 Trigeminal Neuralgia: Viewpoint—Medical Management
Gabapentin
Gabapentin has assumed a major role as an antiepileptic drug
used for neuropathic pain. A number of trials have proven its
efficacy in treating painful diabetic neuropathy and post-
herpetic neuralgia. Despite this, no clinical trials have proven
Gabapentin’s role in trigeminal neuralgia. Nonetheless,
Gabapentin has been advocated for trigeminal neuralgia as
well as other disorders characterized by neuropathic pain.
Gabapentin was developed as an antiepileptic drug with
structural similarity to GABA. The medication, however,
appears to have no action at the GABA receptor. Instead,
Gabapentin is believed to exert its effect through the α[alpha]-
2-δ[delta] calcium channel.
Gabapentin has been proven efficacious in randomized
clinical trials for neuropathic pain syndromes such as painful
diabetic neuropathy and post-herpetic neuralgia but not spe-
cifically for trigeminal neuralgia. The drug has been reported,
however, to provide adequate pain relief for trigeminal neu-
ralgia in small, uncontrolled series [13, 14].
Like many of the other neuropathic pain agents, Gabapentin
is best tolerated when started at a very low dose. Patients may
be started at 300 mg daily with their dose being increased by
300 mg every 3 days up to 600 mg TID. Studies have failed
to show superiority of higher doses of Gabapentin, but some
individuals may require doses as high as 900–1,200 mg TID.
The most attractive aspect of Gabapentin is its apparent
safety. Gabapentin is extremely well tolerated with no appre-
ciable serious medical side effects, and negligible drug inter-
actions. Furthermore, overdosage has not been seen, given
the lack of dose-limiting side effects.
Given the large dosages required by patients for adequate
pain relief, Gabapentin can be quite costly even as a generic.
Furthermore, problematic side effects include dizziness,
lower extremity edema, weight gain, and headaches. Lastly,
a withdrawal syndrome has been reported with rapid cessa-
tion of the medication.
In short, Gabapentin is a very popular drug for neuro-
pathic pain because of its favorable side effect profile.
Evidence to date supports its use in trigeminal neuralgia fol-
lowing trials of the better-established medications.
Lamotrigine
Lamotrigine is a newer antiepileptic drug that acts through a
novel mechanism. It is believed to exert its effect through the
stabilization of the inactive form of the sodium channel.
Although Lamotrigine has a relatively short track record
with regard to neuropathic pain, this agent has already been
shown to be efficacious in treating patients with trigeminal
neuralgia. In a number of uncontrolled series, Lamotrigine
conveyed adequate pain relief to a majority of patients
667
[15, 16]. In one randomized, double-blind, placebo-
controlled, crossover study, Lamotrigine again performed
well, being superior to placebo [17].
Lamotrigine must be started at a low dose and increased
slowly to minimize the risk of a serious rash. The medication
is typically started at 25 mg qd and increased by 25 mg every
3–7 days up to 200 mg qd. The major side effect with
Lamotrigine is the aforementioned rash; otherwise, the med-
ication is safe and well tolerated.
In summary Lamotrigine is another promising agent
whose use in trigeminal neuralgia should increase over time.
The medication is safe when used correctly, apparently
effective and well tolerated.
Topiramate
Topiramate is a novel antiepileptic agent that is believed to
work by blocking sodium channels, blocking certain gluta-
mate receptors, and enhancing activity of GABA via a non-
benzodiazepine site of the GABA receptor. Although it has
never been studied in randomized trials, a number of small
series have demonstrated its efficacy in trigeminal neuralgia
[18, 19]. Topiramate is typically started at 25 mg b.i.d. and
increased by 50 mg at weekly intervals up to 200 mg BID.
On the positive side, Topiramate is safe and reasonably
well tolerated, but it does have some notable drawbacks.
As a new drug, it is relatively expensive. Additionally,
Topiramate appears to cause mental clouding, including
word-finding difficulty. Lastly, it is associated with kidney
stone formation.
To summarize, Topiramate may be a reasonable third-line
agent that is safe and reasonably well tolerated. Future studies
are needed to specifically justify its use in trigeminal neuralgia.
Pregabalin
Pregabalin is a compound designed to be similar to
Gabapentin. It has been proven efficacious in treating painful
diabetic neuropathy but is not specifically approved for tri-
geminal neuralgia. The mechanism of action is believed to
be similar to that of Gabapentin, namely via action at the
α[alpha]-2-δ[delta] calcium channel. Because of its more
recent development, experience with Pregabalin is more lim-
ited than with many of the other agents. Although no specific
studies using Pregabalin for trigeminal neuralgia have been
performed, the medication’s affect on neuropathic pain in
general makes it a reasonable consideration once the more
established agents have been exhausted.
The target dose of Pregabalin is 300 mg daily divided
BID. The medication is typically started at 75 mg BID and
increased up to 150 mg BID after approximately 1 week.
668
Pregabalin appears to be safe and well tolerated, similar
to Gabapentin. Its greater potency, however, allows for lower
dosages and therefore lower pill counts than its predecessor.
Furthermore, cost is similar to that of Gabapentin. Pregabalin
is associated with similar side effects as Gabapentin.
Additionally, though, thrombocytopenia and arthralgias have
been reported.
In summary, Pregabalin may be an important medication
in the future for trigeminal neuralgia. Further studies may
help support its use for this indication.
Phenytoin
Although reported as the first antiepileptic drugs effective in
trigeminal neuralgia, Phenytoin’s role has greatly diminished
in recent years. Like Carbamazepine, Phenytoin is a sodium
channel blocker that works in a rate-related fashion. Phenytoin
was first reported effective in treating trigeminal neuralgia in
1942 [20]. Although a number of reports have been published
since that time [21, 22], no clinical trials demonstrating effi-
cacy of Phenytoin have surfaced. Nonetheless, Phenytoin
may be a reasonable choice for selected patients with trigem-
inal neuralgia.
Phenytoin has a relatively long half-life, allowing for
daily or twice daily dosing. Although BID dosing is optimal,
daily dosing may improve compliance. Dosing of the medi-
cation in a TID fashion is not necessary even though it is
commonplace. Phenytoin can be loaded, but this may not be
necessary in patients with trigeminal neuralgia. Typical dos-
ing schedules consist of 100–200 mg BID with daily doses
around 6 mg/kg per day.
Phenytoin’s primary strong suit is its low cost. Its major dis-
advantages are its modest efficacy and its accompanying cos-
metic side effects. Phenytoin is believed to cause “coarsening”
of facial features, gum hypertrophy and hirsutism in women.
Furthermore, like other older antiepileptic agents, long-term
use of Phenytoin has been associated with osteoporosis.
In summary, Phenytoin may be a reasonable option in
selected patients in whom multiple other medications have
failed or who cannot afford the newer agents and who do not
wish to undergo invasive procedures. Cosmetic side effects
and modest efficacy markedly limit its role in trigeminal
neuralgia.
GABA-Related Agents
Baclofen
Baclofen, an agent used predominately to diminish spasticity
in patients with disturbances of the central nervous system,
has historically been used as a second-line agent behind
Carbamazepine in treating patients with trigeminal neuralgia.
N.C. Porter
Given the advent of newer agents, however, the role of
Baclofen for trigeminal neuralgia has become less certain.
Baclofen was first reported as a treatment for trigeminal
neuralgia in the 1980s [23]. Similar to a number of other
agents used to treat trigeminal neuralgia, Baclofen has never
been proven efficacious in a randomized clinical trial. The
drug was shown to be effective in a double-blind crossover
trial, though [24].
Baclofen is typically dosed in a TID fashion, starting at
5–10 mg TID and increasing moderately slowly up to 20 mg
TID. Baclofen is safe and well tolerated, with dizziness,
drowsiness, and gait instability being the predominate side
effects.
In summary, Baclofen is a safe and reasonably effective
medication for trigeminal neuralgia. Because of its safety
profile and long-term track record, Baclofen should be con-
sidered early for the treatment of trigeminal neuralgia.
Clonazepam
Clonazepam is a long-acting benzodiazepine that has been
reported efficacious at high doses in some patients with tri-
geminal neuralgia [25]. Like other benzodiazepines,
Clonazepam acts by binding to GABA receptors and poten-
tiating the effects of that neurotransmitter. In past years
Clonazepam was used as a third-line agent. With the avail-
ability of more effective neuropathic pain agents in recent
years, however, its use has become negligible.
In contrast to dosing for epilepsy and mood disorders,
relatively high doses of Clonazepam are required to treat tri-
geminal neuralgia. The major advantage of Clonazepam is
its modest cost and long-term safety. Although Clonazepam
is well tolerated at lower doses, the high doses required to
treat trigeminal neuralgia are associated with more profound
side effects such as sedation and cognitive impairment.
Furthermore, dependence must be a consideration, although
this concern is usually less prominent given the long half-life
of the drug.
In summary, Clonazepam like Phenytoin may have a role
in extremely selected patients with trigeminal neuralgia averse
to invasive procedures and refractory to the numerous neuro-
pathic agents that are generally considered more effective.
Local Anesthetics
Capsaicin
Although it has not been widely used in trigeminal neuralgia,
Capsaicin has been shown to be efficacious in some uncon-
trolled series. Capsaicin is a compound derived from chili
peppers. The commercially available formulation consists of
a cream containing the active substance as well as Lidocaine
54 Trigeminal Neuralgia: Viewpoint—Medical Management
to buffer the burning caused by the medication. Capsaicin
acts by depleting substance P, a neurotransmitter involved in
pain pathways, from nerve terminals.
At least two uncontrolled series have been published doc-
umenting the apparent efficacy of Capsaicin in trigeminal
neuralgia. Adequate pain control was obtained in approxi-
mately 30% [26] of patients in one study and 60% in another
[27]. Pain relief was sustained despite only transient use of
the medication.
Capsaicin should be applied to the affected area 2–4 times
daily. Duration of use should be tailored to the patient.
Caution must be used to avoid exposure to the eye.
Capsaicin is extremely safe with no systemic side effects.
Additionally, cost is highly reasonable. The major drawback
to Capsaicin, however, is tolerability. Prior to causing anal-
gesia the agent may cause severe, intolerable burning in the
areas to which the medication is applied.
In summary, Capsaicin appears to be a reasonable option
in refractory cases of trigeminal neuralgia. Patients should be
cautioned against exposure of the agent to sensitive areas.
Additionally, patients should be forewarned of the potential
for extreme burning pain in areas exposed to the medication.
Narcotic Agents
Oral Agents
Oral narcotics of varying potency may ameliorate excruciat-
ing episodes of pain due to trigeminal neuralgia. Although
narcotics are not typically considered neuropathic pain
agents, they are nonetheless effective in treating this type of
pain. Narcotics act at opioid receptors, providing relatively
nonspecific pain reduction. Short-acting agents may be use-
ful for “breakthrough pain.” None, however, has been stud-
ied specifically with regard to trigeminal neuralgia. Dosing
of oral narcotics must be individualized to the patient. The
key to management is finding the minimally effective dose.
Used judiciously, narcotics can be very useful. Obvious con-
cerns, though are tolerance and dependence.
Fentanyl Patch
Long-acting narcotics may provide more sustained pain
relief than the short-acting agents. Unfortunately, given the
degree of bad press surrounding some oral agents, many
physicians are reluctant to prescribe such medications. With
this in mind, controlled release formulations such as the
Fentanyl patch represent attractive solutions to the problem.
Fentanyl is a short-acting narcotic. The patch is comprised
of a matrix that allows slower release of Fentanyl into the
skin over many days. Thus, these patches are less likely to
produce any euphoria that may be the reinforcing aspect of
669
many oral and parenteral products. Fentanyl patches are
applied to the skin, and changed every 3 days. The patches
come in varying strengths. For those individuals naive to
narcotics, the starting dosage should be 25 μg/h, but the dose
can be increased as tolerated up to 100 μg/h. As with other
narcotics, the major initial side effects include sedation and
nausea. The most concerning long-term side effect remains
dependence.
Summary
In conclusion, trigeminal neuralgia is a serious medical con-
dition that can be debilitating when individuals are severely
affected. A number of medical treatment options exist for the
disorder, including various antiepileptic drugs, GABA-
mimetic agents, topical anesthetics, and even narcotics.
Selection of any specific agent should be dictated by the
medication’s relative efficacy and side-effect profile as well
as the patient’s medical history and personal preferences. In
refractory cases nonpharmacological treatments such as
glycerol injections, neurosurgical manipulation of the tri-
geminal nerve, and local irradiation serve as attractive alter-
natives to medication. For the foreseeable future, though,
medical management will remain the first-line treatment for
trigeminal neuralgia.
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 Stereotactic Radiosurgery
for Movement Disorders
Yoshinori Higuchi
Introduction
Stereotactic neurosurgery has evolved rapidly with the devel-
opment of the computed imaging systems, the advances in
the understanding of disease pathophysiology, the discovery
of new therapeutic targets, the increasingly widespread use
of neurophysiological technology such as microelectrode
recording, and the use of deep brain stimulation (DBS), all of
which have contributed to the accessibility of functional ste-
reotaxy. Radiosurgery involves the precise destruction of a
target containing neural structures or tumors, without dam-
age to the adjacent tissues [1]. Leksell first described the
concept of using radiosurgery for the destruction of normal
brain tissue in 1951 [2]. Leksell treated two patients with
intractable cancer pain using the gamma knife (GK) and
published the results in 1968 [3]. The target could not then
be visualized directly; instead, indirect target coordination
was provided by pneumoencephalography. The target tissue
was irradiated at 200–250 Gy using gamma units. In these
patients, autopsy findings revealed a well-circumscribed
lesion in the posterior thalamus, at the pre-calculated site.
The application of stereotactic radiosurgery for the treat-
ment of functional disorders by the pioneers of stereotactic
radiosurgery has received much attention. Extensive intraop-
erative neurophysiological studies have provided extensive
knowledge of the pathophysiology of movement disorders,
particularly of essential tremor (ET) and Parkinson’s disease
(PD). Currently, the standard techniques for the surgical treat-
ment for ET and advanced PD are DBS and ablation surgery.
Y. Higuchi, M.D., Ph.D. (*)
Department of Neurological Surgery, Chiba University Graduate
School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba
260-8670, Japan
e-mail: yhiguchi@faculty.chiba-u.jp
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_55, © Springer Science+Business Media New York 2015
55
Patients with a high-risk factor for surgery (e.g., those
receiving anticoagulant therapy, the aged, or patients with sys-
temic complications) call for an alternative treatment option.
Leksell treated five cases of tremor using GK surgery between
1968 and 1970; however, beneficial results were limited,
mainly due to technical difficulties such as the lack of comput-
erized imaging techniques [4]. The introduction of magnetic
resonance imaging allowed for more refined targeting. Rand
et al. reported the use of radiosurgery treatment for movement
disorders, based on this modern imaging technology [5].
Thereafter, numerous reports have been published. Careful
review of several such reports revealed that the results of
radiosurgery were not always satisfactory and included some
cases with extremely poor outcomes. In fact, this was raised as
a major criticism of the technique [6]. Worldwide, 5 % of GK
surgery procedures are carried out for the treatment of func-
tional disorders, predominantly trigeminal neuralgia. The
ablation of deep brain structures using GK surgery is less
common, because the target for many functional disorders
cannot be visualized even with modern neuroimaging tech-
niques, and there is no opportunity to identify the final target
using neurophysiological evaluation. A great deal of experi-
ence with stereotactic surgery would be required to make the
decision of the target coordination. A recent prospective study
proved the efficacy of treatment using GK thalamotomy for
intractable tremor [7]. GK surgery is still one of the surgical
options for treating tremor-dominant PD and ET.
This chapter will review the current literature and discuss
the use of stereotactic radiosurgery for treatment of move-
ment disorders.
Gamma Knife Thalamotomy
Thalamotomy using GK surgery was initially applied for the
treatment of intractable pain. In the majority of recent
reports, intractable tremor was the main target disease for
GK thalamotomy. Table 55.1 summarizes the recent reports
of gamma knife thalamotomy [7–16].
671
Table 55.1 Summary of gamma knife thalamotomy
Unilateral Prescription
Author Use or bilateral dose (maximum Complication
(year) n Disease Targeting of plug treatment dose, Gy) Follow-up Effects rate (%) Complication
Pan 8 Parkinson’s disease Based on Schaltenbrand and Wahren atlas Yes Unilateral 160–180 4.5 months Tremor 12.5 Transient
(1996) [8] disappears in hemiparesis and
3 cases, reduction edema
in 3 cases
Friedman 15 Parkinson’s disease 3 7–8 mm anterior to PC, 11–13 mm lateral No Unilateral 120–140 3 months 2.1 decrease 46.7 Edema, etc.
(1999) [9] Essential tremor 12 to ACPC line, 2 mm above ACPC line in TRS
Duma 38 Parkinson’s disease 6 mm posterior to the midpoint of ACPC, No Unilateral 34 120–160 Median Reducing and 2.6 Dysarthria
(1999) [10] 15 mm lateral to ACPC line, 4 mm superior Bilateral 4 30 months eliminating tremor
to ACPC line in 90 %
50 % isodose line medially to IC
Duma 42 Parkinson’s disease 6 mm posterior to the midpoint of ACPC, No Unilateral 38 120–160 Median Good or 1.3 Paresthesia, motor
(2007) [11] Essential tremor 15 mm lateral to ACPC line, 4 mm superior Bilateral 4 30 months excellent 54 % weakness, dysphasia
to ACPC line
30 % isodose line medially to IC
Niranjan 11 Essential tremor 8 25 % of the ACPC distance anterior to PC, No Unilateral 130–150 Median Tremor 9.1 Hemiparesis,
(2000) [12] Multiple sclerosis 3 laterality 1/2 third ventricle width + 11 mm (model U) 6 months reduction in all dysarthria
from ACPC, 2 mm superior to the ACPC line
Mathieu 6 Multiple sclerosis 25 % of the ACPC distance + 1 or 2 mm No Unilateral 130–150 Median Tremor 16.7 Hemiparesis
(2007) [13] anterior to PC, laterality 1/2 third ventricle 27.5 months reduction in all
width + 11 mm from ACPC, 2 or 2.5 mm
superior to the ACPC line
Kondziolka 31 Essential tremor 25 % of the ACPC distance + 1 mm anterior Yes Unilateral 130–140 Median Improvement 7.7 Hemiparesis,
(2008) [14] to PC, laterality 1/2 third ventricle 36 months in 88.0 % speech disturbance,
width + 11 mm from ACPC, 2.5 mm dysphagia
superior to the ACPC line. The 20 % isodose
line medial to the internal capsule
Young 161 Essential tremor Based on Schaltenbrand and Wahren atlas No Unilateral 130 141–152 Mean Writing, 77 %; 8.4 Sensory loss, motor
(2010) [15] Staged 44 ± 33 drawing, 81 % impairment, speech
bilateral 42 months disturbance, etc.
Lim 18 Parkinson’s disease 3 25 % of ACPC + 1 mm to PC, 11 mm lateral Yes Unilateral 130–140 Mean Improvement 16.7 Thalamic
(2010) [16] Essential tremor 15 to third ventricle wall, 2–3 mm above ACPC 19.2 ± 7.3 in tremor rating hemorrhage,
months score ADL score sensory disturbance
Ohye 72 Parkinson’s disease 59 Longitudinal thalamic length 45 %, 2 mm Yes Unilateral 130 24 months Improvement 1.4 Motor weakness
(2012) [7] Essential tremor 13 inside external border of internal capsule, in 81.1 %
3–4 dorsally to ACPC
TRS tremor rating scale, IC internal capsule
55 Stereotactic Radiosurgery for Movement Disorders
Indication of GK Thalamotomy
Indications of GK thalamotomy for the treatment of intrac-
table tremor are determined in accordance with more con-
ventional stereotactic surgery. While DBS or conventional
thalamotomy is available, the use of GK thalamotomy has
been reserved for specific patients, such as those who are
poor candidates for conventional surgery (e.g., due to
advanced age or ongoing anticoagulant therapy).
Intractable tremors could be classified as components of
ET, PD, or multiple sclerosis. The most common disease
treated by GK thalamotomy is ET. ET is a common adult
movement disorder, with prevalence estimates derived from
population studies ranging from 0.4 to 5 % [17, 18]. The
incidence and prevalence of ET both increase with advanc-
ing age [18], and conventional thalamotomy or DBS is not
often recommended for aged patients with ET.
PD is another indication for GK thalamotomy; however,
subthalamic DBS improves symptoms of rigidity, bradykine-
sia and motor fluctuation, as well as tremor [19]. In a system-
atic review of PD progression, the non-tremor dominant
subtype at disease onset appeared to favor rapid progression
to Hoehn and Yahr stage III [20]. Tremor seems to predict a
slow progression of PD. If intractable tremor causes signifi-
cant functional impairment, GK thalamotomy is an option
for tremor reduction [7].
Target Coordination
Although the efficacy of GK thalamotomy for intractable
tremor has been evaluated, the prescription dose and target
selection varied greatly among the studies reviewed (see
Table 55.1). Previous studies have selected the ventralis
intermedius nucleus (VIM) as the target for treating intrac-
table tremor. In the majority of studies, target determination
was based on the anterior commissure-posterior commissure
(ACPC) line. Anterior-posterior coordination was 6–8 mm
anterior to PC, or 25 % of the ACPC line from PC, while
right-left coordination was 11–13 mm lateral to the ACPC
line, and rostral-caudal coordination was 2–4 mm above the
ACPC line. Anatomical investigation of formalin-fixed
human brains indicated the anterior tip of ventroposterior
nucleus [21]. Ohye et al. adjusted the tentative target based
on the ACPC line, so that the center of the radiation beam
would cover 45 % of the longitudinal axis of the thalamus for
actual irradiation [22]. No neurophysiological information
aids the refinement of the target and is in fact a disadvantage
in GK thalamotomy. Sato et al. performed depth recordings
around the region of the supposedly optimum target for
tremor, as determined in usual thalamotomy, to provide indi-
rect support for GK thalamotomy, and demonstrated a rhyth-
mic discharge time locked to tremor, and the presence of
kinesthetic neurons within the expected target area [23].
673
Extensive experience using stereotactic thalamotomy with
microelectrode recordings might support GK thalamotomy,
which has the disadvantage of involving no neurophysiologi-
cal examination.
Tolerance of the Internal Capsule
Accurate lateral coordinates are crucial to prevent radiation
injury to the internal capsule. Duma et al. adjusted the 50 %
isodose line medially to the internal capsule [24]. Kondziolka
et al. retained 20 % of the isodose line of the 4-mm collima-
tor medially to the internal capsule [14]. The tolerance of the
internal capsule thus remains unclear. However, Maruyama
et al. used diffusion tensor tractography of the pyramidal
tract when dose planning of GK surgery for treatment of an
arteriovenous malformation and calculated the tolerance of
the pyramidal tract [25, 26]. The maximum dose to the pyra-
midal tract and 20- or 25-Gy volume in the pyramidal tract
significantly correlated with the motor complication.
Interestingly, the internal capsule was found to be more frag-
ile than the coronal radiation. A plugging technique to reduce
the dose of radiation to the internal capsule was applied in
several recent studies (Fig. 55.1) [7, 14, 16]. It is now gener-
ally accepted that the maximum dose of radiation to the
internal capsule should be less than 20–25 Gy.
Prescribed Dose
GK treatment has been commonly performed using a 4-mm
collimator. The prescribed dose varied among the different
studies (see Table 55.1). Steiner et al. reported that a dose of
150 Gy was necessary for the reproducible creation of a
human brain lesion, using an autopsy series of GK thalamot-
omy that used to treat intractable cancer pain [27]. In the
reports published in the early 1990s, a relatively high dose
was selected for lesioning; however, in more recent reports,
a maximum dose of 130–140 Gy was recommended for thal-
amotomy using GK [7, 14, 16]. Okun et al. reported five
cases with complications of GK thalamotomy, including two
cases of bilateral lesioning [6]. Radiation effects were found
to have expanded into the internal capsule and mesencepha-
lon, which caused further motor complications and pseudo-
bulbar symptoms. However, the prescribed dose should be
noted; the target was irradiated at a maximum dose of
200 Gy. Such a high dose is not currently used for the patients
with intractable tremor.
Radiation Efficacy
Previous reports demonstrated the effectiveness of GK thala-
motomy in treatment of tremor; however, the evaluation of
674 Y. Higuchi

Fig. 55.1 Representative GK thalamotomy treatment plan. Treatment plan (MRI) of right hemisphere GK thalamotomy for intractable left-hand
tremor and isodose lines (15 and 50 %) is indicated. The dose to the internal capsule is reduced by using the plugging technique

tremor reduction was not uniform (Table 55.1). The Unified Table 55.2 Onset of clinical effects after gamma knife thalamotomy
Parkinson’s Disease Rating Scale (UPDRS) [28], the Fahn- Author (year) Dose (Gy) Onset of clinical effects
Tolosa-Marin Tremor Rating Scale [29], and tremor-cessation Lindquist (1992) [31] 180 1 month
rates were all used to grade tremor and other symptoms, before Friehs (1995) [32] 160 3–4 weeks
and after treatment. Overall, 70–90 % of the tremor patients Pan (1996) [8] 160–180 3 days (1 case)
obtained an anti-tremor effect from GK surgery. Differences Young (1998) [33] 120–160 2–3 months
in the outcomes of GK surgery in different primary diseases Duma (1998) [24] 120 (160) 1 week to 8 months (2 months)
remain unclear due to insufficient numbers of patients. Friedman (1999) [9] 120–140 4 weeks
In order to clarify the safety and ascertain optimally effec- Ohye (2012) [7] 130 3 months
tive conditions for performing unilateral GK thalamotomy
for treatment of intractable tremors, a prospective multi-
institutional study was published by the Japan Leksell approximately 1 year (Table 55.2) [7–9, 24, 30–32]. A single
Gamma Knife Society (JLGK0301). The study included session of high-dose irradiation requires time to produce the
blinded videotaped assessments and demonstrated the effi- desired lesion. Leksell described autopsy cases in his first
cacy of GK surgery for the treatment of both tremor and report of GK thalamotomy [3]. Lesions irradiated at 200–
rigidity in PD; however, no effects on bradykinesia or gait 250 Gy were confirmed pathologically 2 and 5 months after
disturbance were found [7]. treatment, and the lesions contained necrosis with a marginal
A slow improvement over several months tended to gliotic zone. Radiosurgical lesions are dependent on the dose
characterize the clinical course following GK thalamotomy, received, volume of tissue irradiated, and time [33, 34].
in contrast to the immediate effect of radiofrequency The low dose of irradiation (130–140) used more recently
coagulation. The period over which improvements in clinical would require some time to produce the lesion following
symptoms were observed varied widely, from several days to GK thalamotomy. However, some of the patients treated by
55 Stereotactic Radiosurgery for Movement Disorders
GK thalamotomy experienced treatment effects even before
coagulation necrosis occurred. Kondziolka demonstrated
that the lower doses (80 Gy) used to treat trigeminal neural-
gia cause incomplete axonal degeneration in a baboon model
[35]. Early changes, prior to coagulative necrosis in the thal-
amus, might occur after GK surgery and cause an early
improvement in clinical symptoms.
Comparison of GK Thalamotomy
and Conventional Thalamic Surgery
The anti-tremor effects of GK thalamotomy should be com-
pared with those of other surgical treatment options.
However, a head-to-head comparison with other surgical
procedures was limited, because various methods of tremor
evaluation and variable follow-up terms were applied in each
study. Based on tremor-cessation rates, VIM DBS resulted in
a tremor-absent state in 67–96 % of both PD and ET patients
[36, 37]. VIM thalamotomy also abolished tremor in
65–89 % of PD and ET patients. The tremor-cessation rate
achieved with GK thalamotomy was, however, relatively
low; 79 % of the patients had good tremor control, including
slight or infrequent tremors, which is similar to the results of
VIM thalamotomy [37, 38].
Microelectrode Recording After GK
Thalamotomy
Some failed cases of GK thalamotomy have been reported.
Some of these cases received subsequent conventional thala-
motomy, or DBS. In these cases, intraoperative monitoring
revealed the radiation effects through electrical activity in
the thalamus. Normal neuronal and tremor rhythm were
demonstrated in and adjacent to the lesion of the previously
irradiated target [39]. Target deviation to the anterior and
medial direction, or rhythmic tremor discharge located close
to the internal capsule, was less effective. This seems to
reflect technical limit of GK thalamotomy at present. We
have relatively limited knowledge of the effects of radiation
on neuronal activity in the thalamus. Terao et al. reported
their microelectrode findings after GK thalamotomy and
demonstrated a reorganization of kinesthetic cells in the irra-
diated VIM [40]. Changes in the somatotopography of kines-
thetic cells might make it difficult to perform a secondary
surgery on these failed cases.
Complications
Reported complications from GK thalamotomy varied
between 1.4 and 46.7 % (Table 55.1). These complications
mainly consisted of hemiparesis and speech disturbances.
675
Most of the reported complications were transient; however,
some of patients suffered from severe sequelae [6]. A high
prescribed dose of radiation seemed to be associated with
more complications.
Siderowf et al. reported involuntary movements resulting
from GK thalamotomy [41]. Magnetic resonance (MR)
images revealed extended edema involving the thalamus,
basal ganglia, and midbrain. Dystonia and choreoathetosis
emerged, despite a good response to treatment with a marked
reduction in the tremor.
Okun et al. reported pseudobulbar laughter following GK
thalamotomy [42]; in this case, the tremor persisted follow-
ing GK thalamotomy. MR images demonstrated extended
edema, involving the internal capsule and posterior thala-
mus. The prescribed dose was unknown in both of these
cases. Extended perifocal edema to the neuronal structures
surrounding the target site is the expected cause of these
complications. Ohye et al. reported thalamic reaction on MR
images following GK thalamotomy [7]. Extended T2 elon-
gation surrounding the GK lesion occurred in 10.9 % of the
patients, and the prediction of a thalamic reaction was diffi-
cult in spite of a uniform treatment protocol.
Gamma Knife Pallidotomy
Posteroventral pallidotomy (PVP) has been used to treat
patients with advanced PD, since Laitinen et al. [43] reintro-
duced PVP and confirmed the results that Leksell and
Svennilson et al. [44] and others described earlier [45, 46].
Reviews of controlled studies demonstrated an improvement
in quality of life following surgery [47, 48]. Procedures with-
out the need for battery replacement, risk of infection, or
hardware problems seemed to be beneficial for some patients
with PD. To date, DBS of the subthalamic nucleus and pal-
lidum has become the dominant surgical procedure used for
the treatment of PD.
GK pallidotomy has been reported in a limited number
of publications (Table 55.3) [5, 9, 10, 32, 49]. GK pallidot-
omy resulted in clinical improvement of rigidity, bradykine-
sia, and dyskinesia, in several of the patients. These
treatment results indicate less effectiveness compared with
PVP [50, 51]. However, some of the patients treated using
GK pallidotomy had an inadequate diagnosis of PD (e.g.,
short disease duration (<5 years), nonresponsive to levodopa
therapy). At present, these patients rarely make good surgi-
cal candidates, because of the possibility of them having
parkinsonism of non-Parkinson’s disease. Young et al.
carried out a comparison of treatment results between
GK pallidotomy and radiofrequency pallidotomy for PD
[52]. The authors reported an improvement of rigidity, bra-
dykinesia, and dyskinesia with both treatment modalities.
However, neither group showed a significant improvement
in UPDRS score.
 676

Table 55.3 Summary of gamma knife pallidotomy

Author Unilateral/ Prescription dose Follow-up Complication
(year) n Target coordination bilateral (maximum dose, Gy) (months) Effects rate (%) Complication
Rand (1992) [5] 8 2 mm anterior or posterior to the MC point, Unilateral 140–165 NA Rigidity NA NA
23–25 mm lateral to ACPC, 1–2 mm above reduction
ACPC line in 50 %
Optic tract outside 10 % isodose line
Friedman (1996) [49] 4 2–3 mm anterior to the MC point, 18–21 mm Unilateral 180 12 No effects 25 Severe edema
lateral to ACPC line, 3–6 mm below ACPC line
Young (1998) [32] 28 In the medial globus pallidus just superior Unilateral 24 120–160 12 Improvement 7.10 Visual field defect, hypophonia
to the optic tract and just inferomedial to the Bilateral 4 in bradykinesia
internal capsule in coronal images at 2–3 mm and rigidity in
anterior to MC point 64.3 %
Duma (1999) [10] 18 50 % isodose line of a single or double Unilateral 160 4–40 Improvement 50 Visual field defect, speech and
isocenter on the Gpi in 33 % swallowing disturbance
Friedman (1999) [9] 2 2–3 mm anterior to MC point, 18–23 mm Unilateral 120–140 8 Improvement – Mild edema, lacunar infarction
lateral to ACPC line, 4–6 mm below ACPC line of dyskinesia Hypophonia, dysphagia
ACPC anterior commissure-posterior commissure, MC mid-commissural
Y. Higuchi
55 Stereotactic Radiosurgery for Movement Disorders
Target coordination is again critical, because the medial
globus pallidum is located in the angle between the roof of
the optic tract and the lateral border of the internal capsule.
In most reports regarding GK pallidotomy, the isocenter was
located at Laitinen’s PVP point [43], or the medial globus
pallidum, referring to the optic tract and the internal capsule.
The optic tract is highly vulnerable to irradiation, and
therefore, careful dose planning is required for the successful
treatment of benign disease. Dose and volume in the irradi-
ated optic pathway are strongly associated with optic neu-
ropathy. In previous reports, more than 10 Gy of single-dose
irradiation caused a high incidence of optic neuropathy [53],
and previous radiation therapy increased the incidence of
optic neuropathy, even if dose to the optic tract was 8 Gy or
less [54]. Therefore, the incidence of visual field impairment
was high following GK pallidotomy. Use of GK pallidotomy
has not become widespread due to the anatomical disadvan-
tage of the pallidum for radiosurgery.
Gamma Knife Subthalamotomy
The subthalamic nucleus is a standard treatment target for
DBS in advanced PD [55]. The relationship between the
subthalamic nucleus and parkinsonian conditions has
been demonstrated using an MPTP (1-methyl, 4-phenyl,
1,2,3,6-tetrahydropyridine) monkey model, and hyperactiv-
ity of the subthalamic nucleus is a fundamental pathophysi-
ological sign in the parkinsonian state [56–58]. Lesioning of
the subthalamic nucleus reverses parkinsonian symptoms in
the MPTP monkey model [59–61]. The scientific evidence
promotes stereotaxy of the subthalamic nucleus for treat-
ment of PD. The efficacy of radiofrequency subthalamotomy
has been evaluated in several studies. Alvarez et al. report the
therapeutic efficacy of unilateral subthalamotomy in PD
[62]. Unilateral subthalamotomy provided significant and
sustained motor benefits contralateral to the lesion. However,
15 % of the patients developed postoperative hemichorea-
ballism, which subsequently required pallidotomy.
Subthalamotomy using GK surgery has been described in
only one case report [63]. The preliminary target was identi-
fied at 2 mm posterior to the mid-commissural line, 13 mm
lateral to the midline, and 5 mm inferior to the mid-
commissural line. Small modifications of the target coordi-
nates were made based on the patient’s brain anatomy and on
the Schaltenbrand and Wahren atlas. The target was irradi-
ated at 120 Gy, using a 4-mm collimator. The patient experi-
enced improvement of parkinsonism and was able to reduce
their levodopa dosage following treatment. This limited clin-
ical experience has not clarified the potential of GK subthal-
amotomy in PD yet.
The final decision of electrode placement depends on the
findings of microelectrode recordings in most of DBS facilities.
Further refinement of targeting techniques will be required
677
for subthalamotomy using GK technology. Visualization of
the subthalamic nucleus using MR imaging has improved
significantly in the last decade, and recent MR imaging tech-
nology demonstrates the possibility of direct targeting, as
well as targeting using internal fiducial points (e.g., the red
nucleus) [64]. Future advances will no doubt allow for the
accurate identification of different functional parts of the
subthalamic nucleus and the correlation between the location
of subthalamic lesions and therapeutic effects obtained from
radiofrequency subthalamotomy.
GK Surgery for Other Movement Disorders
Although there have been no studies designed to specially
address this issue, GK surgery applied for the treatment of
movement disorders has been described in several case
reports. Kwon et al. treated hemiballism in a patient with a
history of tuberculous meningitis using GK pallidotomy
[65]. Pan et al. reported clinical improvement following GK
thalamotomy in two cases of cervical dystonia [66], and
Ohye et al. treated a case with dystonia using GK thalamot-
omy [67]. All patients were reported to experience signifi-
cant improvements following treatment.
Treatment of secondary movement disorders treated using
GK surgery has also been reported. Kurita et al. reported
relief of hemiballism resulting from basal ganglia arteriove-
nous malformation [68]. Yen et al. treated cervical dystonia
caused by basal ganglia venous angioma and obtained sig-
nificant clinical improvement [69], and Karampelas et al.
treated a subthalamic nucleus metastasis, which was causing
contralateral hemichorea-hemiballism, and confirmed a
reduction in involuntary movement [70]. Movement disor-
ders due to an intracranial lesion, especially a deep-seated
lesion, would be a good indication for GK surgery.
Conclusions
GK thalamotomy for treatment of intractable tremor is a safe
and effective alternative to radiofrequency or DBS proce-
dures for high-risk patients. Extensive experience of conven-
tional stereotactic surgery is expected to stabilize treatment
results. Collaboration with neurologists or a movement dis-
order team is mandatory to assess treatment options and to
evaluate the treatment results of GK surgery for movement
disorders. Indication of GK pallidotomy in PD has been lim-
ited due to relatively high complication rate arising from the
anatomical disadvantageous position of the globus pallidum.
For other movement disorders, the worldwide experience in
treatment with GK surgery is limited.
Conflict of Interest Notification No actual or potential conflicts of
interest exist.
678
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 Perspective on Radiosurgery Versus
Conventional Surgery for Movement
Disorders
Zion Zibly, Andrew B. Shaw, John Y.K. Lee,
and Ali R. Rezai
Introduction
Among the different surgical techniques of treating movement
disorders, deep brain stimulation (DBS) has become the
procedure of choice around the world, due to its safety com-
pared to other lesioning procedures. Since the introduction
and technical refinements of DBS for the treatment of move-
ment disorders in the 1980s, more than 80,0000 procedures
have been done worldwide. For patients with medically
refractory movement disorders, DBS procedures have largely
replaced neuroablative techniques. This shift away from
ablative procedures is multifactorial. Among the more
important factors are its proven efficacy, the reversibility, and
the perceived minimally invasive nature of DBS compared
with destructive procedures. During the last several years,
there has been an increase in the use of radiosurgical tech-
niques such as Gamma Knife (GK), linear accelerator
(Linac), and more recently high-intensity focused ultra-
sound (HIFU) to perform thalamotomies and pallidotomies.
The preference between radiosurgical techniques and DBS
depends mostly on the surgeons experience and patients
comorbidities [1–5].
The first use of cobalt-based GK was done in 1968 by the
Swedish neurosurgeon Lars Leksell, and between 1968
Z. Zibly, M.D.
Department of Neurological Surgery, The Ohio State University
Medical Center, Columbus, OH, USA
A.B. Shaw, M.D. (*)
Department of Neurological Surgery and Neuromodulation,
Wexner Medical Center at The Ohio State University,
Columbus, OH, USA
e-mail: Andrew.Shaw@osumc.edu
J.Y.K. Lee, M.D.
Department of Neurosurgery, University of Pennsylvania,
Philadelphia, PA, USA
A.R. Rezai, M.D.
Department of Neurological Surgery and Neuroscience,
The Ohio State University, Columbus, OH, USA
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_56, © Springer Science+Business Media New York 2015
56
and 1982, 762 patients were treated for multiple brain and
neurologic disorders; of them, five were treated for parkin-
sonism [6]. The logic behind the utilization of radiosurgical
techniques is that it is even less invasive than chronic brain
stimulation (DBS), thus eliminating the need for an open sur-
gical procedure and hardware-related complications such as
infection and device-related complications such as lead
breakage or failure. In addition, radiosurgery is less time-
consuming than microelectrode-guided radiofrequency
lesioning and can be performed in a subset of patients who
are at higher surgical risk for open procedures secondary to
medical comorbidities including cardiorespiratory, coagu-
lopathy, or any other surgical contraindication. It is also
suitable for patients who cannot tolerate an awake procedure.
Nevertheless, radiosurgery has its limitations, disadvantages,
and complications, which will be further discussed in this
chapter. This chapter reviews the evidence for DBS versus
radiosurgical lesioning in the treatment of patients with med-
ically refractory movement disorders and defines the role of
radiosurgery in the treatment of these patients. We will also
compare the safety and efficacy of DBS compared to radio-
surgery. Finally, we will review the emerging role of HIFU in
treating movement disorders.
Thalamic DBS Versus Radiosurgical
Thalamotomy
Thalamic DBS
High-frequency stimulation of the ventralis intermedius
(VIM) nucleus of the thalamus was first introduced and
described by Benabid in 1987. In his paper, Benabid
described the relief of extrapyramidal tremor in Parkinson’s
disease patients who had bilateral symptoms. In this revo-
lutionary report, DBS was introduced in one side of the
brain, while the other side was treated with radiofrequency
ablation [7]. This subset of patients was chosen because of
the recognition of cognitive complications in patients who
681
682
had undergone bilateral thalamotomies [8, 9]. In this initial
report, all patients achieved some relief of tremor, and this
was the foundation of VIM DBS for the treatment of tremor.
Over the next few years, practitioners in multiple centers
in both North America and Europe confirmed and defined
the benefits of DBS of the VIM nucleus in the treatment of
parkinsonian tremor. In Parkinson’s disease (PD), Benabid
et al. followed approximately 100 patients for up to 8 years
and have documented an 88 % improvement in tremor [10,
11]. Only a minority of patients developed tolerance to DBS
(e.g., a diminished effect over time requiring greater voltages
and higher battery use). Thalamic DBS appeared to improve
parkinsonian tremor but not bradykinesia and rigidity nor the
levodopa-induced dyskinesias which are the other cardinal
features of Parkinson’s disease [5, 12]. In another study,
Koller et al. reported the results of a double-blind, North
American, multicenter study (four centers) for 24 PD patients
[13]. They randomized unilateral thalamic DBS against pla-
cebo, and double-blinded assessments demonstrated a sig-
nificant reduction in resting, postural, and action tremor.
However, DBS of VIM again did not improve the rigidity
and bradykinesia of PD patients, and hence VIM DBS in par-
kinsonian patients is currently reserved for the rare unilateral
tremor-predominant patient. The majority of patients with
medically refractory PD will undergo STN DBS at this time,
which will be discussed later.
DBS of the VIM nucleus for the treatment of essential
tremor is highly effective with more than 90 % of patients
demonstrating a satisfactory result [11, 14–18]. It is the sur-
gical treatment of choice for patients with essential tremor
who experience diminished quality of life despite maximal
medical therapy. With VIM DBS as many as 50 % of patients
have complete abolition of upper extremity and head tremor
with significant improvements in their quality of life [19]. In
the North American and European multicenter trials, DBS of
the VIM thalamus was effective, and beneficial results were
maintained after several years [13, 20].
Adverse effects from VIM DBS are infrequent and usu-
ally mild. Benabid reported mild contralateral paresthesias,
limb dystonia, and cerebellar dysmetria, which were all con-
trolled by adjustments of stimulation parameters [21].
Dysarthria and gait disequilibrium were uncommon and
nearly always limited to patients receiving bilateral stimula-
tion or who had undergone prior thalamotomy. Significant
cognitive deficits have not been observed after thalamic
stimulation, although mild deficits in verbal fluency have
been documented [19]. The great benefit of DBS compared
with permanent lesioning procedures is the ability to control
multiple parameters, including voltage, pulse width, fre-
quency, and contacts allowing for a myriad of ways to modu-
late the affects of DBS. Hence, the therapeutic index (e.g.,
the difference between beneficial effect and adverse effect)
can be navigated through careful programming [22].
Z. Zibly et al.
An important complication of DBS pertinent to all DBS
cases whether targeting VIM, globus pallidus interna (GPi),
or STN is the risk of intraoperative/procedural hemorrhage.
Benabid reported a microhemorrhage rate of six incidences
out of a total of 177 operations, of which three were asymp-
tomatic [11]. The intracranial hemorrhage rate in the North
American and European trials was 2 % and 5 %, respectively
[13, 20]. Starr recently reported a hemorrhage rate of 3.3 %,
but only a subset of these were symptomatic, thus resulting
in a symptomatic hemorrhage rate of 0.6 %. In addition,
there has been some retrospective study evidence that the
hemorrhage rate may increase with the aggressive use of
microelectrode recording (MER). Hariz et al., in a meta-
analysis of reported series, noted that non-MER techniques
were at least five times less likely to have hemorrhagic com-
plications [23]. For example, Palur et al. demonstrated a
slightly higher rate of hemorrhage in cases performed with
MER versus macrostimulation alone (0.4 % versus 0.2 %)
[24]. The DBS Study Group reported a relationship between
the number of microelectrode tracks and the risk of hemor-
rhage: patients without hemorrhage had a mean of 2.9 ± 1.8
passes compared with 4.1 ± 2.0 among those who had hemor-
rhage (p = 0.05) [25]. There are no prospective, randomized
studies of MER versus non-MER strategies, and there is a
large variability in MER techniques used at different centers
with regard to number of passes and equipment employed. In
all studies noted, however, the overall small risk of bleeding
in both MER and non-MER groups indicates the overall
relative safety of both techniques [24–26]. The risk of hem-
orrhage is not negligible, but not all hemorrhages result in
obvious clinical deficit [27], and the risk of hemorrhage must
be considered in relation to the benefit obtained in patients
with medically refractory movement disorders.
Another specific complication of DBS is related to the
need to implant permanent hardware into the body. Bhatia
et al. reported in their systematic review of 3,550 DBS surger-
ies from 35 studies an infection rate of 4.7 % [28]. Boviatsis
et al. reported a total hardware-related complication rate of
4.3 % in their study of 106 DBS procedures. These included
electrode breakage, lead migrations, and infection [29, 30].
Kondziolka et al. documented a similar hardware-related
complication rate in Pittsburgh: 27 % of 66 patients devel-
oped hardware complications [31]. In contrast with these
two reports, other studies have documented lower rates of
hardware-related complications. Fenoy et al. reported in a
large series of 1,333 DBS implanted electrodes and 1,218
implantable pulse generators (IPG) postoperative rate of
infection that required reoperation as low as 1.24 % [32]. In
Koller’s series of 53 patients with unilateral thalamic stimu-
lators, the incidence of infection was 3.8 % with a 1.9 %
malfunction rate [13]. The Grenoble group’s large series of
197 patients contained three patients who experienced infec-
tions and five with scalp erosions leading to exposed hardware,
56 Perspective on Radiosurgery Versus Conventional Surgery for Movement Disorders
Fig. 56.1 Axial T1-weighted contrast-enhanced and T2-weighted MRI scans 4 months following GK thalamotomy
for a total rate of 2.5 % [12]. The European Multicenter Study
yielded an erosion/infection rate of 2.7 %, and the North
American trial reported 2.9 % [20]. None of these large stud-
ies reported data on lead migration or fracture, and in both,
the mean follow-up time was 12 months or less thus limiting
the evaluation of long-term complications. Among the 143
patients in the multicenter prospective series of patients
undergoing GPi or STN DBS, there were 5 leads that
migrated, 4 infected leads, 2 broken leads, 1 scalp erosion,
and 1 incidence of equipment malfunction [25]. With
improved electrode and hardware design as well as improve-
ments in surgical technique, hardware-related complication
rates appear to decrease. Nevertheless, hardware failure con-
tributes to morbidity in patients who undergo the placement
of permanent deep brain stimulators. These complications are
obviously averted in patients who undergo a radiosurgical
lesioning procedure, and the relative risks must be weighed
for each patient.
In summary, thalamic DBS for the treatment of tremor
is effective in Parkinson’s disease and essential tremor as
demonstrated in multiple trials that include double-
blinded, prospective studies. The risk of intraoperative/
procedural hemorrhage is approximately 3 % with less
than one third of these being symptomatic. The risk of
hardware-related complications ranges from 3 to 27 %, but
improvements in technique and hardware development
will limit these problems. It is the opinion of most practi-
tioners in the field that the reversibility, symptomatic con-
trol, and ability to minimize side effects with adjustment
of the DBS system warrant taking the risk associated with
the implantation of hardware.
Radiosurgical Thalamotomy
During the last decade, stereotactic radiosurgery (SRS) has
been widely used to treat a diversity of brain and spine dis-
eases. Advances in neuroimaging, planning systems, and
dosimetry have resulted in the expansion of SRS for functional
683
applications such as movement disorders. Currently, Gamma
Knife thalamotomy (GKT) is the primary SRS method used
to treat movement disorders, although the application of lin-
ear accelerator by creating precise thalamic lesion has been
described and was in fact one of the first functional radiosur-
gical procedures [4, 27, 33, 34] (Fig. 56.1).
In order to discuss the merits of radiosurgical thalamot-
omy, it is beneficial to consider the role of conventional
radiofrequency thalamotomy in the treatment of patients
with tremor. Tasker retrospectively studied patients who had
radiofrequency thalamotomy and thalamic stimulation [1].
He noted tremor recurrence in 15 % of thalamotomy patients,
as opposed to 5 % of DBS patients. Importantly, 23 % of
the thalamotomy patients required repeat procedures for
tremor control. In addition, thalamotomy resulted in a decline
in writing performance in 23 % of patients, as opposed to no
patients in the DBS group. All of the DBS patients achieved
better than 50 % improvement in dexterity, writing, and
drinking ability, where only half of the thalamotomy cohort
obtained that level of benefit. With respect to complications,
Tasker demonstrated that chronic stimulation had a lower
incidence of ataxia and dysarthria, which are common
complications associated with bilateral thalamotomy [1].
Moreover, when these complications occurred in the DBS
group, simply adjusting the stimulation parameters served to
abolish these problems. In another study that was a prospec-
tive, blinded study, Schuurman et al. randomized 68 patients
(45 with PD, 13 with ET, and 10 with multiple sclerosis)
to radiofrequency thalamotomy versus VIM DBS [35]. Both
groups of patients had excellent suppression of tremor, but
the VIM DBS group had greater improvements in activities
of daily living (ADL), and more importantly, the VIM DBS
group had fewer complications. Patients who underwent
thalamotomy were more likely to develop somnolence, cog-
nitive deterioration, and dysarthria, as well as gait or balance
disturbance. Thus, Tasker and Schuurman et al. have both
confirmed the higher complication rates associated with thal-
amotomy compared with VIM DBS, and it is in this context
that the use of radiosurgical thalamotomy must be considered.
684 Z. Zibly et al.

Table 56.1 Summary of Gamma Knife thalamotomy for movement disorders

Author Year published Treated disorder Target Number of procedures Follow-up (months) Complication rate (%)
Young 1998 PD ViM 27 22.3 (mean) 0
Friedman 1999 PD tremor ViM 15 13 46.7
ET
Niranjan 1999 12 24 (median) 8.3
Duma 1998 PD ViM 38 28 (median) 0
Niranjan 2000 ET ViM 11 6 (median) 9.1
MS tremor
Young 2000 PD tremor 158 12–96 1.3
ET
Mathieu 2007 MS tremor ViM 6 25.5 (mean) 16.6
Kondziolka 2008 ET ViM 31 36 (median) 6.4
Lim 2010 PD tremor 18 19.2 (mean) 16.7
ET
Young 2010 Essential tremor ViM 161 44 (mean) 6.9
Elaimy 2010 ET ViM 1 144 0
Ohye 2012 PD tremor ViM 72 24 N/A
ET
Yen 2012 Dystonia ViM 1 72 0
PD Parkinson’s disease, ET essential tremor, MS multiple sclerosis, ViM ventralis intermedius nucleus

As opposed to both radiofrequency thalamotomy and
DBS, GKT offers a noninvasive lesioning method that does
not require a skin incision, burr hole, or passage of elec-
trodes. In addition, it does not harbor any foreign hardware
placement, and the risk of infection/erosion is eliminated.
Hence, the surgical risk of complications is potentially
lower than that of radiofrequency thalamotomy or DBS.
This technique may be ideal for patients who are not suitable
to undergo a surgical procedure due to medical comorbidities
or to those who want to avoid open surgical procedures
with hardware implantations. GKT is effective and reported
to treat parkinsonian tremor, essential tremor, multiple
sclerosis-related tremor, and posttraumatic-related tremor
with different results [36]. A major disadvantage of GKT is
the inability to confirm the target physiologically by using
MER and macrostimulation (electrophysiological monitor-
ing). One has to rely purely on imaging-defined anatomic
targeting, which lacks the accuracy of brain mapping. In
addition, the method of lesion generation is delayed, and as
has been suggested in some recent publications, the lesion
can be variable in size [37]. Hence, GKT has both advan-
tages and disadvantages that may give it a role in the treat-
ment of tremor.
Compared with the large multicenter studies of deep brain
stimulation for tremor, there are only a few published case
series of patients treated by Gamma Knife radiosurgical thal-
amotomy for the treatment of parkinsonian tremor and essen-
tial tremor [6] (Table 56.1). Ohye was one of the first to
advocate radiosurgical lesioning of the thalamus in patients
who had a contralateral radiofrequency lesion or in patients
who had a previously mapped lesion [38]. At present, Ohye
has reported radiosurgical thalamotomy in 70 patients with
PD and has reported tremor suppression of at least two thirds
in more than 80 % of patients with no loss of effect even after
10 years in some patients [37, 39]. Duma et al. has reported
their series of 42 radiosurgical thalamotomies in 38 patients
over a 7-year period. In their series of patients, 24 % had
complete relief of tremor, 55 % had “successful” results in
improvement of their tremor, and 21 % of patients had only
“mild” or no relief of tremor. Median follow-up in this series
was 28 months [40, 41]. Niranjan et al. reported favorable
results in 12 patients who were not candidates for open surgi-
cal procedures (nine patients with essential tremor and three
patients with MS-related tremor) [42]. Eight of their 12
patients with essential tremor had complete tremor arrest,
while the remaining four patients had improvement in tremor.
The largest series of patients undergoing GKT has been pub-
lished by Young et al. who retrospectively reviewed 158
patients who underwent radiosurgical thalamotomy [43]. Of
the 74 patients with parkinsonian tremor followed at least 4
years, 79.7 % were still tremor-free, while 70.6 % of the 16
patients with essential tremor were tremor-free. In this series,
only one patient sustained a transient complication, and two
patients sustained permanent complications including hemi-
paresis and mild facial paresthesias. No cognitive changes
were reported. Kondziolka et al. [44] reported a series of 31
essential tremor patients treated with SRS followed for a
mean of 36 months. Of their patient cohort, 18 (66.6 %)
reported improvement in action tremor and writing, 6
(22.2 %) showed improvement in action tremor alone, and 3
56 Perspective on Radiosurgery Versus Conventional Surgery for Movement Disorders
(11.1 %) showed no improvement. In this study, there were
two complications (7.4 %) that were both permanent, includ-
ing hemiparesis, dysphagia, and speech impairment. Recently,
Lim et al. reported their experience with GKT for treating
disabling tremor [36]. Although this study is derived from a
single center, it is the only prospective blinded independent
observer study that was done for GKT. In this series, assess-
ment of tremor, ADL, complications, and long-term outcomes
were analyzed in 14 patients with mean follow-up period of
7.3 months. They concluded that an improvement is achieved
only in tremor and ADL, but this improvement seems to be
modest, non-sustained, and less impressive than achieved
with DBS. In this study, three patients developed delayed
complications including hemiparesis and speech deficit.
In contrast to the major studies that were done to evaluate
DBS, GKT reports lack the stringent standards to prove effi-
cacy and safety (multicenter, double-blinded, randomization,
long-term follow-up). This makes it difficult to compare
these different modalities; however, the results of these stud-
ies suggest that radiosurgical thalamotomy is less superior to
DBS or even radiofrequency thalamotomy.
In opposition to the immediate response and relief of
tremor following DBS or thalamic radiofrequency ablation,
Gamma Knife radiosurgical thalamotomy effect is delayed,
and different studies reported different time frames from
anywhere between immediate affects to 12 months [37, 40,
42]. Niranjan et al. [44] reported immediate relief in tremor
following GKT. Moro et al. [36] reported in their study of 18
patients an improvement in tremor with a delay of 6–12
months following GKT. Ohye et al. [36] reported in their
study improvement in tremor starting 1 year following
GKT. This gap between treatment and functional progress
must be taken under consideration when making a treatment
decision, since most patients with movement disorders suffer
daily and some cannot tolerate the time between treatment
and clinical effect. This delay is related to neurobiological
sequences that take place in the brain parenchyma following
GKT and the time it takes the ionizing radiation to function-
ally damage or to destroy the tissue targeted. The time to
lesion effect can be modified and accelerated with increased
doses [45]; however, the optimal technique for Gamma Knife
radiosurgical lesioning has not been established. Due to the
different response of tissue to ionizing radiation, lesion size
can be smaller than expected, while in other cases can be
larger and expand to eloquent adjacent structures resulting in
serious adverse effects [46]. Peak central doses can range
from 120 to 200 Gy. Duma et al. reported a difference in
clinical outcome with different doses, suggesting an improve-
ment with higher doses [41]. Despite this correlation, most
surgeons at this time now perform radiosurgical lesioning for
functional disorders at lower doses (e.g., 140 Gy) [42]. This
decision is partially based on the series of eight patients all
treated at the same institution who developed complications
published by Okun et al. [46]. In that series, all except one of
685
the thalamotomy procedures were performed at exceptionally
high doses using 200 Gy (one patient was treated at 150 Gy).
Unfortunately, a systematic study of dose–response compli-
cation rate has not been performed to date.
Because of the delay in effect after GKT, an accurate doc-
umentation of complications requires vigilant follow-up.
The complications that can occur mainly include radiation
necrosis, brain edema, and bleeding. There isn’t an estab-
lished time frame for the occurrence of complication, and
they can happen even years following GKT treatment.
Rothstein et al. [47] reported an intrathalamic hemorrhage in
the precise site of prior GKT 7.5 years after treatment. In
Young’s series, 3 of 74 patients developed a complication
[43]. Other reports are single-center reports of complications
without a denominator to define the total number of proce-
dures or patients who underwent GKT. Siderowf et al.
reported one case of a complex, involuntary movement after
Gamma Knife radiosurgical thalamotomy [2]. Unfortunately,
specific dose parameters were not specified in that case
report. Okun et al. reported a series of eight patients who
developed multiple complications, including hemiplegia,
homonymous visual field deficits, hand weakness, dysar-
thria, hypophonia, aphasia, arm and face numbness, pseudo-
bulbar laughter, and death [46]. Mathieu et al. reported
progressive contralateral hemiplegia following GKT with T2
changes around targeted lesion [48]. These complications all
developed after treatment at different Gamma Knife centers,
and it does not appear that the same rate of complications
have developed at all radiosurgical centers. Nevertheless, the
true incidence of complications after radiosurgical thalamot-
omy is not well known.
One particular explanation of the complications associ-
ated with radiosurgical thalamotomy may be related to the
variability in lesion size. Animal studies in rodents and
nonhuman primates have demonstrated the ability to create
necrotic lesions in animal brain parenchyma [45, 49, 50].
Young et al. reported a clear correlation between lesion vol-
ume and complication. In their study, the mean lesion vol-
ume in which no complications were noticed was 188 m,
while the mean volume for complications was 871 mm
[51]. Dose, volume, and time are the three key factors that
determine the nature of the functional ablation [45]. Higher
doses can create necrosis faster as can the use of a larger-
volume collimator, although almost all movement disorder
GK lesions employ a 4-mm-diameter collimator. This
dose–volume–time response curve can roughly be corre-
lated in humans; however, despite this apparent consistency
in dose delivery and tissue response, Friehs et al. report
variable size on follow-up imaging after GK radiosurgical
ablation for functional procedures. Friehs et al. examined
follow-up imaging after 140 Gamma Knife radiosurgical
lesions produced in the treatment of patients with PD, pain,
and ET [52]. In all cases, the 4-mm collimator was used for
the Gamma Knife, but the postoperative scans demonstrated
686
lesion sizes that ranged from undetectable to 4,000 mm3.
Friehs correlated the higher doses with greater lesion volume
and suggested that doses of 160 Gy and above were associ-
ated with inordinately large volumes. Franzini et al. reported
in their study that older patients have a higher chance of
having an unexpected response, and lesion size cannot be
predicted [53]. Thus, although lesion size appears to be cor-
related with radiation dose, there appears to be a patient to
patient variability in response to Gamma Knife radiosurgical
lesioning. In addition, Ohye reports two different types of
lesions after radiosurgical lesions using the single 4-mm col-
limator isocenter with central doses of 130 Gy: “circum-
scribed round high signal area of approximately 7- to 8-mm
diameter surrounding a smaller low signal area. The other
is characterized by an irregular-shaped high signal zone
extending into the medial thalamic area and/or internal cap-
sule and often accompanied by streaking along the thalamo-
capsular border” [37, 41]. Ohye speculates that the delivery
time may influence lesion size. Since the cobalt sources of
the Gamma Knife need to be replaced over time, delivery of
the same 143-Gy dose may require double the length of time
with old sources compared with new sources [37]. “After
reloading, the restricted lesion was more frequent and the
lesion volume was smaller.”
In conclusion, both DBS of the VIM or GKT have been
employed in the treatment of tremor. Several well-conducted
trials have demonstrated the efficacy and complication rate
of DBS of the VIM thalamic nucleus in the treatment of both
parkinsonian tremor and essential tremor. In contrast, large,
well-conducted trials of Gamma Knife radiosurgical thala-
motomy have not been performed. Thus, it is difficult to
compare directly the efficacy and risks of GKT of the VIM
nucleus for the treatment of tremor. Nevertheless, lesioning
of the thalamus is an alternative treatment for tremor, and
Gamma Knife ablation may be effective when properly per-
formed. Hence, the first-line surgical therapy in the treatment
of patients with medically refractory tremor is VIM DBS,
and GKT remains an option for patients who cannot undergo
an open surgical procedure secondary to medical comorbidi-
ties. Gamma Knife radiosurgery of the VIM thalamus, how-
ever, should only be performed by neurosurgeons who have
experience in both deep brain stimulation and radiofrequency
thalamic procedures to optimize results.
Pallidal DBS Versus Radiosurgical
Pallidotomy
Pallidal DBS
Since its reintroduction by Laitinen and colleagues in 1992,
many successful pallidotomies have been performed through-
out the world in the treatment of Parkinson’s disease [54].
Z. Zibly et al.
The most consistent effect of pallidal ablation appears to be
the relief of contralateral L-dopa-induced dyskinesias,
whereas the amount of improvement in contralateral bra-
dykinesia, rigidity, and tremor differs among the many
studies [55]. In contrast with the number of studies docu-
menting the effects of ablation of the posteroventral GPi,
there are remarkably few studies that extend the initial obser-
vation of Siegfried and Lippitz that chronic high-frequency
stimulation of the internal pallidum may effectively treat
PD [56]. GPi DBS is also becoming increasingly common
procedure as STN DBS for the treatment of Parkinson’s
disease. GPI DBS has also been used for the treatment of
psychiatric disorders such as Tourette’s syndrome. Cannon
et al. reported the implantation of bilateral GPI DBS in 11
patients with medically intractable Tourette’s syndrome. In
their study, there was 48 % improvement in motor tics and
56.5 % reduction in phonic tics [57]. Other studies have
showed that a unilateral GPI DBS may also be effective for
the treatment of Tourette’s syndrome [58].
DBS of the STN is the most common application for
Parkinson’s disease. DBS of the internal segment of the glo-
bus pallidus is also effective [54, 55]. The most consistent
effect produced by pallidal DBS is a marked reduction of
contralateral L-dopa-induced dyskinesias [56, 59–68].
Volkmann et al. demonstrated a 54 % improvement in the
“off”-period UPDRS motor score at 1-year follow-up, with
significant improvement in bradykinesia, tremor, posture,
and gait. “On”-period motor symptoms did not improve sig-
nificantly after surgery except for dyskinesias, which were
reduced by 83 % at 1-year follow-up [68]. It appears that GPi
DBS may directly reduce levodopa-induced dyskinesias,
whereas STN DBS reduces levodopa-induced dyskinesias
indirectly via reduction of overall medication intake. Loher
et al. reported 1-year results of 16 patients showing a 38 %
improvement in medication-off UPDRS motor scores and a
33 % improvement in the ADL score in patients receiving
unilateral stimulation [69]. Bilateral stimulation led to a
slight improvement in these results. Some improvement in
the medication-on state was also noted. A larger series of 36
patients [25] demonstrated that bilateral pallidal stimulation
results in a median motor improvement of 37 % and an
increase from 28 to 64 % of the day without disabling invol-
untary movements [25]. Many reports demonstrate the ben-
eficial effects of GPi stimulation on dyskinesias, on–off
fluctuations, and tremor [3, 61, 66, 68, 70]. Also, pallidal
stimulation has been validated in those patients who have
previously undergone contralateral pallidotomy. In a cohort
of four patients who underwent GPi stimulation contralateral
to a prior pallidotomy, motor scores improved by almost
50 %, while bradykinesia was decreased by 37 % and tremor
by 93 % without serious adverse cognitive or motor effects
[71]. Despite the benefits of GPi DBS, most centers currently
favor STN DBS in the treatment of Parkinson’s disease.
56 Perspective on Radiosurgery Versus Conventional Surgery for Movement Disorders
Dystonia is one movement disorder whose primary surgi-
cal target is the GPi as opposed to the STN or VIM; however,
the treatment of dystonia with DBS remains in its infancy.
Unlike the rapid improvement seen in PD, GPi DBS in dys-
tonia results only in gradual improvement over several
months. Preliminary results suggest that more mobile, fluid
abnormal posturing may respond quicker, whereas fixed
tonic abnormal posturing may require a longer period to
improve [71–74]. Given these encouraging results, there
have been more patients with both primary and secondary
dystonia who have undergone bilateral GPi DBS. Patients
with DYT1 and primary dystonia have proven to respond
more favorably to GPi DBS than some of the secondary dys-
tonias. This may relate to variability in the etiology of the
secondary dystonias. Currently, DBS for dystonia is not
FDA approved and has a humanitarian exemption that limits
the ability for high-quality studies to be performed.
The complication rate of GPi DBS is similar to that of
VIM DBS. The risk of hemorrhage, infection, and hardware-
related complications are similar. Although there are no
direct studies that compare the incidence of cognitive com-
plications after bilateral pallidal DBS, the overall reported
complication rate after bilateral DBS does not appear to be
as high as the rate after bilateral pallidal destructive lesions.
Global scores of cognitive function exhibit little change after
unilateral or bilateral pallidal stimulation, although subtle
worsening of frontal lobe scores including verbal fluency
have been described [61, 65, 74, 75]. Risk factors for cogni-
tive deterioration include preoperative L-dopa dosages and
advanced age [74].
Despite the lack of direct comparison between the effi-
cacy of STN DBS versus GPi DBS, most neurologists/neu-
rosurgeons have selective preference for STN versus GPi
DBS. Recently, the European NSTAPS study assessed
whether GPi DBS gives grater functional improvement
than STN DBS in advanced PD. This was a multicenter ran-
domized study with a total number of 128 patients [76].
The results of this study showed improvement in the off-
medication state in the STN group compared to the GPi
group in the UPDRS score (20.3 versus 11.4), but failed to
show any other benefit of STN DBS over GPi DBS. There
are some who believe that STN DBS may have additional
risk for cognitive compromise in patients who are exhibit-
ing significant cognitive deficits. On the other hand, recent
randomized, controlled multicenter studies showed that
DBS of the STN does not reduce overall cognition or affec-
tivity [77, 78]. Nevertheless, due to the potential risk for
cognitive deficits following STN DBS, baseline neuropsy-
chological studies and evaluation are important and should
be done prior to surgery. Overall both STN and GPi have
similar efficacies for PD; however, STN is the more com-
mon target for PD DBS, while the primary target of choice
for dystonia is the GPi.
687
Radiosurgical Pallidotomy
The pallidotomy is a time-honored surgical procedure that
was performed in the 1950s by many surgeons, including
Guiot, Spiegel and Wycis, Talairach, Riechert, and Leksell.
The reintroduction of Leksell’s posteroventral pallidotomy
by Laitinen in 1992 (after its disappearance, which coincided
with the benefits of L-dopa therapy) initiated a resurgence of
interest in the surgical treatment of movement disorders. One
of the most consistent benefits of radiofrequency pallidot-
omy is improvement in contralateral drug-induced dyskine-
sias. Nearly every study has documented improvement in
L-dopa dyskinesias from 61 to 82 % [55, 79–87]. Tremor
appears to respond by 33 to 90 % at 6 months, although
tremor alone is not significant indication for pallidotomy.
The results for the symptoms of parkinsonian rigidity and
bradykinesia are not as consistent with studies demonstrat-
ing some benefit. In addition, there have only been minimal
benefits in gait. Given the results described above, conven-
tional pallidotomy is only recommended for patients who are
severely disabled by asymmetrical L-dopa dyskinesias and
who are not candidates for implanted hardware systems.
Bilateral pallidotomies are not considered a good option for
most patients given the high rates of cognitive complications
after bilateral destructive lesions in the globus pallidus [61].
Gamma Knife radiosurgical pallidotomy differs from con-
ventional radiofrequency pallidotomy primarily in its less
invasive nature. It can theoretically expect to provide excel-
lent relief of levodopa-induced dyskinesias and tremor with
fewer complications than conventional pallidotomies.
The evidence supporting the use of Gamma Knife palli-
dotomy is even more sparse than the evidence supporting the
use of GKT. Only case reports and case series are available
for study. Indeed, the last published case series of patients
treated with Gamma Knife pallidotomy dates back to 1998
[87], which most likely reflects the established success of
STN DBS in the treatment of Parkinson’s disease and the
high complication rates of GK pallidotomy. Friedman et al.
reported four patients in 1995 who were treated with 180 Gy
to the right posteroventral pallidum for advanced PD [88].
One patient had improvement in dyskinesias but also became
transiently psychotic and demented. The three other patients
neither improved nor suffered a complication. In a later pub-
lication, Friedman et al. reported two patients who underwent
radiosurgical pallidotomy with lower doses of 120 to 140 Gy
[89]. They chose to perform the procedure only in patients
who had undergone a prior radiofrequency pallidotomy with
physiologic mapping. They created a mirror-image lesion,
assuming symmetry between the two sides. Both of these
patients, however, developed complications: hemiparesis in
one patient and hypophonia and swallowing difficulties in
the other patient. In addition, Friedman et al. reported a stroke
in one patient as a complication from GK pallidotomy [90].
688 Z. Zibly et al.

Fig. 56.2 T1 contrast-enhanced MRI scan with a superimposed reformatted Schaltenbrand and Wahren atlas with bilateral electrodes trajectory
targeting the STN

This was attributed to vascular hyalinization and thrombosis.

The largest series of GK pallidotomies comes from Young
et al. who reported a series of 29 patients who underwent
Gamma Knife pallidotomy [87]. He reports that two thirds of
his patients demonstrated improvements in bradykinesia and
rigidity. Only one of these 29 patients developed a complica-
tion—hemianopsia 9 months after the procedure. UPDRS
scores were not consistently evaluated by blinded observers
in this study. With respect to complications, Okun et al.
reported three complications after Gamma Knife pallidotomy Fig. 56.3 Postoperative anteroposterior and lateral skull X-rays dem-
performed in one center [46]. Three patients who had Gamma onstrating the implanted STN DBS electrodes
Knife pallidotomy had been treated with doses of 200, 150,
and 100 Gy. All three experienced visual field loss and/or
hemiparesis and dysarthria.
Compared with GKT, there appears to be a shortage of
published case series of patients treated with GK pallidot-
omy for the treatment of Parkinson’s disease. This most
likely represents a lack of enthusiasm on the part of the treat-
ing surgeons and referring neurologists. There are few stud-
ies that truly document the benefit of GK pallidotomy in a
blinded and unbiased fashion, and there are several reports of
complications after GK pallidotomy. Hence, at this stage,
GK pallidotomy is not performed as a viable method of
lesioning in the treatment of PD. GK pallidotomy have been
reported in case studies as a successful treatment option for Fig. 56.4 Postoperative axial and sagittal T1-weighted MRI scans
dystonia and hemidystonia [91]. showing the implanted STN DBS electrodes

Subthalamic DBS Versus Radiosurgical
Subthalamotomy
Subthalamic DBS
At the present time, DBS of the subthalamic nucleus is the
most widely practiced surgical treatment for patients with
idiopathic Parkinson’s disease (Figs. 56.2, 56.3, and 56.4).
Benabid et al. were the first group to demonstrate the efficacy
of STN DBS in the treatment of PD in the mid-1990s [92].
One-year follow-up of 24 patients implanted with bilateral
STN DBS demonstrated that UPDRS ADL and motor
scores improved by 60 % in the off-medication state [93].
The UPDRS subscores for akinesia (56 %), tremor (80 %),
rigidity (68 %), and gait (55 %) also improved, in contrast
with the results seen with VIM stimulation [11]. However,
the effect in the on-medication state was not as pro-
nounced, with only a 10 % improvement in the motor score
noted. Levodopa drug use was cut in half. These results have
held up at 5-year follow-up [94]. Kumar et al. performed a
56 Perspective on Radiosurgery Versus Conventional Surgery for Movement Disorders
prospective, randomized, double-blinded study comparing
STN DBS with the stimulator on and off [94]. They found a
65 % reduction in off-period motor UPDRS scores, a 40 %
reduction in on-period motor UPDRS scores, and an 85 %
reduction in L-dopa-induced dyskinesias in the seven patients
who were evaluated. Limousin et al. found a 60 % improve-
ment in off-period UPDRS scores but only a 10 % improve-
ment in on-period UPDRS scores.
These two prospective double blind studies comparing
STN DBS with the stimulator on and off found a 60–65 %
reduction in off-period motor UPDRS scores and a 10–40 %
reduction in on-period motor UPDRS scores with an asso-
ciated 85 % reduction in L-dopa-induced dyskinesias [93].
In summary, STN DBS is quite effective in the treatment of
Parkinson’s disease. Levodopa-responsive motor features
typically respond well to STN DBS with the possible
exception of tremor. The axial features of PD such as dys-
arthria, postural instability, and freezing of gait may not
reliably respond to STN DBS. Disease-related progression
of these features over time may compromise overall post-
surgical benefit despite continuing response of limb motor
function.
Preoperative levodopa responsiveness (by varying defini-
tions) is often reported as a predictive factor for a positive
response to surgery [12, 95–102]. A positive response to a
levodopa challenge and correlation with good outcome may
be more evident with STN DBS than with GPi DBS [103,
104]. The mean percent improvement in motor UPDRS dur-
ing the levodopa test ranges from 40 to 70 % in published
studies. As the levodopa response is the main predictor of
outcome after STN DBS [96, 102, 103, 105], the benefit will
be greatest in those patients who have a high off-drug score
and a low on-drug score. In other words, the “best on” may
be a better predictor for functional outcome than the numeri-
cal magnitude of the response.
The hardware complications of STN DBS are similar to
those listed in the section on VIM DBS as are the issues
related to hemorrhage rates (e.g., approximately 3 % hemor-
rhage rate with less than one third being symptomatic).
Complications related to STN stimulation, however, are dif-
ferent from VIM or GPi stimulation. Involuntary movements
can occur during the initial phase of STN stimulation but tend
to be mild and generally respond to changes in the stimulation
parameters [106, 107]. In a retrospective study, Volkmann
noted that STN stimulation appeared to be associated with a
higher incidence of adverse events compared with GPi stimu-
lation at 1-year follow-up periods [108]. The STN DBS group
had higher rates of depression, anhedonia, hypophonia, dys-
arthria, and apraxia of eyelid opening. Nevertheless, the com-
plication rates of STN DBS generally are mild and can be
improved with changes in stimulator settings, and STN is the
most common DBS surgery performed for PD.
689
Radiosurgical Subthalamotomy
Subthalamotomy in the form of ischemic strokes or hemor-
rhages have generally been known to cause hemiballism.
However, despite this conventional teaching, there are case
reports of parkinsonian patients with spontaneous STN
hemorrhage who have experienced motor improvement
without the occurrence of hemiballism [109, 110]. In addi-
tion, there are centers outside of the USA that have reported
on the benefits of therapeutic STN ablative surgery using
traditional radiofrequency lesioning techniques. The Cuban
group reported their results in 18 patients after bilateral dor-
sal subthalamotomy [111]. After a 16-month average fol-
low-up period, there was a 58 % improvement in UPDRS
motor scores in the “off” period. Three patients developed
severe generalized chorea, dysarthria, and balance instabil-
ity that lasted 6 months from which they spontaneously
recovered. The Bristol group reported their results on 50
subthalamotomies in 39 patients [112]. After unilateral STN
lesions, the patients demonstrated a 46 % improvement in
the motor UPDRS score at 24 months. In addition, they
were able to decrease their levodopa dose by 50 %. With
respect to complications, one patient developed an intrace-
rebral hemorrhage, and one patient developed postoperative
hemiballism on the side contralateral to the STN lesion that
lasted for 3 weeks and then spontaneously disappeared.
Hence, subthalamotomy via radiofrequency lesioning is a
procedure in its infancy with a much diminutive number of
patients treated compared to DBS in the reported literature.
The results are promising, but safety and efficacy remains to
be proved.
There is only a single case report in the literature with
one patient treated with Gamma Knife subthalamotomy
for Parkinson’s disease [113]. This one patient had a
prior radiofrequency pallidotomy and then had a Gamma
Knife procedure with a single 120-Gy, 4-mm shot to the
subthalamic nucleus. Forty-two months after the proce-
dure, her postoperative Parkinson’s disease disability rat-
ing score had decreased from 28 to 11, and the patient
had no side effects. Gamma Knife subthalamotomy
results in a small area of ischemia which can be seen and
followed with magnetic resonance imaging studies
(Fig. 56.1). Although this is perhaps a promising case
report, Gamma Knife subthalamotomy cannot be recom-
mended as a safe option in patients with Parkinson’s disease
at this time.
Future of Movement Disorder Surgery
During the last decade, new technologies have emerged with
applications to movement disorder surgery.
690
Intraoperative Magnetic Resonance Imaging
in Treatment of Movement Disorders
During the last years, an increasing number of medical cen-
ters have implicated the use of intraoperative MRI-guided
DBS. The surgical procedure can be done with and without a
frame and uses an image-guided system for targeting and
implanting the electrode. Currently, there is only one real-
time intraoperative MRI-guided system that has been
approved by the FDA to be used. The main drawback of
using an intraoperative MRI-guided DBS system is the
inability to perform MER and macrostimulation in order to
functionally confirm the location, refine initial targeting,
account for anatomical variations, and assess side effects
during stimulation. Also it is only applicable for targeting
areas of the brain which can be identified with an MR imag-
ing, such as the STN, GPi, GPe, and thalamus. The benefits
of MR guidance during DBS surgery include targeting per-
formed after the dura is opened and brain shift has occurred,
high-resolution MR images for confirmation of electrode
position, decreasing the number of MER electrodes passing
through the brain, and reducing surgical time [114]. It also
allows the surgeons to assess the occurrence of intracranial
bleeding and eliminates the need to withhold antiparkinso-
nian medications and the discomfort and additional stress to
the patient being awake. The surgical method chosen is
dependent on both the surgeon and patient preference while
considering the risks and benefits.
Gamma Knife Radiosurgery
GK for the treatment of movement disorders is a growing
field, and since there is a lack of neurosurgeons familiar and
experienced with DBS, it has gained popularity. The proce-
dure appears to be safe, and patients can easily tolerate it as
it is short and does not necessitate hospitalization. In addi-
tion, it is noninvasive and does not require open surgery or
hardware implantation. The patient and practitioner must
weigh the potential complications with the benefits when
choosing any surgical procedure.
High-Intensity Focused Ultrasound
High-intensity focused ultrasound (HIFU) is a new, evolving
technology. This modality provides a promising new noninva-
sive and alternative treatment for a number of conditions such
as movement disorders, tumors, and other conditions [115].
Edmund Harvey Newton in 1929 first demonstrated the
central nervous system’s (CNS) sonographic response with
using ultrasound to stimulate nerves and muscles.
Subsequently, William Fry and colleagues successfully gen-
Z. Zibly et al.
erated functional lesions in the mammalian brain using what
they termed “neurosonic surgery” in the late 1940s [116].
These developments led to the prototypical HIFU devices
described in 1949 by Lars Leksell, which gained notoriety in
the 1950s for the ablation of soft tissue lesions [117].
Furthermore, by the late 1950s, Fry and colleagues were suc-
cessfully using ultrasound to treat movement disorders. The
histological changes in the brain tissue consist of thermal
injury and necrosis. However, ultrasound therapy as a neuro-
surgical approach was largely ignored at the time, with most
procedures needing intensive craniotomies [118].
The combination of MRI and HIFU as a treatment modal-
ity was first introduced and received FDA approval for the
treatment of uterine fibroids. More recently, MRI-guided
HIFU (MRgHIFU) was approved for the treatment of pros-
tate cancer and breast fibroadenomas. MRgHIFU allows for
target acquisition and guidance through “real-time” ther-
mometry giving this modality far greater accuracy than ear-
lier HIFU technology [119]. Additional clinical trials are
ongoing in the treatment of a variety of movement disorders
including essential tremor, dystonia, and Parkinson’s disease
and essential tremor. Its utility in neurosurgery is in its
infancy, and ongoing research may open the door to new pos-
sibilities. The HIFU treatment for essential tremor has been
approved recently in Europe, and a multicenter trial is
expected to begin in the USA. A pilot study utilizing HIFU
in the treatment of Parkinson’s disease is currently been eval-
uated in the USA.
Conclusion
There are several options for neurosurgeons to treat advanced
and intractable movement disorders such as essential tremor,
Parkinson’s disease, and dystonia. DBS of the VIM thala-
mus, STN, and GPi is the most common approach in devel-
oped countries and is proven to be effective and safe in the
treatment of patients with Parkinson’s disease, essential
tremor, and dystonia. Radiofrequency lesioning has also
been performed for decades with established efficacy in
experienced hands.
Gamma Knife radiosurgery for the treatment of movement
disorders has a specific limited role and needs to be further
investigated (Table 56.2). At this time, GKT has been shown
to have some benefits in specific scenarios such as patients
with coagulopathy, older age, and surgical contraindications
to DBS or RF surgery. GK radiosurgery’s role in GPi and
STN for PD and dystonia needs further investigation particu-
larly by the same neurosurgeons who have expertise in DBS.
In addition to movement disorders, a number of other condi-
tions are being investigated with DBS, RF lesioning, and
gamma knife including obsessive–compulsive disorder, major
depression, traumatic brain injury, and Alzheimer’s disease.
56 Perspective on Radiosurgery Versus Conventional Surgery for Movement Disorders 691

Table 56.2 Landmark differences between radiosurgery and deep brain stimulation for movement disorders
Intraoperative MRI-guided
Radiosurgery Radiofrequency lesioning Deep brain stimulation DBS
Experience 45 years 55 years >25 years 7 years
Adjustable? No Lesion may be “sculpted” Yes Yes
in or
Time to clinical 1–12 months Minutes to hours Minutes to hours Minutes to hours
effect?
Reversibility? No No Yes Yes
Repeatable? No Yes N/A N/A
Targeting method Imaging only Imaging plus Imaging plus Imaging only
microelectrode recording microelectrode recording
and macrostimulation and macrostimulation
Possible Necrosis Lesion spread to adjacent Hardware infection/ Hardware infection/erosion
complications structures erosion
Lesion spread to Higher incidence of Electrode breakage Electrode breakage
adjacent complications when
structures performed bilaterally

12. Benabid AL, Benazzouz A, Hoffmann D, Limousin P, Krack P,

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 Movement Disorders:
Viewpoint—Medical Therapy
Abraham N. Lieberman and Sara S. Dhanani
Movement Disorders: Viewpoint—Medical
Therapy
Movement disorders are a diverse group of diseases that
constitute either an excess of movement or a paucity of
movement. The former are known as hyperkinetic and the
latter as hypokinetic disorders. Parkinson disease (PD), next
to essential tremor (ET), is the most common movement dis-
order, and unlike ET is more debilitating. PD encompasses
both hypokinesia (slowness and paucity of movement) and
hyperkinesia (tremor). In addition many PD patients on
levodopa treatment develop dyskinesias, a hyperkinetic
movement disorder, a combination of chorea (dance-like
involuntary movements) and dystonia (altered tone).
Parkinson disease shares many features with a number of
Parkinson-plus or Parkinson-like disorders. These disorders
usually do not respond to treatment with levodopa, usually
run more rapid courses, and rarely have hyperkinetic features.
These disorders have pathology different from PD; they
include multiple system atrophy (MSA), progressive supra-
nuclear palsy (PSP), and corticobasilar degeneration (CBD).
Essential tremor (ET) is the most common movement
disorder. Although troublesome, it is usually not debilitating.
Among the more prominent hyperkinetic movement disorders
are Huntington disease and Tourette’s syndrome. Hyperkinetic
disorders include movements such as athetosis, ballism, cho-
rea, myoclonus, tics, and tremor. These can occur as isolated
phenomena or as the results of strokes or in association with
liver, kidney, endocrine, or metabolic disorders. They can also
occur as the result of drugs including amiodarone (tremor),
lithium (tremor), metoclopramide (dystonia, parkinsonism),
A.N. Lieberman, M.D. (*)
Department of Neurology, Barrow Neurological Institute,
St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA
S.S. Dhanani, M.D.
Department of Neurology, Banner Sunreach Research Institute,
Sun City, AZ, USA
e-mail: sara.dhanani@dignityhealth.com
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_57, © Springer Science+Business Media New York 2015
57
neuroleptics (dystonia, parkinsonism), and valproate (tremor).
The term tardive dyskinesia is used to describe drug-induced
movement disorders. Tardive can signify a delay in the appear-
ance of the movement disorder after the drug has begun, or
delay in the appearance of the movement disorder after the
drug has been discontinued. The focus of this chapter will be
on the two most common disorders: PD and ET.
Parkinson Disease
PD is a disorder characterized by four cardinal features that
include tremor at rest, bradykinesia (a slowness and paucity
of movement), rigidity, and postural instability. Other fea-
tures that at times can be as troubling as the cardinal features
include mental changes ranging from minimal cognitive
impairment to dementia, depression, apathy, difficulty walk-
ing, freezing of gait, and autonomic insufficiency. Additional
features may include a postural kinetic tremor, speech and
swallowing difficulties, sialorrhea, and abnormal flexed pos-
tures of the hands, the legs, and the trunk. Although tremor is
strongly associated with PD, 30 % of PD patients have no
tremor.
The disorder was first described in 1817 by James
Parkinson who wrote An Essay on the Shaking Palsy [1]. PD
usually begins asymmetrically with slowness of movement of
an arm or leg and/or a rest tremor (of the hand). PD is a rarity
among movement disorders in that it usually appears asym-
metrically. Corticobasilar degeneration (CBD), a disorder
that occurs 1/100th as often as PD, also presents asymmetri-
cally. In PD, over several years the disorder progresses to
involve the contralateral side and trunk [2]. If a disorder diag-
nosed as PD presents with symmetrical signs and progresses
rapidly, the evolving disorder which may have initially been
diagnosed as PD will likely turn out to be one of PD-plus
disorders. This is especially so if postural instability with
falls appears early in the evolution of the disorder [3].
Several studies have identified non-motor features of
PD, features that may precede the diagnosis of PD [4].
695
696
These include loss of olfaction, a rapid eye movement (REM)
sleep behavior disorder (RBD), constipation, autonomic
insufficiency, apathy, depression, and mild cognitive impair-
ment [5]. Loss of olfaction may be one of the first signs
of PD, appreciated in retrospect. Loss of olfaction is not
improved or worsened by anti-PD drugs [6]. Although the
cause of PD is unknown, it has been speculated, by some, a
prion, utilizes the olfactory pathway to enter the brain and
cause PD. While RBD is not a specific marker for PD, it is
present in a higher frequency in people who develop PD. The
locus ceruleus, a noradrenergic nucleus in the brainstem, a
nucleus affected in PD, may also be affected in RBD. The
progression of PD from caudal sites such as the dorsal vagal
nucleus in the medulla to the locus ceruleus to the substantia
nigra suggests to some, a causative process that progresses in
a caudal rostral direction [7].
The pathology in PD is characterized by progressive
degeneration of the dopaminergic nigrostriatal system and
also by degeneration of other neuronal systems including
involvement of acetylcholine neurons in the nucleus basalis
of Meynert, serotonin neurons in the dorsal raphe nucleus,
and noradrenalin neurons in the locus ceruleus as well as
neurons in the cortex, the spinal cord, and the central and
peripheral autonomic nervous system [8]. Recent studies
utilizing positron emission tomography (PET scans) and
single photon emission tomography (SPECT scans) suggest
that despite the presence of PD for many years, degeneration
of the dopamine neurons and the loss of dopamine in the
putamen and caudate nucleus are incomplete [9].
The loss of dopamine neurons in the nigra and the loss of
dopamine in the putamen may account for the hypokinetic
component of PD. These symptoms are helped by levodopa
(which replaces the depleted dopamine). An impairment of
circuits including tracts from the motor cortex to the putamen
then to the globus pallidus, then to the subthalamic nucleus,
then to the thalamus, and back to the supplementary motor
cortex may account for the hyperkinetic components of PD.
The manifestations of PD range from a barely perceptible
rest tremor to significant dysfunction resulting in freezing of
gait with falls, loss of postural stability, falls, and cognitive
decline progressing to dementia. Most of the motor manifes-
tations of PD are related to the deficiency of dopamine in the
striatum. A major advantage in identifying a prodromal PD
state would be the opportunity to introduce therapy at an
earlier time point than is currently possible with, perhaps, a
delay in the progression of some symptoms.
Therapy in early PD is guided by the effect of symptoms
on function and quality of life, consideration of complica-
tions associated with the long-term use of drugs, particularly
levodopa and the likelihood of the development of response
fluctuations such as “wearing off” (gradual loss of efficacy of
a dose of levodopa), “on off” (abrupt loss of efficacy of a
dose of levodopa), and dyskinesias. Several studies suggest
A.N. Lieberman and S.S. Dhanani
that early treatment may provide benefits that may not be
achieved if the drugs are introduced later [10].
Monoamine oxidase (MAO) type B inhibitors, such as
Rasagiline or Selegiline, are effective as monotherapy in
patients with early PD and as adjunctive therapy to dopamine
agonists or levodopa in patients with more advanced PD [11].
Monoamine oxidase B inhibitors, unlike MAO-A inhibitors
(drugs used in psychiatry), do not result in elevations of tyra-
mine, an amine found in certain cured meats, red wines, and
cheese. Unlike with MAO-A inhibitors, dietary restrictions
are not necessary with MAO-B inhibitors provided the rec-
ommended doses are used. There is a question as to whether
Rasagiline, through mechanisms unrelated to monoamine
oxidase B inhibition, may slow the progression of PD [11].
Approximately 50 % of patients improve mildly or moder-
ately. Improvement continues throughout the illness.
Other drugs used in PD, drugs that can be used as initial
treatment, include amantadine and the dopamine agonists.
Amantadine, originally introduced as a drug to prevent the
flu, both enhances dopaminergic transmission, resulting in
an anti-PD effect, and blocks NMDA glutamate receptor.
The anti-glutaminergic affect may account for the ability of
amantadine to lessen the dyskinesias that often complicate
long-term levodopa treatment [12]. Dopamine agonists,
drugs that mimic the effects of dopamine in the brain, may be
used as initial treatment and as adjuncts to levodopa.
Dopamine agonists, including Ropinirole, Pramipexole, and
Rotigotine (administered as a skin patch), are longer acting
than levodopa. In early PD they have an anti-PD less than
levodopa but they do not result in “wearing off” or “on off”
and they do not result in dyskinesias. Used in combination
with levodopa they may allow for a reduction in the dose of
levodopa, a lessening of the “wearing off” and “on off effect”
and a decrease in dyskinesias [13]. Approximately 50–75 %
of patients with early PD improve. Improvement maintained
throughout most of the course of the disease. Adverse effects
associated with the dopamine agonists include hallucinations
(which also occur with levodopa), peripheral edema, hyper-
somnolence, and impulse control disorders including patho-
logic gambling, hypersexuality, and hyperphagia. Although
impulse control disorders also occur with levodopa, they are
more prominent with the dopamine agonists.
Levodopa remains the single most effective drug for the
relief of PD symptoms. Levodopa is combined with carbi-
dopa, a peripherally acting dopa-decarboxylase inhibitor, a
drug that blocks the nausea associated with levodopa and
allows more levodopa to enter the brain. Carbidopa is usually
combined with levodopa in a 1:4 ratio, carbidopa/levodopa
25 mg/100 mg, or sometimes a 1:10 ratio. Long-term use of
levodopa may be associated with complications including
“wearing off,” “on off,” and dyskinesias. In patients with
cognitive impairment levodopa, like the dopamine agonists
and like amantadine, may be associated with delusions,
57 Movement Disorders: Viewpoint—Medical Therapy
hallucinations, and paranoia. As PD advances drug treatment
becomes less satisfactory. In part this is related to progres-
sion of the underlying disease with involvement of non-
dopaminergic systems and in part to the complications of the
drugs [14, 15]. All patients improve on levodopa which
failed to improve usually. It indicates the disorder is not PD
but a PD-plus disorder, such as progressive supranuclear
palsy or multiple system atrophy. Improvement is main-
tained but as the disease progresses higher doses are needed.
The introduction of deep brain stimulation (DBS) has
altered the treatment of PD. DBS of selected nuclei, unilater-
ally or bilaterally, may improve tremor, lessen dyskinesia, and
lessen “wearing off.” Targets of DBS include the subthalamic
nucleus, the globus pallidum interna, and the thalamus.
Properly choosing patients for DBS and selecting the appro-
priate targets is an ongoing work in evolution.
Essential Tremor
Essential tremor (ET) is the most common movement
disorder. It’s estimated that 5.0 % of the population has
ET. However in only about 5.0 % is it of sufficient concern to
warrant a consultation with a neurologist. The tremor of ET,
unlike the tremor of PD, begins bilaterally. Unlike the tremor
of PD, it usually involves the index, middle, ring, and little
finger before it involves the thumb. The tremor is present on
sustaining or maintaining a posture (sustention or postural
tremor) or on movement (action or kinetic tremor). Rarely the
tremor of ET may be present at rest. In ET the rest tremor is
usually a late manifestation, whereas in PD it is an early man-
ifestation. The tremor of ET can involve the head. It uncom-
monly involves the legs. A tremor that begins in one hand and
spreads to the ipsilateral leg is usually PD. There is often a
family history in ET. A family history is less common in PD.
Initially it may be difficult, on the basis of a single obser-
vation, to distinguish the postural and/or kinetic tremor of
ET from a postural or kinetic tremor of PD. Usually within
two years the differences become obvious as the patient with
PD develops, in addition to the tremor other symptoms of
PD. A specialized SPECT scan called a DAT scan that labels
the dopamine transporter protein in the caudate and putamen
can distinguish ET from PD with high sensitivity and speci-
ficity. In ET dopamine is present in the caudate and putamen;
in PD, dopamine is depleted in the putamen. These patterns
are readily recognized on the DAT scan.
The tremor of ET is usually slowly progressive but over
the years many patients may experience difficulties perform-
ing basic daily activities [16], thereby impairing their quality
of life. In addition, although postural and kinetic tremors are
the main features of ET, intention tremors, which impair
activities of daily living, may also occur in some patients [17].
697
Other symptoms that may rarely complicate ET include
ataxia and postural instability. Recent studies have revealed
the presence of abnormalities in the cerebellum (including
loss of Purkinje neurons) and the locus ceruleus. The func-
tion of the Purkinje neurons is to inhibit the outflow nuclei of
the cerebellum that in turn stimulate the thalamus. Loss of
Purkinje neurons result in less inhibition of the cerebellar
outflow nuclei with increased stimulation of the thalamus—
resulting in a hyperkinetic movement disorder: tremor. DBS
of the thalamus (presumably with inhibition) is treatment for
refractory ET. In addition to the presence of motor signs,
there may be, in a few patients, cognitive impairment and
depression [18–20].
The decision to treat patients with ET is based primarily
on the functional impact of the tremor. The most commonly
used, and generally most effective, medications for essential
tremor are propranolol (a beta-blocker) and primidone (an
anticonvulsant), administered either as monotherapy or in
combination. In addition, there are other drugs that can be
used to treat tremor in patients not responsive to propranolol
or primidone. These medications include alprazolam (a ben-
zodiazepine), atenolol (a beta-blocker), gabapentin (an anti-
convulsant), topiramate (an anticonvulsant), and zonisamide
(an anticonvulsant) [21]. Some hand tremors that are diag-
nosed as ET are really dystonic tremors and may respond to
botulinum toxin injections [22]. In those patients who have
marked tremors that results in disability or prevent them
from working and who do not respond to medical therapy,
surgical options are available. The benzodiazepines, beta-
blockers, and anticonvulsants are beneficial to a moderate
degree in approximately 40 % of patients. DBS is 95–100 %
successful in alleviating tremors. The most common proce-
dure performed is DBS targeting the ventralis intermedius
(VIM) nucleus of the thalamus [23].
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 Radiosurgery for Drug-Resistant
Epilepsies: State of the Art, Results,
and Perspectives
Jean Régis, Romain Carron, Fabrice Bartolomei,
and Patrick Chauvel
Rationale
Radiosurgery is a neurosurgical technique where energy is
delivered in a single session to a small sharply limited target
with a stereotactic accuracy, with the aim either to create a
lesion or to induce a desired biological effect [1, 2]. Since the
first attempt of the pioneers in Stockholm, the practice of
radiosurgery has dramatically changed with, nowadays in the
vast majority of the indications, the use of nondestructive
low dosage inducing subtle biological effect like apoptoses
in tumors or endothelial proliferation in AVM.
The Differential Effect Concept
This is a classical clinical observation that in 85 % of the
AVM associated to a resistant epilepsy radiosurgery is fol-
lowed by seizure cessation or dramatic improvement occur-
ring much before the occlusion of the AVM itself. When the
AVM is located in a highly functional area, the seizure cessa-
tion is obtained without clinical deficit. This observation has
led us in 1992 to propose the concept of clinical differential
effect: radiosurgery can induce a functional effect as making
the cortex surrounding the AVM no longer epileptic without
destroying the underlying function of this cortical area thanks
to its capacity to alter specifically some systems while spar-
ing others. The first proof of concept came from the demon-
stration of the existence of such an effect at the biochemical
level in the striatum of rats [3]. A group of rats received a
single isocenter of 4 mm in the left striatum with a maximum
J. Régis, M.D. (*) • R. Carron, M.D., Ph.D.
Department of Functional Neurosurgery, Aix-Marseille
University—Timone University Hospital, Marseille, France
e-mail: jregis@ap-hm.fr
F. Bartolomei, M.D., Ph.D. • P. Chauvel, M.D.
Department of Neurophysiology, Aix-Marseille
University—Timone University Hospital, Marseille, France
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_58, © Springer Science+Business Media New York 2015
58
dose of 50 Gy using the GK. Biochemical analyses
demonstrated a stability of the level of the GABA Acetyl
decarboxylase in spite of the dramatic decrease of the level
of the CAT indicating an injury of the catecholaminergic sys-
tem in spite of the sparing of the GABAergic system.
Similarly direct dosage of the GABA itself has shown its sta-
bility in spite of the major decrease of the amino excitatory
acids (glutamate and aspartate). This experimental demon-
stration led us to consider radiosurgery as a neuromodulation
therapy [1–3] and encouraged us to organize several prospec-
tive clinical trials [4–8]. More recently the demonstration of
the existence of a differential effect at the cellular level came
from the Charlottesville group [9]. In epileptic rats irradiated
with 40 Gy in the temporal lobe using the GK immunohisto-
chemical study suggested that at least one subtype of hippo-
campal interneurons is selectively vulnerable to Gamma
Knife (GK) radiosurgery. Neuronal cells appear to have
undergone a phenotypic shift with respect to calbindin and
GAD-67 expression. There is a growing body of evidence
nowadays in favor of a neuromodulatory effect [1, 2, 10].
A series of successive clinical trials have been organized
in Marseille in order to evaluate Gamma Knife surgery in
epilepsy. In 1993 we organized a phase II prospective trial in
four MTLE patients with a goal of dose ranging and toxicity
evaluation [6, 8]. In 1995, the good safety and the impressive
efficacy in the patient receiving the 24 Gy dosage led us to
organize a phase III prospective single center study in four
mesial temporal lobe epilepsy (MTLE) patients (24 Gy
7–8 cc) in order to evaluate the reproducibility of the efficacy
[4]. In 1996, we organized a prospective multicentric
European study (21 MTLE patients) confirming the repro-
ducibility of the safety and efficacy [7]. In 1998 a dose de-
escalation study (24, 20, 18 Gy) has shown that the efficacy
was decreasing dramatically when the marginal doses were
lower than 24 Gy [5]. Finally, our neurologists performed a
long-term evaluation (>5years FU) in the first 15 consecutive
patients treated according to our standard protocol [11]. This
paper confirmed the good safety and efficacy of GKS in this
group of patient on the long term with a rate of 60 % of Engel
699
700
I at a mean FU of 8 years [6–10] comparing well with the
safety and efficacy of open surgery on the long term. More
recently a multicentric prospective trial in the USA has con-
firmed all our findings [12]. Since this time, radiosurgery is
the current practice for pure MTLE in our group [13].
There are convincing arguments for such an investigation
of the potential role of radiosurgery in epilepsy surgery. We
know that:
• Radiosurgery (since its introduction in the 1950s) has
been demonstrated to have advantages in terms of safety
and efficacy, for the treatment of numerous small deeply
seated intracerebral lesions.
• Radiosurgical treatment of small cortico-subcortical
lesions associated with epilepsy has been demonstrated to
lead to seizure cessation in a high percentage (58–80 % in
AVM) of cases, long before the expected treatment of the
lesion and sometimes even in spite of failing to cure the
lesion itself.
• Radiotherapeutic treatment of epilepsies with or without
space-occupying lesions can lead to a reduction in seizure
frequency and/or severity.
• Experimental models of epilepsies treated with radiation
therapy have demonstrated a dose-dependent positive
effect of radiation on the frequency and severity of the
seizures, and on the extent of discharge propagation.
Lars Leksell initially conceived of Gamma Knife (GK)
radiosurgery as a tool for functional neurosurgery [14, 15].
Accordingly, he used GK in movement disorders, trigeminal
neuralgia, and other pain syndromes, but not for epilepsy
surgery [16]. The first radiosurgical treatments for epilepsy
surgery were performed by Talairach in the 1950s [17].
Talairach was another pioneering expert in stereotaxis.
Unlike Leksell, he had specific involvement in epilepsy sur-
gery and led one of the first large comprehensive programs
for epilepsy surgery. As early as 1974, he reported on the use
of radioactive Yttrium implants in patients with MTLE with-
out space-occupying lesions, and showed a high rate of sei-
zure control in patients with epilepsies confined to the mesial
structures of the temporal lobe [17]. In 1980, Elomaa [18],
apparently unaware of Talairach’s work, promoted the idea
of the use of focal irradiation for the treatment of temporal
lobe epilepsy, based on the preliminary reports of Tracy, Von
Wieser, and Baudouin [19, 20]. Furthermore, clinical experi-
ence of the use of GK- and Linac-based radiosurgery in arte-
riovenous malformations (AVMs) and cortico-subcortical
tumors (mostly metastases and low-grade glial tumors)
revealed an antiepileptic effect of radiosurgery in absence of
necrotizing effect [21–23]. A series of experimental studies
in small animals confirmed this effect [24, 25] and has
emphasized its relationship to the dose delivered [26–29].
Barcia Salorio et al., and later Lindquist et al., reported small
and heterogeneous groups of patients treated with the aim of
seizure cessation; results were however poor [30–33].
J. Régis et al.
Unfortunately, these data were never published in peer-reviewed
papers and precise data are unavailable.
The Department of Stereotactic and Functional Surgery in
Marseille has two major fields of expertise: epilepsy surgery
and radiosurgery. This context has therefore facilitated the
investigation and development of a potential role for GK
radiosurgery in the treatment of intractable epilepsy. The
first attempt to treat an MTLE occurred in Marseille in March
1993 [6]. Since 1993, we have performed 217 cases of epi-
lepsy surgery using GK radiosurgery.
Among 11,066 Gamma Knife surgery procedures accom-
plished in our neurosurgical unit in a 20-year period (between
July 1992 and December 2012), only 217 were proposed in
patients referred for epilepsy surgery (roughly ten patients/
year). During the same period, we have performed 759 non
radiosurgical neurosurgical intervention operations for epi-
lepsy surgery. By the way, the philosophy of our team is to
define the niche of patients in whom the safety-efficacy ratio
makes it advantageous or at least comparing favorably to
open neurosurgery [34]. Obviously, this represents a small
subset of patients in our present experience (23 %). However,
a part of the patients we are actually operating by GKS are
directly referred to us for this specific procedure. The real
percentage of patients coming from our own clinical pro-
gram of investigation for epilepsy and operated by GKS is
only 14.6 %.
Hypothalamic Hamartomas
Hypothalamic hamartomas (HH) may be asymptomatic,
associated with precocious puberty or with neurological dis-
orders (including epilepsy, behavior disturbances, and cog-
nitive impairment), or both. Usually the seizures begin early
in life and are often particularly drug resistant from the out-
set. The evolution is unfavorable in the majority of the
patients because of behavioral symptoms (particularly
aggressive behavior) and mental decline, which occur as a
direct effect of the seizures [35], due to an epileptic encepha-
lopathy. Interestingly, in our experience, the reversal of this
encephalopathy after radiosurgery seems to start even before
complete cessation of the seizures and seems to be correlated
to the improvement in background EEG activity. We may
speculate that these continuous discharges are leading to the
disorganization of several systems, including the limbic sys-
tem, and that their disappearance accounts for the improve-
ment seen in attention, memory, cognitive performance,
impulsive behavior, etc. Here, the goal of radiosurgery is the
reversal of the epileptic encephalopathy more than seizure
cessation. Consequently, we consider that it is essential to
operate on these young patients as early as possible, what-
ever the surgical approach considered (resection or
radiosurgery).
58 Radiosurgery for Drug-Resistant Epilepsies: State of the Art, Results, and Perspectives
The intrinsic epileptogenicity of HH has been demon-
strated [36, 37] even though the mechanisms of the epilepsy
associated with HH are still debatable. The boundary of the
target zone of treatment is that of the lesion visualized on
magnetic resonance (MR) imaging. This contrasts greatly
with cases of MTLE where there is no such clear delineation
of an epileptogenic zone on the images used for planning
radiosurgical intervention.
We retrospectively analyzed radiosurgery in a series of
ten patients collected from centers around the world [38].
The very good safety-efficacy ratio (all improved, 50 %
cured, and no adverse effects except one case of poikilother-
mia) led us to organize a prospective multicenter trial. Our
trial of 64 prospectively evaluated patients is unique by the
number of patients and the strict methodology of this evalu-
ation. We have published preliminary reports of this study
[39–41] and the final evaluation is to be published. These 64
patients operated between 1999 and 2007 have been all fol-
lowed more than 3 years (36–107 months). According to our
policy, the patient and the family are offered a second radio-
surgery in case of partial benefit when the lesion is anatomi-
cally small and well defined. Due to significant but incomplete
efficacy, 25 patients (62.5 %) were treated twice. The preop-
erative cognitive deficits, behavioral disturbances, and inves-
tigated relationship of seizure severity and anatomical type
to cognitive abilities were characterized [42, 43]. The goal of
the preoperative work-up was to adequately select the candi-
dates for inclusion and to evaluate the baseline neurological
and endocrinological functions. All radiosurgical procedures
were carried out using a Gamma Knife model B, C, 4C, or
Perfexion (Elekta Instrument, Stockholm). Consistently we
elaborated multi-isocentric complex dose planning of high
conformity and selectivity. We used low peripheral doses to
take into account the close relationship with optic pathways
and hypothalamus (median 17 Gy; range 13–26 Gy). The
lesions treated are generally small one (median 9.5 mm;
range 5–26). We pay special attention to the dose delivered
to the mammillary body and to the fornix and we always try
to tailor the dose plan for each patient, based on the use of a
single run of shots with the 4 mm collimator. Patients were
evaluated with respect to seizures, cognition, behavior, and
endocrine status 6, 12, 18, 24, and 36 months after radiosur-
gery and then every year. Results are demonstrating that in
65 % of these patient an Engel I+II is achieved. An Engel III
is observed in 20 % of the patients. The frequency of seizures
before radiosurgery was 92 seizures/month (Mean,
427 ± 1,009; min 3.3) and after fell to six seizures/month
(Mean 34.6 ± 78; min = 0; max = 425). In the majority of
these patients, a dramatic behavioral and cognitive improve-
ment is observed. Psychiatric and cognitive comorbidity was
cured in 28 %, improved in 56 %, and stable in 8 % of the
patients. Globally a very good result has been obtained in
60 % of the patients. A microsurgical approach has been per-
701
Fig. 58.1 Hypothalamic hamartomas topological classification. The
exact location of the lesion in relation to the interpeduncular fossa and
the walls of the third ventricle correlates with the extent of excision
required, the seizure control, and the complication rate. Although it
may be an exceptional observation, Type V (pedunculated) tend not to
have neurological symptoms (no epilepsy, no cognitive deterioration,
and no behavioral disturbances). They may present with precocious
puberty or be symptom-free. Types I, II, III, and IV may cause seizures
in many cases, as well as mental retardation, behavioral abnormalities,
and precocious puberty. Type VI HH are frequently found in patients
with especially severe clinical presentations. We consider radiosurgery
as a first-line treatment for small Type I, II, III, or IV HH. From Regis
J, Hayashi M, Eupierre LP, Villeneuve N, Bartolomei F, Brue T, Chauvel
P. Gamma Knife surgery for epilepsy related to hypothalamic hamarto-
mas. Acta Neurochir Suppl 91:33–50, 2004; Used with permission
formed in six patients (9.3 %) with quite large HH and poor
efficacy of radiosurgery. After this microsurgical approach, 1
is cured (Engel I), 2 improved (Engel III), and 3 not improved
(Engel IV). We found no permanent or even transient neuro-
logical deficit. A transient increase in seizures was observed
in seven patients (17.5 %). A transient non-disabling poikilo-
thermia was observed in three cases.
Topological classification (Fig. 58.1) of the lesion based
on a good high resolution MRI is a key feature in the
decision-making process [39]. Previous classification is
based on anatomical [44–46] or surgical [47] consideration.
These classifications are not describing the large diversity of
these lesions and their therapeutic consequences. As under-
lined by Palmini and coworkers, the exact location of the
lesion in relation to the interpeduncular fossa and the walls
of the third ventricle correlates with the extent of excision,
seizure control, and complication rate [48]. On this basis, we
classify the HH according to their topology based on our
original classification [39, 40]. In our experience this classi-
fication correlates with the clinical semiology and severity
and is especially critical for surgical strategy selection. Type
I (small HH located inside the hypothalamus extending more
or less in the third ventricle) are certainly the best candidates
for GKS. In this population the risk of microsurgical removal
is likely to be potentially high.
702
In Type II (when the lesion is small and mainly in the
third ventricle) radiosurgery is certainly the safer alternative.
Even though the endoscopic and transcallosal interforniceal
approaches have been proposed, the risks of short-term
memory worsening, endocrinological disturbance (hyper-
phagia with obesity, low thyroxine, sodium metabolism dis-
turbance), and thalamic or thalamocapsular infarcts have
been reported also by the more enthusiastic and skillful neu-
rosurgeons. However in cases of very severe repeated status
epilepticus we propose as a salvage surgery either a transcal-
losal interforniceal approach or an endoscopic approach
(depending on the width of third ventricle). In an emergency
situation if the lesion is small and the third large, the endo-
scopic approach is chosen.
In Type III (lesion located essentially in the floor) the
extremely close relationship between the mammillary body,
the fornix, and the lesion is clearly leading us to prefer
GKS. We speculate that sessile hypothalamic hamartomas
have always more or less an extension in the hypothalamus
close to the mammillary body. Thus when a lesion is classi-
fied as a Type II, it means that the lesion appears on the MR
like mainly located in the third ventricle but is likely to have
a root in the hypothalamus. The same assumption is made for
Type III.
In Type IV (the lesion sessile in the cistern) a disconnection
can be discussed (pterional approach with or without orbitozy-
gomatic osteotomy). However, if the lesion is small, GKS can
be recommended due to its safety and to its capability to reach
at the same time also the small associated part of the lesion in
the hypothalamus itself, frequently visible on the high resolu-
tion MR. In Delalande experience only two patients among 14
are seizure free after a single disconnection through a pteri-
onal approach [49]. Consequently, we do use this approach in
case of lesion too large for GKS as a first step of a staged
approach. In most circumstances, the patient is improved but
not seizure free after the first surgical step and GKS is orga-
nized at 3 months as a second step of the treatment.
Type V (pediculate) are rarely epileptic and can be easily
cured by radiosurgery or disconnection through a pterional
approach. In case of severe epilepsy the second therapeutic
modality will allow certainly a faster seizure cessation.
However a distant extension of the HH in the hypothalamus
close to the mammillary bodies must be cautiously searched
on high resolution MR and its discovery will eventually lead
to prefer GKS allowing to treat both parts of the lesion, espe-
cially in cases in which if the cisternal component is small.
Type VI (giant) do not represent good indications for first
intention radiosurgery, as in nearly all the cases a combina-
tion of several therapeutic modalities should be utilized.
Even if GKS does not seem to be suitable when the lesion is
large, radiosurgical disconnection can be considered (target-
ing only the superior part in the hypothalamus and/or the
third ventricle leaving untreated all the lesion lower than the
J. Régis et al.
floor) but has been systematically disappointing. In our opin-
ion, this strategy may cause loss of a precious time for the
child to be treated effectively. Consequently, we do not advo-
cate for such a strategy. When microsurgical resection has
left a small remnant in the third ventricle and a still active
epilepsy, re-operation can be envisaged by GKS.
Two major questions remain. First, we know that com-
plete treatment or resection of the lesion is not always man-
datory [50–52] but we do not know how to predict in an
individual patient the amount (and mapping) of the HH that
must be treated in order to obtain a complete antiepileptic
effect. Secondly, we know that these patients frequently
present with an electro-clinical semiology suggesting
involvement of the temporal or frontal lobe and which can
mimic a secondary epileptogenesis phenomenon [37, 49].
In our experience, some of these patients can be completely
cured by the isolated treatment of the HH, while in others, a
partial result is obtained, with residual seizures despite a sig-
nificant overall psychiatric and cognitive improvement. In
this second group, it is tempting to propose that such a sec-
ondary epileptogenic area accounts for the partial failure.
Our initial results indicate that GKS is as effective as
microsurgical resection and much safer [53]. GKS also
avoids the vascular risk related to radiofrequency lesioning
or stimulation. With transcallosal interforniceal approach,
both cognitive (long-term memory impairment) and severe
endocrinological complications (23 % long-term appetite
stimulation and major weight gain) have been reported [54,
55]. Stabell et al. have reported with endoscopy a serious
deterioration of memory and reading skills associated with a
permanent oculomotor paresis [56]. Using interstitial
implants (Iodine 125 seeds), Schulze-Bonhage et al. [57]
reported in a series of 24 patients, 5 patients developing a
symptomatic edema; 4 patients having a weight gain of more
than 5 kg, which was severe in 2; and a persistent decline of
episodic memory in 2 patients. None of these complications
have been observed after Gamma Knife surgery. The main
disadvantage of radiosurgery is its delayed action. Longer
follow-up is mandatory for proper evaluation of the role of
GKS. Results are faster and more complete in patients with
smaller lesions inside the III ventricle (Stage II). The early
effect on subclinical EEG discharges appears to play a major
role in the dramatic benefit to sleep quality, behavior, and
cognitive-developmental improvement. Gamma Knife sur-
gery can safely lead to the reversal of the epileptic encepha-
lopathy [38, 40, 41, 58].
Due to the very poor clinical prognosis of the majority of
these patients with HH and the invasiveness of microsurgical
resection, GK can now be considered the first-line interven-
tion for small middle size HH associated with epilepsy, as it
can lead to dramatic improvements to the future of these
young patients. The role of secondary epileptogenesis or of
widespread cortical dysgenesis in these patients needs to be
58 Radiosurgery for Drug-Resistant Epilepsies: State of the Art, Results, and Perspectives
better evaluated and understood, in order to optimize patient
selection and define the best treatment period.
Mesial Temporal Lobe Epilepsy
The first Gamma Knife surgery operations for MTLE were
performed in Marseille in March 1993. As far as no similar
experience was available at this time in the literature, we
were obliged to base our technical choices on hypothesis
and experience of radiosurgery for other pathological condi-
tions. Four patients were treated with different technical
strategies (dose, volume, target definition). The delayed
huge radiological changes observed some months after
radiosurgery [59] led us to stop such treatment and follow
these first four patients. Due to the clinical safety of the pro-
cedure in these patients and the gradual disappearance of the
acute MR changes after some months, we treated several
new series of patients under strict prospective controlled
trial conditions (with ethical committee approval). The treat-
ment for the following 16 patients was based upon that of
the first patient who had a successful outcome (as opposed
to the three others who had partial or no effect). This “classic
planning” was based on the use of two 18 mm shots, cover-
ing a volume of around 7 cc at the 50 % isodose (24 Gy), and
has turned out to produce a high rate of seizure cessation
[60, 61]. For epileptological reasons, as well as for safety
reasons, the targeting was very much centered on the para-
hippocampal cortex and spared a significant part of the
amygdaloid complex and hippocampus. The refinement of
the Gamma Knife surgery technique, and the desire to find a
dose which would create less transient acute MR changes,
led us to reduce the dose from 24 Gy to 20 and 18 Gy at the
margin. However, this brought about a significant decrease
in the rate of seizure cessation. We have reviewed the long-
term follow-up of our first 15 patients operated by GKS for
MTLE at the state of the art (24 Gy). The mean follow-up
was 8 years and at the last follow-up 73 % were seizure free.
These long-term results are comparing favorably to micro-
surgical one. No permanent neurological deficit was reported
out of a visual field deficit in nine patients [11]. After micro-
surgery for MTLE on the dominant side, a verbal memory
deficit is typically observed in 30–50 % of the patients [62, 63].
This is of special importance to note that none of our patients
have observed a neuropsychological worsening (using the
evaluation published by Clusman et al.) and specifically no
verbal memory decline [4, 5, 7, 11]. This finding of our four
prospective trials has been confirmed by the US prospective
trial [64].
The timetable of events after radiosurgery and the follow-
up are quite standardized. Patients are informed that delayed
efficacy of radiosurgery is its main drawback. Typically, the
frequency of the seizures is not modified significantly for the
703
first few months. Thereafter, there is a rapid and dramatic
increase in auras for some days or weeks and then the sei-
zures disappear. Usually the peak in seizure cessation is
observed around the 8th–18th month with a clear variability
in the delay in onset. In one patient, this occurred 26 months
after GK radiosurgery. We usually consider a delay of 2
years as a minimum for post-radiosurgery follow-up. In the
absence of initial radiological changes or clinical benefit, the
recommendation is to wait for the onset of the MRI changes
and their subsequent disappearance. All our patients had the
same pattern of MR changes regardless of marginal dose
(18–24 Gy) and treatment volume (5–8.5 cc). However, the
degree of these changes and their delay of onset varied
according to the dose delivered to the margin, the volume
treated, and the individual patient. In order to allow an opti-
mal evaluation, we recommend that subsequent microsur-
gery not be considered before the third year after radiosurgery.
Similarly, we believe that a patient who undergoes a corti-
cectomy before the onset of the MR changes has occurred
cannot be assumed to have failed radiosurgical treatment. Of
course, before consideration of any further surgery, the ques-
tion of the reason for the failure needs to be addressed. After
reviewing files of patients treated for MTLE with radiosur-
gery, it was sometimes possible to identify likely causes of
failure, such as:
1 Poor patient selection (e.g., patients with epilepsy involv-
ing more than the MTL structures)
2 Patients with the diagnosis of “treatment failure”
(<3 years) who had been operated upon too early after
radiosurgery [65]
3 Targeting of the amygdala and hippocampus (which is not
in our opinion the optimal target in terms of safety and
efficacy) instead of parahippocampal cortex [66]
4 Insufficient dosage [65–67]
Our current strategy of treatment is based on our first
series of MTLE patients who were strictly selected and
treated systematically with a very simple but very reproduc-
ible dose planning strategy [4, 6]. The identification of puta-
tive improvements in the methodology requires a systematic
analysis of the influence of the technical data from our
experience and from the literature on the outcome of those
patients.
The “Technical” Questions
The Dose Issue
The first targets used in functional GK radiosurgery (capsu-
lotomy, thalamotomy of VIM or the centromedianum, palli-
dotomy) were treated using high dose (300–150 Gy)
delivered in very small volumes (3–5 mm in diameter) [16].
The goal was to destroy a predefined very small anatomical
704 J. Régis et al.

structure with stereotactic precision. Quite a significant

variability in the delay and amplitude of the MR changes
has been reported with fixed regimen of doses [28, 68].
Barcia Salorio et al. have presented several times a small
and heterogeneous group of patients treated with different
kinds of devices and dosage regimens [69]. Apparently
some of those patients had no expanding lesion and were
treated with very large volumes and very low dosage (around
10 Gy). Based on this experience, several teams have made
the assumption that very low doses, as low as 10–20 Gy at
the margin, should be as effective as the 24 Gy protocol (at
the margin) that we used for our first series of patients with
MTLE [4]. A cautious examination of the last proceeding of
Barcia Salorio et al. shows that the individual information
concerning the dose at the margin, the volume, and the
topography of the epileptogenic zone are not provided.
Moreover, among the 11 patients reported, the real rate of
seizure cessation is apparently only 36 % (4/11), which is
much lower than what we would expect with resection in
MTLE [30]. In a heterogeneous group of 176 patients, Yang
et al. confirmed that only a very low rate of seizure control
is achieved when low doses (from 9 to 13 Gy at the margin)
are used [67].
The experience of the radiosurgical treatment of HH indi-
cates that 18 Gy at the margin appears to be a threshold in Fig. 58.2 Dosimetry in a case of a typical right mesial temporal lobe
terms of probability of seizure cessation [38]. In this group epilepsy (24 Gy at the 50 %)
of patient (36 cases), only one showed MR changes. The
majority of the AVM cases with worsening of the epilepsy
were treated with a range of doses between 15 and 18 Gy. to our clinical experience in humans, a similar maximum
Similarly, poor results have been reported by Cmelak et al. in dose range of 40–50 Gy is currently the range of dose pro-
one case of MTLE treated with Linac-based radiosurgery, viding the optimal safety-efficacy ratio.
with 15 Gy at the 60 % isodose line, who underwent surgical
resection 1 year later. In this case, the authors first observed
a slight improvement followed by an obvious worsening The Target Definition
[65]. A recent de-escalation study has allowed us to demon-
strate poorer results in patients receiving doses of 18 or When the target is a lesion that is precisely defined radio-
20 Gy at the margin as compared to 24 Gy [59, 70]. Due to logically, the question of the selection of the marginal dose
the rate of seizure cessation that is achievable by conven- can be quite easily addressed by correlating safety-efficacy
tional resection, a radiosurgical strategy associated with a individual outcome to the marginal dose (Fig. 58.2). This
much lower rate of seizure cessation appears unacceptable. can be refined based upon stratification according to volume,
Fractionated stereotactically guided radiotherapy has been location, age, etc. However, in patients presenting with
demonstrated to fail systematically in controlling seizures. MTLE, this process is invalid for two reasons. Firstly, there
Among 12 patients treated by Grabenbauer et al., none have is no consensus regarding the requirement for extent of
achieved seizure cessation [71, 72]; only seizure reduction mesial temporal lobe resection. Secondarily, the concept of
was obtained in this series. MTLE syndrome with a stable extent of the epileptogenic
Experimental studies on small animals have demonstrated zone and surgical target is increasingly the topic of debate
the antiepileptic effect of radiosurgery [26, 28, 73], the dose [75, 76].
dependence of this effect [26, 27, 28, 74], and the possibility The volume (in association with marginal dose) is well
of obtaining clear antiepileptic effect without macroscopic known to be a major determinant of the tissue effect, as
necrosis using certain doses [27]. Of course, the rat models shown in integrated risk/dose volume formulae [77]. In the
of epilepsy are far from being good models of human first series of patients that we treated, this marginal isodose
MTLE. However, taking into account the huge difference in volume (or prescription isodose volume) was approximately
volume of the target, it is intriguing to notice that according 7 cc (range 5–8,5).
58 Radiosurgery for Drug-Resistant Epilepsies: State of the Art, Results, and Perspectives
An attempt to correlate dose/volume and the effect on
seizures and on the MR changes (as evaluated by volume
of the contrast enhancement ring, extent of the high T2 sig-
nal, and the importance of the mass effect) has been pub-
lished recently [70]. In this study, we found, not
surprisingly, that the higher the dose and the volume, the
higher the risk of having more severe MR changes, but also
the higher the chance of achieving seizure cessation.
However, these data have limited value. Hence, more pre-
cise identification of those structures of the mesial tempo-
ral lobe which need to be “covered” by the radiosurgical
treatment may allow more selective, but just as efficacious,
dose planning strategies, in spite of smaller prescription
isodose volumes.
There is growing evidence to support the organization of
the epileptogenic zone in networks, meaning that several dif-
ferent and possibly distant structures are discharging simulta-
neously at the onset of the electro-clinical seizure. This kind
of organization explains why the risk of failure is so high
when a simple topectomy (without preoperative investiga-
tions) is performed in severe drug-resistant epilepsies associ-
ated with a benign lesion [78]. This has been also reported in
MTLE [75, 76]. Certain nuclei of the amygdaloid complex,
the head body and tail of the hippocampus, the perirhinal,
entorhinal (EC) and parahippocampal cortices may be asso-
ciated with the genesis of the seizures. The role of the EC
cortex in epilepsy is supported by experimental studies in
animal [79, 80]. The EC is considered to be the amplifier of
the “amygdalohippocampal epileptic system.” The pattern of
the associated structures, including that of the structure play-
ing the leader role, can vary significantly from one patient to
another [75, 76]. There is a subgroup of patients who have
clonic discharges and the involvement of the EC, amygdala,
and head of the hippocampus, with a clear leader role of the
EC. Wieser et al. have analyzed the postoperative MR images
of patients operated by Yasargil (amygdalohippocampec-
tomy) and were able to correlate the quality of the resection
of each substructure of the mesial temporal lobe area and the
outcome with respect to seizures [81]. Only the quality of the
removal of the anterior parahippocampal cortex was corre-
lated strongly with a higher chance of seizure cessation [81].
We tried to perform a similar study in patients treated with
GK radiosurgery [70]. We defined and manually drew the
limits of subregions on the stereotactic images of all these
patients. The amygdala, the head, the body, and the tail of the
hippocampus were first delineated. The white matter, the
parahippocampal cortex, and the cortex of the anterior wall
of the collateral fissure were then separately drawn and
divided into four sectors in the rostrocaudal axis, correspond-
ing to the amygdala, the head, the body, and the tail of the
hippocampus [70].
705
Patient Selection
Whang (without having first performed specific preoperative
epileptological work-up) treated patients with epilepsy asso-
ciated with slowly growing lesions and observed seizure ces-
sation in only 38 % (12/31) of the patients [82]. This kind of
observation emphasizes the importance of preoperative
definition of the extent of the epileptic zone and of its
relationship with the lesion [78, 83]. In our institution, the
philosophy is to adapt the investigations for each individual
case. In some patients, the electro-clinical data, the structural
and functional imaging, and the neuropsychological exami-
nation are sufficiently concordant for surgery of the temporal
lobe to be proposed without depth electrode recording.
In other cases, the level of evidence for MTLE is judged
insufficient, and a stereoelectroencephalographic (SEEG)
study is performed. The strategy of SEEG implantation is
based on the primary hypothesis (mesial epileptogenic zone)
and alternative hypotheses (early involvement of the tempo-
ral pole, lateral cortex, basal cortex, insular cortex, or other
cortical areas). The goal of these studies is to record the
patient’s habitual seizures, in order to establish the temporo-
spatial pattern of involvement of the cortical structures dur-
ing these seizures. Clearly in these patients, the high
resolution of depth electrode recording allows fine tailoring
of surgical resection, according to the precise temporospatial
course of the seizures. The main limitation of radiosurgery is
that of size of the target (prescription isodose volume). The
radiosurgical treatment of MTLE is certainly the most selec-
tive surgical therapy for this group of patients. The require-
ments for precision and accuracy in the definition of the
epileptogenic zone are consequently higher. Furthermore, if
depth electrode investigation enables demonstration of a par-
ticular subtype of MTLE, this can lead to tailoring of the
treatment volume and frequently allows this to be reduced.
The Potential Concerns
The risk of long-term complications must always be cau-
tiously scrutinized in functional neurosurgery. Radiotherapy
is most frequently used in the brain for short-term life-
threatening pathologies. The use of radiotherapy in young
patients with benign disease, such as pituitary adenomas or
craniopharyngiomas, has been associated with a significant
rate of cognitive decline [61, 68] and tumor genesis [84]
including some carcinogenesis [85]. If the risk of radiation-
induced tumor was similar with radiosurgery, we should
have by now already observed numerous cases. However,
such reported cases [86–88] are extremely rare and fre-
706 J. Régis et al.

quently fail to meet the classical criteria by which tumors are
deemed to be “radiation induced” [89]. In fact it is consid-
ered that, if this risk exists, it is likely to be around 1/10,000
which is far lower than the mortality risk associated with
temporal lobectomy [60, 90–93].
Epilepsy is a life-threatening condition. The risk of sud-
den unexplained death in epileptic patients (SUDEP) is
higher than in the general population [94, 95]. This risk is
higher in patients treated with more than two antiepileptic
drugs and IQ lower than 70 (as independent factors). Because
seizure cessation after surgery reduces the mortality risk to
that of the general population [95], microsurgical resection
of the epileptogenic zone may confer a benefit in terms of the
possibility of immediate seizure cessation and therefore
reduced mortality risk, as compared to the more delayed
benefits of radiosurgical treatment. Our patients are system-
atically informed about this disadvantage of radiosurgery.
tory due to the rarity of surgical complications and a high
rate of seizure freedom. In our experience, the most impor-
tant selection parameters are the demonstration of the purely
mesial location of the epileptogenic zone, as well as clear
understanding by the patient of the advantages, disadvan-
tages, and limitations. Best candidates are young patients,
with middle severity epilepsy (working, socially well
inserted), with a high level of functioning (able to understand
well the limits and constraints of radiosurgery), a quite high
risk of memory deficit with microsurgery (MTLE on the
dominant side with few or no atrophy, few deficit of the
verbal memory preoperatively), and potentially huge social
and professional consequences in case of postoperative
memory deficit [2, 13, 96]. One other very good indication in
our experience is that of patients with proven MTLE but pre-
vious failure of microsurgery, supposedly due to insufficient
posterior extent of the resection.

What Are the Current Indications?

The demonstrated advantages of radiosurgery are the com-

fort of the procedure, the absence of general anesthesia, the
absence of surgical complications and mortality, the very
short hospital stay, and the immediate return to the previous
level of functioning and employment. In MTLE the potential
sparing of memory function is still a matter of debate and
needs to be established using comparative studies. There is
also a requirement for further demonstration of long-term
Fig. 58.3 Radiosurgical anterior corpus-callosotomy in a young
efficacy and safety of radiosurgery. Worldwide, microsurgi- patient with a bilateral mesial frontal lobe epilepsy (MR negative).
cal corticectomies for MTLE are proving to be very satisfac- Dose planning displayed on a sagittal view (160 Gy at max)

Fig. 58.4 Periventricular

heterotopia in a young female
with severe drug-resistant
epilepsy (24 Gy at the 50 %).
SEEG investigation has allowed
location of the epileptogenic
zone as confined to a tiny part
of the periventricular heterotopia
in front of the posterior part of
the left temporal lobe. Seizure
cessation has occurred more than
1 year after radiosurgery. The
patient has been able to stop the
medication
58 Radiosurgery for Drug-Resistant Epilepsies: State of the Art, Results, and Perspectives
Callosotomy can be performed by radiosurgery quite
safely as previously reported by Shrottner et al. (Fig. 58.3).
When the epileptological context makes realistic an anterior
callosotomy and when the invasivity of a microsurgical
approach is a concern, radiosurgery can be a very appealing
alternative (six cases in our material).
Finally, we have started some years ago to treat epilepsies
associated with benign lesions in highly functional areas (21
patients). We have treated small benign lesions like dysplasia
or periventricular heterotopia (Fig. 58.4). The high func-
tional risk of any epilepsy surgeries in these patients has led
us first to perform a cautious analysis of the extent of the
epileptogenic zone relying on SEEG investigation. When the
SEEG is confirming the ictal onset in the lesion or its close
vicinity and when the EZ is confined to a small area, radio-
surgery is systematically discussed.
Conclusions
The field of epilepsy surgery is a new and promising one for
radiosurgery. However, determination of the extent of the
epileptogenic zone requires specific expertise, which is cru-
cial in order to achieve a reasonable rate of seizure cessation.
In addition, the huge impact of fine technical detail on the
efficacy and eventual toxicity of the procedure means that, at
present, its use for these indications remains under evalua-
tion, and further prospective work is absolutely required. It is
difficult to know whether we really are at the dawning of a
broader indication for the use of radiosurgery in forthcoming
years; our ability to identify the correct technical strategies
should determine whether this is so!
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 Epilepsy: Viewpoint—Surgery
David Carter and Zulma Tovar-Spinoza
Introduction
Epilepsy is the occurrence of two or more unprovoked
seizures. About 50 million people in the world suffer from epi-
lepsy, with age-adjusted prevalence rates of 0.2–4.1 % [1].
Fundamentally, there are two types of epilepsy, primary
generalized and localization-related epilepsy. Primary gener-
alized epilepsy is considered to have a genetic etiology,
whereas most localization-related epilepsy is presumed to be
the result of a cerebral insult, even though the insult cannot
be determined in about half of all epileptic patients, regard-
less of age [2]. Localization-related epilepsy accounts for
about 60–75 % of all epilepsy. It has mostly a temporal lobe
location in adults and an extra temporal source in children.
Candidates for epilepsy surgery have medically refractory
epilepsy, defined as inadequate seizure control in spite of
appropriate medical therapy with at least two of the specific
antiepileptic drugs (AED) for the specific type of seizure, or
with controlled seizures but with unacceptable drug-related
side effects [3–5].
Presurgical Evaluation
In order to obtain the best result for seizure control and
minimize complications, the selection of the appropriate
surgical intervention is essential by identifying the patient’s
epilepsy syndrome and, where relevant, localization. Most
centers follow a standard, staged protocol for evaluation of
patients [6, 7]. Phase I involves noninvasive testing. This
includes history, neurologic evaluation, MRI, video-EEG
monitoring, neuropsychological evaluation and functional
D. Carter, M.D., Ph.D. (*) • Z. Tovar-Spinoza, M.D.
Department of Neurosurgery, SUNY Upstate
Medical University, Syracuse, NY, USA
e-mail: carterda@upstate.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_59, © Springer Science+Business Media New York 2015
59
imaging (magnetoencephalography [8], magnetic resonance
spectroscopy [9], fluorodeoxyglucose positron emission
tomography (FDG-PET), and single-photon emission com-
puted tomography (SPECT). Phase II consists of a cerebral
angiogram and a bilateral intracarotid amobarbital procedure
(Wada test) to evaluate lateralization of language function
as well to evaluate the integrity of memory function on
each side. Phase III involves invasive (intracranial) EEG
monitoring (Fig. 59.1). Phase IV is the actual resective
surgery with intraoperative functional mapping and elec-
trocorticography as needed.
Based on the results of the neuroimaging studies, patients
are divided into those with and without space-occupying
lesions. A space-occupying lesion is generally a tumor, a
vascular anomaly, or a well-defined developmental abnor-
mality such as a hamartoma or focal cortical dysplasia.
Resective surgery could proceed without phase III inves-
tigation if an interictal or ictal EEG or both demonstrated
abnormal activity in the same area as the space-occupying
lesion, and there is no contradictory localizing information
from other tests. In these cases, the resection includes the
lesion and is extended to surrounding cortex to an extent
determined by results of intraoperative electrocorticography,
pathological evidence of normal cytoarchitectonic margins,
or both. If the resection area is adjacent to or in important
functional cortex, intraoperative mapping/monitoring can be
used. For patients with space-occupying lesions who do not
fit these criteria, phase III is done to provide EEG localiza-
tion as well as extraoperative functional mapping as needed.
Patients without space-occupying lesions fall into two
categories: those with suspected neocortical epilepsy or
those with temporal epilepsy. In patients with mesial tempo-
ral lobe epilepsy, if there is concordance with the informa-
tion from phases I–II, resective surgery could proceed
without phase III investigations. If no area of resection is
defined or further functional information is required, then
intracranial recording (phase III) is considered necessary for
localization of epileptogenic area and functional mapping.
711
712
Fig. 59.1 Intracranial monitoring with grids and strips
After the evaluation is complete, patients are deter-
mined to be eligible for resective surgery or not. Ineligible
patients for resective surgery are considered for surgery
that disconnect and prevent propagation of epileptic dis-
charges such as multiple subpial transections [10] or
vagus nerve stimulation [11].
Novel techniques include radiosurgery [12] and magnetic
resonance-guided laser-induced thermal lesioning protocols
of epileptogenic foci [13].
Medial Temporal Lobe Epilepsy
Background
The temporal lobe was postulated as a site for onset of sei-
zures in the late 1800s [14]. The behavioral and electroen-
cephalographic characteristics of these seizures were
becoming increasingly understood by the middle of the last
century [15–18] enough that subtotal anterior temporal
resections—to include the mesial structures (inferior amyg-
dala, hippocampus, and parahippocampus), as well as
anterolateral neocortex—began to be performed for intrac-
table temporal seizures [19, 20]. Surgeons found the mesial
structures often were sclerosed—but the cause was uncertain
(and remains incompletely understood [18]).
The syndrome of medial temporal lobe epilepsy (MTLE)
is now well described, allowing it to be generally distin-
guished from seizures beginning outside the temporal lobe,
and it remains important to aim to differentiate them from
seizures arising in the lateral temporal lobe [21]. Febrile sei-
zures are a risk factor. Family history of seizures may be
reported. Clinically, visceral sensations are the most com-
mon auras; the next most common is fear. Electrophysiological
features of temporal seizure activity, particularly medial
temporal lobe location are observed, both interictal and ictal.
D. Carter and Z. Tovar-Spinoza
On MRI, the most common lesion is hippocampal sclerosis
(hippocampal shrinkage and increased T2 signal), but other
abnormalities can be seen such as dysplasias (some are
microdysplasias and only appreciated pathologically),
tumors, and vascular malformations. These lesions can be
considered examples of “dual pathology” in the temporal
lobe and may suggest a more generous resection than lesio-
nectomy is needed [22].
When an adequate constellation of features is present,
they permit a diagnosis of MTLE with enough confidence to
consider surgical resection for seizure control. Corroborative
testing for localization can include magnetoencephalogra-
phy, PET, ictal SPECT, magnetic resonance spectroscopy, or
invasive monitoring [23]. Neuropsychological testing and
testing for language and memory (e.g., WADA, fMRI) can
provide further information on function and localization,
help plan resections, predict functional reserve after surgery,
and establish baselines. The precise “origin” of the seizure(s)
is generally not known; but rather the investigations impli-
cate the mesial structures but also more widespread con-
nected regions [21, 24–26].
Procedures
Penfield and Baldwin [19] described the basic resection,
beginning with anterolateral temporal cortex, limited
posteriorly to the vein of Labbe, and below the Sylvian fissure,
but they often individualized this by pathologic findings and
electrocorticography with mapping, frequently with the
patient conscious. As mentioned above, the mesial structures
were removed to the pia overlying the basal cisterns, includ-
ing uncus, inferior amygdala, and hippocampus [19, 20]
(Fig. 59.2).
Over the past 60 years, one of the interests in the surgical
procedure for MTLE has been to decrease the extent of tissue
removal aiming to minimize any deficit while maintaining
the benefit of surgery. Also, in this endeavor, there was often
a goal to better identify the structure(s) whose removal is
critical for success at relieving seizures. This conceivably
could lead to increasing surgical success rate. Study of modi-
fications of subtotal anterior temporal resections continues
today. However, no modification is known to be most effica-
cious for seizure control, nor is there consensus on the
structure(s) to be removed for surgical cure of seizures [27].
This is reflected in the fact that the basic procedure described
by Penfield and Baldwin [19] and Falconer [28] has a good
success rate (comparable to the range of techniques
described), favorable side effect profile and remains a stan-
dard contemporary surgical treatment [29]. A major determi-
nant in developing operative variations in the temporal lobe
was the location of temporal neural tissue critical to language
function, generally felt to be largely in the superior and more
59 Epilepsy: Viewpoint—Surgery
Fig. 59.2 Schematic of cross section of the temporal lobe demonstrat-
ing the medial temporal lobe (a) and lateral temporal lobe (b). Temporal
resections for epilepsy may focus on lateral temporal cortex, medial
temporal structures, or resection of both. Specific approaches through
or “around” the lateral temporal structures, to approach the medial
structures more specifically, include: transsylvian (1), transtemporal
(2), and subtemporal (3)
posterior temporal lobe. The operation of Penfield and
Baldwin [30] and Falconer [20] frequently used lateral tai-
loring during awake craniotomy to avoid this language cor-
tex. Ojemann et al. [31] emphasized and further developed
this issue.
For surgery under general anesthesia, more standardized
or measured resections were developed: the lateral neocortex
was resected approximately 5–6 cm from the temporal pole
on the nondominant cortex (slightly less on the dominant
side) with mesial structures removed [32–34]. Although
such margins if electrically mapped could include some pos-
itive language sites, experience indicates including some of
these sites with standardized resections is still safe for lan-
guage outcome [29, 32, 35, 36]. These “standard” lateral
resection margins have continued to decrease in recent
decades. Frequently the superior temporal gyrus resection is
minimized [32, 37], while lateral resections of the other lat-
eral temporal gyri (both dominant and nondominant) have
been considered at 4.5 or 3.5 cm [29, 37, 38] or even smaller
at about 2 cm [39]—although our understanding of the
effects of these variations remains incompletely understood.
Other approaches have been described, including: the
approach of Niemeyer [40] who described a lateral approach
through the lateral temporal cortex into the ventricle, thus
permitting resection of mesial structures; transsylvian
approaches for mesial excision [25, 41]; and subtemporal
approaches [42, 43] (Fig. 59.2).
The development of intraoperative neuronavigation has
lead to further refinement of the surgical approach [44]
(Fig. 59.2).
713
In addition to these frequently used open surgical
approaches, stereotactic approaches have also been evolving
for lesioning of mesial structures. Radiofrequency lesions of
mesial structures have been described to result in success
rates for seizure control similar to that of open surgery, but
experience is limited [45]. These centers have also examined
the question of which structure must be lesioned to obtain
seizure control. Although there was a general relationship
between lesioning of mesial structures and outcome, they did
not find a significant correlation between lesion of particular
mesial structures (e.g., hippocampus, amygdala, entorhinal
cortex) and outcome [46]. Recently, successful magnetic
resonance-guided stereotactic laser-induced thermal lesion-
ing of mesial structures for epilepsy has been described in a
case report [13].
Outcomes
Outcomes in terms of seizure control, for these variations on
this procedure, have been described by many groups and
have been notably similar. In surveys, Engel et al. [47]
reported seizure freedom before 1985 at 56 % (2,336 pts)
and 1986–1990 at 68 % (3,579 pts) (1 year or more follow-up).
Wiebe et al. [48] performed a randomized trial of epilepsy
surgery (subtotal anterior temporal lobectomy) compared to
medical treatment and reported that at 1 year 58 % of patients
in the surgical group were free of disabling seizures com-
pared to 8 % in the medical group (Class I evidence for sig-
nificant benefit). Engel et al. [36], in 2003, surveyed the
surgical literature since 1990 and included 24 papers with
retrospective descriptive data and reported 67 % of 1,952
patients were free of disabling seizures—emphasizing the
similarity of this result to the evidence from the Class I study
[48]. Seizure outcomes across the different methods of par-
tial temporal resection, as mentioned above, continue to
appear similar [27].
The critical structure(s) for excision for successful treat-
ment of seizures remains uncertain despite many years of
attention. Although most evidence implicates the mesial
structures (hippocampus, inferior amygdala, parahippocam-
pus), the correlation between their removal and outcome is
not tight [27] (for review see Schramm et al. [27]). For
instance, resections that retained the hippocampus could pro-
vide seizure control [49], but not as great as when the hip-
pocampus was also removed. Jack [50] reported that seizure
outcome did not seem related to the extent of removal of any
particular mesial structure, but to some damage to all based
on post-op MRIs. Also based on post-op MRIs, Siegel [51]
reported with transsylvian mesial resections that seizure out-
come appeared more related to the extent of removal of the
parahippocampal gyrus than the amygdala or hippocampus.
Wyler et al. [52], in a randomized study, reported that seizure
outcome was significantly better with surgery aimed at hip-
714
pocampal removal to the level of the posterior midbrain
(69 % seizure-free at 1 year) compared to mesial resections
only to the anterior midbrain (38 % at 1 year). Bonilha et al.
[53], from post-op MRIs, reported a significant correlation
between the extent of hippocampal removal and outcome
and further improvement when combined with entorhinal
cortex removal. Schramm et al. [54] in a randomized study,
reported that 2.5 cm vs. a 3.5 cm hippocampal removal was
not associated with difference in seizure outcome (74 % vs.
73 % free of disabling seizures) (included post-op MRI con-
firmation of significantly differing resection volumes).
It has been suggested the variety of resections utilized in
the anterior temporal lobe for MTLE may be effective by
“severing a critical proportion of the connections” [55], nec-
essary to support a seizure. Although this circuitry is likely
concentrated medially in the temporal lobe, its more wide-
spread and possibly variable nature [56] may be why
20–40 % of surgically treated patients are not cured by sur-
gery and a consistently critical structure for removal has not
been identified. It should also be noted that long-term out-
comes need to be considered and have been reported to
decrease gradually at longer post-op periods [57], but further
longer-term data is needed. Reported success rates of reop-
eration for continuing or recurrent seizures are variable but
most commonly below 50 %. Patient selection appears to be
important in this situation [58].
Since the effectiveness for seizures is similar for the dif-
ferent resective approaches, focus on other outcomes has
also been of major interest. Wiebe [48] in their randomized
study demonstrated a significant improvement in quality of
life (QOL) in the surgical arm. Engel et al. [36] reviewed and
described that improved QOL measures were primarily
related to freedom from disabling seizures post-op. Other
evaluations have included neuropsychological testing and
this remains a major area of interest today. In a recent review
Sherman et al. [59] describe decreases in verbal memory and
naming after left-sided surgery as being the most consistent
change after temporal resections (different resection types
included), but with patients usually not self-reporting
changes. Loss of visual memory was less common but simi-
lar after surgery on either side.
Advantages in neuropsychological outcomes after more
selective resections compared to resections with generous
lateral removal have been reported [60–62], but this was not
seen in other studies [63, 64]. Further complicating the situ-
ation, there may be different effects of different procedures
in the different hemispheres. For example, Helmstaedter
et al. [39] describe how left resections were worse for verbal
memory with selective amygdalohippocampectomy being
more deleterious than an anterior neocortical temporal resec-
tion plus mesial resection. Right resections were worse for
figural memory, but on this side the anterior temporal resection
plus mesial resection was worse than the selective mesial
D. Carter and Z. Tovar-Spinoza
resection. Tanriverdi et al. [65] described that verbal memory
decreases more with left-sided selective amygdalohippo-
campectomies compared to more standard left temporal
resections. On the right, nonverbal memory decreased espe-
cially after the standard temporal resections compared to the
selective resection.
There is a general agreement that an important effect on
neuropsychology after resections involves the functionality of
the resected tissue; for example, there are higher risks to mem-
ory associated with resections that include a normal-appearing
hippocampus vs. sclerotic [66]. However, this remains an
evolving area—partly because of ongoing interest in defining
meaningful behavioral results that may vary between surgical
methods described above and radiosurgery [12].
Complications can occur with any of these resective pro-
cedures, for example, diplopia from irritation of cranial
nerve III or IV, a stroke from injury of the arteries or veins in
the basal cisterns or insula, and injury to the basal ganglia
superior to the amygdala (for further discussion, see [29, 38,
67]). Postoperative dysphasia can occur but is usually tran-
sient [29]. Lastly an upper quadrantanopsia is common from
involvement of visual fibers variably sweeping around the
temporal horn [68].
Hypothalamic Hamartoma
Hypothalamus hamartomas (HH) are rare, congenital hetero-
topic lesions in the region of the third ventricle and tuber
cinereum that are intrinsically epileptogenic when closely
connected to the mammillary bodies [69]. The prevalence is
1 in 50,000–100,000 [70].
Patients classically present with isolated fits of ictal
laughter (gelastic epilepsy) or a combination of gelastic and
other types of seizures during the first years of life that are
often particularly drug resistant from the onset [71].
Although there are several classifications available for
these lesions, two clinical syndromes have been recognized:
precocious puberty and intractable epilepsy including gelas-
tic seizures. A significant number of children have both
problems. The natural history is unfavorable in the majority
of patients because of behavioral symptoms and mental
decline; these include oppositional defiant disorder (83.3 %),
attention-deficit/hyperactivity disorder (75 %), high rates of
conduct disorder (33.3 %), speech retardation/learning
impairment (33.3 %), and anxiety and mood disorders
(16.7 %). Significant rates of aggression have been noted
with 58 % of the seizure patients meeting criteria for the
affective subtype of aggression and 30.5 % having the preda-
tory aggression subtype [72].
Typically, medium/large sessile lesions within the third
ventricle are more likely to lead to the seizure disorder [73]
than pedunculated lesions, which hang inferiorly from the
59 Epilepsy: Viewpoint—Surgery
tuber cinereum and are more likely to result in central preco-
cious puberty. Resection of pedunculated lesions causing
precocious puberty reverses the hormonal abnormalities.
The first successful and safe removal of an HH was
reported by Paillas et al. in [74], but the interest for the sur-
gical cure of this specific group of patients was primarily
developed in the 1990s. The association between the HHs
and epilepsy was obscured by the fairly generalized spike
and wave EEG patterns usually observed. Consequently,
patients underwent temporal and frontal resections without
seizure relief. The emphasis changed, however, due to the
information gleaned from ictal single-photon emission com-
puted tomography (iSPECT) and ictal depth recordings
from the lesion itself [75] implicating the epileptogenicity
of the hamartoma. High-quality magnetic resonance (MR)
imaging has strongly facilitated the diagnosis of HH in
cases of severe epilepsy in children. Delalande classified
HHs into four types: Type I has a horizontal implantation
plane inferior to the floor of the third ventricle; Type II
within the third ventricle, with a vertical insertion plane;
Type III is a combination of Types I and II; and Type IV
includes all giant hamartomas [76].
Delalande et al. [76, 77] and Choi et al. [78] have empha-
sized that the goal of surgery is to resect and/or disconnect
the hamartoma from the adjacent hypothalamus and to pre-
serve the mammillary bodies (which may be malpositioned
and deformed), mammillothalamic tracts, tuber cinereum,
and hypothalamic nuclei. The spread of seizures occurs in
part via the mammillary body. The surgery should ideally be
performed before the onset of secondary generalized epi-
lepsy [70, 79, 80]. Larger lesions might require more than
one disconnection procedure, and some might require a mul-
tistep surgical approach.
The microsurgical resection in this critical area is attended
by a significant risk of oculomotor palsy, hemiparesis, hypo-
thalamic deficit, and/or visual field defect, and many epi-
lepsy surgeons have therefore abandoned this type of
approach [81]. Resections have often been subtotal and only
partially effective in controlling seizures, but still associated
with significant complications.
There are three typical microsurgical approaches:
• Transcallosal interforniceal approach, entering the third
ventricle from superiorly [82]
• Pterional approach, exposing the inferior and lateral
aspect of the hypothalamus [76]
• Anterior midline approach, entering the third ventricle
through the lamina terminalis [72]
Comparing the three approaches, the transcallosal ante-
rior interforniceal offers the best chance of seizure freedom
with less morbidity than the pterional route. Concerns
regarding the impairment of short-term memory in children,
who are cognitively intact, have promoted the exploration
of surgical alternatives, e.g., endoscopic disconnection,
715
radiofrequency obliteration [83–85], or magnetic resonance
stereotactic laser ablation [13], and also nonsurgical thera-
pies such as radiosurgery [86].
Removal, disconnection, or ablation of hypothalamic
hamartomas affects the seizure and behavioral outcomes of
these often-desperate patients. The ideal approach to the
treatment of the patient with a hypothalamic hamartoma and
intractable epilepsy has yet to be defined [87–89].
Surgical Techniques
There is literature describing the success rate of resection of
just the lesion (lesionectomy) vs. lesion resection plus sur-
rounding tissue (that may demonstrate electrographic abnor-
malities). Although lesionectomy is quite successful for
seizure control, the excision of adjacent irritated cortex likely
can provide further benefit—particularly in patients with a
longer history of seizures [90–92]. Disconnective procedures
are based on the concept of interrupting the spreading of the
epileptic discharge in the brain, by isolating the primary epi-
leptogenic zone. This is the basic concept for hemispherec-
tomy, multilobar disconnection, hypothalamic hamartoma
disconnection, corpus callosotomy, and multiple subpial
transections.
Hemispherectomy and Hemispherotomy
Dandy [93] first reported the anatomical hemispherectomy
in 1928 for the treatment of gliomas. In 1938, McKenzie [94]
first reported its use in the treatment of epilepsy. Anatomical
hemispherectomy was popular until 1966, but became more
selectively utilized because of postoperative complications,
which could include superficial cerebral hemosiderosis and a
significant incidence of hydrocephalus [95, 96]. A major fac-
tor leading to the development of hemosiderosis was the
large cavity created following removal of the hemisphere.
Hence, various surgical modifications have evolved as alter-
natives, attempting to minimize the removal of brain but
maximize the disconnection of white matter.
One of the most popular techniques, the functional hemi-
spherectomy, was described by Rasmussen [97] in 1983,
who modified the technique of the anatomical hemispherec-
tomy to remove part of the central and temporal regions
while disconnecting the rest. In the early 1990s, a new era in
functional hemispherectomy was initiated with the intro-
duction of the hemispherotomy, with the aim of removing as
little brain as possible, and two different approaches were
described almost simultaneously by Delalande [98] and
Villemure [99, 100]. Since the first description of those tech-
niques, a number of modifications have been made to reduce
the number of complications [70]. The hemispherotomy
716
techniques described include the vertical parasagittal
hemispherotomy by Delalande and associates [98], the
periinsular hemispherotomy by Villemure and Mascott
[100–102], and the transsylvian keyhole hemispherotomy
by Schramm et al. [103].
Other Disconnective Techniques
Daniel et al. [104] reported the posterior quadrantectomy
for patients with refractory temporo-parieto-occipital epi-
lepsy. Three variants were utilized in this series, namely, (1)
anatomical posterior quadrantectomy, which entails the
removal of the temporal, parietal, and occipital lobe; (2)
functional posterior quadrantectomy, where an extended
temporal lobectomy is performed and then parieto-occipital
lobe is disconnected; and (3) periinsular posterior quadran-
tectomy; in this surgery no lobe is resected, and the entire
temporo-parieto-occipital is disconnected but remains viable
because of the preservation of vessels supplying or draining
the disconnected lobes [105]. They reported excellent results.
Chabardes et al. [106] published a series of 47 patients with
temporal disconnection procedures guided by neuronaviga-
tion. Outcomes and complications are within the range of
that expected with resective procedures described in a prior
section.
Corpus Callosotomy
First described in 1940 [107], corpus callosotomy has been
reserved for the treatment of generalized epilepsy or partial
epilepsy with secondary generalization where the onset
cannot be localized. Corpus callosotomy is particularly
effective for the drop seizures of Lennox-Gastaut syndrome
[108], a severe childhood epilepsy disorder characterized
by encephalopathy and multiple, often intractable, seizure
types. The drop attack is the most frequently recognizable
seizure type in this patient population and is also the most
dangerous physically, thus severely limiting quality of life.
The diagnosis is confirmed by electroencephalography, for
which the classic pattern is a slow 2.5 Hz generalized spike
and wave [109]. Seizure improvement ranges between 50
and 81 % with complete callosotomy [110–112]. The com-
plete callosotomy is a palliative procedure reserved for
nonverbal patients with severe intractable epilepsy because
it often produces a hemisphere disconnection syndrome
that can result in disabling symptoms of intermanual con-
flict [113]. The 2/3 anterior partial callosotomy does not
usually have significant cognitive consequences. It is
because of the potential for the development of this discon-
nection syndrome that partial callosotomy is usually under-
taken initially, and the section can be completed if there is
an inadequate seizure control.
D. Carter and Z. Tovar-Spinoza
Multiple Subpial Transections
First described by Morrel in 1969, the multiple subpial tran-
sections (MST) procedure was designed to treat patients with
epileptogenic zones in functionally critical cortical areas
where respective surgery could cause unacceptable neuro-
logical deficits [114]. The rationale is based on the principle
that vertical columns are essential in the propagation of nor-
mal cortical activity from cortex to subcortical structures.
Therefore, the transection of horizontal cortical-cortical
interneuronal connections will interrupt local synchroniza-
tion of epileptogenic activity and the spread of the epileptic
discharges [115].
Although it is a well-known technique, MST is the least
frequently performed procedure in epilepsy surgery (on the
order of 0.6 %). It is difficult to assess the effectiveness of
MST because the majority of the reports used MST in com-
bination with resective surgery [116–118]. The use of MST
as a stand-alone procedure has been reported by Schramm
[119], Smith [120], and Whisler [121] with a seizure-free
outcome of 5 %, 37.5 %, and 63 %, respectively.
Tellez-Zenteno et al. [122] in a meta-analysis study con-
cluded that MST has the lowest rate of long-term seizure-
free outcome (16 %) among all epilepsy procedures.
Electrical Stimulation for Epilepsy
Advantages of electrical stimulation therapy for epilepsy
include reversibility, adjustability and that inaccessible and
multiple targets may be influenced. Presumably the stimula-
tion disrupts the abnormal electrical “buildup” of the seizure,
but both the mechanism and circuitry remain unclear.
Vagal Nerve Stimulation
Vagal nerve stimulation (VNS) had been known to amelio-
rate experimental seizure activity since the 1950s [123],
and a series of clinical studies supported its utility in the
mid- and late 1990s. In patients with primarily focal sei-
zures, after VNS implant, patients were randomized
between stimulation that was either “high” (“typical” and
felt to be active) or “low” (low frequency and hypothesized
to be ineffective). Blinding was not likely complete as some
patients and observers may have intuited the group they
were in. In the initial randomized study (n = 114), there was
a 24.5 % reduction of seizures in the “high” stimulation
group at 14 weeks—6 % in control [124]. In the 2nd study
(n = 196) after 3 months, the seizure frequency declined 28 %
in the “high” stimulation group—vs. 15 % in the “low” [125].
59 Epilepsy: Viewpoint—Surgery
DeGiorgio et al. [126] reported on patients from this latter
trial who were followed unblinded with “high” stimulation
and reported a 45 % decrease at 1 year. Over 400 patients
from early trials [127] were followed, and seizure reduc-
tions of 35 % at 1 year, 44 % at 2 years, and 44 % at 3 years
were reported. Approval for the device was received for
adjunctive treatment for intractable focal seizures in the
United States in the late 1990s.
Beneficial effects appear to be maintained in the longer
term (for at least a decade) according to Elliott et al. [128],
with seizure reduction rates reported in excess of 50 % at a
mean of 5 years as part of medical management in a com-
prehensive program. Although only approved for use in
patients over 12 in the USA for focal seizures, there is evi-
dence for general usefulness in generalized seizures [129].
It is approved in Europe for this indication in pediatric
patients [130]. The effect presumably occurs by retrograde
stimulation thru the vagus to the brainstem and then ros-
trally into thalamus and limbic system. A number of side
effects can occur (e.g., voice alteration, coughing) but these
are generally tolerated with adjustment of stimulation
intensity and time.
Brain Stimulation
Electrical stimulation of the brain has also received consider-
able interest as a treatment for epilepsy. Studies in animals
have supported the concept that deep brain stimulation
(DBS) can be effective and clinical studies have raised hopes
for a variety of effective stimulation sites [131, 132].
Currently most attention is focused on electrical stimula-
tion of the anterior nucleus of the thalamus for treatment of
refractory epilepsy (SANTE trial—Fisher R. et al. [133]).
The nucleus has extensive interconnections with the limbic
system. In the multicenter trial, data from 110 patients with
intractable partial seizures (± secondary generalization and
not amenable to resection) were randomized into low (pre-
sumed ineffective) or high (hypothesized to be effective)
stimulation of the anterior nucleus of the thalamus. At the
end of the blinded 3-month period, seizure reduction was
45 % in the high stimulation group compared to 14 % in the
low stimulation group. After 3 months all patients received
high stimulation and followed at least 13 months with 54 %
having greater than 50 % reduction of seizures. Complications
were within an acceptable range for typical DBS procedures
and the underlying condition [133]. It was shown to be most
effective for seizures of temporal and frontal origin. The
treatment is currently approved in Europe and Canada.
Another approach for electrical stimulation for epilepsy
consists of “responsive neurologic stimulation.” Electrodes
that sense seizure onset are implanted along with a stimulat-
ing electrode targeted to the focus or seizure-modulating
717
structure thus aborting the seizure [131]. An example of this
type of system has been in clinical trial, which demonstrated
a significant benefit [134]. In this trial, 191 patients were
implanted (97 randomized to stimulation and 94 control) and
assessed in a blinded fashion over a 12-week period. There
was a 37.9 % decrease in seizures in the stimulated patients
vs. a 17.3 % decrease in the placebo patients. Benefits com-
pared to baseline were sustained after unblinding. While
promising this treatment remains under assessment. Other
experimental neuromodulation strategies include cell graft-
ing, gene therapy, focal cooling, and drug delivery [131].
Acknowledgment We want to thank Sean Huckins for his help with
illustrations.
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 Epilepsy: Viewpoint—Medical
Gregory K. Bergey
Introduction
A number of the intracranial lesions that would appropriately
be treated with stereotactic radiosurgery are associated with
epileptic seizures. Indeed meningiomas, metastatic brain
lesions, cavernous malformations, arteriovenous malforma-
tions, and primary brain tumors often have seizures as the
presenting manifestation, leading to the evaluation that
detects the lesion for the first time. Lesions located in supra-
tentorial brain cortex are much more likely to produce epi-
leptic seizures than will lesions in white matter or deep brain
structures (e.g., pituitary tumors, pineal tumors). Those
located in the posterior fossa (e.g., acoustic tumors) are
unlikely to produce seizures. Lesions in the frontal or tempo-
ral lobes, particularly those involving or adjacent to mesial
temporal structures (amygdala, hippocampus), can fre-
quently be epileptogenic.
In addressing the medical management of seizures associ-
ated with lesions being treated with stereotactic radiosur-
gery, it is appropriate to think of medical treatment in terms
of the natural history of this treatment, before radiotherapy,
in the period soon after radiotherapy (the first 1–2 years), and
then in the remote period after successful treatment. While
these delineations are conceptually operational, it is useful to
think in these terms since the brain pathology and treatment
considerations evolve over time.
G.K. Bergey, M.D. (*)
Department of Neurology, Johns Hopkins Hospital,
Baltimore, MD, USA
e-mail: gbergey@jhm.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_60, © Springer Science+Business Media New York 2015
60
Initial Presentation: Seizure Types
and Treatment Considerations
Epileptic seizures produced by focal lesions are always par-
tial seizures. Even if a patient presents with a generalized
convulsive seizure, it will be a secondarily generalized sei-
zure, reflecting propagation of the partial seizure from a
focal brain region. Although a new classification of epileptic
seizures is being discussed, it is not yet formally accepted; it
is still useful to think of seizures in terms of partial (simple
and complex) or focal seizures and generalized seizures, and
these concepts will be largely preserved in any new classifi-
cation. Generalized seizures can be either primary general-
ized or secondarily generalized. A further classification of
seizures can be into idiopathic, cryptogenic, or symptomatic;
when discussing seizures related to lesions treated with
radiosurgery, these seizures are always symptomatic. The
symptomatology of partial seizures observed will reflect
the region of the brain involved. For example, lesions in the
temporal lobe may produce complex partial seizures, often
with an aura (e.g., unusual sensation, déjà vu, abdominal
feelings) with associated automatisms and alteration of con-
sciousness. Lesions involving the primary motor cortex may
produce focal motor seizures. There are some brain regions
(e.g., orbitofrontal) that, although potentially quite epilepto-
genic, are silent regions, and clinical manifestations only
occur if the seizures propagate to adjacent areas capable of
producing clinical signs.
Therefore all epileptic seizures produced by structural
brain lesions will be symptomatic partial seizures with or
without secondary generalization. Seizures due to structural
lesions are more likely to recur than are idiopathic seizures,
and because the risk is probably in the range of 30–50 % or
greater, antiepileptic (AED) therapy is warranted. Structural
lesions do not produce primary generalized seizures (myo-
clonic seizures, absence seizures, or primary generalized
tonic–clonic seizures). The patient who presents with brief
periods of staring and altered awareness in conjunction with a
723
724
newly diagnosed structural lesion is almost certainly having
complex partial seizures not petit mal or absence seizures
which are primary generalized seizures. Complex partial sei-
zures by definition have associated altered awareness. Patients
experiencing complex partial seizures will typically be con-
fused and have difficulty responding or processing informa-
tion, but their eyes will be open and they will not fall (although
they may). Complex partial seizures typically will last only
1–2 min [1] and then will be followed by a postictal recovery
period of variable length but often several minutes. In contrast
to complex partial seizures, simple partial seizures, although
also typically of short duration, do not produce alteration of
consciousness. As noted above, the clinical manifestations
reflect the region of the brain involved by the seizure.
In assessing the patient with a seizure disorder, it is impor-
tant to determine whether the lesion to be treated with radio-
surgery is the symptomatic cause of the seizures. As
mentioned, such lesions as meningiomas, oligodendroglio-
mas, arteriovenous malformations if they involve cortical or
mesial temporal structures can be highly epileptogenic.
Seizures are the most common initial symptom in patients
with low-grade gliomas [2]. About 40 % of patients with pri-
mary brain tumors will present with seizures and about
30–70 % of patients with supratentorial tumors will have sei-
zures at some time [3]. In one series, oligodendrogliomas
and grade 2 astrocytomas were the most likely to present
with seizures [3]. About 30 % of patients with arteriovenous
malformations may present with seizures [4]. Brain metasta-
ses, a common indication for radiosurgery, frequently cause
seizures because of their locations involving cortical or sub-
cortical structures. In one study [5], 12 % of patients with
metastatic lung carcinoma experienced seizures. Patients
with metastatic melanoma may have a higher incidence of
associated seizures, in part because of the propensity of met-
astatic melanoma to have associated hemorrhage [6]. Indeed
an epileptic seizure, either partial or generalized, may be the
first presentation prompting evaluation; in one study, 20 % of
patients with metastases presented with seizures [3].
Conversely, some lesions can be incidental and not pro-
duce seizures or other symptoms. Most patients with multi-
ple cavernous malformations or multiple metastases have
seizures originating from only one site. MRI imaging can
determine whether the lesion is in an area where it reason-
ably could be expected to be epileptogenic, but only the EEG
can determine this definitively. It is also important to corre-
late the seizure type and symptoms with the location of the
structural lesion. An EEG may also be useful in establishing
a relationship between the lesion and the seizures. If a rou-
tine interictal EEG demonstrates potentially epileptogenic
activity from the region of the lesion (e.g., focal spikes or
sharp transients), this is good supporting evidence. It should
be recognized that about 30 % of patients with known seizure
disorders may have unremarkable EEGs between seizures
G.K. Bergey
and that many focal EEG abnormalities may be relatively
nonspecific (i.e., only focal slow activity rather than epilep-
togenic features). Sometimes continuous video-EEG moni-
toring of patients during actual ictal events is necessary to
provide a definitive association between a lesion and the par-
tial seizures. Such monitoring is usually reserved for the pre-
surgical evaluation prior to resective surgery and is not
necessary for medical management of seizures.
There is no evidence to support prophylactic treatment
with AEDs in patients with primary brain tumors, metasta-
ses, or vascular malformations who have not yet had seizures.
Most of the best studies on AED prophylaxis in lesional epi-
lepsy have been done on brain tumors, primary and second-
ary [7, 8]. Indeed there is a published AAN guideline [9]
regarding brain tumors, based on published evidence-based
studies that have failed to demonstrate a benefit of AED pro-
phylaxis. While there is a paucity of controlled trials of sei-
zure prophylaxis in patients with vascular malformations
(e.g., cavernomas, arteriovenous malformations) at the pres-
ent time, it is appropriate also not to administer prophylactic
AEDs to these populations before an actual seizure occurs.
Any patient presenting with seizures thought due to a
lesion that will be treated with radiosurgery should be placed
on antiepileptic drug (AED) therapy. As mentioned, since
these patients have experienced a symptomatic seizure, the
risk of recurrence is significant. Obviously the MRI will be
abnormal; these patients should receive AED therapy even if
the EEG is unremarkable or reveals only nonspecific abnor-
malities (e.g., focal slowing) if the history is convincing for
clinical seizures. Even patients presenting only with simple
partial seizures (i.e., no alteration of consciousness) that are
not disabling seizures should be started on AED therapy
because of the potential for simple partial seizures to propa-
gate and produce disabling complex partial symptomatology
or to secondarily generalize to convulsive events. However,
patients already on AED therapy who are only experiencing
non-disabling simple partial seizures (e.g., several seconds
of visual symptoms due to an occipital lesion) do not neces-
sarily need AED adjustment, and this usually does not war-
rant adding an additional agent. Indeed the simple partial
seizures reflecting the lesion at the seizure onset zone may be
more difficult to prevent than are seizures resulting from
propagation (e.g., secondarily generalized tonic–clonic sei-
zures) and aggressive AED polytherapy may produce addi-
tive side effects without abolishing the seizures. The goal of
AED therapy should be to control and prevent disabling sei-
zures (i.e., seizures with alteration of consciousness).
Since, as mentioned, the seizures due to focal structural
lesions will be partial or focal with or without secondary gen-
eralization, the selection of an AED includes many possible
choices. Indeed all AEDs, with the exception of ethosuxi-
mide, are effective agents for partial seizures (Table 60.1).
The lack of an FDA monotherapy indication does not mean
60 Epilepsy: Viewpoint—Medical
Table 60.1 Antiepileptic drugs for partial seizures (with or without
secondary generalization)
First generation Second generation Third generation
Carbamazepine Felbamatea Clobazam
Phenytoinb,c Gabapentin Ezogabinea
Phenobarbitalb Lamotrigine Lacosamideb,c
Primidone Levetiracetamb,c Perampanel
Valproateb,c Oxcarbazepine Pregabalinb
Tiagabine Rufinamide
Topiramate Vigabatrina
Zonisamide
a
Use limited by significant safety or side effect concerns
b
Available as a parenteral formulation
c
Can be introduced rapidly without undue side effects or sedation
that an AED is not effective as monotherapy, only that specific
monotherapy trials were not performed. In contrast to
European regulatory agencies which only require non-
inferiority trials for a monotherapy indication, the FDA still
requires superiority trials, and these are difficult to do, even
with the recent modification to allow historical controls
[10, 11]. It is generally felt by epilepsy experts that all AEDs
that are effective as adjunctive therapy are effective as
monotherapy and that the standard of care allows for such use
independent of the formal indications.
Treatment selection of an AED should include consider-
ations regarding efficacy and tolerability as well as side effect
profile, pharmacokinetics, and the need for rapid introduc-
tion. Although there are comparative trials [12] between the
first-generation AEDs that have shown phenytoin and carba-
mazepine to be superior (combined efficacy and tolerability)
to the other older agents, no such comparative trials between
newer AEDs have been performed that have demonstrated
superiority between the newer agents or between the newer
and older agents. There is a general trend away from initial
therapy with sedating AEDs (e.g., phenobarbital, primidone)
and AEDs that have powerful hepatic enzyme induction (e.g.,
phenytoin, phenobarbital, carbamazepine) that may result in
drug–drug interactions or promote bone mineral density loss.
Agents with nonlinear kinetics (e.g., phenytoin) can be more
likely to produce toxicity at higher doses and serum levels.
Most of the newer second- and third-generation AEDs require
much less monitoring of hematologic and metabolic param-
eters, and titration of these medications can be done based on
clinical parameters (i.e., seizure control and lack of dose-
related side effects) without a need for frequent monitoring
of serum levels of these AEDs.
When a patient has experienced a disabling seizure (i.e.,
with alteration of consciousness), it is desirable to institute
antiepileptic therapy promptly. As mentioned above, in these
patients with symptomatic epilepsy, it is not necessary
to wait for a second seizure; this is likely to occur without
AED therapy. The limits on the ability to introduce an AED
725
rapidly are governed by a number of factors including
sedative or cognitive side effects (e.g., phenobarbital,
topiramate), the risk of hypersensitivity reactions (e.g.,
lamotrigine), or pharmacokinetic considerations. It takes five
drug half-lives to reach a steady state; an AED with a long
half-life like phenobarbital or perampanel (~100 h t 1/2)
can take weeks to reach a steady state. Conversely AEDs
with short half-lives such as levetiracetam or lacosamide
(7–8 h t 1/2) reach steady state levels about 35 h after starting
a maintenance dose.
The past popularity of phenytoin was in large part due to
the ability to load this agent, either orally or parenterally,
providing early effective therapy. To a large degree, leveti-
racetam has replaced phenytoin for acute therapy.
Levetiracetam has a much more favorable pharmacokinetic
and side effect profile compared to phenytoin, with no
enzyme induction, no drug–drug interactions, few hypersen-
sitivity reactions, linear kinetics, and no significant sedative
side effects. There is good level A evidence to support the
use of levetiracetam as monotherapy for partial seizures [11].
Available in both oral and parenteral formulations, oral load-
ing with levetiracetam achieves a cMax in 45 min [13] and is
well tolerated [14]. The generic formulation of the immedi-
ate release formulation has excellent bioavailability com-
pared with the proprietary compound [15]. Table 60.1 lists
other AEDs that can be introduced relatively rapidly and are
available in parenteral formulations. Lacosamide, a new
third-generation AED, can also be introduced rapidly in
many patients, and a parenteral formulation is available,
although rapid loading is not quite as well tolerated as leve-
tiracetam. Lacosamide has no significant hepatic induction
and few drug interactions. In patients requiring two AEDs,
the combination of levetiracetam and lacosamide is particu-
larly well tolerated. Gabapentin and pregabalin have identi-
cal mechanisms of action; pregabalin is preferred because of
its linear kinetics which increases CNS bioavailability at
higher doses. Pregabalin is very safe and has no drug interac-
tions. At high doses, particularly if introduced rapidly, some
nonspecific CNS side effects can occur with pregabalin;
often these are initiation side effects and abate with time.
Carbamazepine, an excellent AED for partial onset sei-
zures, produces autoinduction, requiring slow introduction
over several weeks to avoid toxicity. Carbamazepine also is a
powerful hepatic enzyme inducer with multiple drug interac-
tions and the potential for rare but serious blood dyscrasias.
The congener oxcarbazepine has much less hepatic induc-
tion and no epoxide metabolite, allowing somewhat more
rapid introduction than carbamazepine, although tolerability
is enhanced with slow titration. Hyponatremia, much like
SIADH, can occur particularly in the elderly and can be sig-
nificant (i.e., serum sodium levels below 125 mEq) [16]. The
acute use of lamotrigine, an otherwise well-tolerated agent
with little sedation and no hepatic induction, is limited by the
726
need for slow introduction over weeks to months to mini-
mize the risk of hypersensitivity reactions which can on
occasion be severe (e.g., Stevens–Johnson syndrome). With
appropriate slow introduction, the risk of such severe rashes
is no greater than phenytoin or carbamazepine [17].
Topiramate and zonisamide need to be introduced over sev-
eral weeks because of the potential for cognitive side effects,
particularly with topiramate.
In women of childbearing age, levetiracetam and
lamotrigine have good profiles regarding associated major
fetal malformations and development. Other AEDs can also
be used in this patient population, but phenobarbital and val-
proate should be avoided unless absolutely necessary.
Acute/Subacute Effects of Radiosurgery
on Epileptic Seizures
Treatment with radiosurgery is designed to produce focal
injury to the targeted lesion. In the weeks and months after
stereotactic radiosurgery, while the maximal effects and ben-
efits of treatment are being accrued, there is local tissue reac-
tion which can include edema and other local tissue effects
[18, 19], typically with onset after 3–5 months. Patients with
preexisting seizures due to the underlying lesion may have
transient worsening of seizures requiring adjustment of AED
therapy. Series studying complications of radiosurgery typi-
cally include heterogenous patient populations of patients
with and without seizure histories and with lesions unlikely
to produce seizures (e.g., acoustic neuromas, schwannomas)
making assessment of these studies difficult. Patients with-
out a history of previous seizures may develop seizures after
radiotherapy of potentially epileptogenic lesions. In one
report [20], 21 % of patients undergoing radiosurgery had
seizures attributed to the radiosurgery treatment, with 15 %
of patients having seizures in the early months after therapy.
Interestingly four of six (67 %) patients with treated lesions
near the motor cortex experienced seizures, suggesting that
lesion location might be predictive of post-radiosurgery sei-
zures. This is a reasonable hypothesis since even untreated
lesions located in the frontal and temporal regions, involving
neocortical or mesial temporal structures, may have a higher
incidence of epileptogenicity.
In patients with preexisting seizure disorders, AEDs should
be maintained during the acute and subacute radiotherapy
period, with adjustments being made as needed based on sei-
zure recurrence. In patients with new onset seizures shortly
after radiotherapy, AEDs should be introduced employing the
considerations for selection discussed above. The seizures
in some patients may be more difficult to control during
this subacute time period after radiotherapy when local tis-
sue reactions are most prominent. As the local reaction sub-
sides, seizures typically are much easier to control or manage.
G.K. Bergey
There is no data to support prophylactic treatment with AEDs
in patients undergoing radiosurgery who do not have a seizure
history; there are no good controlled studies of AED prophy-
laxis in patients undergoing radiosurgical therapy.
Treatment Implications After Successful
Radiosurgery
The obvious major benefit of stereotactic radiosurgery is the
ability to avoid a craniotomy and resective surgery. Successful
treatment will slow or stop tumor growth or obliterate arte-
riovenous malformations, eliminating the risk of serious
intracranial hemorrhage. But obviously the original lesion,
although significantly altered anatomically and pathologi-
cally, still remains. What happens to previously symptomatic
seizures in these patients? While radiosurgery has been suc-
cessfully used to treat patients with drug-resistant partial epi-
lepsy due to mesial temporal sclerosis [21, 22], the selection
of radiosurgery for treatment of intracranial lesions is typi-
cally done independent of considerations of seizure control,
specifically to reduce or eliminate risk of hemorrhage from a
vascular malformation or to stop tumor growth. Indeed many
patients may have not have had seizures or have had seizures
that were readily controlled and not drug-resistant prior to
radiosurgery. In all these patients, the decision to treat a
lesion with radiosurgery is independent of seizure control
but is based on these other important considerations.
The success of resective surgical therapy for drug-resistant
lesional epilepsy is best with total resection of the epilepto-
genic lesion. Residual hemosiderin after cavernoma resec-
tion, or residual tumor, even if benign and nonprogressive
(e.g., DNET, ganglioglioma) can compromise total seizure
control or at least limit the ability to discontinue AEDs. It
would be reasonable, therefore, to infer that since the under-
lying lesion is not removed with radiosurgery, the lesion
including the associated hemosiderin, although altered, is
still potentially epileptogenic. But there is reasonable evi-
dence that radiosurgery may also reduce or eliminate the
associated epileptogenicity of the lesion much like total
resection. In the trials of treatment of drug-resistant seizures
in patients with mesial temporal sclerosis (MTS), the per-
centage of patient achieving seizure freedom was compara-
ble to results with standard open anterior temporal lobectomy
with 77 % of patients in a recent small randomized trial
achieving seizure freedom [21] with the higher regimen. As
expected, the maximal beneficial effects of radiosurgery are
not achieved until >1 year after treatment. The mechanisms
of this beneficial effect of radiosurgery are not known but
may include neuromodulatory effects or ischemic necrosis of
epileptogenic tissue [22]. There are no comparative studies
of AED discontinuation in patients successfully treated with
anterior temporal lobectomy and stereotactic radiosurgery,
60 Epilepsy: Viewpoint—Medical
but the goal of any surgical procedure for drug-resistant
epilepsy, resective or radiosurgical, is to provide seizure
control in these patients with previously uncontrolled partial
epilepsy. Therefore radiosurgery should best be thought of as
adjunctive therapy with AEDs for these patients.
One indication for open resection of a favorably located
cavernous malformation is drug-resistant epilepsy, and
radiosurgery offers an alternative for lesions in critical loca-
tions. A recent report [23] of 49 patients with cavernomas in
or near eloquent cortex and drug-resistant epilepsy treated
with radiosurgery found 53 % seizure-free with another
20 % achieving a significant reduction, and only 26 % show-
ing little or no improvement. These patients often remained
on some medical therapy for their seizures. While these
numbers for seizure control are less than would be expected
with open resective surgery [24], radiosurgery of caverno-
mas and arteriovenous malformations in patients with drug-
resistant therapy remains an option in patients where open
resection poses unacceptable risks [25, 26].
Arteriovenous malformations often present with seizures
or hemorrhage. Radiotherapy is one modality used in treating
these lesions to reduce the risk of subsequent hemorrhage. A
report of 65 patients with AVM and single or recurrent sei-
zures found that 51 % were seizure-free after radiosurgery at
3-year follow-up including over 50 % of patients with medi-
cally intractable partial epilepsy [27]. The patients with low
seizure frequency (<4) and small AVM size did best from the
standpoint of seizure control. However, a recent report of 229
patients found no difference in the 5-year risk of seizures
whether the patients received AVM treatment or were treated
conservatively [28]. The incidence of patients with seizures
and patients with seizures who achieved seizure control was
not significantly different in either group. The incidence of
patients having seizures associated with AVM is higher in
patients who have experienced an intracranial bleed [28].
In assessing the patient with epilepsy due to lesions treated
with radiosurgery, patients can be grouped based on response
to therapy and degree of seizure control. Patients with ongo-
ing seizures obviously should remain on AEDs, recognizing,
as discussed above, that after the acute and subacute local tis-
sue reactions subside, that seizure control may be more easily
attained. Patients being treated with radiosurgery for lesions
that have not progressed, who only had seizures associated
with the therapy, i.e., occurring in the first year after treat-
ment, may be candidates for AED withdrawal. It is reasonable
to maintain these patients on AED therapy for 1–2 years until
all reversible changes of therapy (e.g., edema) have resolved
and then, if a routine interictal EEG does not reveal poten-
tially epileptogenic activity, to wean the patient off AEDs.
During this period of AED reduction, the patient should mini-
mize potentially dangerous activities. In patients with seizure
recurrence after AED withdrawal, most seizures occur in the
first few months after discontinuation of therapy.
727
Fig. 60.1 T-weighted FLAIR MRI image of 30-year-old female who
presented >10 years ago with right occipital hemorrhage from docu-
mented 2.5 cm AVM. Successfully treated with radiosurgery; posttreat-
ment angiography documented obliteration of vascular malformation.
No history of seizures until possibly after hemorrhage. Was given a trial
off AEDs 2 years after radiosurgery and had GTCS 6 months after ces-
sation of AEDs. Has now been seizure-free on AED monotherapy for
>9 years. Image shows residual cavity from hemorrhage and surround-
ing increased signal
Are there other patients with a previous history of seizures
who are candidates for AED reduction or withdrawal after
radiotherapy? Even in patients undergoing resective surgery
for drug-resistant partial seizures, there is about a 10–15 %
risk of seizure recurrence in patients who achieve two years
of seizure freedom [29]. Because of this risk and the excel-
lent side effect profile of selected second- and third-
generation AEDs, many epileptologists, including this
author, often leave these patients with controlled seizures,
seizure on a small amount of a single AED (e.g., 1,000 mg/
day of levetiracetam or 200 mg/day of lamotrigine), unless
the patient clearly understands the risk of seizure recurrence
and wishes to be off medication. Because radiosurgery is
non-resective, it is reasonable to assume that the risk of sei-
zure recurrence treated with radiosurgery is somewhat higher
than those treated with surgical resection of the epileptogenic
lesion. Figure 60.1 illustrates an example of a young woman
with a small occipital AVM that presented with hemorrhage
and a single seizure. Radiotherapy successfully obliterated
her lesion, eliminating the risk of subsequent hemorrhage,
and she had no seizures on 200 mg daily of lamotrigine until
an attempt was made to wean her off seizure medications
resulting in a GTCS. She has achieved long-term seizure
control (>5 years) on the previous medical regimen. In sum-
mary, there may be patients with symptomatic seizures
treated with radiosurgery who can successfully be weaned
off all seizure medications and the percentage may be half or
more than half of patients with small lesions, but with a risk
of recurrence that is not trivial and may be in the range of
728
30–50 %, it is reasonable to continue low-dose therapy that is
well tolerated. This recommendation is based on the fact that
the previously epileptogenic lesion, while clearly altered by
radiosurgery, still remains. In patients with previously hem-
orrhagic vascular malformations, the associated hemosiderin
is also present and thought to contribute to epileptogenicity.
If a patient with total seizure control on low-dose AED
monotherapy wishes to be given a trial off AEDs, an EEG
should be performed. An interictal EEG showing potentially
epileptogenic activity should raise concern for a high risk
(i.e., >50 %) of seizure recurrence. If the EEG is unremark-
able, the patient understands the risks of recurrence and can
refrain from driving or other potentially dangerous activity
for 6 months, then a cautious trial off AEDs may be under-
taken. Any seizures occurring more than 2 years after radio-
surgery indicate the need for lifelong AED therapy.
Conclusion
Seizures are the presenting symptom of many patients with
cerebral lesions destined to be treated with radiosurgery.
Partial seizures with or without secondary generalization
will be the seizure type. All patients with partial seizures,
even those with only simple partial seizures, deserve AED
therapy to reduce the risk of disabling seizures. Comparative
trials between AEDs demonstrating superiority are limited
and are not available for the newer agents. Therefore the
selection of AED should be based on consideration other
than relative efficacy, considerations such as side effect pro-
file or pharmacokinetics. Some of the newer second- and
third-generation AEDs offer distinct advantages over the
first-generation agents, and the use of phenytoin, phenobar-
bital, primidone, and valproate has appropriately declined in
recent years. Levetiracetam is a particularly useful agent
both for acute and long-term use, and newly approved lacos-
amide offers similar benefits.
The local tissue reaction produced by radiosurgery may
temporarily exacerbate preexisting seizures or on occasion
produce seizures in patients with no previous seizure history.
These effects abate with time. Successful radiosurgical treat-
ment in addition to its primary treatment goals may also
reduce the epileptogenicity of lesion, but because the patho-
logically altered (e.g., obliterated vascular malformation)
lesion remains, it is recommended that most patients
with controlled seizures remain on low-dose AED therapy
unless seizures occurred only in the period shortly after
radiotherapy treatment. Patients with surgically accessible
lesions and drug-resistant disabling partial seizures may be
candidates for resective seizure surgery even after successful
radiosurgery treatment.
G.K. Bergey
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 Stereotactic Radiosurgery
for Psychiatric and Pain Disorders
Chun-Po Yen and Jason P. Sheehan
Introduction and Historical Perspective
Despite great advances in the medical management of pain
and psychiatric disease, there remains a group of patients
who are refractory to the best medical therapies. For exam-
ple, despite therapeutic progress in recent years, conven-
tional treatment of anxiety disorders fails or has only a
temporary effect in 20 % of patients. Pain and psychiatric
disorders are often severely disabling and are associated with
rates of suicide comparable to those of depression. When
medical therapy fails, options include open surgical proce-
dures, consisting of lesioning or implantation of deep brain
stimulators (DBS), and radiosurgery. Radiosurgical options
are well-suited for functional neurosurgery, in which the
neurosurgeon strives to create a focused lesion without injur-
ing or affecting adjacent structures.
Historically, the Gamma Knife was developed in the late
1960s as an alternative to open stereotactic lesioning for
functional disorders. With the development of the Gamma
Knife and a limited understanding of the neurophysiology of
pain and psychiatric disorders, Dr. Leksell was obsessively
interested in the treatment of patients with intractable pain
and psychiatric disorders [1–4]. In his book Brain Fragments,
Dr. Leskell wrote, “One can accept death, but one cannot
accept the deep, devastating pain. Sharp, intractable pain is
like hell ‘without escape, without hope and without
Heliotrope when Venom burns.’ Standing at the bedside
without ever having experienced pain, it is impossible to
imagine the patient’s agony, and it is impossible to under-
stand that a short time without pain can be extreme happi-
ness” [2]. Since then, the Gamma Knife and other
radiosurgical devices have been utilized to treat patients with
medically refractory psychiatric and pain disorders.
C.-P. Yen, M.D. • J.P. Sheehan, M.D., Ph.D. (*)
Department of Neurological Surgery, University of Virginia,
1215 Lee Street, Charlottesville, VA 22908, USA
e-mail: Cy4f@virginia.edu; jps2f@virginia.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_61, © Springer Science+Business Media New York 2015
61
Radiosurgery and Somatic Pain
Leksell had a special interest in pain disorders likely in part
due to the fact that a person close to him died a painful death.
He focused upon acute pain associated with cancer and tri-
geminal neuralgia. Leksell did not really explore treatment
for chronic pain. When Leksell started to treat acute pain, the
understanding of the pathophysiology of pain was limited.
Therefore, the results for surgical treatment of pain were
fairly discouraging.
He was perhaps overly optimistic about the radiosurgical
results for pain syndromes. As soon as he developed a new
technique, Leksell would try it in the management of both
intractable pain and tic douloureux. In fact, Leksell designed
the radiation pattern of the first Gamma Knife to be lens-
shaped so that its effect would be similar to that of a knife
blade cutting pain fibers. Leksell wanted to prove that radio-
surgery could selectively ablate pain transmitted by C fibers.
In Brain Fragments, Leksell described the treatment of a
33-year-old accountant with facial dolorosa secondary to
basal cell cancer of the tongue using the Gamma Knife. “The
treatment lasts 1 h, and the dose given is 15,000 rad.
Meanwhile we eat sandwiches and drink Pilsner in the con-
trol room. When the radiation treatment is finished, the pain
has already diminished” [2].
Radiosurgery and Trigeminal Neuralgia
With the Gamma Knife unit installed in Stockholm, he
asked Dr. Hakanson to find the two patients he previously
treated with stereotactic technique using orthovoltage x
rays for trigeminal neuralgia. The two patients remained
pain free 17 years after the treatment. Following the suc-
cessful long-term outcome of these two patients, Dr.
Leksell and Dr. Hakanson treated 48 patients between
1970 and 1978, using plain stereotactic skull X-rays and
transoval cisternography using tantalum dust for stereotactic
targeting [5].
731
732
Radiosurgery and Psychiatric Disorders
Leksell also first described psychoradiosurgery, in which he
targeted the frontolimbic connections in both anterior inter-
nal capsules (capsulotomy) for selected cases of intractable
anxiety and severe central pain [6]. Leksell first employed
stereotactic radiosurgery to treat some psychiatric disorders.
Disease Pathophysiology and Radiosurgical
Targeting for Pain and Psychiatric Disorders
The radiobiology of treating these disorders differs from
other disease entities in that the targeted area is a brain struc-
ture that appears radiographically normal; targets for such
procedures include the thalamus, pituitary gland, or internal
capsule. The radiosurgical treatment of pain and psychiatric
disease relies heavily on the concept that adjacent normal
structures receive a markedly lower dose (due to rapid radia-
tion dose fall-off). A higher dose rate (larger dose in an
equivalent amount of time or same total dose applied over a
shorter period of time) increases the lethality of the dose to
the target due to greater interference with intrinsic cellular
repair mechanisms during irradiation. The significance of
this effect is seen most clearly at a threshold dose rate of
1 Gy/min [7].
In order to understand the radiobiology of a single high
dose of radiation on normal brain, the effect of GKS on the
4
6
8 CINGULUM BUNDLE
9
24
SCR
25
UM
10 PT
SE
13
12
DB
14
HYP
UB OT
INS AMYG
OB
HIPPOCAMPAL GYRUS
Fig. 61.1 Limbic system: OB olfactory bulb, LOT lateral olfactory
striae, INS insula, UB uncinate bundle, DB diagonal band of Broca,
AMYG amygdala, SCR subcallosal radiations, HYP hypothalamus, AT
anterior thalamus, MB mammillary body, MTT mammillothalamic
tract, ATR anterior thalamic radiations, ST stria terminalis, HAB
habenula, MFB medial forebrain bundle, SM stria medullaris, HPT
C.-P. Yen and J.P. Sheehan
normal parietal lobe of rats was studied. A dose of 50 Gy
caused astrocytic swelling and fibrin deposition in capillary
walls without changes in neuronal morphology or break-
down of the blood–brain barrier at 12 months. At 75 Gy,
more vigorous morphological changes were seen in astro-
cytes within 4 months. In addition, necrosis, breakdown of
the blood–brain barrier, and hemispheric swelling were
noted. At 120 Gy, astrocytic swelling occurred within 1 week
of irradiation and necrosis was seen at 4 weeks, but it was not
associated with hemispheric swelling [8].
Unlike treating a tumor or arteriovenous malformation,
there is not a pathological target for functional radiosurgery.
Effective radiosurgical management of pain and psychiatric
disease depends upon selecting appropriate targets. This, in
part, relies on an understanding of the anatomical circuitry
and pathophysiological mechanisms underlying the func-
tional disorder. The organization of the limbic system is the
basis of understanding for pain and psychoneurosurgery
(Fig. 61.1) [9]. Neuroanatomical sites for various pain and
psychosurgeries are depicted in Fig. 61.2 [10].
Pain
Radiosurgery has been used to treat different forms of pain
including somatic pain (i.e. cancer-related or non-cancer-
related), central pain, trigeminal neuralgia, and sphenopala-
tine neuralgia. All of these types of pain are a manifestation
23
CC
ATR FORNIX
ST
AT
SM HAB
MTT
HPT
MFB
IP
MB
PIT
HIPPOCAMPUS
CG
LMA
PRESUBICULUM G
SOMATIC AND
VISCERAL
AFFERENTS
habenulointerpeduncular tract, IP interpeduncular nucleus, LMA limbic
midbrain area, G nucleaus of Gudden, CG central gray, and CC corpus
callosum. From Mindus P: Capsulotomy in Anxiety Disorders- A
Multidisciplinary Study, Dissertation at the Karolinska Institute and
Hospital, in. Stockholm, Sweden, 1991
61 Stereotactic Radiosurgery for Psychiatric and Pain Disorders 733

Fig. 61.2 Neuroanatomical Coronal plane of anterior tip

sites for various of lateral ventricle
psychosurgeries are
illustrated. From Mindus Ant. commissure
P: Capsulotomy in Anxiety
Post. commissure
Disorders—A
Multidisciplinary Study, Cingulate gyrus
Dissertation at the
Karolinska Institute and
Hospital, in. Stockholm,
Sweden, 1991

Hippocampal gyrus
Corpus callosum
Orbital cortex
Uncus

CORONAL PLANE OF:

BIMEDIAL LEUCOTOMY (FALCONER-SCHURR, JACKSON)
INFERIOR-MEDIAL LEUCOTOMY (BAKER et al)
Cingulotomy: (BALLANTINE et al)
(MEYER et al)
SITE OF LEUCOTOMY: (BAILEY et al)

SITE OF 90Y LESION OF KNIGHT (IN SUBCOSTICAL WHITE MATTER)

CONNECTIONS ORBITAL CORTEX TO UNCUS (VAN HOESEN et al)

RECIPROCAL CONNECTIONS FRONTAL GRANULAR CORTEX GYRUS

CINGULI (NAUTA)

ANTERIOR CAPSULOTOMY (LEKSELL et al)

of different pathophysiological processes. There is not a
single anatomical circuit or target that is most appropriate.
Treatment can target central anatomic structures that mediate
the pain sensation (e.g., thalamus) or can target the nerve that
carries the pain sensation (e.g., trigeminal nerve in trigemi-
nal neuralgia). The complexity of neuronal network mediat-
ing pain makes its management by open or closed stereotactic
techniques largely unsatisfactory. Chronic pain targeting
with radiosurgery has been typically performed at the level
of the medial thalamus. Young targeted the intralaminar,
mediodorsal centromedian, and parafascicular nuclei in
chronic pain patients [11–13]. PET or functional MRI-
guided cingulotomies have also been proposed for chronic
pain treatment [14].
Trigeminal neuralgia (TGN) is a paroxysmal lancinat-
ing pain confined to a distribution encompassing one or more
of the branches of the trigeminal nerve on one side of the
face. As early as 1941, Olivecrona understood and described
that mechanical pressure along the root or at the level of
the ganglion could be the cause of trigeminal neuralgia [15].
In pioneering work, Granit, Leksell, and Skoglund (1944)
demonstrated that local pressure on nerve fibers could result
in painful afferent discharges from the injured neural seg-
ment [16]. More recently, Jannetta and others have suggested
that vascular compression of the trigeminal nerve may be a
causal agent in trigeminal neuralgia [17–19]. This fact led to
the hypothesis of a causal relationship between vessel com-
pression and trigeminal neuralgia and the devising of micro-
vascular decompression surgery. Despite such hypotheses,
the fact that balloon compression of the nerve can lead to
symptomatic improvement in some patients and infections and
demyelinating conditions may also affect the trigeminal nerve
and illicit pain underscores the true lack of understanding as
to the pathophysiology of trigeminal neuralgia [20, 21].
With radiosurgery, the usual target for treating trigemi-
nal neuralgia is the trigeminal nerve root entry zone or the
cisternal segment of the trigeminal nerve at the level of
the pons. Much has been written about whether or not the
trigeminal nerve should be targeted more proximally or
distally [22–24].
734 C.-P. Yen and J.P. Sheehan

Rare cases of glossopharyngeal and sphenopalatine been more simple yet elegant. Drawing from the work of
neuralgia treatment with radiosurgery have been described Henry Wycis in Philadelphia and the anatomical studies of
[25, 26]. Neither the radiosurgical targeting nor the outcome Professor Meyer in London, Leksell used thermal injury to
for these types of neuralgia is well defined. perform a stereotactic capsulotomy on a successful indus-

Obsessive-Compulsive Disorder
and Depression

The most common radiosurgical target for obsessive-

compulsive disorder (OCD) is the anterior limb of the inter-
nal capsule. A capsulotomy can be performed on the right
hemisphere, left hemisphere, or both. The anatomical site for
a capsultomy is depicted in Fig. 61.3 [27] and the appearance
on MRI is shown in Fig. 61.4. Lippitz et al. noted a correla-
tion between clinical success and radiological lesioning of
the middle of the anterior limb of the internal capsule [28].
This was defined as parallel to a plane encompassing the
anterior commissure-posterior commissure line level at the
level of the foramen of Monro and 4 mm rostral by a plane
defined by the internal cerebral vein [29]. Cingulotomy can
also be performed for OCD and depression [30]. In addition,
limbic leucotomy involving bilateral lesions of the cingulum
with subcaudate tractotomy have been advocated for intrac-
table depression [31–33].

Anxiety

Leksell was impressed with the result, yet disappointed

with the prefrontal lobotomy technique made famous by
Egas Moniz and Almeida Lima. He believed that the fron-
tal lobes should have been surgically treated with more
finesse, and that psychosurgery in general should have
Fig. 61.3 An axial slice of the brain depicting the target areas for bilat-
eral capsulotomies (asterisk). From Mindus P: Capsulotomy in Anxiety
Disorders—A Multidisciplinary Study, Dissertation at the Karolinska
Institute and Hospital, in. Stockholm, Sweden, 1991

Fig. 61.4 Gamma Knife dose plan with isocenters depicted in yellow and the 6-month post-Gamma Knife coronal MRIs illustrating the imaging
appearance of bilateral capsulotomies for intractable obsessive-compulsive disorder
61 Stereotactic Radiosurgery for Psychiatric and Pain Disorders
trialist who was completely incapacitated by anxiety [2].
The result from their early case was good and prompted
more psychosurgery using electrodes and later the Gamma
Knife. For intractable anxiety disorders, bilateral capsu-
lotomies have been performed with a similar target to that
for OCD [28, 34, 35].
Treatment Alternatives
Chronic pain is initially treated with pharmacological treat-
ment. Pain specialists utilize opioid agonists, nonsteroidal
anti-inflammatories, local anesthetics, antidepressants, cer-
tain anticonvulsants, and muscle relaxants to optimize pain
control. More recently, implantable drug delivery systems
(e.g., morphine pumps), transcutaneous electrical nerve
stimulation, spinal cord stimulators, and vagal nerve stimula-
tors have been implanted to assist with the treatment of
chronic pain [36–38]. Pain rehabilitation programs can also
be of use.
For trigeminal neuralgia, medical management is the first
line of treatment for patients. Medications such as carbam-
azepine, oxcarbazepine, phenytoin, gabapentin, and pregab-
alin are used to treat trigeminal neuralgia. However, many
patients with this condition eventually fail medical therapy
because of refractory pain or intolerable medication side-
effects. More invasive treatment options include microvascu-
lar decompression (MVD) and percutaneous procedures
such as glycerol rhizolysis, radiofrequency rhizotomy, per-
cutaneous balloon microcompression, and peripheral nerve
blocks [1, 18, 20, 21, 39–41].
Obsessive-compulsive disorder, depression, and anxiety
are initially managed with pharmacological agents and psy-
chiatric intervention/counseling. Heterocyclic compounds,
monoamine oxidase inhibitors, selective serotonin reuptake
inhibitors, bipolar agents, and anxiolytics/hypnotics have all
been applied to these conditions with limited efficacy. Many
of the patients with intractable OCD, depression, or anxiety
have a high rate of comorbid Axis I diagnoses including per-
sonality disorders and other functional impairments further
complicating the treatment and reducing the chances of a
favorable therapeutic outcome [42]. Unfortunately, pharma-
cological therapies only benefit between 50 and 70 % of all
OCD patients [43]. Fava and Davidson estimate that 29–46 %
of depressed patients fail to respond to pharmacological
agents [44].
In addition to pharmacological treatment, deep brain
stimulation, vagal nerve stimulation, and transcranial mag-
netic stimulation have been utilized for OCD and depression
[45]. The ability to reverse or modulate these neurological
interventions adds to the attractiveness of these interventions
over a more static lesioning achieved with radiosurgery.
735
Electroconvulsive therapy has been utilized for depression.
It typically has a transient benefit and must be readministered
with some regularity.
The Argument in Favor of Radiosurgery
In most cases, radiosurgical treatment of pain and psychiatric
disorders should be reserved for patients who demonstrate
fairly severe symptoms and who fail medical management.
However, as noted, this is not an inconsequential number of
patients. In patients with psychiatric disease who require
surgical intervention, functional radiosurgery offers several
important clinical as well as scientific advantages over open
techniques. The most important is patient tolerance. It is our
experience that this psychologically vulnerable group of
patients is much more willing to undergo a closed stereotac-
tic procedure, which in contrast to open surgery, leaves
minimal, if any, external marks. Theoretically, the gradual
development of the radiosurgical lesion may also allow the
patient to better psychologically adjust. The psychological
rehabilitation phase is an important part of any psychosurgi-
cal procedure.
Stereotactic radiosurgery also does not carry the same type
and degree of immediate or severe risks that open surgery
(e.g., microvascular decompression, deep brain stimulation,
etc) does. For instance, in a long-term series of microvascular
decompression patients, there were the following risks from
the series by Dr. Jannetta: 0.2 % death; 0.1 % brain stem
infarct; and 1 % hearing loss 1. None of these complications
were observed in our series nor were they associated with
radiosurgical treatment of trigeminal neuralgia in other major
centers. Complications from hardware and the risk of hemor-
rhage for deep brain and vagal nerve stimulators combine to
yield a risk of 10–27 % [46–48]. Ultimately, the patient must
choose the type of intervention he or she is willing to undergo.
Such a choice inevitably involves a weighing of the relative
risks and benefits of each intervention.
Of all the indications, stereotactic radiosurgery has been
most embraced for the treatment of medically refractory tri-
geminal neuralgia. The widespread application of radiosur-
gery for trigeminal neuralgia is in part a testament to its
acceptable degree of pain relief and few side effects.
Radiosurgery for chronic pain, OCD, intractable anxiety, and
depression has been applied with far less frequency. This fact
stems in part from the notion that such patients are usually
managed by other types of physicians (e.g., psychiatrists, pain
specialists, etc.) who have little familiarity with radiosurgery.
Moreover, radiation oncologists and neurosurgeons are gener-
ally uncomfortable with treating these types of disorders with-
out the close involvement of appropriate specialists to evaluate
and assist in the pre- and postoperative management.
736
Surgical Treatment Alternatives for Pain
and Psychosurgeries
Open lesioning—Although the results of stereotactic or per-
cutaneous lesioning (e.g., thalamotomy, radiofrequency rhi-
zotomy, glycerol injection) have been well studied, and the
beneficial effects are immediate, there remains the potential
for complications such as intracranial hemorrhage, stroke,
and infection. In addition, these procedures carry with them
an anesthetic risk too.
Deep brain stimulation and vagal nerve stimulation—The
advantages of stimulation techniques include the reversible
nature of the process and the ability to modulate the neural
stimulation over time. However, patients are again exposed
to the risks of open surgery including infection, hemorrhage,
and anesthesia. In addition, rates of hardware complications/
failure are not trivial, and the batteries need periodic replace-
ment necessitating another albeit minor surgical procedure
[46–48].
Microvascular decompression for trigeminal neuralgia—
This procedure remains the gold standard for surgical
approaches to treat trigeminal neuralgia. Barker et al. reported
excellent pain relief in 70 % of patients and partial pain relief
in another 4 % at 10 years postoperatively from a microvascu-
lar decompression [17]. However, there were the following
risks from the series by Dr. Jannetta: 0.2 % death; 0.1 % brain
stem infarct; and 1 % hearing loss [49]. Burchiel et al. in 1988
noted a 3.5 % major recurrence rate and 1.5 % minor recur-
rence rate following invasive surgical approaches [50]. All
surgical approaches including radiosurgery appear to have a
“wearing off” effect in terms of pain relief over the years.
Radiosurgical Treatment Dosimetry
The dose must be planned so that the steepest isodose gradi-
ent of the dose distribution (usually between the 50 and
70 % isodose lines) coincides with the periphery of tissue
being treated. This may require several overlapping fields of
radiation, each using a different collimator size and a sepa-
rate stereotactic focal point. Changing the relative time of
radiation at each target may also change the isodose distri-
bution. Finally, the radiation field may be altered by blocking
some of the radiation sources, also known as plugging or
shielding.
For radiosurgical capsulotomies and thalamotomies, focal
lesions can be produced using a 4-mm collimator and 1–3
isocenters on each side for overlapping fields, creating a
cylindrical lesion, with a maximum dose within the target
volume of 200 Gy. The development of the lesions using
such a plan has been followed by MRI and CT scans every 3
months. On T2-weighted images, a high signal appears in the
C.-P. Yen and J.P. Sheehan
target area after approximately 3 months. This signal is most
likely produced by local edema. The edema extends a maximal
volume at around 9 months and then slowly subsides. The
edema is directly related to the dose and to the volume radi-
ated. It may be sufficient to use only one isocenter and the
4-mm collimator. With these treatment parameters and a
maximal dose of 180 Gy, a lesion measuring approximately
4 to 5 mm three can be expected within several weeks with
only minimal transient edema. Centers have utilized maxi-
mal target doses of 120–200 Gy for radiosurgical treatment
of OCD, intractable anxiety disorders, depression, and
chronic pain [11, 13, 34, 35, 42, 51, 52].
Kihlstrom et al. propose that a minimum dose of 110 Gy using
the 4 mm collimator is required to create a permanent lesion [35].
Friehs et al. in 1996 reported the following lesion size after deliv-
ering a dose of 160 Gy using a 4 mm collimator [51]:
Time (months) Diameter of necrosis (mm)
1 3
3 6
6 8
12 4
For trigeminal neuralgia, dose selection has been studied
much more extensively. Most centers utilize maximal doses
of 70–85 Gy [53–58]. Doses of 90 Gy or higher have been
associated with increased risk of post-radiosurgical compli-
cations [55].
Case reports and small case series glossopharyngeal and
sphenopalatine neuralgia treatment with radiosurgery have
been published [25, 26]. We reported on the pain relief of a
patient with glossopharyngeal neuralgia delivering 80 Gy
to the glossopharyngeal meatus [59]. Pollock and Boes
(2011) reported on a series of five patients with glossopha-
ryngeal neuralgia who underwent Gamma Knife radiosur-
gery with a dose of 80 Gy to the distal portion of the
glossopharyngeal and vagus nerves at the level of the jugu-
lar foramen [60]. Of these five patients, three experience
benefit from radiosurgery, whereas two had no benefit and
underwent microsurgery too with no apparent pain relief
[60]. Pollock and Kondziolka performed Gamma Knife
surgery twice on a patient with sphenopalatine neuralgia
using a maximal dose of 90 Gy [25]. The patient underwent
repeat Gamma Knife surgery for partial pain recurrence
and remained pain free 2 years after repeat treatment. The
North American Gamma Knife Consortium recently
reviewed 17 patients who underwent Gamma Knife surgery
for intractable sphenopalatine neuralgia. Favorable pain
relief (Barrow Neurological Institute Grades I–IIIb) was
achieved and maintained in 10 (59 %) of 17 patients at a
median follow-up of 34 months.
61 Stereotactic Radiosurgery for Psychiatric and Pain Disorders
Outcomes Based upon the Type
of Radiosurgical Device
No trials have been performed to look at the results of
psychosurgeries using different radiosurgical devices. In fact,
very few psychosurgeries have been done with radiosurgical
devices other than the Gamma Knife. However, other radio-
surgical devices (e.g., the Cyberknife or Novalis) may be
well suited for treating psychiatric conditions too.
For trigeminal neuralgia, the results of linear accelerator
(LINAC)-based and Gamma Knife radiosurgery appear
comparable [57, 61, 62]. Outcomes appear generally favor-
able so long as the team is experienced and the device is
optimized for radiosurgical treatment.
Radiosurgical Treatment Outcomes
Pain Other than Trigeminal Neuralgia
Early results using the Gamma Knife to produce thalamoto-
mies for pain control were published by Steiner et al. in
1980. All of the 52 patients treated suffered from terminal
cancer and were treated prior to the advent of CT or
MRI. Pneumoencephalography was used to target the tha-
lamic centrum median-parafasciculus (CM-Pf complex).
Good pain relief was obtained in 8 patients and moderate
pain relief in 18. The patients had in general only temporary
relief of pain. Of those with good pain relief, five died with-
out recurrence of pain between 1 and 13 months after the
procedure, and three had recurrence of pain at 3, 6, and 9
months, respectively. Doses between 100 and 250 Gy were
tested. Observation of an actual lesion was only possible in
21 of 36 patients that had a postmortem examination. Not
surprisingly, the presence of a lesion was associated with
relief. Lesions were only reliably created with doses greater
than 160 Gy. The collimators used were 3 × 5 and 3 × 7 mm.
The most effective lesions were more medially located near
the wall of the third ventricle, and the greatest relief was for
face or arm pain [63].
These results were not particularly encouraging. However,
with improvements in neuroimaging and alternate target
selection, it is possible that more effective lesions can be pro-
duced. Recent reports seem to support this expectation.
Hayashi et al. in 2003 reported significant pain reduction in
patients with severe cancer pain and post-stroke thalamic
pain after Gamma Knife lesioning of the hypophysis [64].
Using the 4 mm collimator and doses of 140–180 Gy, Young
et al. have published effective pain relief in patients with
chronic, intractable pain following medial thalamotomy with
the Gamma Knife [11–13]. In a series of 15 patients fol-
lowed for more than 3 months after a radiosurgical-induced
medial thalamotomy, four (27 %) were pain free and five
737
others (33 %) had greater than 50 % pain relief [13].
Additional investigation must be conducted before the role
of the Gamma Knife for pain treatment can be fully defined.
Psychiatric Disease: Anxiety and Obsessive-
Compulsive Disorder
Mindus and colleagues at the Karolinska Institute reported
the effects of bilateral anterior radiosurgical capsulotomies
on the anxiety symptoms and personality characteristics.
Using independent observers, the Comprehensive Psycho-
pathological Rating Scale (CPRS), and the Karolinska Scales
of Personality (KSP, designed to asses frontal lobe dysfunc-
tion and anxiety proneness), they compared patients who had
been treated with conventional thermocoagulation and fol-
lowed for 1 year with patients who had been treated with
Gamma Surgery and followed for 7 years. The two groups
were otherwise similar, each including patients who had a
mean duration of psychiatric illness of 15 years and who had
failed multiple other treatment interventions. The results of
Gamma Knife capsulotomy were found to be comparable to
those of capsulotomy performed by the thermocoagulation
technique. In both groups, freedom from symptoms or con-
siderable improvement was noted in 70–80 % of patients,
and none were worse after the operation. Negative effects on
the personality were not noted. Representative KSP scores
are illustrated in Figs. 61.5 [65] and 61.6 [66]. A number of
patients who were preoperatively unable to work or function
normally in society due to preoccupation with personal
cleanliness and the inability to use public transportation
resulting in domestic confinement, aggravated psychological
problems, deterioration of family relationships, and devasta-
tion of personal economy were able to return to their previ-
ous occupation and to a normal social function. In five of
seven patients who underwent Gamma Knife capsulotomies,
a lesion was demonstrated by MRI, and those were the
patients who benefited from the procedure. The lowest effec-
tive target dose was 160 Gy, whereas 100, 120, and 152 Gy
failed to produce lesions [29, 35].
Preliminary results from an ongoing study of bilateral ante-
rior capsulotoy using the Gamma Knife, Greenberg et al. in
2003 reported 4 out of 15 patients had at least a 35 % decrease
in the Yale-Brown Obsessive-Compulsive scale and a mini-
mum 15 point improvement in the Global assessment scale on
5-year follow-up. In another group of 16 patients who under-
went two pairs of bilateral lesions during one session, 10 out of
16 patients met the aforementioned criteria at the 3-year fol-
low-up time point. Once achieved, this group noted generally
stable benefits [42]. Kondziolka et al. (2011) recently reported
on the radiosurgical treatment of three patients with medically
intractable OCD. They observed no morbidity and significant
improvement in the Yale-Brown Obsessive-Compulsive Scale
in all three patients [67]. However, recently, the group at Brown
738 C.-P. Yen and J.P. Sheehan

Somatic anxiety
Musular temsion
Psychic anxiety
Psychasthenia
Inhibition of aggression
Impulsivity HJ
Monotony avoidance Post
Socialization
Pre
Social desirability
Detachment
Indirect aggression
Verbal aggression
Irritability
Suspicion
Guilt
–1 SD 50 1 SD

Fig. 61.5 Karolinska Scales of Personality (KSP) scores reported by Capsulotomy in Anxiety Disorders—A Multidisciplinary Study,
Mindus for a patient who underwent a capsulotomy for non-obsessive- Dissertation at the Karolinska Institute and Hospital, in. Stockholm,
compulsive disorder anxiety. SD standard deviation. From Mindus P: Sweden, 1991

Fig. 61.6 Karolinska Scales of Personality (KSP) scores reported by Capsulotomy in Anxiety Disorders—A Multidisciplinary Study,
Mindus for a patient who underwent a capsulotomy for obsessive- Dissertation at the Karolinska Institute and Hospital, in. Stockholm,
compulsive disorder anxiety. SD standard deviation. From Mindus P: Sweden, 1991

University has reportedly put its use of the Gamma Knife on thermocoagulation and cryprobes to a perform limbic
hiatus for treatment of OCD patients. This hiatus arose after leucotomy may give direction to future work using radio-
three patients were noted to have cyst formation after treatment surgical devices to treat depression [31, 68].
with the Gamma Knife Perfexion.

Complications of Functional Radiosurgery

Psychiatric Disease: Depression
The long-term outcomes of radiosurgery for depression
have not been well studied. Radiosurgery of patients with
intractable depression requires a multidisciplinary approach
and warrants further investigation [63]. The work using
Although stereotactic radiosurgery is not associated with
some of the immediate risks of open surgical procedures, it
nonetheless has risks. Except for trigeminal neuralgia, dose
selection is not well studied. The wide range of doses may
lead to an unpredictability of lesion size and subsequent out-
61 Stereotactic Radiosurgery for Psychiatric and Pain Disorders
come. Kihlstrom et al. noted that parenchymal reaction and
time course to development of a lesion following radiosur-
gery for refractory anxiety disorders may be difficult to pre-
dict [34]. Other potential complications associated with
radiosurgery include radiation-induced parenchymal changes
(some of which are reversible and others are irreversible),
delayed cyst formation, radiation-induced neoplasia, and
vascular injury [69, 70]. More worrisome side effects of
radiosurgical or thermocoagulation tractotomies, capsuloto-
mies, cingulotomies, and limbic leucotomies include head-
ache, confusion, somnolence, transient disinhibition,
personality changes, seizures, incontinence, exacerbation of
mania, apathy, and amotivation [29]. The exact incidence of
these complications is difficult to discern based upon the
existing reports.
Future Directions
The treatment of psychiatric and pain disorders with stereo-
tactic radiosurgery will require coordination by a multidisci-
plinary team. While a neurosurgeon and radiation oncologist
can utilize modern stereotactic radiosurgery devices to create
precise lesions in the brain, the long-term efficacy and safety
of this approach has not been well defined. Advanced neuro-
imaging modalities such as PET, SPECT, or diffusion tensor
imaging may help to demonstrate overactive areas of the
brain in patients afflicted with intractable psychiatric and
pain disorders. Such imaging modalities may provide a bet-
ter defined target for selected patients and enable clinicians
to track a radiologic response to radiosurgery.
Conclusions
Leksell’s personal battles with pain and his desire to perform
more elegant psychosurgeries than prefrontal lobotomies led
to the use of radiosurgical devices for the treatment of psy-
chiatric disorders and pain. With the exception of trigeminal
neuralgia, the application of radiosurgery to treat these prob-
lems has not been widely embraced and is largely considered
investigational. Obsessive-compulsive disorder has been the
only psychiatric disorder for which radiosurgery has been
reasonably well received.
It is unfortunate that Leksell, who developed the Gamma
Knife for functional disorders, never saw it embraced for
such indications. Competing surgical approaches with deep
brain stimulation and pharmacological alternatives make the
widespread embracement of radiosurgery for pain and psy-
chosurgery unlikely. Initial experiences dating over the past
30 years have demonstrated limited efficacy for radiosurgery
to treat some of the most intractable of psychiatric disorders
739
and chronic pain. Advances in neuro-imaging, neuro-
anatomy, and psychiatry may lead to a resurgence of interest
in this field. Any future application of radiosurgery to treat
these disorders should be done in the context of a multidisci-
plinary team.
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 Ocular and Orbital Lesions
Yan Michael Li, Gabriela Šimonová, Roman Lisčák,
Josef Novotný Jr., Amit Singla, and Lawrence S. Chin
Introduction
Radiation, including radiosurgery, plays an indispensable
role in the treatment of benign and malignant orbital and
ocular diseases, since the clinical benefits of improving sur-
vival and preserving vision in many cases outweigh the risks.
Technological advances in medical imaging, treatment plan-
ning, and radiation dose delivery have led to dramatic
improvements in radiosurgery and radiotherapy [1, 2]. Now
it is also possible to recognize intraocular tumors and other
ophthalmologic diseases at an earlier stage because of the
availability and use of both direct and indirect ophthalmos-
copy, fluorescein angiography, ultrasonography, and mag-
netic resonance imaging (MRI).
Orbital anatomy and ocular radiosensitivity provide
unique challenges for radiosurgery. The basic advantage of
radiosurgery is the possibility of applying relatively high
Y.M. Li, M.D., Ph.D.
Department of Neurosurgery, UT MD Anderson Cancer Center,
1400 Holcombe Boulevard, Unit 442, Houston, TX 77030, USA
e-mail: YanLi@gmail.com
G. Šimonová, M.D., Ph.D.
Department of Stereotactic Radioneurosurgery, Hospital Na
Homolce, Prague, Czech Republic
R. Lisčák
Department of Stereotactic Radioneurosurgery, Hospital Na
Homolce, Prague, Czech Republic
Department of Neurosurgery, Charles University, U Vojenské
nemocnice 1200, Praha 6, Střešovice,
Prague 169 02, Czech Republic
J. Novotný Jr.
Department of Radiation Oncology, University of Texas
Southwestern Medical Center, Dallas, TX, USA
A. Singla, M.D. • L.S. Chin, M.D., F.A.C.S., F.A.A.N.S. (*)
Department of Neurosurgery, SUNY Upstate Medical University,
750 East Adams Street, Syracuse, NY 13210, USA
e-mail: singlaa@upstate.edu; chinL@upstate.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_62, © Springer Science+Business Media New York 2015
62
doses in a single session to well-defined intracranial targets.
The first experiences with ophthalmologic indications
involved the treatment of patients suffering from uveal mela-
nomas [3–5]. However, it would appear that the potential of
radiosurgery to provide effective treatment for ophthalmo-
logic indications is far greater and, besides uveal melano-
mas, the current spectrum of treated indications also includes
vascular lesions, eye metastases, advanced glaucoma, and
age-related macular degeneration. This chapter reviews the
radiobiology, clinical indications and applications, technical
aspects, and side effects and complications of stereotactic
radiosurgery in the treatment of benign and malignant orbital
and ocular lesions.
Radiobiology and Technique
Stereotactic radiosurgery (SRS) or stereotactic radiotherapy
(SRT) was originally designed for the treatment of rigid
centrally or almost centrally located intracranial targets [2],
but now also extends to cover the extracranial target [1, 6].
Stereotactic radiosurgery or radiotherapy of ophthalmic
lesions is far different from the standard intracranial treat-
ment due to very eccentric target location and motion of the
eye. These aspects specific to the treatment of ophthalmic
lesions need to be taken into account. First of all, a proper
eye fixation or eye motion monitoring system is required
because the eye can move during the treatment procedure.
Very eccentric target volume location can also cause some
inaccuracies in the treatment planning calculations including
relative dose distribution as well as absolute dose calcula-
tions (calculation of treatment time or monitor units). Finally,
there may be also some technical inconveniences to treat
patients due to limitations in the range of coordinate system
in this very eccentric target location. Despite all these diffi-
culties, SRS or SRT is an excellent alternative for ophthal-
mic lesion treatment mainly due to its very high accuracy
and delivery of high conformal dose distribution to the small
volume of the treatment target.
743
744
Eye Fixation
For all kinds of SRS or SRT, it is imperative to employ a
patient fixation system that is highly reproducible and meets
the accuracy requirements for high-precision treatments.
Additionally, for treatment of ocular lesions, it is not suffi-
cient to fixate the patient’s head but the eye itself has to be
fixated in the same position during imaging for treatment
planning and during delivery of all treatment fractions.
Several different eye-immobilization systems and techniques
have been described in the literature [4, 7–9]. In principle,
eye-immobilization techniques can be divided into two
groups: (1) passive immobilization techniques where the eye
is immobilized by different mechanical means from outside
and (2) active immobilization techniques where the patient
controls the eye position (e.g., by fixation on a light source).
Tokuuye et al. described a mask fixation technique with a
plastic mold gently pressed down over the orbit to restrict
ocular movements [5]. Zehetmayer et al. reported on a suc-
tion immobilization technique for SRS of intracranial malig-
nancies at the Leksell Gamma Knife [9]. Langmann et al.
used an invasive fixation method of the globe by means of
retrobulbar anesthetic blocking for eye treatments with the
Leksell Gamma Knife [10]. Simonova et al. reported a series
of patients with uveal melanomas treated with the Leksell
Gamma Knife when an eye fixation was achieved by apply-
ing two sutures in the rectus muscles and attaching these
sutures to the Leksell stereotactic frame [4]. The same tech-
nique of eye fixation was also reported by Vladyka et al.
when patients with glaucoma were treated with the Leksell
Gamma Knife [7].
Active eye-immobilization techniques, where the patient
controls the eye position (e.g., by fixation on a light source),
have been described in the literature for proton/helium ion
beam therapy and recently also for linac-based SRT of
malignant tumors [11]. For proton/helium ion beam therapy,
a surgical intervention is performed to position tantalum
clips at the border of the visible tumor under diaphanoscopi-
cal control. These clips are used during treatment planning
to define the target volume and to verify the position of the
tumor during treatment delivery by using X-rays [12].
Recently, Petersch et al. described a new, noninvasive eye
fixation system for the application of linac-based image-
guided/gated SRT of uveal melanoma [8]. The system is
attached to a commercially available head-and-neck ther-
moplast mask system and is based on the patient’s fixation
on a light point. Computer-controlled eye monitoring pro-
vides quantitative information about the quality of the
patient repositioning, both about the repositioning of the
patient’s head within the mask and about the eye’s rotational
state with respect to the reference position as determined
during imaging for treatment planning prior the actual treat-
ment. When eye position exceeds the preset geometric limits,
Y.M. Li et al.
Fig. 62.1 (a) Example of invasive eye fixation by applying two sutures
in the rectus muscles and attaching these sutures to the Leksell stereo-
tactic frame. (b) Example of noninvasive eye fixation used for image-
guided/gated SRT (From Petersch B, Bogner J, Dieckmann K, et al.
Automatic real-time surveillance of eye position and gating for stereo-
tactic radiotherapy of uveal melanoma. Med Phys 2004; 31:3521–3527.
Used with permission)
the system is able automatically initiate interruption of
patient irradiation.
When invasive stereotactic frame fixation to a patient’s
head or invasive eye fixation is used, then the treatment itself
is limited to one single fraction or a very small number of
fractions due to patient comfort. A prerequisite for fraction-
ated SRT is the reproducible and reliable immobilization of
the irradiated structures throughout the whole treatment.
Whereas this is achieved in the region of the skull by invasive
or noninvasive fixation systems, treatments of intraocular
lesions are more complicated due to the additional degrees of
freedom caused by eye movements. Consequently, special
eye motion monitoring devices as described above have to be
employed during radiation delivery.
An example of invasive fixation by means of eye fixation
by applying two sutures in the rectus muscles and attaching
these sutures to the Leksell stereotactic frame and an exam-
ple of noninvasive eye fixation used for image-guided/gated
SRT are presented in Fig. 62.1.
Treatment Planning
A prerequisite for correct treatment planning is good imag-
ing of the target and surrounding structures, especially
organs at risk. A typical imaging modality for ophthalmic
lesions is MRI, which can be supplemented by computed
tomography (CT). Generally, MRI brings better contrast
compared with CT when imaging intracranial and intraocu-
lar structures. However, whereas CT is supposed to be free
of geometric distortions, MRI may produce some geomet-
ric image distortions (sometimes a few millimeters) that are
not acceptable for SRS or SRT treatment planning.
Generally, MRI geometric distortion is mainly a function of
the MRI scanner employed, the MRI sequence used, image
slice orientation, position in imaged object, and material
and geometric parameters of the stereotactic frame [13, 14].
62 Ocular and Orbital Lesions
Fig. 62.2 (a) Special y coordinate extender developed at Na Homolce
Hospital used for the treatment of eye lesion when y coordinate exceeds
the limits of the commercially available Leksell stereotactic frame.
(b) Typical treatment of eye lesion on the Leksell Gamma Knife with
patient in the prone position
The issue of image geometric distortion is even more crucial
in the case of eye imaging when a target and other structures
of interest are in a very frontal location. It is essential to
check the extent of geometric distortions for each MRI scan-
ner and sequence employed for eye imaging.
Leksell Gamma Knife
Treatment planning for intraocular targets is very similar as
for intracranial targets in the case of the Leksell Gamma
Knife. Four different collimator helmets (4, 8, 14, 18 mm)
are available to create isocenters of essentially spherical dose
distributions. To cover optimally the target volume, a combi-
nation of all four collimator helmets can be used. Dose dis-
tribution can be tailored to the target volume by means of
proper isocenter size selection, proper position in the stereo-
tactic space, and proper weighting factor for each isocenter.
To protect surrounding healthy tissue and mainly structures
at risk, additional shaping of dose distribution can be done
by blocking any of the 201 Cobalt-60 beams. Shielding of
properly selected number of beams can effectively reduce
dose to critical structures such as optic nerve or eye lens. The
target volume is usually covered by 50 % isodose line.
Treatment planning process is also a compromise between
sufficient conformity required for the treated target and treat-
ment time (with increased number of isocenters, total treat-
ment time is increased).
Because of the very frontal location of eye volume, some
mechanical difficulties can occur when treating a patient with
the Leksell Gamma Knife. Depending on a patient’s head
shape and volume, it might be difficult to adjust properly the
frame position to reach all Leksell stereotactic coordinates.
Specifically, y (posterior–anterior) Leksell stereotactic coor-
dinate can sometimes exceed limits engraved on the Leksell
stereotactic frame. Because of this, a special y coordinate
extender was developed at Na Homolce Hospital to be able to
treat also y coordinates exceeding the limits of the commer-
cially available Leksell stereotactic frame (Fig. 62.2).
745
Treatment of eye lesions with the Leksell Gamma Knife
requires typically an extremely large neck rake (when supine
position is used) that can be hardly tolerated or even impos-
sible to perform for some patients. Consequently, for a
patient’s better comfort, the treatment is typically done in the
prone patient position (Fig. 62.2).
The most up-to-date system called the LGK PERFEXION
was introduced in 2006 [15]. The entire radiation unit was
redesigned with a beam geometry different from that of the
previous Gamma Knife Models U, B, C, and 4C. A total of
192 Co-60 sources are arranged in a cylindrical configura-
tion in five concentric rings. This differs substantially from
the previous hemispherical arrangements and results in a dif-
ferent source-to-focus distance for each ring that varies from
374 to 433 mm. The primary and secondary collimators are
replaced by a single large 120-mm-thick tungsten collimator
array ring, which eliminates the need for changing different
collimator helmets and allows greater flexibility in treatment
planning by mixing collimator sizes with each dose of radia-
tion. There are greater time savings in treatment length and
improved safety features for patients and practitioners.
Improved helmet clearance allows for fewer modifications to
treat eccentrically located orbital lesions.
Linear Accelerator
The LINAC is now the most frequently used device for deliv-
ery of conventional radiotherapy and radiosurgery. Linear
accelerators use electromagnetic waves to accelerate a
stream of electrons to nearly the speed of light and then hit a
high-density metal target. A small portion of the energy is
converted to X-rays through the process of braking radiation
and this produces a poly-energetic beam of photons (X-rays)
with energies in the MV range. The treatment plans can be
individualized for each patient by adjusting the variables of a
multiple arc plan. These variables include the number of
arcs, the gantry start and end angles of each arc (amplitude),
the couch angle (the separation between arcs), different beam
energies (arc weighting), and different sized collimators
(5–50 mm).
Non-coplanar arcs represent the standard treatment tech-
nique. Non-coplanar arcs treatments use circular collimators
with fixed diameters. The resulting isodose distribution is
essentially spherical and very similar to the one created in
the case of the Leksell Gamma Knife. There is usually a
wide range (typically 5–40 mm) of circular collimators
depending on the manufacturer of the system. Individual
dose distribution can be further optimized by combination of
proper number and size of circular collimators. However,
total number of isocenters is much smaller compared with
the Leksell Gamma Knife (usually does not exceed 5).
Another option is non-coplanar conformal static fields.
Non-coplanar conformal static fields can be applied using
customized blocks or miniature-multileaf collimator with leaf
746
width in the millimeter range. The use of miniature-multileaf
collimator has several advantages compared with custom-
ized blocks: (1) generating miniature-multileaf collimator
shapes takes less time than molding blocks, (2) there is no
need to reenter the treatment room during multiple field
treatments, and (3) any modification in the shape can be
performed easily. Single-isocenter technique with selected
number of conformal fields (typically 5–15) is used.
Individual fields are shaped using beam’s-eye view tech-
nique. Weighting factors of single individual beams, gantry
angles, and table angles are used for final dose distribution
optimization.
Dynamic non-coplanar arcs are another treatment tech-
nique. A selected number of conformal isocentric arcs are
used. Beam’s-eye view technique is used for individual beam
shaping.
Finally, intensity-modulated SRS or SRT is an option for
the treatment planning. A selected number of fields opti-
mized by proper weighting factor, gantry, and table angles
are used as in the non-coplanar conformal static fields tech-
nique. Inverse treatment planning is used to generate optimal
intensity through individual beams.
Georg et al. compared different dosimetric characteristics
of treatment plans when using the above-mentioned tech-
niques for the treatment planning of uveal melanomas [16].
They concluded that static conformal and dynamic as treat-
ment techniques that have dosimetric advantages over con-
ventional non-coplanar arcs using circular collimators while
being simultaneously highly efficient in treatment planning
and delivery. Dynamic arc SRS or SRT combines the homo-
geneous dose distribution and the high degree of static con-
formal beams with the steep dose gradients and smeared-out
low-dose volumes of arc beam therapy. Intensity-modulated
SRS or SRT does not show clear impact on further reduction
of doses to organs at risk and depends probably on the target
volume location within the eye.
Dosimetry
Because of very eccentric target volume location, some inac-
curacies in the treatment planning calculations including
relative dose distributions as well as absolute dose calcula-
tions (calculation of treatment time or monitor units) can be
expected. This issue is even more important for surface
structures of eye (e.g., eye lens, eye lid, cornea) than for tar-
get volumes itself as these structures are located in depths
smaller than buildup of employed photon energies.
Petersch et al. reported excellent agreement between
measurements and treatment planning system calculations
for uveal melanomas at depth 15–20 mm [8]. However, at
small depths (<10 mm), the treatment planning system can-
not model the influence of absorption in eye motion monitor-
Y.M. Li et al.
ing device accurately if beam passed perpendicularly through
it. Consequently, Petersch et al. suggested avoidance of fron-
tal beams when doing treatment planning as a solution to
reduce significantly dosimetric errors.
Detailed dosimetric measurements including the treat-
ment planning system calculations of target volume relative
dose distributions and absolute dose calculations in different
depths were compared with experimental measurements.
Various treatment plans for different ophthalmic indications
(uveal melanoma, glaucoma, retinoblastoma) calculated for
the Leksell Gamma Knife were evaluated. There was
observed good agreement between treatment planning sys-
tem relative dose distribution calculations for target volume
and performed measurements (Fig. 62.3). For the calculation
of absolute doses, there was observed very good agreement
at depths 15–20 mm. Typical deviations between treatment
planning system calculations and actual measurements were
within 3 %. However, measurements performed at depth less
than 10 mm showed large deviations of about 15–20 % com-
pared with the treatment planning system calculations. The
dose delivered to patient was always smaller than that calcu-
lated by the treatment planning system. To improve inaccu-
racies in absolute dose calculations in surface structures, it
was suggested to use proper tissue equivalent built-up mate-
rial that is attached on the treated eye (Fig. 62.3) and
improves treatment planning system calculations.
Clinical Application
Stereotactic radiosurgery or radiotherapy currently plays an
important role as primary treatment, adjuvant therapy, or pal-
liation of ocular and orbital tumors. The clinical situation,
radiation source, and desired result determine the prescribed
radiation dose. The following reviews the published experi-
ence with stereotactic radiosurgery or radiotherapy for ocu-
lar and orbital lesions (Table 62.1) [3, 4, 17–41].
Uveal Melanomas
Pathophysiology
Uveal melanoma represents the most common primary malig-
nant tumor of the eye in adults with a peak incidence between
ages 55 and 70 years. It affects 6–7 people per million each
year, and approximately 50 % of patients with diagnosed
melanomas of the chorioid or ciliary body will die from this
tumor within 15 years [17]. The incidence is rare in patients
younger than 20 years. The incidence of cutaneous melano-
mas has been increasing in frequency over the past several
decades and the dependence on latitude has been observed,
reflecting levels of exposure to ultraviolet light. This trend
has not been evident for patients with uveal melanomas.
62 Ocular and Orbital Lesions 747

Table 62.1 Indications and radiotherapy doses for ocular and orbital
disease
Orbital radiation doses (Gy)
Pathology Average or recommended dose (Range)
Tumor
Uveal Melanoma 35 (35–50)
[3, 4, 30–33]
Retinoblastoma [35] 43 (40–50)
Orbital metastasis 40 (30–40)
(breast, lung) [38, 52]
Lymphoma [39] 32 (15–46)
Meningioma [53–55] 45 (45–54)
Optic nerve glioma [56] 50 (42–54)
Basal cell carcinoma [57] 50 (34–50)
Squamous carcinoma 50 (50–64)
[58, 59]
Sebaceous carcinoma [60] 55 (45–63)
Rhabdomyosarcoma 45 (32–72)
[61, 62]
Vascular
Cavernous hemangioma 14.5 (12.5–40)
[40, 41]
Choroidal haemangiomas 10 (10)
[42]
Uveal angiomas (Sturge 12 (12–30)
Weber) [63]
Capillary hemangioma— 4.5 (1.5–7.5)
orbit [43]
Others
Age-related macular 12 (12–20)
degeneration [47, 48]
Glaucoma 15 (7–15)
1 Gy = 100 Rads

The uveal tract is a vascular structure with no lymphatic

Fig. 62.3 (a–c) Example of relative dose distribution treatment plan-
ning system calculations verification with polymer gel dosimeter.
(a) Three-dimensional treatment plan in LGP. (b) Polymerization that
occurred in the polymer gel. (c) Relative dose profiles (calculated by
LGP—solid line, measured with polymer gel—dotted line). (d) Tissue-
equivalent built-up material that is attached to the treated eye to improve
inaccuracies in absolute dose calculations in surface structures.
(e) Corresponding MR localization scan visualized in LGP together
with head contour
Uveal melanomas are neoplasm arising from the uveal tract,
which includes the iris, ciliary body, and chorioid. Two types
of tumor growth were recognized, nodular and infiltrative.
Histologically, the tumor consists of spindle cells, epithelioid
cells, and intermediate cells similar to those of cutaneous
melanoma, but the prognosis is better than that associated
with cutaneous melanomas.
drainage. Lymphatic node involvement (auricular, subman-
dibular, and cervical nodes) can be diagnosed on rare occa-
sions when subconjunctival extension of primary tumor
has been observed. The major routes of spread are local
growth and by bloodstream, with a predilection for hema-
togenous dissemination to the liver, lung, and brain. Liver
metastases are diagnosed in two-thirds of patients with
disseminated diseases. Systemic examination is recom-
mended for all patients and includes CT of the chest and
abdomen, and MRI of the brain to detect metastases. Wide
variations in the grading of malignancy can be observed,
from relatively benign types with several years’ survival
without dissemination, to other tumors with fast multiorgan
dissemination, which lead to the patient’s death within a
few months.
Tumor Location
The iris melanomas (incidence about 10 %) are single
or multiple elevated lesions with changes of iris color.
748
These types of melanomas are much more benign, smaller in
size, readily visible, and early diagnosed. It can be difficult
to assess the potential of the malignant cells, even in those
with documented growth, because iris nevi may also grow.
For this reason, local resection is usually effective whenever
it seems to be necessary.
Choroidal melanomas typically grow in nodular form,
and in cases of continuing growth many tumors break
through the Bruch membrane. The Bruch membrane is a
basement membrane–connective tissue complex lying
between the retina pigment epithelium and the choriocapil-
laries. When the melanomas break through the Bruch mem-
brane, they extend into the subsensory retina space, which
gives them a mushroom or collar-button shape. These char-
acteristics, as well as the detachment of the retina, are typical
for uveal melanomas. This type of tumor growth is some-
times accompanied by vitreous hemorrhage with symptoms
of sudden visual loss.
Melanomas involving the ciliary body are rare, carry a
poor prognosis, and are often diagnosed late. Melanomas
can also have diffuse, infiltrative growth to the ciliary body
and a pattern called ring melanoma. These tumors are diag-
nosed with difficulty and late, because they are accompanied
by relatively little visible tumor mass effect and they occur in
the diagnostically “silent” eye area. Any extra scleral exten-
sion of the tumor usually confers a poor prognosis. The dif-
fuse growing melanomas are usually more aggressive, with
more malignant cell types.
Tumor growth is also influenced on the potential doubling
time (T pot) which varies widely between 60 and 350 days
(the median of T pot being about 70 days) [18]. A longer T
pot for a significant proportion of tumors can explain the
relatively long survival of these patients and also the rela-
tively slow tumor response after irradiation.
Primary Tumor Diagnosis
Melanoma of the ciliary body and chorioid have typical
clinical features, and the correct diagnosis for a majority of
patients can be made by taking a history and performing a
complete ocular examination. The ophthalmologic exami-
nation includes external ocular examination, indirect oph-
thalmoscopy, fluorescein angiography, and ultrasonography
A, B. Magnetic resonance imaging plays a fundamental role
in the treatment planning of radiosurgery or stereotactic
radiotherapy.
Ultrasonography plays a basic role, not only at the time of
diagnosis but during follow-up and is used to obtain precise
measurement of the tumor base and height. The height of
tumor in particular represents one of the most important fac-
tors influencing the treatment decision, and it is used during
follow-up to evaluate the tumor response.
Y.M. Li et al.
Several staging systems have been used, one of the most
commonly reported was based on the 2010 American Joint
Staging System (Tables 62.2 and 62.3) [19]
Treatment Methods
Treatment modalities strongly depend on the site of the primary
tumor and its volume and metastatic extent. Historically, the
first known treatment modality was enucleation [20].
Surgical Treatment
Surgical methods include resection of the eye wall (for very
small visible melanomas of the iris), enucleation, and orbital
exenteration [20]. The role of enucleation in the management
of posterior to equator localized melanomas is controversial,
but enucleation remains the standard option for most large
choroidal melanomas that cause severe secondary glaucoma
or are invading the optic nerve.
Radiotherapy
Preoperative or postoperative irradiation is a promising
approach under evaluation that could also decrease the
chances of malignant dissemination, however recent study
observed no benefit [21]. Postoperative external beam radio-
therapy has been used in patients with large tumors with
extrascleral or extraocular extension. The recommended
total applied dose is 60 Gy with daily fractionation.
Brachytherapy
The most frequently used therapeutic system for delivering
radiation is brachytherapy (plaque radiotherapy). A number
of radionuclides, including cobalt-60, gold-198, iodine-125,
ruthenium-106, iridium-192, and palladium-103, have been
used for plaque therapy with varying results according to the
retrospective studies [22, 23]. A metal shield containing
small radioactive seeds is sutured to the outside of the sclera
overlying the tumor with radiation doses principally deliv-
ered to the base of the tumor. The radioactive plaque is left in
place for approximately 5–7 days. Cobalt-60 was one of the
first isotopes to be used in brachytherapy, but it is a high-
energy gamma emitter and thus there exists a risk of damag-
ing healthy ocular structures several millimeters from the
source. Other isotopes have been used: iodine-125 is also a
gamma emitter but has lower energy than cobalt-60 and,
because of this, it is associated with a lower rate of complica-
tions. Brachytherapy leads to long-term local tumor control
in 85–90 % of patients and can be used to treat small mela-
nomas [22, 23]. The best results can be achieved in tumors
less than 10 mm in height and with a base diameter not
exceeding 16 mm. Patients with extrascleral tumor exten-
sion, ring melanoma, and tumor involvement of more than
half of the eye are not suitable for plaque therapy.
62 Ocular and Orbital Lesions 749

Table 62.2 Definitions of TNM staging of uveal melanoma (American Joint Staging System, 2010) [19]
Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Iris
T1 Tumor limited to the iris
T1a Tumor limited to the iris not more than 3 clock hours in size
T1b Tumor limited to the iris more than 3 clock hours in size
T1c Tumor limited to the iris with secondary glaucoma
T2 Tumor confluent with or extending into the ciliary body, choroid, or both
T2a T2 with secondary glaucoma
T3 Tumor confluent with or extending into the ciliary body, choroid, or both, with scleral extension
T3a T3 and secondary glaucoma
T4 Tumor with extrascleral extension
T4a Tumor with extrascleral extension ≤5 mm in diameter
T4b Tumor with extrascleral extension >5 mm in diameter
Ciliary body and choroid
T1 Tumor size category 1
T1a Tumor size category 1 without ciliary body involvement and extraocular extension
T1b Tumor size category 1 with ciliary body involvement
T1c Tumor size category 1 without ciliary body involvement but with extraocular extension ≤5 mm in
diameter
T1d Tumor size category 1 with ciliary body involvement and extraocular extension ≤5 mm in diameter
T2 Tumor size category 2
T2a Tumor size category 2 without ciliary body involvement and extraocular extension
T2b Tumor size category 2 with ciliary body involvement
T2c Tumor size category 2 without ciliary body involvement but with extraocular extension ≤5 mm in
diameter
T2d Tumor size category 2 with ciliary body involvement and extraocular extension ≤5 mm in diameter
T3 Tumor size category 3
T3a Tumor size category 3 without ciliary body involvement and extraocular extension
T3b Tumor size category 3 with ciliary body involvement
T3c Tumor size category 3 without ciliary body involvement but with extraocular extension ≤5 mm in
diameter
T3d Tumor size category 3 with ciliary body involvement and extraocular extension ≤5 mm in diameter
T4 Tumor size category 4
T4a Tumor size category 4 without ciliary body involvement and extraocular extension
T4b Tumor size category 4 with ciliary body involvement
T4c Tumor size category 4 without ciliary body involvement but with extraocular extension ≤5 mm in
diameter
T4d Tumor size category 4 with ciliary body involvement and extraocular extension ≤5 mm in diameter
T4e Any tumor size category with extraocular extension >5 mm in diameter
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
M1a Largest diameter of the largest metastasis ≤3 cm
M1b Largest diameter of the largest metastasis 3.1–8.0 cm
M1c Largest diameter of the largest metastasis ≥8 cm
750 Y.M. Li et al.

Table 62.3 Anatomic stage/prognostic groups of uveal melanoma applied minimal dose ranged from 25 to 45 Gy in two fractions
(American Joint Staging System, 2010) [19] and 15 Gy in three equal fractions. Local tumor control,
Stage T N M defined as freedom of local progression, was reported in 98 %
I T1a N0 M0 of patients [29]. Further clinical studies using fractionated
IIA T1b–d N0 M0 stereotactic irradiation are justified to optimize the effective
T2a N0 M0 dose and fractionation pattern.
IIB T2b N0 M0
T3a N0 M0 Radiosurgery
IIIA T2c–d N0 M0
The first experiments with radiosurgery for the treatment of
T3b–c N0 M0
uveal melanomas were conducted using the rabbit eye mela-
T4a N0 M0
noma model, with reported tumor lethal dose range from 60
IIIB T3d N0 M0
to 90 Gy applied in a single session. A preliminary study of
T4b–c N0 M0
IIIC T4d–e N0 M0
11 treated patients with uveal melanomas was published in
IV Any T N1 M0 1992 and suggested that local tumor control could be
Any T Any N M1a–c achieved with a minimal dose between 60 and 90 Gy in a
single dose using the Leksell Gamma Knife. Some observa-
tions were made on patients after radiosurgery who had their
Proton Beam Therapy eyes secondarily enucleated. All eyes with secondary enucle-
Patients with tumors too large for brachytherapy or tumors ations presented an initial height exceeding 9 mm and also
considered too close to the optic nerve have been recom- had a large number of ciliary body tumors [30]. Several
mended for proton beam therapy (PBT). Early studies with authors reported the results of radiosurgery in uveal melano-
PBT recognized that severe damage was caused to the eyelid mas and some of them observed relatively high radiation-
and the anterior parts of the eye. Patients with tumors local- related toxicity [4, 30, 31].
ized near the eye surface had a higher incidence of severe Dinca et al. reported the UK experience in treating ocular
toxicity because the sparing effect of Bragg peak was absent. melanoma over the last 20 years [3]. One hundred seventy
Many of these patients had chronically painful and cosmeti- patients who were treated with Gamma Knife radiosurgery
cally unsatisfactory eyes. Local tumor control in 90–98 % of were compared with 620 patients treated with eye enucle-
patients was achieved by this method in a large series [24]. ation. Different peripheral doses (at the 50 % isodose) were
The technique was subsequently improved and the complica- employed. There was no significant difference in survival
tion rate has dropped accordingly. between the 35-Gy, 45-Gy, and 50–70-Gy groups when com-
pared between themselves (p = 0.168) and with the enucle-
Charged Particle Therapy ation group (p = 0.454). The 5-year survival rates were: 64 %
Helium ion irradiation is uniquely suited to the precise local- for 35 Gy, 62.71 % for 45 Gy, 63.6 % for 50–70 Gy, and
ization of irradiation because of the sharp falloff of the dose 65.2 % for enucleated patients. Clinical variables influencing
at the distal end of the Bragg peak, the sharp lateral edges of survival for radiosurgery patients were tumor volume
the beam, and the ability to tailor the depth penetration and (p = 0.014) and location (median 66.4 months for juxtapapil-
spread by a modulated Bragg peak. Uveal melanomas are lary vs. 37.36 months for peripheral tumors, (p = 0.001).
indicated for this treatment. When the charged particles are Regarding complications, using 35 Gy led to more than a
used to treat the uveal melanoma, the normal tissue of the 50 % decrease in the incidence of cataract, glaucoma and
anterior part of the eye can receive a radiation dose compa- retinal detachment, compared with the 45-Gy dose.
rable with the tumor dose. This fact causes radiation toxicity Retinopathy, optic neuropathy, and vitreous hemorrhage
in the anterior parts of the eye leading to side effects such as were not significantly influenced. Blindness decreased dra-
eyelash loss, lacrimal damage, conjunctival changes, dry eye matically from 83.7 % for 45 Gy to 31.4 % for 35 Gy
syndrome, keratitis, and neovascular glaucoma [25, 26]. (p = 0.006), as well as post-radiosurgery enucleation: 23.9 %
Local tumor control is achieved in 96 % of patients and the for 45 Gy vs. 6.45 % for 35 Gy (p = 0.018). Visual acuity,
enucleation rate is 19 % (3 % for local failure and 16 % due recorded up to 5 years post-radiosurgery, was significantly
to complications) [26]. better preserved for 35 Gy than for 45 Gy (p = 0.0003). It
appears that using 35 Gy results in a dramatic decrease in
Stereotactic Radiotherapy complications, visual loss, and salvage enucleation, while
The advantage of stereotactic irradiation using a linear accel- not compromising patient survival.
erator is the possibility of fractionated treatments compared Sarici et al. reported on 50 eyes from 50 consecutive
with the Leksell Gamma Knife. Fractionation may decrease patients with uveal melanoma that were treated with GKRS
late-radiation-related toxicity, and this fact was the subject of and had a median follow-up time of 40 months. They used a
intensive study [8, 9, 11, 16, 27–29]. The reported mean dose of 30 Gy, which is an eye-sparing outpatient option for
62 Ocular and Orbital Lesions 751

Table 62.4 Toxicity scoring system (RTOG/EORTC LENT SOMA)

Grade 1
Cornea Increased tearing on exam
Iris Rubeosis only
Optic nerve Afferent pupillary defect
with normal-appearing nerve
Lens Asymmetric lenticular
opacities, no visual loss
Retina Microaneurysms, nonfoveal
exudates, minor vessel
attenuation, extrafoveal
pigment changes
Sclera Loss of episcleral vessels
Grade 2
Noninfectious keratitis
Rubeosis, increased
intraocular pressure
≤¼ pallor with asymptomatic
visual field defect
Moderate lenticular changes
with mild-moderate visual
loss
Cotton wool spots
≤50 % scleral thinning
Grade 3 Grade 4
Infectious keratitis, Panophthalmitis, corneal scar,
corneal ulcer ulceration leading to perforation
of globe/loss of globe
Neovascular Neovascular glaucoma without
glaucoma, ability to ability to count fingers at 1 m;
count fingers at 1 m complete blindness
>¼ pallor or central Profound optic atrophy,
scotoma complete blindness
Moderate lenticular Severe lenticular changes
changes with several
visual loss
Massive macular Opaque vitreous hemorrhage,
exudation, focal complete retinal detachment,
retinal detachment blindness
>50 % scleral thinning Scleral or periosteal graft
required due to perforation

patients with medium- or large-sized posterior uveal melanomas

who are not eligible for brachytherapy or particle therapy.
The tumor control rate was 90 %, and the eye retention rate
was 82 %. Metastases developed in 18 % of patients with
14 % dying of metastases during follow-up. Cataracts (34 %)
and radiation maculopathy (30 %) were the most frequent
complications, and 14 % of patients developed neovascular
glaucoma. Visual acuity (VA) also decreased significantly
after treatment (p < 0.0001) [32].
Šimonová, et al. studied a group of 126 patients with
uveal melanoma treated using the Leksell Gamma Knife
over a period of 8 years with all survivors undergoing mini-
mal follow-up 24 months after the treatment. The late effect
of normal tissue (LENT) subjective objective management
analysis (SOMA) scoring system is acceptable for measure-
ment of radiation side effects (Table 62.4).
Imaging and Treatment Planning
MRI plays a fundamental role in the imaging of ocular
tumors for treatment planning. The native T1- and
T2-weighted sequences, postcontrast T1-weighted sequences
and three-dimensional with slice thickness 1–3 mm have
been used. The melanotic uveal melanomas are well defined
on native T1 (Fig. 62.4a) and T2 (Fig. 62.4b) sequences and
have typical postcontrast enhancement on T1-weighted MRI
(Fig. 62.4c). This postcontrast enhancement of melanomas
differentiates the boundary between the tumor volume and
the accompanying retinal detachment (Fig. 62.4c). The rare
amelanotic melanomas are difficult to differentiate on native
T1 (Fig. 62.5a) but are well defined on T2-weighted mag-
netic resonance sequence (Fig. 62.5b). The postcontrast

Fig. 62.4 Melanotic type of uveal melanoma. (a) Native T1-weighted MRI. (b) T2-weighted MRI. (c) Postcontrast T1-weighted MRI
752
Fig. 62.5 Amelanotic type of uveal melanoma. (a) Native T1-weighted MRI. (b) T2-weighted MRI. (c) Postcontrast three-dimensional MRI
Fig. 62.6 (a) Axial, (b) coronal plane, and (c) sagittal plane. Uveal
melanoma. Characteristics: The tumor base is 9 mm and the tumor
height is 3 mm. Gross tumor volume is 84 mm3, the planned treatment
enhancement is not so intensive as in the melanotic forms
(Fig. 62.5c). The treatment planning volume (PTV) includes
the growth tumor volume and 1–2-mm safety margins in all
three diameters. The minimal dose for radiosurgery ranged
from 35 to 45 Gy with a median dose of 41 Gy in our series.
The majority of melanomas are irradiated using 4- and 8-mm
collimator helmets (Fig. 62.6) and the plugging pattern aim
to spare critical structures such as cornea (Fig. 62.7) or optic
nerve (Fig. 62.8).
Follow-Up
Patients should be examined by an ophthalmologist at regu-
lar intervals (24 h, 1 week, 3 months, and then every 6
months after SRS; MRI can be repeated every year for the
first 2 years after radiosurgery and then every 2–3 years
after the treatment). The following ophthalmologic methods
were employed for diagnostic investigation and patient fol-
low-up at regular intervals 6 months after radiosurgery:
Y.M. Li et al.
volume is 183.3 mm3, minimum dose is 44 Gy on a 60 % isodose, maxi-
mum dose is 73.3 Gy. The maximum doses to critical structures: lens
4 Gy, cornea 2 Gy, eyelid 2 Gy
ultrasonography, indocyanine and fluorescein angiography,
optical coherence tomography, ultrabiomicroscopy (for
tumors located anterior to the equator), visual function, and
biomicroscopy.
Local Tumor Response
Tumor regression is defined as a decrease in tumor height
registered by A and B ultrasonography scans and by control
MRI. In our personal experience, the tumor regression can
be achieved in 70 % of patients. The maximum local effect
has been recorded during the interval of 20–30 months after
radiosurgery. Most tumor response has been achieved within
24 months after SRS (Figs. 62.9, 62.10, 62.11, and 62.12).
Patients with tumor growth progression or without any
response 30 months after treatment were candidates for
retreatment by radiosurgery, and patients with a tumor height
of more than 10 mm or extra scleral growth were indicated
for enucleation (5 %).
62 Ocular and Orbital Lesions 753

Fig. 62.7 Demonstration of the effect of plugged sources for protec- plan with plugging. The dose to cornea in this case did not exceed
tion of cornea for patient with uveal melanoma treated by 8-mm and 14 Gy (given on displayed 20 % isodose). (c) Plug pattern used for
14-mm collimators. (a) Treatment plan without plugging. (b) Treatment 14-mm collimator. Plugged sources are indicated in black

Fig. 62.8 Demonstration of the effect of plugged sources for protec- plan with plugging. (c) Plug pattern used for plugging both 4-mm col-
tion of optic nerve for patient with uveal melanoma treated by two limators. Plugged sources are indicated in black
4-mm collimators. (a) Treatment plan without plugging. (b) Treatment

Fig. 62.9 Post-equatorial uveal melanoma. (a) Pretreatment funduscopy and treatment planning MRI. (b) Native T1-weighted MRI.
(c) T2-weighted MRI
754
Fig. 62.10 (a) The tumor response 12 months after radiosurgery and the development of postradiation retinopathy (funduscopy control). (b, c)
Control MRI 12 months after radiosurgery
Fig. 62.11 (a) Pretreatment, postcontrast T1-weighted
(b) T2-weighted MRI
Fig. 62.12 Control MRI 18 months after radiosurgery. (a) Post-
contrast T1-weighted MRI. (b) T2-weighted MRI
Survival
Patients younger than 50 years have the best prognosis,
with a pre-equatorial location of the tumor, when tumor
height does not exceed 5 mm, gross tumor volume is not
larger than 500 mm3, and there is no other organ
dissemination.
Y.M. Li et al.
Prognostic Factors
The main aim of radiosurgery is not only to preserve the bulb
and visual function but also to achieve long-term local tumor
control and to protect against hematologic dissemination of
malignant melanoma. The prognosis of patients with uveal
melanoma is determined by tumor size, cell type, tumor
location (poor results for ciliary body tumors), and the extent
of the disease [4, 12, 20, 21, 23, 25]. Five-year survival rates
MRI. of patients with small tumors (heights less than 8 mm) and
with no detected metastatic disease outside the eye are above
80 %, and for lager tumors (over 10 mm in height) with
metastases outside the eye, the 5-year survival period ranged
from 10 to 30 %. The most important prognostic factor is the
presence or absence of the organ dissemination at the time of
uveal melanoma diagnosis. The potential dissemination has
been discussed several times. Some authors maintain that
dissemination from uveal melanomas starts when the tumor
is larger than 7 mm in diameter, and growth from a 7- to
10-mm diameter increases the risk of metastatic disease to
approximately 16 % [18]. There still exists a serious gap in
our knowledge of growth of melanomas in situ and the docu-
mentation of the time intervals between the diagnosis of pri-
mary tumor and the appearance of the other organ
dissemination. Tumor growth strongly depends on tumor
doubling time. The numerous accounts of tumor doubling
times in uveal melanomas have been reported, and in the
majority of them the estimated doubling time was longer
than 69 days. On theoretical grounds, it has been suggested
that metastatic death (after the primary tumor has released
malignant cells into the systemic circulation) will occur at a
time interval derived from multiplication of the tumor dou-
bling time by 35–40 [18]. Taking these two assumptions
together, it may be accepted for practical prognostic consid-
eration in individual patients that death from dissemination
is unlikely to occur before 6 years after dissemination of the
62 Ocular and Orbital Lesions
first viable embolus of malignant tumor cells. The minimum
latent interval of 6 years implies that metastatic death within
7–8 years after local treatment on the uveal melanoma is
nearly always due to pretreatment dissemination [29]. The
chance of metastasis-caused death within 5 years totally
depends on the presence or absence of hematologically dis-
seminated tumor cells or diagnosed metastases at the time of
local treatment. Some data from the analyzed clinical studies
strongly supports the assumption that the rate of death by
metastatic disease is influenced by local tumor control:
improvement in local tumor control rate results in a longer
survival. One of the fundamental experiments and analysis
of results was reported from study based on 15 years of treat-
ment of uveal melanomas with proton beam therapy [26].
The minimal latent interval of 5 years implies that metastatic
death 5 years after local treatment is nearly always due to
pretreatment dissemination. This is the one reason that statis-
tically significant prognostic factors for survival in tumors
less than 8 mm in diameter should never be established 5
years after local treatment, and the recommended interval of
follow-up and analysis seems to be 8–10 years after the treat-
ment. The minimal interval for the evaluation of tumor
response and treatment-related toxicity is about 3–5 years.
Other Aspects of Eye Preservation Methods
The psychosocial aspect of conservative treatment can also
be intensively studied. The psychological problems of some
conservatively treated patients can be caused by frequent
follow-up tests, treatment of any reoccurrence, treatment of
complications, and the possibility of persistent malignant
cells in the eye involved. On the other hand, the impact of
enucleation on vision-dependent daily activities must also be
discussed.
Trials and Treatment Comparison
The clinical trials and studies about management of uveal
melanomas are still going on. The multicenter Collaborative
Ocular Melanoma Study (COMS) was initiated at 32 clinical
centers in the USA and in Canada in 1986 and ended in 1998.
Participating patients were followed for 5–15 years, depend-
ing upon date of enrollment, before all clinical follow-up
ended in 2003. No difference in survival outcomes and little
difference in quality-of-life outcomes were observed
between patients in the iodine-125 brachytherapy arm and
those in the enucleation arm. Five-year survival was substan-
tially better than anticipated based on a review of the litera-
ture when the trial was designed. The multidisciplinary
COMS Group successfully conducted a randomized trial that
755
answered the primary study questions and contributed to
clinical and epidemiologic knowledge of choroidal mela-
noma. As a consequence of the COMS, a standard approach
to I-125 brachytherapy for treatment of choroidal melanoma
became widely available to affected patients [22].
Proton beam therapy was analyzed in Switzerland, and
the treatment results over 15-year periods were reported.
Effective local tumor control was achieved in 90 % and later
in 96 % of treated patients. Ten years survival of patients
with local controlled tumors was 72.6 and 47.5 % in patients
with local recurrence of melanoma. The helium ions therapy
trial documented local tumor control of 85–90 % [25, 26].
The radiosurgery series reported the local tumor control of
about 70–75 % [4, 30, 31].
Treatment Methods Comparison
Brachytherapy represents two surgical interventions: the first
is plaque application and the second replacement. Proton
beam therapy is accompanied by pretreatment application of
target markers to the exposed sclera using tantalum clips.
Stereotactic radiotherapy uses the fractionation regimes.
Radiosurgery is combined with the stereotactic frame and
eye fixation. The treatment results in terms of tumor response
and local control are similar to those of brachytherapy, ste-
reotactic irradiation, helium ions therapy, proton beam ther-
apy, or enucleation and range between 85 and 97 % [20, 25, 26].
Long-term local tumor control of more than 90 % and an
incidence of rubeosis of iridis in 34 % of patients have been
achieved using proton beam therapy after a median follow-
up of 36 months [25]. A major predictive factor for the devel-
opment of rubeosis iris and later neovascular glaucoma was
a large tumor size unsuitable for brachytherapy. Stereotactic
irradiation using a linear accelerator with applied doses of
45–70 Gy delivered in one or three fractions is an effective
method with the following results: tumor height reduction
was achieved in 97 %, secondary enucleation were per-
formed in 13 %, and the incidence of secondary glaucoma
was 20 % also including iris or chamber angle neovascular-
ization [3, 29]. In a prospective study of helium ion therapy,
the incidence of secondary glaucoma was 29 % after a mean
observation period of 53 months [25].
Radiosurgery data was reported by Rennie, and in this
study, after delivering a single fraction of 35–70 Gy, the
majority of patients developed significant complications
after a median follow-up of 24 months [3, 32, 33].
Retinopathy was found in 78 % and secondary neovascu-
lar glaucoma in 43 % of patients. Our radiosurgery data
were mentioned above. Comparison of different treatment
methods is given in Table 62.5 [3, 4, 17–20, 35–38, 48,
52, 54, 55].
756 Y.M. Li et al.

Table 62.5 Comparison of different treatment methods

Median follow-up Minimal Tumor 5-year local Radiation-related Neovascular Enucleation
Treatment method (months) dose (Gy) response (%) tumor control (%) retinopathy (%) glaucoma (%) rate (%)
Brachytherapy [23] 39–96 70–250 69–96 82–92 22–63 3–11 10–21
Proton beam therapy 40 40–70 F 91–100 87–100 NA 8 9
[35–38]
Helium-ions therapy [64] 96 50–80 F 87–96 80 NA 35 20
Stereotactic radiotherapy 36 45–60 F 94 NA 26 9–20 NA
[27, 29]
Radiosurgery [3, 4, 30–33] 36 35–90 70–90 NA 23–70 18–23 18
Fractionated treatment is indicated in the table by F; NA indicates data not available

Treatment Decision Radiosurgery

Rationale criteria for selecting a treatment modality should
be dependent upon the interrelations between the clinical
characteristics of tumor and the morbidity associated with
the available treatment modalities. Small tumors (less than
10 mm in height) and localized pre-equatorially can be suc-
cessfully treated using brachytherapy. Tumors localized
equatorially or posterior to the equator and not higher than
10 mm can be irradiated using the Leksell Gamma Knife.
Small melanomas (height 5–10 mm) can be treated effec-
tively using Leksell Gamma Knife and in cases with PTV not
exceeding 1,000 mm3 with less than 7 % risk of neovascular
glaucoma. Tumors more than 10 mm in height, especially
melanomas of the ciliary body, progression of growth after
irradiation, tumors combined with neovascular glaucoma, or
vitreous hemorrhage are candidates for enucleation (Case
Studies 62.1 and 62.2).
Retinoblastoma
Pathophysiology
Retinoblastoma represents the most common primary malig-
nant tumor of the eye in children. Although this tumor
accounts for only 1 % of all malignant tumors in children, it
has been studied intensively because of its genetic features.
Diagnosis and Treatment
The majority of cases are diagnosed within the first 2 years
of life. The treatment strategy depends on clinical staging
(disease confined to the retina, disease confined to the globe,
extraocular extension, and presentation of distant metasta-
ses) and includes the following methods: tumor resection,
enucleation, chemotherapy, and external beam radiotherapy,
which continues to play an important role in the treatment of
extrascleral and intraneural extension of retinoblastoma.
The role of stereotactic irradiation and radiosurgery in the
treatment of primary tumors still remains unclear. Pica et al.
reported preliminary experience on 11 children (15 eyes)
with macular and/or papillary retinoblastoma treated with
SRT. The mean age was 19 months (range, 2–111). 7, 6, and
2 eyes were classified as International Classification of
Intraocular Retinoblastoma Group B, C, and E, respectively.
The delivered dose of SRT was 50.4 Gy in 28 fractions using
a dedicated micromultileaf collimator linear accelerator.
The median follow-up was 20 months (range, 13–39). Local
control was achieved in 13 eyes (87 %). The actuarial 1- and
2-year local control rates were both 82 %. SRT was well tol-
erated. Late adverse events were reported in four patients. Of
the four patients, two had developed focal microangiopathy
20 months after SRT; one had developed a transient recur-
rence of retinal detachment; and one had developed bilateral
cataracts. No optic neuropathy was observed [34]. Linear
accelerator-based SRT for papillary and/or macular retino-
blastoma in children resulted in excellent tumor control rates
with acceptable toxicity. Additional research regarding SRT
and its intrinsic organ-at-risk sparing capability is justified in
the framework of prospective trials [35].
Šimonová summarized four patients were admitted for
stereotactic irradiation using the Leksell Gamma Knife and
they had vitreous seeding of malignant cells. All patients
were pretreated according to SIOP (Society International of
Pediatric Oncology) protocol and relapsed after standard
treatment. The only other possibility was enucleation. The
whole vitreous body was irradiated using the Leksell Gamma
Knife in a single session, collimator diameter 14 mm, the
median PTV 2,900 mm3, and the median minimum dose was
15 Gy. To avoid growth retardation of the irradiated eye and
bony structures, the minimal dose did not exceed 15 Gy in all
patients, and for this as well as the risk of complications
from the previous treatment, the applied doses were rela-
tively low and three of the four patients were enucleated
with a median of 2 months after radiosurgery for local
progression.
62 Ocular and Orbital Lesions 757

Orbital and Ocular Metastases

Pathophysiology

Metastatic lesions in every subsite of the eye and the orbit

have been described several times but predominately affect
the posterior uveal tract [36, 37]. The autopsy studies esti-
mate the incidence of these metastases to be 4–12 % in
adult patients with cancer of all histologic types. Mostly Fig. 62.13 (a, b) Pretreatment MRI of a spinocellular cell carcinoma
derived from breast cancer in women and from lung cancer case (patient treated by Leksell Gamma Knife, minimum applied dose
in men, other primary sites include the prostate, colon, kid- was 25 Gy on a 50 % isodose curve) (a) in axial and (b) in coronal plane
ney, thyroid, and skin. Most ocular metastases occur
towards the end of life, are asymptomatic, undiagnosed,
and are left untreated. The overall incidence of ocular
metastases is difficult to quantify, as many patients remain
asymptomatic. However, with improvements in systemic
treatment, patients may be living longer and may, therefore,
manifest intraocular and intraorbital lesions more fre-
quently than in the past.

Diagnosis

A careful history and ophthalmologic examination is gener-
ally sufficient to diagnose ocular metastases, and the com-
plete examination should include slit-lamp examination,
funduscopy, ultrasonography, and MRI postcontrast
T1-weighted sequence. When the patient has no prior history
of malignant tumors, a systemic examination should be per-
formed to identify the primary tumor and metastatic extent
outside the eye. Choroidal metastases generally appear as a
creamy yellow subretinal mass, often accompanied by reti-
nal detachment. Ultrasonographic findings can usually
clearly differentiate choroidal metastases from choroidal
melanomas.
Treatment
Brachytherapy
Plaque therapy is a standard treatment method using the
same radionuclides as for uveal melanomas. Candidates for
this type of irradiation are patients with a solitary lesion and
a mean diameter of the pathologic lesion not exceeding
8–10 mm.
Fig. 62.14 Control MRI 2 years after radiosurgery documents tumor
regression
Stereotactic Radiotherapy
This treatment modality applies higher radiation doses using
a fractionation scheme but, at present, there is still a lack of
information about its use in clinical practice.
Radiosurgery
Radiosurgery may extend treatment options for uveal
metastases because of its specific advantages: (1) the pos-
sibility of applying a high radiation dose and (2) evidence
of its sparing effect on the surrounding critical structures.
The recommended minimal doses are similar to those for
brain metastases, ranging between 20 and 30 Gy, and depend
on the tumor volume, location, and histology (Figs. 62.13
and 62.14).
Additional study of the efficacy and complications of this
technique compared with external beam radiotherapy is indi-
cated as the role of this method still remains open.

Radiotherapy
External beam fractionated radiotherapy represents the local
effective treatment with a low rate of late complications.
The recommended total dose is 30–40 Gy with 2–3 Gy per
fraction per day [38].
Prognosis
The diagnosis of ocular metastases generally carries a poor
prognosis with a median survival period of 9 months, with
the literature reporting a range of 4–13 months.
758
Ocular and Orbital Malignant Lymphomas
and Leukemia Infiltrates
This special group is represented by orbital malignant lym-
phomas and leukemia pathologic infiltrates. These types of
malignancies are typically radiosensitive and chemosensi-
tive. The tumor lethal doses ranged from 30 to 40 Gy, with
2 Gy per fraction per day, and external beam radiotherapy is
highly effective with a low incidence of radiation-related
toxicity caused by the fact that the effective tumor dose is
lower than the tolerance doses for critical structures [39]. At
present, there is no real indication for using radiosurgery in
these types of radiosensitive malignancies, and the question
of its use in persistent or recurring pathologic lesions after
previous radiotherapy and chemotherapy is still open.
Vascular Lesions
Cavernous hemangioma of the orbit typically occurs within
the muscle cone and can cause proptosis, optic nerve compres-
sion, and corneal exposure. Asymptomatic orbital cavernous
hemangiomas can be followed by serial ophthalmic examina-
tion and radiographic imaging. When symptomatic, most
orbital cavernous hemangiomas can be removed by surgical
excision. However, when cavernous hemangioma extends into
the orbital apex, or cavernous sinus, superior orbital fissure, is
within bone, or is nonresectable, these tumors pose diagnostic
as well as therapeutic challenges for removal.
Khan and Lunsford reported eight symptomatic patients
with cavernous sinus or orbital hemangiomas underwent
SRS. The median target volume was 6.8 mL (range, 2.5–
18 mL). The median prescription dose delivered to the mar-
gin was 14.5 Gy (range, 12.5–19 Gy). The dose to the optic
nerve in all patients was less than 9 Gy (range, 4.5–9 Gy).
The median follow-up period after SRS was 80 months (40–
127 months). Six patients had symptomatic improvement;
two patients reported persistent diplopia. Follow-up imaging
revealed tumor regression in seven patients and no change in
tumor volume in one patient. All the patients improved after
SRS [40]. Rootman et al. reported on the use of fractionated
stereotactic radiotherapy (SFRT) for the treatment of surgi-
cally complicated cavernous malformations. A total dose of
4,000 cGy divided into 20,200 cGy fractions was applied for
three cases, while two other cases were treated with total
doses of 4,563 and 4,959 cGy divided into 28 × 162 cGy and
29 × 171 cGy fractions, respectively. Rapid resolution of
visual field defect was noted by 3 months, and overall tumor
shrinkage was on average 60 % (range, 32–79). Follow-up
was on average 23.4 months (range, 5–50). No complica-
tions of treatment were noted [41].
Y.M. Li et al.
For adult orbital and intraocular vascular tumors, including
retinal capillary hemangioma, choroidal hemangioma, radio-
therapy is particularly effective and typically given to older
patients for localized disease. Due to the limited penetration
and low dose required to treat many of these tumors, elec-
tron-based EBRT can be employed. Kim reported gamma
knife radiosurgery for seven symptomatic patients with cho-
roidal hemangioma (circumscribed form in three patients
and diffuse form in four). All patients presented with exuda-
tive retinal detachment (RD) involving the macula that
resulted in severe visual deterioration. The prescription dose
to the target margin was 10 Gy in all cases. The mean tumor
volume was 536 mm3 (range, 151–1,057) and mean follow-
up of 34.4 months (range, 9–76). The resolution of exudative
RD was achieved within 6 months, and the visual acuity of
the affected eye had improved at the latest follow-up exami-
nation (p = 0.018) in all patients. No recurrence of exudative
RD occurred. Thinning of the hemangioma was observed in
most patients. Symptomatic radiation toxicity had not devel-
oped in any of the patients [42].
Infantile hemangiomas can occur in the eyelids and orbit
and cover the visual axis, deviate the eye, and induce ambly-
opia. When posterior to the eye, these tumors can also pro-
duce proptosis, corneal exposure, and optic nerve
compression. Though capillary hemangiomas are very radio-
sensitive, mean dose 4.5 Gy (5–7.5 Gy), those not causing
optic nerve compression, amblyopia, or strabismus should
be watched for spontaneous regression over 3–4 years or
treated with intralesional or oral steroids, interferon, vincris-
tine, and propranolol. Due to concerns about secondary car-
cinogenesis and long-term effects of ocular irradiation,
radiotherapy for infantile hemangiomas should be consid-
ered a last resort. It could be used as a potentially life-saving
method when airway obstruction is involved or when other
treatments are not possible or have failed [43].
Age-Related Macular Degeneration
Pathophysiology
Age-related macular degeneration (ARMD) is characterized
by degeneration in the retinal layers accompanied by forma-
tion of subfoveal neovascular membrane that compromises
vision. The growth factors such as vascular endothelial
growth factor plays a fundamental role in age-related macu-
lar degeneration, and these growth factors are produced by
inflammatory cells and hypoxic or ischemic retinal tissues,
including the neurosensory layer and the retinal pigmented
epithelium. This pathologic process induces scarring and
destroys the macular retina, causing severe visual changes
and visual loss in people over 50 years of age [44].
62 Ocular and Orbital Lesions
Diagnosis
A complete ophthalmologic examination, including fluorescein
angiography, is needed to diagnose age-related macular
degeneration. The membrane mass can be diagnosed using
postcontrast T1-weighted MRI.
Treatment Methods
Radiotherapy
The aim of radiotherapy (as for radiosurgery) seems to be (1)
to control growth-factor formation and (2) to alter the degen-
erative process. The persistence of hypoxic stimuli that
upregulate growth factors may explain why the membrane
regrows and disease recurs. ARMD is a degenerative process
with proliferative component, and irradiation can play an
anti-proliferative role. The experience from radiotherapy
showed that neovascular membranes are composed of endo-
thelial cells with proliferation more rapidly than the endothe-
lial cells of the retina and may be more sensitive than the
retinal vasculature [44, 45]. Radiotherapy uses the fraction-
ation scheme and recommended doses ranged from 14 to
20 Gy in 8–10 daily fractions. The experience of radiotherapy
shows that this modality can affect active subretinal neovas-
cularization but is unlikely to prevent new neovascularization
lesions being produced by this chronic disease.
Proton Beam Therapy
The proton beam therapy was reported as local effective
treatment, and the recommended minimal dose is 14 Gy in a
single session [45].
Photocoagulation
The management of choroidal subuveal neovascularization
is still controversial and difficult. Laser photocoagulation,
which is indicated for patients with uveal membrane that
adjoins but does not involve the macula, can control the
evolving membrane. The strict criteria of the Macular
Photocoagulation Study for patient selection shows that only
10 % of patients are eligible for this type of treatment [46].
Other Methods
The pilot studies of surgical excision of membrane and the
use of anti-angiogenic agents to prevent new vessel forma-
tions have not been successful.
Radiosurgery
Initial results from patients treated by Leksell Gamma Knife
for ARMD showed that radiosurgery is able to affect tissues
beneath the retina (neovascular membrane in ARMD) with-
out damaging the overlying retinal structures. Haas in his
pilot study had investigated the effect of single-fraction
(10 Gy at the 90 % isodose) Gamma Knife surgery in patients
759
with classic subfoveal neovascular membrane due to ARMD
[47]. The regression was observed in one of ten patients.
Henderson et al. reported seven patients with ARMD were
treated with gamma knife radiosurgery. The median duration
of follow-up was 2.2 years. Treatment was delivered in a
single shot of 12 Gy. The majority of patients maintained
stable visual acuity after treatment [48].
In our study, we treated 11 patients with neovascular
membrane (NM) in ARMD with a dose of 15 Gy at a 50 %
isodose in a single fraction. Both ultrasonography and fluo-
rescein angiography demonstrated a regression of the neo-
vascular complex or its stabilization in 90 % of patients. An
enlargement of the NM was found in one patient.
The patients have to undergo the same procedure as in
treatment of uveal melanomas. The planning treatment vol-
ume includes the postcontrast enhanced lesion (neovascular-
ization membrane) on a three-dimensional T1-weighted
sequence. The effective minimal dose based on personal expe-
rience is 15 Gy, generally applied on a 50 % isodose curve,
and the use of 8- or 4-mm collimators is recommended to
decrease the doses to the critical structures, especially to the
disk of the optic nerve. The adequate dose to the optic nerve in
patients with useful visual function has not to exceed 10 Gy.
Eye structures other than the retina received doses lower than
10 Gy. Figure 62.15 documents the neovascular membrane on
postcontrast T1-weighted MRI and 15 Gy and 10 Gy isodose
curves. Regression of neovascular membrane after radiosur-
gery (typically late effect) is observed after median time rang-
ing from 9 to 24 months after radiosurgery (Fig. 62.16),
pretreatment angiography, and ultrasonography and Fig. 62.17
documents regression 12 months after radiosurgery). The
application of a stereotactically guided single-dose irradiation
is another promising treatment modality.
Follow-Up
Careful follow-up is necessary to integrate into the treat-
ment, and the intervals at which this takes place depends on
estimates as to when local effect—responses and recurrences
of diseases or radiation-related toxicity—might occur. A rea-
sonably careful follow-up schedule might be every 3 months
for the first year after treatment and then every 6 or 12
months for up to 5 years. Radiosurgery could play a signifi-
cant role in very advanced forms of neovascular membranes,
which are not treatable using other procedures. On this basis,
we have constructed a new prospective, nonrandomized
study, which is now under way.
The definitive analysis of results and complications in
age-related macular degeneration after radiosurgery still has
not been completed, and further investigation is warranted.
Additional study of the efficacy and complications of this
technique in comparison with external beam radiotherapy is
indicated, and the role of this method still remains open.
760 Y.M. Li et al.

Fig. 62.15 (a–c) The treatment planning of age-related macular degeneration with 15 and 10 Gy isodose curves

Fig. 62.16 (a, b) Pretreatment angiography and (c) ultrasonography of age-related macular degeneration

Fig. 62.17 (a, b) Control angiography of ARMD and (c) ultrasonography 12 months after radiosurgery

with glaucoma become uni- or bilaterally blind [7, 49].

Glaucoma
Pathophysiology
Glaucoma is a chronic, slowly progressive, usually bilateral
neuropathy of the optic nerve. Untreated glaucoma eventu-
ally leads to complete loss of vision. About 10 % of patients
We currently understand the pathophysiology of glaucoma
to be a progressive loss of ganglion cells resulting in visual
field damage related to the intraocular pressure. Although
many clinicians now feel that there are several factors
involved in the pathogenesis of glaucoma, the only rigor-
ously proven treatment method is the lowering of intraocular
pressure.
62 Ocular and Orbital Lesions
Fig. 62.18 The whole ciliary body irradiated with minimal dose 15 Gy on a 50 % isodose curve shown on (a) axial, (b) coronal, and (c) sagittal
images
Treatment Methods
Conventional Treatment
The conventional antiglaucomatous treatment—local and
systemic pharmacotherapy, laser and cryotherapy, and inci-
sional surgery—sometimes fails, and progressive optic nerve
head neuropathy is manifested. Then we face a difficult situ-
ation of advanced and sometimes painful glaucoma with
major defects in visual functions and, in the final stages of
the disease, enucleation of the painful blind eye must be con-
sidered. Therefore, a new effective method of treatment has
to be sought.
Radiosurgery
During radiosurgical treatment of patients with uveal mela-
nomas localized near the ciliary body, in the past years at our
center we observed that the radiation exerted a positive influ-
ence on painful secondary glaucoma with decrease of intra-
ocular pressure [7]. The influence on pain is well-known
from radiotherapy of degenerative and proliferative benign
processes. The mechanism of this effect has still not been
fully explained. The ciliary body, as the source of intraocular
aqueous production, had been simultaneously irradiated
using four 8-mm collimators with median of minimal dose
15 Gy on a 50 % isodose curve (Fig. 62.18). The dose to
cornea should not exceed 7–8 Gy, and in some cases the use
of plugging can help to decrease the dose to this structure.
The ciliary body as a target volume is located near the
anterior to equator, and the doses for cornea, lens, and ante-
rior chamber are higher than to the optic nerve and retina.
A typical acute, transient reaction is lacrimation with inci-
dence of 30 %. The transient erythema on eyelid was
observed after a single dose of 7 Gy and higher. Late-toxicity
changes grade 1 or 2 of cornea was observed after Dmax
10 Gy. The worsening of lens opacity (grades 3 or 4) was
recorded after the maximum dose to this structure higher
than 10 Gy. The disappearance of pain after radiosurgery
761
was observed in 77 % with secondary glaucoma, and in all
these patients no medication (analgesics) was required. The
median period of the analgesic effect was 6 weeks (range,
2–32 weeks). In secondary glaucoma, the median of intra-
ocular pressure (IOP) was 51.3 mmHg (range, 23–68 mmHg)
but the median of IOP fell to 27 mmHg (range, 8–48 mmHg)
after radiosurgery. In primary open angle glaucoma, the less
raised IOP also fell from a median of 25.3 mmHg (range,
17–35 mmHg) to 16.1 mmHg (range, 12–28 mmHg) after
radiosurgery [7].
Patients with advanced glaucoma (after standard treat-
ment) have been included into a prospective, nonrandomized
trial, and future investigation and analysis of results and
complications is warranted. The risk of radiation in benign
diseases must be balanced against the risk of alternative
treatments, which are not negligible.
Side Effects and Complications
The tolerance of normal tissues is in general the limiting fac-
tor for the dose that can be given to target volume. Radiation
therapy is associated with a broad spectrum of normal-tissue
reactions, and no reporting of outcome of radiotherapy or
radiosurgery is satisfactory without a thorough description of
the treatment-related toxicity.
Radiation toxicity is relatively well-known from external
beam fractionated radiotherapy, and the most common com-
plication is primarily due to radiation vasculopathy.
Neovascular glaucoma has been described as the most seri-
ous problem after external beam radiotherapy and radiosur-
gery [50]. The development of severe radiation-induced
toxicity for the various eye critical structures is complicated
by other factors (such as hypertension, diabetes), the local
effects of pathologic process, the segment of the eye involved,
the size and location of the tumor, the type of radiation, and
the technique used.
762
Complications related to radiation therapy can be acute or
chronic. Chronic changes are delayed in onset and may not
improve. Acute reactions are rapid in onset and typically
reversible. For example, acute radiation blepharoconjuncti-
vitis is commonly seen after EBRT. There are also two other
types of complications defined: any radiation-related mor-
bidity that occurs within the first 90 days after the end of
treatment is usually regarded as early and all other complica-
tions as late. The clinical course of the two types of reactions
is different, early reactions tending to be transient whereas
late reactions are often irreversible. Biologically, it has been
established that higher grades of reactions are on average
seen at later times than lower grades and that increased treat-
ment toxicity may considerably shorten the latent period
[54, 55]. Many schemas have been devised for recording the
late effects of radiotherapy treatments including the Radiation
Therapy Oncology Group (RTOG) and LENT SOMA scales
widely used in clinical practice. The tables for scoring ocular
toxicity are documented in Table 62.4 [51].
The most common late toxicity for all types of irradiation
is retinopathy, cataracts, secondary glaucoma, and optic neu-
ropathy [4, 20, 27, 29, 50, 51]. The presence of iris rubeosis
can be chosen as a marker of severe ocular damage, and
many authors have reported that secondary neovascular glau-
coma is the most common cause of the toxicity-related enu-
cleation [50]. Every new treatment method needs detailed
and qualified radiation morbidity scoring. The initial steps
identify the tolerance doses for critical structures and the
effective doses for the target volume. In an analysis of late
toxicity (126 patients), we recorded the following results:
significantly lower toxicity in the optic nerve was observed
when the maximum dose was less than 10 Gy (incidence of
grades 3 or 4 only in 2.4 %), in the cornea when maximum
dose did not exceed 10 Gy (incidence of toxicity grades 3 or
4 in 3 %), in the lens when the maximum dose did not exceed
7 Gy (incidence of toxicity grades 3 or 4 in 7.7 %), and in the
iris when the maximum dose did not exceed 15 Gy (inci-
dence of grades 3 or 4 late toxicity in 4.6 %).
Detection of risk factors can improve treatment results
and decrease the adverse effects, and an appropriate length
of follow-up is needed for patients after radiosurgery (a min-
imum of 2 years, preferably 5 years) because the hazard of
late toxicity is increased with the follow-up time. An accept-
ably low incidence of late radiation-related complications for
cornea, iris, and optic nerve is observed when the maximum
dose to these structures does not exceed 10 Gy. The most
frequent and severe radiation-related side effect was secondary
radiation-related retinopathy, secondary neovascular glau-
coma, and optic neuropathy. Severe grades 3 or 4 retinopathy
was noticed in 15 % of treated patients, radiation-related late
toxicity grades 3 or 4 in lens was observed in 26 %, optic
neuropathy in 9 %, and secondary glaucoma in 18 % of cases,
Y.M. Li et al.
and 11 % patients were enucleated for this reason during the
first 2 years after radiosurgery. The median time to occur-
rence of secondary neovascular glaucoma was 18 months
and so a higher incidence of enucleation during a longer
follow-up could be expected. In our series, we did not
observe any significant influence of the minimum dose and
tumor location, but a significantly lower incidence of sec-
ondary glaucoma was noticed when the volume planning
target volume (PTV) of the peripheral (prescribed) isodose
was less than 1,000 mm3 with an incidence of 6.9 %.
The worsening of useful vision caused by radiation-
related toxicity during 3 years after radiosurgery was
observed in 35 % of patients and was due to tumor progres-
sion in 3 %, optic nerve neuropathy in 8 %, retinopathy in
9 %, and neovascular glaucoma in 14 %.
There exists a difference in the area of severe complica-
tions and it is based on the radiation damage of different eye
tissues. The most acceptable are complications concerning
the lens because ophthalmologists can treat them more eas-
ily. The main problems in the eye bulb are complications of
the iris, cornea, and optic nerve. The optic nerve tolerance is
well defined from other radiosurgery procedures especially
from the irradiation of pituitary adenomas, meningiomas,
and craniopharyngiomas. The tolerance dose of the optic
nerve ranged from 8 to 10 Gy and the same doses are well
tolerated by other critical ocular structures with an incidence
of late complications not higher than 5 % [4].
Late radiation responses occur after latent periods of 3
months and many years [4, 50]. An extended follow-up
period is therefore required in order to obtain a reliable esti-
mate of the incidence of late complications. Care must be
taken when evaluating late effects in a group of patients with
short life expectancy or a short follow-up, who may not be at
risk long enough to develop any late complications of inter-
est. The majority of side effects are recorded 9–36 months
after radiosurgery and radiotherapy and, for example, the
latent period between irradiation and development of cata-
ract is about 4 years, depending on the dose to this structure,
and the shortest observed latency is 6 months.
Conclusion
The treatment of ocular tumors and other eye or orbital
lesions can extend conservative therapeutic options for these
types of diseases with vision or eye preservation. Further
clinical studies using radiosurgery in ocular disease are nec-
essary to optimize effective doses and to analyze factors
influencing the length of survival with a careful evaluation of
the side effects. The main aim of further clinical studies is to
improve local treatment effects while decreasing severe
radiation-related complications.
62 Ocular and Orbital Lesions
Case Study 62.1
Uveal melanoma in intimate contact with the disk of
optic nerve. Characteristics: The gross tumor volume
(GTV) was 951 mm3, the treatment planning volume
(50 % isodose curve) was 2,700 mm3, the tumor height
was 10 mm, and the minimal dose applied on 50 % iso-
dose curve was 40 Gy, using 1 isocenter (14-mm col-
limator) (Fig. 62.9). The maximum doses to the critical
structures: optic nerve 40 Gy, cornea 6 Gy, lens 10 Gy,
eyelid 6 Gy. The ultrasonography and control MRI 12
months after radiosurgery documented tumor regres-
sion and the development of postirradiation retinopa-
thy grade 2. No acute toxicity was observed.
Progression-free survival is 24 months after radiosur-
gery (Fig. 62.10).
Case Study 62.2
Patient with useful vision and a diagnosis of uveal
melanoma. The gross tumor volume was 480 mm3, the
tumor height was 6 mm, the planning treatment vol-
ume (57 % isodose curve) was 890 mm3, and the mini-
mal applied dose 50–57 % isodose curve was 40 Gy.
The maximal dose to critical structures: optic nerve
10 Gy, lens 7 Gy, cornea 4 Gy, eyelid 3 Gy. Pretreatment
MRI scan is shown in Fig. 62.11.
Control MRI was performed 18 months after radio-
surgery and documented the tumor regressions
(Fig. 62.12). No acute or late toxicity was recorded and
no change of vision. Progression-free survival is 30
months.
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 Ocular and Orbital: Viewpoint—
Surgery
Bryant P. Carruth, Robert H. Hill, and Thomas A. Bersani
Introduction: Surgical Considerations
for Orbital Lesions
Tumors of the orbit are fortunately rare; however, surgical
intervention including diagnostic biopsy or excision is often
necessary. A decision to proceed surgically is based on mul-
tiple factors including clinical and radiographic appearance,
anatomic location, and potential risk to important ocular and
orbital structures. Advances in radiation therapy have led to
improved outcomes in certain radiosensitive lesions; how-
ever, in a majority of these patients, a tissue diagnosis must
be established first.
An orbital biopsy can be either incisional or excisional.
Infiltrative masses frequently require incisional biopsy to
establish the exact nature of the disorder after which addi-
tional surgical or medical treatment can be instituted.
Alternatively, well-defined or cystic masses tend to be benign
and are amenable to complete excisional biopsy. Certainly,
there are exceptions to these rules, the most common being
lymphoid masses which are often well circumscribed.
Despite this, lymphoid lesions should be addressed with inci-
sional biopsy as both malignant and benign forms are treated
with either radiation if focal or chemotherapy if systemic [1].
B.P. Carruth, M.D. (*)
Department of Ophthalmology, SUNY Upstate Medical University,
3400 Vickery Rd Suite A, Syracuse, NY 13212, USA
Albany Medical Center, Albany, NY, USA
e-mail: carruth426@gmail.com
R.H. Hill, M.D.
Department of Ophthalmology, SUNY Upstate Medical University,
3400 Vickery Rd Suite A, Syracuse, NY 13212, USA
e-mail: rhhill27@gmail.com
T.A. Bersani, M.D.
Department of Ophthalmology and Otolaryngology,
SUNY Upstate Medical University, 3400 Vickery Rd Suite A,
Syracuse, NY 13212, USA
e-mail: Tombersani1@gmail.com
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_63, © Springer Science+Business Media New York 2015
63
The Surgical Approach
When considering the surgical approach to an orbital process,
several factors have to be considered including location
(anterior or deep), surgical space occupied, position relative
to the optic nerve, and goal of biopsy (incisional or exci-
sional). The anterior–posterior position of an orbital mass is
often the most important factor when considering surgical
approach. Most anterior lesions can be approached by an
anterior orbitotomy via “swinging” lower eyelid or superior
lid crease incision. Deeper lesions posterior to the equator of
the globe require more advanced deep surgical approaches
often with removal and replacement of bone. These deeper
approached are often dictated by the lesion’s position relative
to the optic nerve. After considering each of these factors, the
safest approach is chosen and then consideration is also given
to incision placement in an attempt to hide scars [1–3].
Surgical Spaces of the Orbit
The surgical spaces of the orbit include the intraconal space,
the extraconal space, the extraocular muscles, the subperios-
teal space, Tenon’s space, and the extraorbital space.
The intraconal space contains the optic nerve and orbital
fat. Examples of tumors commonly found in this location
include optic nerve gliomas and optic nerve meningiomas.
The extraconal space contains the lacrimal gland, the superior
oblique muscle, and nerves and vessels that course through
the extraconal orbital fat. The lacrimal gland is a common
source of pathological processes and is accessible with ante-
rior orbitotomy through an upper lid crease incision.
The subperiosteal space is a potential space between the
periorbita and the orbital bones. A hematoma or abscess may
collect here, but it is not a common place to find a mass.
Also rarely involved in orbital pathologic processes is
Tenon’s space, which lies between the eye and the fibrous
Tenon’s capsule. Finally, the extraorbital space includes all
765
766
the structures surrounding the orbit including bone, brain,
sinuses, skin, and conjunctiva [1, 4].
Radiation Responsive Processes
Thyroid Eye Disease
Thyroid eye disease, the ophthalmic manifestation of Grave’s
disease, is the most common cause of unilateral and bilateral
exophthalmos in adults [5]. This disorder is characterized by
progressive inflammation particularly of orbital fat and extra-
ocular muscles and results in lid swelling, proptosis, lid
retraction, and restrictive strabismus. The treatment of thy-
roid eye disease is dictated by whether the patient is in the
active or chronic stage of the disease. It is during the active
phase of the disease that the ophthalmologist must monitor
the patient’s visual function as severe inflammation can cause
optic nerve compression. Many patients require medical
management during the acute phase, which often consists of
oral prednisone (80 mg/day). However, in patients where the
symptoms are progressing rapidly or when restrictive strabis-
mus predominates, external beam radiation therapy is consid-
ered with a typical dose of 2,000 rad [6]. In the most drastic
cases of active inflammation in thyroid eye disease, optic
neuropathy can be severe and surgical intervention in the
form of orbital bone and fat decompression may be required.
Lymphoid Lesions
Orbital lymphoproliferative disease usually presents as a
slowly progressive, painless mass. These occur more com-
monly in the elderly, and about 25 % of patients carry a pre-
vious diagnosis of lymphoma. The most common periocular
lymphoma, representing over 50 % of orbital lesions, is the
MALT type. These lesions most commonly present in the
superior quadrant of the orbit in the extraconal space and will
often involve the lacrimal gland.
Lymphoid lesions continue to be poorly understood; how-
ever, most periocular lymphomas are non-Hodgkin type.
After a tissue diagnosis is made, all patients with lymphoid
hyperplasia or lymphoma should undergo a systemic evalua-
tion. In the absence of systemic disease, most of these lesions
can be treated with external beam radiation with high suc-
cess rates [1, 5].
Metastatic Tumors to the Orbit
Fortunately, metastatic tumors of the orbit are uncommon.
The most common primary malignancies metastasizing to
the orbit are lung cancer in men and breast carcinoma in
women. On CT scan, metastases will appear as infiltrative
B.P. Carruth et al.
masses often extending into multiple orbital spaces. A defin-
itive diagnosis is made by incisional biopsy after which a
systemic workup is required to define the extent of the dis-
ease. If the orbit is the only site of metastasis, radiation ther-
apy may be appropriate. However, with systemic involvement,
treatment with chemotherapy is most often employed [7].
Uveal Melanoma
The pigmented, vascular layer of the eye, termed the uveal
tract, consists of the iris, ciliary body, and choroid. When
uveal melanocytes undergo malignant transformation and
proliferation, a melanoma results. Based on the location, this
may be an iris, ciliary body, or choroidal melanoma.
Melanoma is the most common primary intraocular tumor
with an incidence of 6–7 cases per million, primarily affect-
ing individuals in their 50s and 60s. Risk factors include
light complexion, smoking, oculodermal melanocytosis, and
genetic predisposition [8, 9].
Mortality data underscore the significance of this disease.
Five-year melanoma-related mortality after treatment is
10 % for small tumors, 30 % for medium, and 50 % for large
tumors. In addition to tumor size, risk factors for mortality
include: anterior location, extraocular extension, old age,
tumor regrowth and juxtapapillary location. Histologic and
molecular factors include epithelioid cells, high mitotic
index, monosomy 3, trisomy 8, and some newly identified
gene expression profiles [10–13].
In the distant past, enucleation was the only accepted treat-
ment for uveal melanoma. As eye-sparing treatment modali-
ties were developed, enucleation has become less common.
Despite these advances, enucleation as primary treatment
remains a viable option in some cases [8]. The defining crite-
ria are not without controversy, but the best prospective ran-
domized trial to date, the Cumulative Ocular Melanoma Study
(COMS), outlined those situations in which enucleation is the
best option. This study concluded that primary enucleation is
appropriate for large melanomas and that no mortality benefit
exists for presurgical external beam radiotherapy [14].
Further, secondary enucleation after failure of other therapies
leading to a blind and painful eye is often required.
There are two primary surgical options for removing an
eye: evisceration and enucleation. Evisceration is removal of
the contents of the eye leaving the sclera and extraocular
muscles intact, whereas enucleation removes the entirety of
the eye leaving only the orbital contents. For many cases of
blind and painful eyes requiring removal, the selected method
is left to surgeon and patient preference; however, the pres-
ence of an intraocular tumor such as choroidal melanoma is
an absolute contraindication to evisceration, and enucleation
is the surgical treatment of choice.
The specific steps of enucleation may vary slightly from
one surgeon to another, but the principles remain the same.
63 Ocular and Orbital: Viewpoint—Surgery
The conjunctiva and tenon’s capsule are separated from the
underlying sclera, and the extraocular muscles are removed
from the eye. The globe is brought forward so that the optic
nerve can be identified and cut. The remaining intraconal
space is then filled with an orbital implant of silicone,
hydroxyapatite, porous polyethylene, or another material. The
recti muscles are secured to the implant or donor scleral wrap-
ping and the tenon’s connective tissue and conjunctiva are
closed over the implant. A conformer is placed in the conjunc-
tival cul-de-sacs to hold their form while healing occurs, and
approximately 6 weeks later, an ocular prosthesis is molded,
crafted, and painted. Inconspicuous custom-made prostheses
are capable of providing an excellent cosmetic result [15].
Advances in treatment of melanoma in the past decades
have been abundant, and thus, enucleation is less commonly
performed [16]. Other treatment modalities include surgical
tumor excision, thermotherapy, photodynamic therapy, and
radiotherapy. The most common treatment for uveal mela-
noma is brachytherapy in which a radioactive plaque, most
commonly Iodine 125, is sutured to the sclera overlying the
base of the uveal tumor. This is accomplished with ultrasonic
guidance and posterior globe exposure similar to that
described for enucleation. The plaque is left in place to
deliver radiation for 3–7 days and then removed. Local tumor
control rates with brachytherapy have been reported as high
as 95 % [17]. Dose-dependent radiation complications, how-
ever, particularly retinopathy and neuropathy, become visu-
ally significant in up to 50 % of patients especially those with
tumors close to the optic nerve or macula [17].
Radiotherapy has been used in a specific localized man-
ner to treat uveal melanoma by means of charged particle, or
proton-beam, radiation. Only a few centers have the capacity
to perform such a procedure, but success comparable to
brachytherapy has been reported. A combined surgical
approach attaching clips to the sclera outlining the tumor is
necessary with high linear-energy homogenous dose radia-
tion then applied. Local tumor control has been reported at
98 %. Unfortunately, a higher dose of radiation is also
applied to anterior ocular structures. The resulting complica-
tions of neovascular glaucoma and visual loss have been
somewhat prohibitive [8, 18].
A second arm of the aforementioned COMS trial exam-
ined mortality in patients with medium-sized tumors under-
going brachytherapy vs. enucleation and concluded that
survival was equivalent at 82 % in 5 years. Retention of
visual function in the radiated eyes was somewhat poor with
63 % having visual acuity of 20/200 or worse at 3 years
though clearly this is better functioning than those eyes lost
to enucleation [17, 19].
Globe-sparing tumor excision with or without adjuvant
radiation has been successfully reported in cases of small to
medium melanomas. This technique, called partial lamellar
sclerouvectomy, is surgically complex and suffers from an
inability to monitor margins as well as possible damage to
767
adjacent structures [20, 21]. Transpupillary thermotherapy
has been reported to reduce tumor volume in small melano-
mas but may have an increased rate of recurrence relative to
brachytherapy. Of course, external radiation by traditional or
stereotactic means, sometimes combined with surgery, has a
role in the treatment of melanoma and will be discussed in
detail by our colleagues.
Lastly, any physician treating uveal melanoma should be
aware of the current recommendations regarding tumor sur-
veillance. A significant body of literature exists regarding the
incidence of metastatic disease with reports of 25 % at 5
years, 34 % at 10 years, and as high as 50 % at 25 years
[14, 22]. Thus, ongoing surveillance is a necessity. The cur-
rent recommendation is for screening every 6–12 months by
physical examination and liver imaging by ultrasound, CT,
MRI, or PET scan with consideration given to liver function
tests and chest X-ray [8, 16, 23].
Retinoblastoma
Retinoblastoma is a malignant tumor representing uncon-
trolled growth of neurosensory retinal elements and is the
most common malignant ocular tumor in children. Ninety
percent of cases are diagnosed before 3 years of age and
30–40 % of patients have bilateral tumors [8, 24–27].
Retinoblastoma rarely presents with visual symptoms
given the young age of those affected. Rather, the most com-
mon presentation is leukocoria followed by signs of intraoc-
ular inflammation, strabismus, hypopyon, anisocoria, and
proptosis. Extraocular extension of retinoblastoma most
commonly occurs directly via the optic nerve, but malignant
cells can also exit vascular channels or directly extend into
the orbit. In rare cases, direct intracranial extension or sys-
temic metastasis may occur [8, 28, 29].
The primary goal of retinoblastoma treatment is, of
course, preservation of life with preservation of the eye and
vision secondary. Retinoblastoma confined to the eye has a
survival rate of greater than 95 %, but the number drops to
50 % with extraocular spread. Globe-sparing treatments for
retinoblastoma include tumor resection, photocoagulation,
cryotherapy, brachytherapy, radiation, systemic chemother-
apy, and most recently, intra-arterial chemotherapy [30, 31].
While eye-saving treatments are becoming increasingly
useful particularly in cases of bilateral disease, tumor exci-
sion by means of enucleation is the definitive treatment.
Specifically, enucleation is indicated when a tumor involves
greater than 50 % of the eye, has invaded the anterior seg-
ment of the eye or has extended into the optic nerve or orbit.
As described above, enucleation is removal of the entire eye
and contiguous optic nerve with preservation of the extraoc-
ular muscles and other orbital soft tissues. Removal of a long
segment of optic nerve, typically greater than 10 mm, is pref-
erable to be sure of a negative margin [30–33].
768
Small, well-circumscribed tumors may sometimes be
treated conservatively with laser photocoagulation, thermal
therapy, or cryotherapy. These techniques are frequently
augmented by chemotherapy and/or radiation [8].
The early onset and rapid growth of retinoblastoma make
this tumor responsive to radiation with globe salvage rates
reported up to 86 %. The use of EBRT is limited by concerns
regarding secondary malignancies, as well as radiation-
induced side effects including facial hypoplasia, cataract for-
mation, optic neuropathy and retinopathy. The role of EBRT
may be linked to chemoreduction and adjuvant use of photo-
coagulation or cryotherapy [34, 35].
The risk of secondary malignancies may be avoided by
the use of localized radiation with plaque brachytherapy. The
surgeon attaches a plate containing radioactive material, typ-
ically iodine 125 or ruthenium 106, onto the sclera overlying
the tumor. The plaque is sutured under ultrasound guidance
to ensure accurate placement and then removed 3–7 days
later. Brachytherapy results in persistent tumor regression in
up to 87 % of cases [36, 37].
When the tumor is small or bilateral, primary or chemore-
ductive chemotherapy is often used. Tumor shrinkage by
chemotherapeutic means may allow for subsequent treat-
ment with focal laser, cryotherapy, or radiation. In addition
to systemic administration, periocular chemotherapy with
subconjunctival carboplatin has proven to be an effective
adjuvant therapy. With these methods of chemoreduction,
control of less advanced cases nears 90 % [38, 39].
Administration of low-dose melphalan chemotherapy to the
ophthalmic artery under radiologic guidance has recently
gained favor. The utility of this technique lies in the theoretical
ability to cure disease and spare the eye and vision while reduc-
ing systemic side effects and toxicity. Some studies have shown
encouraging success, but the jury is still out. Failure and long-
term recurrence with these regimens is not uncommon and sur-
gical tumor control by enucleation remains important [39, 40].
Vision-sparing and globe-preserving therapies show
increasing promise in the treatment of retinoblastoma and
further advances continue to be made. Absolute tumor con-
trol however remains achievable only through enucleation.
Complicated cases, as well as advanced tumors, are often
best treated with removal of the eye in order to achieve the
main goal of any cancer treatment, preservation of life.
Age-Related Macular Degeneration
Age-related macular degeneration (ARMD) is the most
common cause of significant visual loss in the elderly popu-
lation, estimated to affect 19.7 % of people over age 75.
ARMD causes degeneration of the macula, the area of neu-
rosensory retina responsible for central visual acuity. This
occurs by the deposition of waste products and deterioration
B.P. Carruth et al.
of supporting cells. Significant visual loss occurs when
atrophy becomes extensive or when the damage leads to
ischemia and neovascularization under the retina. This
causes subretinal bleeding, edema, and scarring with sig-
nificant consequences for vision [9, 41].
Medical therapy for atrophic ARMD consists of vitamin
supplementation to reduce the likelihood of progression to
neovascular ARMD. Antioxidant vitamins have been shown
to reduce the risk of progression to neovascular ARMD by
25 % in patients with intermediate or advanced atrophic
ARMD [42, 43]. Otherwise, treatment of atrophic macular
degeneration is focused on patient education and regular
screening for neovascular disease.
Some studies have reported surgical techniques for non-
neovascular ARMD. A technique has been described,
whereby choroidal tissue, retinal pigment epithelium, and
Bruchs membrane are transplanted from the healthy periph-
ery of the eye to the diseased macula. Despite the theoretical
promise, this has been performed only rarely and results are
thus far underwhelming [44].
Treatments for neovascular ARMD may not be consid-
ered strictly surgical, but their promise bears noting in this
space. Until recently, treatment of ARMD with laser photo-
coagulation was the standard of care. Use of an argon laser to
thermally coagulate a choroidal neovascular membrane was
found to be beneficial in stabilizing vision though the num-
ber of patients retaining good visual acuity was still low [45].
Photodynamic therapy (PDT) is the systemic administra-
tion of a photosensitizing drug followed by application of
light to affected tissues inducing reactive oxygen species and
leading to destruction of new vessels. PDT resulted in 21 %
of eyes progressing to severe visual loss compared with 48 %
of placebo-controlled eyes [46, 47].
While important historically, these modes of treatment
have largely been replaced by antiangiogenesis in the form
of anti-vascular endothelial growth factor (VEGF) com-
pounds. VEGF is a growth factor specific to vascular endo-
thelial cells that can induce angiogenesis, vascular
permeability, and lymphangiogenesis and plays a key role in
the development of choroidal neovascularization. Antibodies
against VEGF are delivered by intravitreal injection and
have revolutionized treatment of neovascular ARMD, not
just slowing visual loss but actually improving visual acuity.
Major trials have demonstrated the effectiveness of ranibi-
zumab, a recombinant antibody fragment directed against
VEGF. These studies showed an astonishing rate of vision
improvement of 40 % and stabilization of 95 % in the first
year with 80 % of patients having stable or improved vision
at 24 months. Bevacizumab, a full-length monoclonal anti-
body against VEGF used off-label for ARMD, has recently
demonstrated equally impressive efficacy [48–51]. Based on
these data, anti-VEGF therapy has become the standard of
care for neovascular ARMD.
63 Ocular and Orbital: Viewpoint—Surgery
Surgical therapy for ARMD had been an area of active
research until the advent of antiangiogenic pharmacologics.
Macular translocation was discussed above and had been
used in neovascular disease with similar limited efficacy
[44]. Techniques for submacular surgical removal of hemor-
rhage and CNV membranes have also been described though
a systematic review of the literature reported no benefit [52].
Delivery of anti-VEGF medications carries risks of endo-
phthalmitis and retinal detachment as well as suffering from
the need for repeated injections. Because of this, methods are
being developed for subretinal drug delivery. These surgical
techniques are in their infancy but may herald a new future
for ARMD treatment. There has also been some interest in
stem cell transplantation in eyes damaged by ARMD though
this work remains in the early stages [53].
Low vision aids located outside the eye for patients with
ARMD have been of benefit for many. Recently, however,
miniature telescopes and mirrored lenses have been devel-
oped for intraocular implantation. These fill a small niche at
this time but may become more widely beneficial in the
future [54].
Glaucoma
Glaucoma is a term used to describe a group of diseases with
the common characteristic of optic neuropathy and associated
visual field loss for which elevated intraocular pressure is a
primary risk factor. The World Health Organization (WHO)
estimated from data collected in the 1980s and 1990s that the
incidence of primary open angle glaucoma was 2.4 million
people per year and that the prevalence of blindness for all
types of glaucoma was more than 8 million people [55].
The mainstay treatments for glaucoma include local and
systemic pharmacotherapy and incisional surgery. In resis-
tant types of glaucoma, ciliary body ablation procedures
including cyclocryotherapy and thermal lasers such as
continuous-wave Nd:YAG, argon, and diode can be used to
inhibit the secretory activity of the ciliary body epithelium.
There is one report on the use of gamma knife radiation for
the treatment of refractory glaucoma showing its ability to
decrease pain and intraocular pressure [56]. To the best of
our knowledge, radiation therapy is not routinely utilized for
the treatment of glaucoma, and for reduction of discomfort
in essentially blind eyes, cyclophotocoagulation has equal if
not better results as well as being more cost effective
[57, 58]. Cyclophotocoagulation also avoids the potential
secondary risks of radiation.
Finally, in end-stage glaucoma, the eye may become blind
and painful. The authors who support the use of gamma
knife radiation for the treatment of glaucoma advocate one
of its uses as a means to avoid evisceration or enucleation.
While this certainly is the goal of any ophthalmologist, often
769
a chronically blind eye can become physical and cosmeti-
cally displeasing. With advances in anophthalmic surgery
and ocularistry, these procedures have been made relatively
simple, and they give an improved cosmetic result with con-
sequent improvement in self-esteem and happiness.
In summary, glaucoma is a chronic and progressive optic
neuropathy that can in some cases be very difficult to treat.
There are different modalities available for the treatment of
refractory glaucoma including gamma knife radiation. We, as
ophthalmologists, support cyclophotocoagulation as it histori-
cally has good success rates and avoids the potential risks of
radiation treatment. For eyes that are blind and painful, evis-
ceration and enucleation procedures offer a surgical alterna-
tive that often leads to improved cosmesis and quality of life.
The Surgeon’s Application of Stereotactic
Radiosurgery in the Orbit
The central tenet of orbital surgery is amelioration of disease
with preservation of health and function. This task is made
challenging by the complex anatomy of the orbit which
includes many vital neurologic, vascular, and muscular
structures. Some entities like cavernous hemangioma lend
themselves to careful but complete excision. Others like
lymphoproliferative disease require biopsy for tissue diagno-
sis but can be well treated with external beam radiation.
Medicine being the humbling practice it is, however, not
every pathological process, is so straightforward. Many dis-
eases and tumors involve or invest themselves with integral
structures making surgery difficult. Further, many of these
entities respond only to techniques and dosages of radiation
that can cause significant morbidity. In these instances, a
more nuanced approach involving subtotal surgical excision
combined with specific, localized radiation delivered by a
team of orbital surgeons, neurosurgeons, and radiation
oncologists is emerging as an encouraging alternative to
traditional therapies.
The location of an orbital tumor determines the level of
caution a surgeon must have for two reasons. The first is ease
of access. Masses located in the anterior orbit, particularly the
lacrimal fossa and lateral and inferior extraconal spaces can
be approached without excessive manipulation of surround-
ing structures. Those in the medial and superior orbits and,
even more importantly, in the posterior orbit and orbital apex
pose a greater challenge. Access to these locations requires
significant manipulation of orbital structures such as the
globe, the major vessels, and the optic nerve. Further, some
lesions involve not just the orbital apex but adjacent struc-
tures like the optic canal, superior orbital fissure, and cavern-
ous sinus. Clearly, aggressive surgical exploration in these
locations involves significant risk and is undertaken only
when radical control is necessary to preserve life or other
770
vital functions accepting that ocular motility and/or vision
may be sacrificed. As an example, Rootman et al. reported
successful treatment of cavernous hemangiomas located at
the orbital apex with stereotactic fractionated radiotherapy
[59]. This is a typically benign lesion lending itself to com-
plete excision, but when the apex and superior orbital fissures
are involved, surgical risk increases significantly.
The second reason tumor location may give a surgeon
pause relates to the tissue of origin. Some lesions may be
sacrificed without consequence; however, processes origi-
nating from the optic nerve or the meninges do not easily
lend themselves to physical manipulation. Because the focal
nature of radiosurgery may have effects on blood supply to,
and function of, the optic nerve similar to mechanical sur-
gery, fractionated radiotherapy likely remains the treatment
of choice for optic nerve sheath meningiomas as elegantly
demonstrated by Bloch et al. Their review found excellent
tumor control and good vision preservation with the use of
conformal fractionated radiotherapy [60].
Further, some tumors located outside the orbital apex may
invest themselves with other integral structures or their
unique pathologic composition may not be amenable to sur-
gical excision. In these cases, like a paraganglioma presented
by Kim and Lee, radiosurgery may augment intentional
incomplete excision [61].
Because the orbit is contiguous with the CNS via the optic
canal and orbital fissures, many orbital apex tumors share
pathology with intracranial tumors. The application of ste-
reotactic radiosurgery on these primary CNS processes is
adequately covered elsewhere in this text and the same logic
applies when the orbit is invaded by these tumors. Kim et al.
recently reported on the success of Gamma knife radiosur-
gery for orbital tumors. They reported tumor control in 12 of
15 patients with preservation of vision in 13 of 15 [62].
CyberKnife radiosurgery has also been evaluated in orbital
tumors with Hirschbein et al. reporting encouraging results
in 16 patients with good tumor control, vision preservation,
and pain relief [63].
Just as orbital tumors may invade or affect the central ner-
vous system, CNS tumors can invade the orbit. Even lesions
not located in the orbit can affect the ocular apparatus includ-
ing the optic canal and chiasm. The strongest evidence sup-
porting use of stereotactic radiosurgery for lesions abutting
the visual pathways comes from Adler et al. These authors
reported remarkable success using CyberKnife multisession
radiosurgery to treat perioptic tumors with tumor stability or
regression as well as visual field preservation in 94 % of
patients with mean follow-up of 49 months [64].
Another limitation of surgical intervention for orbital
tumors is multifocal or bilateral disease. Specifically, orbital
metastases may occur in multiple locations and/or bilaterally
and therefore risks of surgery may outweigh the palliative
benefit of tumor removal. In these cases, palliation with
B.P. Carruth et al.
stereotactic radiotherapy may be of benefit. Such a case
was recently presented by Kim et al. in which bilateral meta-
static breast cancer was successfully treated with palliative
SRT [65].
As discussed above, some tumors simply cannot be com-
pletely excised from the orbit. Lymphoproliferative disease
is just such an entity. Thankfully, these tumors are highly
radiosensitive using traditional fractionated radiotherapy.
These too, however, have been treated with radiosurgery
with benefits including lower incidence of dry eyes and cata-
racts owing to the focal delivery of collimated radiation as
well as improved patient comfort with 5-day frameless sur-
gery. In addition, lymphoid lesions are frequently ill-defined
or irregularly shaped, and therefore the computer-generated
treatment mapping and contouring possible with radiosur-
gery is particularly beneficial [66].
Complications of orbital radiation include dry eyes, cata-
ract formation, retinopathy, optic neuropathy, and diplopia. It
is important to keep in mind that these untoward effects of
radiation on the optic apparatus, specifically neuropathy and
retinopathy, are often late sequelae, and therefore the long-
term effects of these treatment modalities remain to be fully
elucidated.
For tumors or processes located at the orbital apex and
those emanating from or involving critical structures, radia-
tion and radiosurgery may be the best therapeutic options. In
some cases such as sphenoid wing meningiomas, a com-
bined approach can be taken where the surgeon excises as
much tumor as can be safely removed and the remainder is
specifically targeted with stereotactic radiation.
Intricate anatomy and complex pathology demand a
unique therapeutic approach. For those patients and diseases
whose management is not clear-cut or simple, an individual-
ized treatment plan involving multiple specialists with surgi-
cal, medical, and radiotherapeutic expertise is invaluable.
The progress and development of the field of stereotactic
radiosurgery has only just begun to potentiate the benefits of
traditional surgery, and we hope that the future is bright for
further collaboration.
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 Ocular and Orbital Tumors: Viewpoint-
Fractionated Radiation
Nicolas Girard, Françoise Mornex, and Alain Vighetto
Fractionated radiotherapy is a standard treatment of ocular
and orbital tumors, including optic nerve sheath meningioma
(ONSM). ONSM is a rare benign tumor that derivates from
the arachnoid tissue. ONSM represents only 1 % of all
meningiomas while accounting for up to 15 % of intraorbital
tumors [1]. ONSM originating from the intraorbital or the
intracanalicular portion of the optic nerve is referred to as
primary ONSM; secondary ONSM originates from the
medial cerebral fossa and spreads to the optic nerve through-
out the optic canal [1]. While the World Health Organization
distinguishes three histologic grades—grade I, benign; grade
II, atypical; and grade III/IV, malignant [2]—and three histo-
logic types, meningothelial, fibroblastic, and transitional [2],
the main challenge of the treatment is actually related to the
anatomic extent of the tumor that predicts the visual out-
come, as patients progressively develop blindness due to
optic nerve atrophy. Such evolution has also been reported
for other intraorbital tumors, such as uveal melanoma or reti-
noblastoma, as discussed in Chap. 63 of this book.
ONSM represents a model of treatment of orbital and
ocular tumors using fractionated radiotherapy, as the chal-
lenge of optic nerve preservation is amplified given the loca-
tion of the tumor. Radiotherapy has emerged as the treatment
of choice for ONSM over the last two decades [1]. While
surgical resection had been seen as a standard in earlier
reports, allowing the control of the intracranial extension of
the tumor, as well as a definite pathological diagnosis, the
high risks of functional impairment precipitating blindness
N. Girard, M.D.
Department of Respiratory Medicine Oncology, Hospices Civils
de Lyon, 28 avenue Doyen Lépine, 69677 Lyon, France
F. Mornex, M.D., Ph.D. (*)
Department of Radiation Oncology, Centre Hospitalier Lyon Sud,
Hospices Civils de Lyon, Université Claude Bernard Lyon 1,
EMR 3738, 69310 Lyon-Pierre Benite, France
e-mail: francoise.mornex@chu-lyon.fr
A. Vighetto
Neurology Service, Hospital neurologique, Université Lyon 1 et
Hospices Civils de Lyon, 59 boulevard Pinel, 69677 Bron, France
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_64, © Springer Science+Business Media New York 2015
64
secondary to optic nerve vasculature damage led to reconsider
this approach. Surgery remains the treatment of choice in
case of a mass effect requiring urgent decompression, or in
secondary ONSM with intracranial extent.
The technical improvements in radiation planning and
delivery also contributed to this paradigm switch toward
radiotherapy. In most reports, radiotherapy has been deliv-
ered using conformal or fractionated stereotactic techniques
that may control the tumor growth while preserving sensitive
structures including the optic nerve and the retina, to ulti-
mately limit the risks of visual impairment.
Here we describe the modalities, the risks, and the results
of definite radiotherapy treatment for ONSM as a model for
all orbital and ocular tumors, based on evidence available in
the literature, including our own experience. We also discuss
the possible ways to optimize radiation delivery through the
use of next-generation techniques.
Modalities of Radiotherapy
Timeframe
The appropriate timeframe to treat ONSM has to be deter-
mined taking into account the following points: first, observ-
ing a patient with the aim of starting treatment when the
patient ultimately becomes blind is inappropriate; second,
any treatment will lead to a risk of acute and late side effects
that may precipitate visual impairment; and third, a time
interval after diagnosis is of importance to assess the tumor
growth, especially in pauci-symptomatic patients. In our
practice, radiotherapy is proposed after a documented dete-
rioration of visual acuity and/or visual field or when symp-
toms become incapacitating for patient’s everyday life [3].
In our series, the median elapsed time between ONSM diag-
nosis and radiotherapy was 23 months [3].
While no prospective cohort of patients has actually been
reported, our data, as well as those from other groups, indi-
cate that patients who experienced vision improvement or
773
774
stabilization with radiotherapy tended to have been treated
earlier after diagnostic than patients who had a visual wors-
ening [3–6]. Similarly, visual acuity was better at time of
radiotherapy for patients who experienced visual improve-
ment [3–6]. A standard recommendation is to start treating
ONSM when visual acuity is below 20/40, after documented
deterioration [7, 8].
Volumes
ONSM typically grows circumferentially around the optic
nerve, between the nerve and its blood supply [9]. Treatment
planning is usually based on computed tomography scan
with the patient in the treatment on a lying down position.
The gross tumor volume (GTV) is defined as the primary
tumor mass. Delineation of GTV may benefit from integrat-
ing magnetic resonance imaging (MRI) data which have
become the gold standard for visualizing and diagnosing
intraorbital tumors [9]; gadolinium-enhanced, fat-suppressed
T1-weighted sequences are the best sequences in this setting.
In our series of 10 patients, MRI was used to define the GTV
that corresponds to the area of contrast enhancement on the
axial and coronal images, in eight cases.
Additional margins, ranging from 3 to 7 mm, are usually
added to the GTV to define the planning target volume
(PTV). Dose-volume histograms for critical organs, includ-
ing the eye, the retina, the lens, and the chiasm, are used to
establish treatment planning and beam orientation. In our
practice, the 100 % isodose line is defined as the isocenter of
the treatment plan, and the dose is prescribed at this point.
Beam-eye-view display (in case of conformal treatment) is
used to ensure optimal target volume coverage and normal
tissue sparing.
The volume of nerve to be treated is critical. Patterns of
failure are always the proximal and not the distal compo-
nent of the nerve [3–6, 10]. In the surgical series, intraocu-
lar extension was rare, and enucleation was exceptionally
required [11]. Therefore, significant components of the
retina do not need to be included, reducing the risk of retinal
deficit. Proximally the whole length of the nerve needs to
be treated. In cases of secondary meningioma with intracra-
nial extension, part of the chiasm also needs to be included
in the PTV. In this setting, the use of stereotactic techniques
facilitates the radiation delivery through easier focusing of
the beams.
Techniques
While historical studies demonstrated the radiosensitivity of
ONSM using two-dimensional treatment planning, most
series have now integrated the use of conformal radiotherapy
N. Girard et al.
(Table 64.1) [3–6, 10, 12–36]. Given the need for sparing of
normal tissue through rapid dose fall-off and conformality of
the irradiated volume to the lesion, stereotactic conditions
are preferred. As radiation is usually delivered over several
weeks (see below), the fixation of a stereotactic head ring, as
used in stereotactic radiosurgery, is not possible, as these
devices may not be left in place for a period of more than
24–48 h. Several devices that provide a relocatable coordi-
nate system have been developed. Generally, these are based
on mask and/or bite block systems.
In a series of 34 patients from Amsterdam University, the
radiotherapy technique was not a predictor for visual out-
come [6, 19]. However, this study relied primarily on visual
acuity measured by Snellen eye chart testing to assess visual
outcomes and did not utilize more sensitive measures for
visual acuity or visual fields. Type of radiotherapy did not
appear as a predictor of efficacy in other series, provided that
54Gy is delivered to the tumor [17, 20].
Doses, Constraints, and Fractionation Schemes
For ONSM, the high sensitivity of critical organs to radia-
tion, including the optic chiasm and the retina, favors radia-
tion delivery using fractionated schemes. As shown in
Table 64.1, most studies reported the use of total doses rang-
ing from 45 to 54 Gy that are delivered using a standard frac-
tionation scheme (1.8–2 Gy fractions, 5 days/week) with
high-voltage beams. Limiting the maximal dose below 50 Gy
does not appear to substantially reduce the risk of complica-
tions compared to a total dose of 50–54 Gy, and no differ-
ence in risk is observed with fractional doses lower than
2 Gy. Although higher doses have been used treating menin-
giomas by radiotherapy, there is little chance, based on the
excellent results of current protocols, that a better outcome in
terms of local control would be obtained (Table 64.1).
Besides total dose and fractionation, dosimetry has to
integrate mean eye dose and maximal eye dose received,
which are considered the most significant predictors of radi-
ation efficacy and toxicity.
Results of Radiotherapy
Endpoints
Assessing the results of radiotherapy for ONSM remains
challenging and has to include both ophthalmologic and
oncologic endpoints while taking into account the benign
nature of the tumor. Long-term follow-up is mandatory to
accurately evaluate these endpoints. We recommend that
all patients have a systematic follow-up schedule with at
least a biannual neuro-ophthalmologic examination and an
Table 64.1 Selected series reporting on fractionated radiotherapy for ONSM
Visual outcome Tumor outcome Radiation-induced toxicities
Total Dose per
dose fraction Improved Stable Worse Control Progression Re-progression
Author Year Reference n Technique (Gy) (Gy) (%) (%) (%) (%) (%) (%) Acute (%) Late (%)
Smith et al. 1981 [12] 5 2DRT 53 2 80 20 0 100 0 0 None Dry eye (20 %)
Cataract (20 %)
Kupersmith et al. 1987 [13] 4 2DRT 55 1.8 75 25 0 100 0 0 NR NR
Sarkies et al. 1987 [14] 4 2DRT 40 3.3 0 50 50 100 0 0 NR NR
Kennerdell et al. 1988 [7] 6 2DRT 55 1.8 100 0 0 100 0 0 None None
Becker et al.a 2002 [4] 42 FSRT 54 1.8 31 67 2 100 0 0 Erythema (25 %) None
Alopecia (100 %)
Turbin et al. 2002 [15] 18 3DCRT 40–55 1.4–1.8 44 NR NR 100 0 0 NR NR
Andrews t al. 2002 [16] 33 FSRT 51 1.8 42 50 8 100 0 0 NR Optic neuritis (3 %)
Pitz et al.a 2002 [17] 16 FSRT 54 1.9 40 60 0 100 0 0 Erythema (30 %) Pituitary disorder (7 %)
Alopecia (68 %)
Liu et al. 2002 [18] 5 FSRT 45–54 1.8 80 20 0 100 0 0 None None
64 Ocular and Orbital Tumors: Viewpoint-Fractionated Radiation

Saeed et al. 2003 [19] 6 FSRT 14 14 83 0 17 100 0 0 NR NR

Narayan et al. 2003 [20] 14 3DCRT 45–54 1.8–2.0 36 50 14 100 0 0 Eye pain (7 %) Dry eye (7 %)
Retinopathy (7 %)
Baumert et al. 2004 [21] 23 FSRT 43–45 1.8–2.0 70 22 8 100 0 0 Eye pain (4 %) Retinopathy (7 %)
Richards et al. 2005 [22] 4 FSRT 50–54 1.7 100 0 0 100 0 0 NR NR
Landert et al. 2005 [23] 7 FSRT 52–59 1.7–1.8 86 0 14 100 0 0 NR NR
Sitathanee et al. 2006 [24] 12 FSRT 45 1.8 33 58 9 100 0 0 None None
Litré et al. 2007 [25] 8 FSRT 50 1.8 100 0 0 100 0 0 None Vitreous hemorrhage (13 %)
Arvold et al. 2009 [10] 22 FSRT 50–58 1.8 63 32 5 100 0 1 None Retinopathy (14 %)
Milker-Zabel 2009 [26] 32 FSRT 50 1.8 38 59 3 100 0 0 NR Optic neuritis (3 %)
et al.
Smee et al. 2009 [27] 12 3DCRT 50–54 1.8–2.0 92 0 8 100 0 0 None None
Saeed et al. 2010 [6] 34 3DCRT/ 45–54 1.8 41 50 9 100 0 0 Erythema (47 %) Dry eye (15 %)
FSRT Alopecia (10 %) Cataract (9 %)
Retinopathy (9 %)
Lesser et al. 2010 [6] 11 3DCRT 54 1.8 91 9 100 0 0 NR NR
Liu et al. 2010 [28] 30 SRS 10–17 NR 36 44 20 100 0 0 None None
Kurt et al. 2010 [29] 2 SRS 10–17 3.5–6.5 100 0 0 100 0 0 None None
Metellus et al. 2011 [30] 9 3DCRT 58 1.8 78 22 0 100 0 0 NR NR
(continued)
775
Table 64.1 (continued)
776

Visual outcome Tumor outcome Radiation-induced toxicities

Total Dose per
dose fraction Improved Stable Worse Control Progression Re-progression
Author Year Reference n Technique (Gy) (Gy) (%) (%) (%) (%) (%) (%) Acute (%) Late (%)
Abouaf et al. 2011 [3] 10 2DRT/ 54 1.8–2.0 60 10 30 100 0 0 Conjunctivitis Dry eye (20 %)
3DCRT/ (10 %)
FSRT/ Alopecia (10 %) Cataract (40 %)
IMRT
Retinopathy (20 %)
Adeberg et al. 2011 [31] 19 FSRT 54 1.8 47 48 5 100 0 0 None None
Marchetti et al. 2011 [32] 21 SRS 25 5 35 65 0 100 0 0 None Optic neuritis (5 %)
Pacelli et al. 2011 [33] 5 FSRT 54 1.8 100 0 0 100 0 0 NR NR
Romanelli et al. 2011 [34] 3 SRS 20 5 100 0 0 100 0 0 None None
Solda et al. 2012 [35] 51 FSRT 50 1.5–1.7 32 58 10 None Retinopathy (10 %)
Paulsen et al. 2012 [5] 109 FSRT 54 1.8 13 75 12 96 4 NR Erythema (2 %) None
Eye pain (3 %)
Alopecia (21 %)
Most cases correspond to primary ONSM
2DRT two-dimensional radiotherapy, 3DCRT three-dimensional conformal radiotherapy, IMRT intensity-modulated radiotherapy, FSRT fractionated stereotactic radiotherapy, SRS stereotactic
radiosurgery, NR not reported
a
Overlap among patients
N. Girard et al.
64 Ocular and Orbital Tumors: Viewpoint-Fractionated Radiation
annual brain imaging. Visual acuity and visual field testing
must be performed.
As reported by other groups, our primary evaluation crite-
rion is the visual acuity at the latest available examination
after radiotherapy is compared to the baseline data [3]. When
visual acuity is stable, visual fields are a major criterion to
assess. The gain of more than two lines on Snellen chart
equivalent or the reduction of more than 3 dB of corrected
mean defect (cMD) on static perimetry is considered a sig-
nificant improvement. The loss of two lines or more on
Snellen chart or the increase of 3 dB or more of cMD on
static perimetry is considered as deterioration. Other cases
are considered as showing a stabilized function. The
Goldmann perimetry tests may also be used, with improve-
ment of more than 50 % of the score with V4 object (the
larger and more intense object) considered as an improve-
ment. Secondary criteria include the evolution of visual
symptoms and other clinical symptoms.
Visual Outcome
Our review of the literature indicates that about 60–80 % of
patients receiving radiotherapy for ONSM experience visual
improvement; 20–30 % of patients have a visual stabiliza-
tion, while 10 % experience visual impairment, in most
cases because of radiation-induced toxicities (see below;
Table 64.1). Most studies actually reported data only for
visual acuity.
In our series, median elapsed time from radiation therapy
to the best visual acuity evaluation was 17.5 months (range,
2–55 months). At best evaluation, median maximal gain of
visual acuity was 0.50 logMAR. We actually defined two
groups of patients: one was composed of patients who expe-
rienced visual acuity improvement or stabilization, and the
other was composed of patients for whom visual acuity
worsened at final endpoint. At the latest examination, visual
acuity continued to improve in six cases, remained stable at
pretreatment level in one case, and became worse in three
cases compared to the pretreatment evaluation. Visual out-
come was clearly linked with the visual state at time of radio-
therapy: in the first group, the median visual acuity was 1.3
logMAR before radiotherapy (Snellen equivalent, 20/400;
range, 20/2,000–20/40). In contrast, patients in the second
group had a median visual acuity of 0.3 logMAR (=20/40;
range, 20/28–20/50), which was significantly better than in
group 1 (p = 0.037). Regarding visual field, cMD values had
significantly improved after radiotherapy (p = 0.018). At the
best evaluation, the median visual field gain (i.e., a decrease
of the deficit) was 3.3 dB (median cMD at best = 7.6 dB). At
the latest examination, visual fields improved in six patients,
stabilized in two, and worsened in two. Overall, four patients
777
had improved both visual acuity and visual field, two patients
had only improved visual acuity, two patients had only
improved visual field, one patient had stabilized visual field
but had deteriorated visual acuity, and one patient had dete-
riorated both.
With regard to other treatment modalities, Turbin et al.
reported a series of 64 patients with ONSM treated by vari-
ous modalities [15]; of the 59 patients with vision greater
than no light perception at diagnosis, 13 patients were
observed only, 12 had surgery only including 8 complete
resection, 18 received radiation alone, and 16 had surgery—
mostly consisting of a biopsy—and radiation. Visual acuity
measurements at diagnosis among the four groups were not
different (p = 0.186). Visual acuity fell significantly for the
observed group only (p = 0.002), surgery only (p = 0.019),
and the surgery with radiation groups (p = 0.030). The
radiation-only group showed a decrease in visual acuity that
was not significant (p = 0.301) [15]. In another study, the
visual improvement with radiotherapy was estimated to be as
high as 150 % compared to a historical group of observed
patients [16].
Ophthalmologic Examination Outcome
At ophthalmologic examination, the classical signs of
ONSM, referred to as the Walsh triad, include optic atrophy
and optociliary vessel shunting [7, 9]. These signs are not
specific, as these may be found in other disorders—
inflammatory, compressive, and ischemic—that lead to optic
nerve dysfunction. After radiotherapy, shrinkage of optocili-
ary shunt vessels and resolution of optic disk swelling and
proptosis may be immediate [20, 22]. Papilledema disap-
pears, and the relative afferent pupillary defect may resolve.
Patients then do experience rapid symptomatic improve-
ment, including relief of pain or regression of proptosis, che-
mosis, or diplopia. Furthermore, ipsilateral ocular motility
improves in about 20 % of patients [3, 5].
Oncologic Outcome
In the reported literature, radiotherapy leads to tumor control
in virtually all patients (Table 64.1). This actually mostly
consists of tumor size stabilization, when radiological objec-
tive response to radiotherapy is observed in 20–30 % of
cases. In the global series reported by Turbin et al., 21
patients (33 % of the cohort) experienced radiographic pro-
gression, including four patients who were observed, seven
patients who had surgery alone, eight patients who had
biopsy and radiation, and only two patients who received
radiation alone [15].
778
Safety of Radiotherapy
Historically, the major fear with the use of radiotherapy for
the treatment of ONSM, at a time when evidence of efficacy
was limited, was the risk of acute and—of more impor-
tance—late toxicity and ultimately acceleration of visual
impairment. In irradiating orbit tumors, the main difficulty is
due to the fact that the optic nerve passes through the target
itself. Radiation-induced toxicity in patients with ONSM
treated with radiotherapy is actually hard to evaluate from
the existing literature, as (1) these data may not be reported,
(2) acute vs. late toxicities may not be differentiated, (3)
radiation-induced toxicities on the optic nerve may produce
similar symptoms as the tumor, and (4) follow-up of patient
may not be sufficiently long to capture these data.
Historical data reported the occurrence of eye necrosis in
up to 5 % of cases treated to a total dose of 54 Gy [4]. In our
experience, acute toxicity occurred in 40 % of patients but
was moderate and transient in all cases. In the reported litera-
ture, late toxicities (more than 2 years after the end of radio-
therapy) are observed in 10 % of patients and include
retinopathy, optic neuritis, but also alopecia, dry eye, and
cataracts. Overall, retinopathy represents about 30 % of late
toxicities and ranges from retinal pigment epithelium atro-
phy and minor retinal hemorrhages with macular edema to
extensive formation of epiretinal membranes, polypoidal
choroidal vasculopathy, and even peripapillary serous retinal
detachment. Photodynamic therapy may be required. With
regard to neuritis, cranial nerves, optic chiasm, and contralat-
eral optic nerve within the target are usually spared by ste-
reotactic technique. This is even better accomplished with
the use of a low fraction size: if the daily fraction size is kept
below 2 Gy with a total dose to the GTV of 50–54 Gy, the
risk of optic nerve injury is estimated to be as low as 3 % at
10 years [36]. Of note, another organ at risk is the pituitary
gland, but a minimum dose of 50 Gy to the anterior part of
the gland has been described to produce a significant risk of
an endocrinopathy [37].
A major dosimetric predictor of radiation-induced toxicity
is the median mean eye dose; in our study, this dose was
significantly lower in the group of patients experiencing
visual improvement after radiotherapy, with 6.1 Gy vs.
39.4 Gy in the group of patients experiencing deterioration
(p = 0.025) [3]. Other radiation characteristic differences did
not reach significance, including median total dose and max-
imal eye dose. Total dose to the GTV has been reported by
several authors as a predictor of toxicity, mostly in patients
treated before the conformal treatment planning era.
Additionally, radiation retinopathy tends to be associated
with more anterior lesions where higher doses are delivered
at close proximity to the retina [17, 20].
N. Girard et al.
Optimization of Radiotherapy
Given the efficacy of conformal stereotactic radiotherapy,
with high rates of visual improvement and preservation with
steadily decreasing complications, the role of new radiother-
apy techniques is not established. Intensity-modulated radio-
therapy (IMRT) consists of a real-time modeling of the
contours and the amount of photons delivered within the
radiation beam, using a programmed movement of the blades
of the collimator. This allows the administration of beams of
variable shapes during a single sequence, possibly proving to
be helpful to target tumors that are close to critical tissues.
IMRT may be useful to optimize the focalization of the bal-
listics, as reported by our group and others [3, 7].
Stereotactic radiosurgery corresponds to the administra-
tion of high daily doses of radiation (theoretically higher
than 3 Gy, but usually ranging from 10 to 17 Gy) in a low
number of fractions (1–4 on average), for a total dose equiva-
lent to 50–54 Gy using standard fractionation schemes.
Although this technique may be less toxic as it uses highly
focalized radiation beam, it has not been generally used for
ONSM because of the high toxicity to the optic nerve when
high-dose single fraction radiation is given [36, 38]. As
shown in Table 64.2, several series of patients with ONSM
treated with stereotactic radiosurgery have been reported
[28, 29, 32, 34]. Radiosurgery was delivered using various
modalities, from one fraction of 10–17 Gy to 5 fractions of
5 Gy, respectively. Collectively, visual improvement was
observed in 35 % of patients and deterioration in 20 %; these
rates are higher than that observed after fractionated stereo-
tactic radiotherapy. Similarly, tumor response rates are
higher, ranging from 40 to 60 %. No serious acute or late side
effect was observed.
Proton beam radiotherapy delivers protons instead of
photons and has been in development since the 1950s.
Protons do not scatter significantly in tissues and allow the
maximum dose to be delivered at a precise depth. Tissues
situated beyond the maximum intensity peak receive no radi-
ation. As for uveal melanoma, proton beam radiotherapy
would then represent an alternative, especially for ONSM
that is the closest to organs at risk, especially the retina [36].
In a dosimetric study comparing treatment planning for
ONSM using IMRT or proton beam radiotherapy, both tech-
niques achieved a similar optimal dose homogeneity in the
target volume; dose-volume histograms favored in every
case of the use of protons due to an inferior low-to-medium
dose range in the organs at risk, but the clinical significance
of these results remains elusive [36].
To conclude, fractionated stereotactic radiotherapy is the
standard treatment of ONSM, allowing visual improvement
in 80 % of patients, tumor control in all cases, with limited
Table 64.2 Selected series reporting on stereotactic radiosurgery for ONSM
Radiation-induced
Visual outcome Tumor outcome toxicities
Total dose Dose per
Author Year Reference n (Gy) fraction (Gy) Improved (%) Stable (%) Worse (%) Control (%) Progression (%) Re-progression (%) Acute (%) Late (%)
64 Ocular and Orbital Tumors: Viewpoint-Fractionated Radiation

Liu et al. 2010 [28] 30 10–17 NR 36 44 20 100 0 0 None None

Kurt et al. 2010 [29] 2 10–17 3.5–6.5 100 0 0 100 0 0 None None
Marchetti et al. 2011 [32] 21 25 5 35 65 0 100 0 0 None Optic
neuritis
(5 %)
Romanelli et al. 2011 [34] 3 20 5 100 0 0 100 0 0 None None
Most cases correspond to primary ONSM
NR not reported
779
780
risk of radiation-induced effects. The mean eye dose has to
be considered as a limiting constraint in treatment planning,
and it is related to the tumor size and location. Treatment has
to be done early when visual impairment occurs. Further
evaluation of the role of new techniques is mandatory.
Collaborative studies have to be encouraged in the field given
the rarity of the tumor. These points may also be considered
for other ocular and orbital tumors.
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102:143–6.
 Part V
Patient Care and Socio-Economic Issues
 Complications and Management
in Radiosurgery
Igor J. Barani and Minesh P. Mehta
Introduction
The central nervous system (CNS) is exposed to ionizing
radiation in a number of clinical situations, predominantly
those involving cancer treatment. Radiotherapy remains a
major treatment modality for primary and metastatic neo-
plasms located in the CNS, and exposure of the brain and
spinal cord is often unavoidable in the radiotherapeutic man-
agement of tumors located close to the CNS such as head and
neck cancers. In addition, there is the increasing application
of radiation in the eradication of arteriovenous malforma-
tions (AVMs) and other benign disorders of the brain, such
as trigeminal neuralgia and epilepsy [1, 2]. In each of these
situations, the radiation dose that can be administered safely
is limited by the potential for injury to the normal CNS tis-
sue. Because of the potential severity of CNS damage
induced by radiation, the response of normal brain and spinal
cord to radiation exposure has been a subject of considerable
research. As a result, this type of injury has been well
described in terms of histological and functional criteria as
well as radiobiologic parameters [3–5]. In contrast, the cel-
lular and biochemical processes responsible for the expres-
sion of radiation-induced CNS injury remain poorly defined.
Stereotactic radiosurgery (SRS) is a treatment technique
that utilizes very focal ionizing radiation to inactivate or
eradicate a defined target(s) (AANS/CNS/ASTRO Definition
of Stereotactic Radiosurgery, March 20, 2006). The target is
defined by high-resolution imaging, either magnetic reso-
nance (MR) or computed tomography (CT) and is registered
to a stereotactic coordinate space. This space can be defined
I.J. Barani, M.D.
Department of Radiation Oncology, University of California,
San Francisco, San Francisco, CA, USA
M.P. Mehta, M.B.Ch.B., F.A.S.T.R.O. (*)
Department of Radiation Oncology, University of Maryland,
22 South Greene Street, Baltimore, MD 21201, USA
e-mail: mineshpmehta@gmail.com; mmehta@ummm.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_65, © Springer Science+Business Media New York 2015
65
using a variety of fiducial systems that are referenced to a
component of the treatment device (e.g., head-frame + its
corresponding adapter). SRS is usually performed in a single
session, using a rigidly attached stereotactic guiding device,
or other mask-based immobilization systems that are often
combined with stereotactic image guidance system, but can
be performed in a limited number of sessions (≤5). Various
technologies can be used to perform SRS, including linear
accelerator specifically modified for this purpose, particle
beam accelerators, and multisource 60Co units (e.g., Gamma
Knife).
SRS techniques can safely deliver high doses of radiation
to a precisely defined target by exploiting multiple beamlets,
each of which does not transport much energy, that converge
on the target. With this approach, the dose within tumor is
much higher than the dose in the surrounding normal brain
tissue, as a result of a sharp dose gradient (“dose falloff”)
achieved by the multiple intersecting beams of radiation.
Since normal tissue interface is larger and dose falloff is less
rapid for larger lesions, increasing the exposure of the sur-
rounding normal brain tissue, the prescribed dose for brain
metastases is inversely proportional to the maximum tumor
diameter, generally resulting in better control rates of smaller
lesions. This physical phenomenon largely limits the appli-
cation of SRS to lesions ≤3–4 cm in diameter.
Side effects from SRS are dependent on target location,
dose of radiation delivered, volume of treatment, and prox-
imity to critical neurologic structures [6, 7]. Larger target
volumes have also been associated with higher rates of radia-
tion toxicity [8]. Comorbidities such as smoking, diabetes
mellitus, hypertension, certain autoimmune conditions, cer-
tain somatic genetic perturbations, and immunosuppression
increase the risk of complications from conventionally frac-
tionated radiation therapy [9, 10], and they also appear to
increase the risks of radiosurgery-related complications [11].
Radiation-induced toxicity can be minimized or prevented
by judicious application of SRS principles, techniques, and
dose–volume planning constraints. This chapter will primarily
focus on radiation necrosis, arguably the most troublesome
785
786
and dreaded complication of SRS, but specific complication
management related to SRS treatment of brain metastases,
AVMs, and meningiomas will also be discussed.
Definitions of Radiation Toxicity
Based on time of expression, therapeutic radiation-induced
CNS injury has been classically divided into three reactions:
acute, early delayed and late delayed [3–5]. Acute injury
(acute radiation encephalopathy) is expressed in days to
weeks after irradiation and is fairly uncommon under current
radiotherapy protocols. Early-delayed injury commonly
occurs from 1 to 6 months and can involve transient demye-
lination with somnolence and Lhermitte’s syndrome after
brain and spinal irradiation, respectively. Although acute and
early-delayed injuries can result in severe reactions, they are
normally reversible and resolve spontaneously. Recently, it
has been recognized that changes in delayed memory recall
possibly also represent an early-delayed response, becoming
manifest within 3–4 months of cranial radiotherapy and
putatively linked to a radiosensitive stem cell compartment.
The phenomenon of pseudoprogression, best described in
the context of concurrent chemoradiotherapy in the manage-
ment of glioblastoma is yet another example of an early-
delayed reaction, generally occurring within 1–6 months of
completion of therapy, and putatively a consequence of a
dysregulated blood–brain barrier either through endothelial
damage to the abnormal vasculature surrounding a tumor or
through a robust inflammatory/immunogenic response to
tumor cell death. In contrast, late-delayed effects, which
occur at times greater than 6 months after irradiation, are
usually irreversible and progressive. Late-delayed injury is
characterized by demyelination, stem cell depletion, vascu-
lar abnormalities, sclerosing phenomena, and ultimately
necrosis that is generally restricted to the white matter. A
consequence of such white matter injury is the clinical/radio-
graphic phenomenon of leukoencephalopathy and nonob-
structive hydrocephalus.
This classification also helps make the important distinc-
tion between radiation injury and radiation necrosis. The
term radiation “necrosis” has been loosely used to refer to
any changes noted on MR imaging that are felt to represent
“treatment effect” rather than recurrent tumor. These imag-
ing changes are noted to reverse partially or completely in
some patients, raising the possibility that rather than repre-
senting dead tissue, they represent reversible vascular and
parenchymal abnormalities. Radiation necrosis in this dis-
cussion relates primarily to “late-delayed injury” with the
morphologic correlates of necrosis. It is this late-delayed
injury that will be addressed below in detail.
Radiation necrosis may be classified further based on the
pattern of brain involvement. Diffuse and focal patterns of
I.J. Barani and M.P. Mehta
radiation necrosis are recognized. In diffuse necrosis,
widespread periventricular white matter abnormalities are
noted. In the focal pattern, circumscribed lesions are present.
Focal radiation necrosis may be peritumoral or distant, as
well as uni- or multifocal [12].
Historical Perspective
Brain radiation necrosis has been recognized as a potential
complication of radiation therapy for at least five decades.
Some of the earliest experiments demonstrating radiation
necrosis in the CNS were performed in primates and small
animals [13, 14]. In 1950, Lowenberg-Scharenberg and
Bassett described amyloid degeneration of the human brain
following x-ray therapy [15]. Subsequently, multiple
instances of cerebral radiation necrosis were reported [16–
19]. It soon became apparent that this pathology could simu-
late the disease originally treated with radiation, a dilemma
that is still a common clinical problem [20, 21]. In many
cases, pathologic examination of surgical or autopsy speci-
mens was necessary for definitive diagnosis.
Interestingly, MR imaging abnormalities of radiation
necrosis do not always correlate with clinical symptoms such
as cognitive decline, seizures, and weakness. The converse is
also true; some patients with symptoms felt to be treatment
related may have minimal changes on imaging. A major
challenge of current neuro-oncology practice is to achieve
the best possible balance between providing the benefits of
treatment while minimizing its long-term deleterious effects
on normal brain.
Dose and Volume Dependence
The radiation tolerance of normal tissues depends on total
dose, dose per fraction, total time of exposure, volume, radi-
ation quality, and adjunctive therapies such as chemotherapy,
as well as several host parameters. In 1980, Sheline et al. [5]
published a pioneering study on brain radiation tolerance
based on dose and fraction size. They created a log–log plot
of megavoltage dose versus number of treatment fractions
from 80 published cases of brain radionecrosis and deter-
mined an isoeffect line below which few cases of necrosis
were observed (See Fig. 65.1). They then modified the exist-
ing equivalent dose formula of the era, the Ellis formula for
nominal standard dose in “ret,” to create a formula for brain
tolerance in “neuret” where
neuret = D ´ N -0.44 ´ T -0.06
with D, total radiation dose in rad (cGy); N, number of radia-
tion fractions; and T, total time in days [5]. Of note, the nega-
tive exponents indicate that a delivery of radiation dose in
65 Complications and Management in Radiosurgery
Fig. 65.1 Megavoltage dose equivalent in rads (cGy) versus number of
treatment fractions for cases of brain radionecrosis. These data were
used to derive the neuret formula. Most cases of radiation necrosis
occurred for dose/fraction combinations above the line with a slope of
fewer fractions and a shorter time course is more deleterious
and that fraction size (a function of N) is much more impor-
tant to brain radiation tolerance than is treatment time. The
threshold for necrosis was about 1,000–1,100 neuret.
The influence of fraction size was also assessed by Lee
et al. [22] using a product of total dose (D) and fraction size
(d) in Gy2. The product (Dd) was found to be the most sig-
nificant predictive factor for necrosis in a multivariate analy-
sis of seven treatment parameters [22, 23]. A study by Ruben
et al. [24] confirms the significance of Dd and also demon-
strates that average fraction size ≥2.25 Gy is a significant
independent risk factor. Shorter overall treatment time from
giving twice daily radiation treatment was also found to be a
significant risk factor in the study by Lee et al. [23]
In the 1970s, a linear quadratic (LQ) model was devel-
oped to describe cell survival after exposure to ionizing radi-
ation, where the surviving fraction of cells S after exposure
to a dose D is represented by
(
- a D + b D2 )
S =e . TD5/5 is estimated to be 50 ± 10 Gy for the whole brain,
The constant α describes the initial slope of the survival
curve at low doses and β describes the quadratic component
of cell killing [25]. A common related formula first intro-
duced in the early 1980s[26] is for biologically effective
dose (BED):
é d ù
BED = D ê1 + , conventionally fractionated radiation had a significantly
ë a / b úû
where D is the total dose and d is the size of a single radiation
fraction in Gy. The ratio of α/β has no units, because both α
787
0.44. From Sheline GE, Wara WM, Smith V. Therapeutic Irradiation
and Brain Injury. Int J Radiat Oncol Biol Phys. 1980;6(9):1215–1228;
used with permission
and β are expressed in units of dose in Gy and the ratio tends
to be in the range of 2–3 for late effects such as lung fibrosis
or CNS injury versus around 8–10 for acute-responding tis-
sues such as hair follicles, mucosa, and rapidly dividing
tumor cells, although a considerable range exists. As an
example, 50 Gy total dose prescription given at 2 Gy per
daily fraction will have a BED value of 100, assuming α/β = 2
(a ratio often used for late effects). A biologically equivalent
dose for late effects given at 3 Gy/fraction can be determined
by solving the formula 100 = D(1 + 3/2), which gives D = 100/
(1 + 3/2) = 40. Thus, 39 Gy at 3 Gy/fraction is approximately
equivalent to 50 Gy at 2 Gy/fraction in terms of late effects.
As fraction size increases, comparable values for BED for
either tumor or late effects can be computed. However, data
surrounding the use of this approach with very few fractions
or very large dose per fraction are sparse and unreliable.
Useful tolerance parameters are the 5 and 50 % probabili-
ties of brain injury at 5 years (TD5/5 and TD50/5, respectively).
At “standard” fractionation of 1.8–2.0 Gy per fraction, the
60 ± 10 Gy for a portion of the brain, and 45–50 Gy for a
10-cm segment of spinal cord [27, 28]. Thresholds of 54 [29]
and 57.6 Gy[30] have been reported for cerebral radiation
necrosis, but it is apparent that radionecrosis may occur
below these limits with conventional therapeutic radiation
[5, 31]. In the North Central Cancer Treatment Group low-
grade glioma trial, patients who received 64.8 Gy with
higher actuarial incidence of necrosis (6 patients out of 102)
than those who received 50.4 Gy, and only one patient (out
of 101) treated with 50.4 Gy in 28 fractions developed radio-
necrosis [31]. In a report by Marks et al. [29], only 1 patient
788
out of 139 developed necrosis in an area irradiated to <50 Gy
in 27 fractions. In the study by Sheline et al. [5], only 3 of 80
cases of brain radionecrosis were in patients receiving doses
≤50 Gy, in fraction sizes <2.5 Gy. In contrast, 17/20 cases of
radionecrosis occurring at ≤50 Gy were associated with
fraction sizes ≥2.5 Gy. This implies the relative safety of
doses in 50 Gy range, but only so long as fraction sizes are
maintained under 2.5 Gy.
In single-fraction radiosurgery, the risk of brain necrosis
increases rapidly above 12 or 13 Gy, and there is a higher
risk with larger nontarget volume encompassed by the
12-Gy isodose line, particularly over 10 mL [32, 33].
Although the LQ model and BED concept are presumed to
“break down” in the context of single fraction radiosurgery,
it is noteworthy that a single fraction of 13 Gy would yield
a BED of 97.5, assuming an α/β ratio of 2, very similar to
the 100 Gy BED value obtained with 50 Gy in 2 Gy frac-
tions, with both representing lower, relatively “safe” thresh-
olds. A dose-finding protocol, Radiation Therapy Oncology
Group 90–05, found a similar relationship between higher
risk of CNS toxicity from single-fraction radiosurgery and
larger tumor volume, with lower “maximum tolerated doses”
for larger tumors [34].
Latency
The mean interval from the end of radiotherapy until onset
of necrosis was 11.6 months in a recent study [24], though
radiation necrosis has been reported to manifest as early as
3 months [35] and as late as 47 years after radiotherapy
[36]. Peritumoral parenchyma seems to be more vulnerable
to damage from radiation, and the potential role of chemo-
therapy in enhancing this effect was suggested by the
observation that the latency period for the development of
radionecrosis in glioma patients (typically treated with
chemoradiation) appears to be approximately five times
shorter than in other patients receiving equivalent radiation
dose, such as those with nasopharyngeal carcinoma, often
treated with radiotherapy alone [5, 23, 31, 37, 38]. An alter-
native explanation for this comes from the observation that
higher rates of radiation necrosis from radiosurgery are
observed when treating recurrent malignant gliomas as
opposed to brain metastases, and the putative hypothesis is
that malignant gliomas are endowed with a significantly
more disrupted and leaky peritumoral vasculature, with
endothelium that is more susceptible to damage from large-
fraction radiation. Indirect support for this stems from
studies of aggressively hypofractionated chemoradiotherapy
for glioblastoma in which the concomitant use of bevaci-
zumab, known to stabilize the endothelium, significantly
reduced observed rates of necrosis (relative to historic
expectations) [39].
I.J. Barani and M.P. Mehta
Incidence
The incidence of cerebral radiation necrosis after conven-
tional radiotherapy for primary brain tumors in modern radia-
tion oncology practice is poorly defined. This is partially due
to limited data on radiation dose-fractionation schedules and
lack of both the numerator and the denominator for patient
populations within which cases of radiation necrosis are
described [5]. Additional barriers relate to the difficulty of
distinguishing necrosis from tumor recurrence by neuroimag-
ing and the low rates of reoperation and autopsy in these
patients [35] and to limited survival time in patients with
malignant brain tumors. Despite advances in magnetic reso-
nance imaging (MRI) and functional imaging, necrosis or
necrosis combined with tumor is still probably frequently
mistaken for tumor progression alone, likely resulting in
underestimation of the true incidence of brain radionecrosis.
A recent review of 426 patients treated for glioma and
followed until death or for at least 3 years identified 21
patients with cerebral radionecrosis [24]. Most patients were
treated with conventional radiotherapy along with
chemotherapy, but ten of the patients who developed radio-
necrosis had additional boost or salvage stereotactic radia-
tion, usually 18 Gy in three fractions. The crude radionecrosis
incidence was 4.9 % and the actuarial incidence was 2.9, 5.1,
9.3, and 13.3 % at 6, 12, 24, and 36 months post-treatment,
respectively [24]. When the analysis was restricted to patients
treated with a radiation dose biologically equivalent to at
least 45 Gy in 25 fractions, the crude incidence of radione-
crosis increased to 6 %.
The use of radiosurgery or interstitial radiation after con-
ventional radiotherapy clearly increases the risk of radione-
crosis, though reporting rigor, fidelity of follow-up, technique
variability and patient population heterogeneity complicate
estimation of the rate of radionecrosis, which ranges from
2.6 to 56 % in reported series [29, 31–34, 40–44].
It is important to note that many studies of brain radione-
crosis include patients treated with chemotherapy in addition
to radiotherapy. Although some investigators have suggested
that injury is more often related to radiation than chemother-
apy [45], others reported changes similar to “radiation”
necrosis from treatment with chemotherapy only for extra-
cranial malignancies [46]. It is now widely accepted that
both treatment modalities are injurious to normal brain, with
the risk of necrosis increasing when they are used together.
Histopathologic Features
The end point of irreversible radiation injury in the brain is
necrosis that may develop months to years after the comple-
tion of radiation therapy [3, 16]. Histopathologically, radiation
65 Complications and Management in Radiosurgery
necrosis occurs most commonly in the white matter around
blood vessels. The most frequent histopathologic feature is
fibrinoid necrosis of blood vessel walls with surrounding
perivascular parenchymal coagulative necrosis with or with-
out an inflammatory response (sometimes referred to as
“dirty necrosis”) [47]. Focal radiation necrosis may be peri-
tumoral or distant, as well as unifocal or multifocal [12].
Extension and confluence of multiple perivascular foci of
necrosis result in large serpentine or confluent zones of
parenchymal necrosis [3, 48]. Over time, dystrophic calcifi-
cations can develop in these necrotic areas. An additional
vascular lesion that is often observed consists of clusters of
abnormally dilated, thin-walled telangiectasias. Late vascu-
lar changes include vessel wall thickening caused by hyalin-
ization, with resultant luminal narrowing, and ultimately, in
some cases, aneurysmal dilation. White matter changes may
also be focal or diffuse; in the diffuse pattern, widespread
periventricular demyelination is seen [16].
Diagnosis
Radiation necrosis should be in the differential diagnosis for
any patient with progressive neurological symptoms or a
new or enlarging enhancing brain lesion with a history of
prior intracranial radiation therapy to a dose of at least 12 Gy
in a single dose (Fig. 65.2) or 50 Gy with at 1.8–2.0 Gy per
daily fraction. A major dilemma in the diagnosis of radiation
necrosis is differentiating it from recurrent or persistent
tumor. Tumor recurrence and radiation necrosis often have a
similar appearance on conventional contrast-enhanced MRI
[49, 50]. Because of this, it is often difficult to distinguish
which entity is responsible for the appearance of an enlarg-
ing lesion. Traditionally, a patient’s clinical course, biopsy,
and serial imaging for several months have been used to try
to distinguish between tumor recurrence and radionecrosis
[49–51]. Any investigation short of extensive tissue exami-
nation lacks diagnostic sensitivity and specificity. Anatomic
and physiologic MRI, positron emission tomography (PET),
and thallium single photon emission computed tomography
(SPECT) imaging have all been used in an attempt to define
the best noninvasive method to diagnose radiation necrosis,
though there is no evidence to date that any of these investi-
gations is clearly superior to the other modalities.
MRI
Radiation necrosis can closely resemble recurrent tumor on
anatomic (“conventional”) MRI because of the following
shared features: (a) focus at or close to the original tumor site,
which is commonly the site of maximum radiation dose,
789
(b) contrast enhancement, (c) progressive enlargement, at
least over several months, (d) surrounding edema, and (e)
exertion of mass effect [52]. On MRI, brain necrosis usually
consists of a somewhat irregular rim-enhancing mass with a
central area of low signal on T1-weighted images (Fig. 65.2,
upper center panel). The contrast enhancement of these
lesions is thought to be secondary to radiation-induced endo-
thelial damage resulting in breakdown of the blood–brain
barrier. On T2-weighted images, the surrounding edema has
high signal intensity, the solid portion of the radionecrotic
lesion has low signal intensity, and the central necrotic com-
ponent may show either increased or decreased signal inten-
sity (Fig. 65.2, lower center panel). Later, focal brain atrophy
develops, and sometimes large cysts develop. The arcuate
fibers in white matter are relatively resistant to radiation
necrosis and are usually involved late in the disease process.
The predilection for periventricular white matter involvement
in radiation necrosis may, on some occasions, mimic multiple
sclerosis. Multiple lesions can resemble multiple metastases,
and radiation-induced necrotic lesions can also spread subep-
endymally and mimic subependymal tumor spread.
Despite the many commonalities in radiographic appear-
ance between tumor and necrotic tissue, several investigators
have attempted to define patterns of radiation necrosis on
conventional MRI with the aim of distinguishing tumor from
necrosis. A recent study of 59 patients treated with radiosur-
gery for metastatic brain tumors who underwent subsequent
craniotomy for symptomatic lesion enlargement analyzed
the following features: (a) arteriovenous shunting, (b) gyri-
form lesion or edema distribution, (c) perilesional edema, (d)
cyst formation, and (e) pattern of enhancement [53]. The
authors also defined a radiographic feature, the lesion quo-
tient, which is the ratio of the nodule as seen on T2 imaging
to the total enhancing area on T1 imaging, and suggested that
a lesion quotient ≥0.6 correlates with recurrent tumor,
whereas a quotient of ≤0.3 correlates with radionecrosis.
The examined radiographic features, taken together, achieved
80 % or greater predictive value but had either low sensitivity
or low specificity [53]. In an older study, Kumar et al. [12]
cite two radiographic features that are consistent with radia-
tion necrosis, the “Swiss cheese” pattern and the “soap bub-
ble” pattern. The first pattern is characterized by diffuse
areas of enhancement affecting the cortex and white matter
and intermixed with necrotic areas. The soap bubble appear-
ance refers to smaller lesions with heterogeneously enhanc-
ing necrotic cores.
The key point is that radiation necrosis should be included
high in the differential diagnosis if some of the described
imaging features or patterns are recognized. However, no
radiographic pattern is pathognomonic for radiation necrosis
and as such, supplementary functional imaging is often nec-
essary and even then, surgical excision may still be required.
790
Fig. 65.2 T1-weighted, post-contrast MRI (upper panels) and FLAIR
images (lower panels) for a patient with a breast cancer brain metastasis
treated with Gamma Knife radiosurgery with a single fraction of 18 Gy,
prescribed to 50 % isodose line (upper, left panel). Symptomatic radia-
tion necrosis developed 10 months later (center panels). Five months
MRS
Magnetic resonance spectroscopy (MRS) has been explored
as a noninvasive means of diagnosing radiation necrosis and
distinguishing it from tumor recurrence. The technique
allows metabolites from an area of interest to be quantified
and compared with those of surrounding normal tissue [54].
Metabolites such as N-acetyl aspartate (NAA), phosphoryl-
choline/glycerophosphorylcholine (Cho), creatine (Cr), lac-
tate (Lac), and mobile lipids (Lip) provide different spectra
in tumors compared with normal brain or radiation necrosis.
Elevated levels of choline compounds have been repeatedly
reported in the “peritumoral region” for gliomas [55–59] but
not metastases [56].
In general, tumor is characterized by NAA/Cho ratio <1 and
Lip/Cho ratio <3. In contrast, Lip/Cho ratio >3 or significant
decrease of all metabolite levels within the lesion or surround-
ing brain are considered characteristic of radiation-induced
necrosis [60]. The technique has evolved significantly from
single-voxel, low-resolution studies to multi-voxel acquisitions
that have a much higher resolution [60, 61].
I.J. Barani and M.P. Mehta
after the onset of necrosis, the patient underwent a 2-month long treat-
ment with dexamethasone resulting in significant clinical and radio-
graphic improvement (right panels). Symptoms resolved rapidly after
initiation of dexamethasone therapy and did not recur after discontinu-
ation of steroids
In practice, MRS has been used alone in an attempt to
reduce the need to biopsy new enhancing lesions on MRI
[62, 63] and in combination with biopsy to help guide sam-
pling and improve diagnostic yield [64, 65].
DWI
Diffusion-weighted imaging (DWI) is another interesting
approach for utilizing MR technology to diagnose radiation
necrosis. The technique depends on the diffusion of water
molecules within the tissue under study and generates an
apparent diffusion coefficient (ADC) map [54]. Areas with
high ADC appear dark on DWI whereas low ADC areas pro-
duce increased signal. The differences in ADC in various tis-
sues are thought to result from both changes in the balance
between intracellular and extracellular water and changes in
the structure of the two compartments. In theory, areas of
radiation necrosis should have higher (or better) diffusion
coefficients than areas of hypercellular tumor so that the
technique could be used to differentiate the two conditions.
65 Complications and Management in Radiosurgery
This explanation represents a gross simplification of the
biologic milieu of both tumor and necrosis, but high diffu-
sion on ADC has been reported in cerebral radiation necrosis
caused by treatment of brain tumors [66–69].
Previous studies applied this technique to evaluate cellu-
larity in gliomas with the aim of predicting tumor grade [70].
Signal intensity and ADCs in neoplastic tissue, peritumoral
edema, and normal brain tissue have been reported for low-
and high-grade gliomas, meningiomas, and brain metastases
[71]. Necrotic brain tissue in the temporal lobe after radia-
tion therapy for nasopharyngeal carcinoma has been charac-
terized using DWI as well [72]. Previously reported ADC
values for high-grade glial tumors vary from 1.1 to
1.37 × 10−3 mm/s2 [73–75]. ADCs in peritumoral edema or
temporal lobe necrosis were reported as 1.29 and
2.88 × 10−3 mm/s2 in two notable studies [72, 76]. Although
ADC maps can provide useful information that may help dis-
tinguish tumor from necrosis, DWI has not been studied suf-
ficiently to permit unequivocal diagnosis. Presently, DWI is
primarily used as an adjunct to other studies.
Perfusion MRI
Dynamic, contrast-enhanced perfusion MRI (pMRI) of the
brain provides hemodynamic information that complements
the anatomic information available from conventional
MRI. Contrast-enhanced pMRI methods exploit signal
changes that accompany the passage of a paramagnetic con-
trast agent (gadolinium) through the cerebrovascular system
to derive relative blood volume and flow information [77, 78].
Analysis of dynamic data from pMRI yields quantitative
estimates of the relative cerebral blood volume (rCBV) of
the lesion versus other regions of interest such as surrounding
tissue or contralateral normal tissue. For CBV measurements,
a series of images is acquired at intervals of approximately
1 s before, during, and after bolus injection of the contrast
agent. Rapid gradient-echo or echo-planar imaging is gener-
ally used to acquire multiple T1-weighted slices at each time
point during the imaging interval. When a paramagnetic
contrast agent passes through the cerebral vascular system,
it induces differences in local magnetic susceptibility
between the intravascular space and the surrounding normal
tissue, with a transient and differential loss of relaxation signal.
This enables calculation of the contrast concentration–time
curve, and rCBV can then be estimated from the area under
this curve and corrected for contrast leakage using a refer-
ence measurement in the contralateral, unaffected centrum
semiovale white matter.
Sugahara et al. [79] were among the first to propose that
this technique should be utilized when it is necessary to dif-
ferentiate tumor recurrence from radiation necrosis. In a series
of 20 cases, these authors found that a normalized rCBV of 2.6
791
or higher indicated tumor recurrence and a ratio of 0.6 or less
was suggestive of nonneoplastic contrast-enhancing tissue.
A more recent approach, described by Barajas et al. [80],
uses three hemodynamic variables to describe the shape of
the signal intensity–time curve obtained from dynamic sus-
ceptibility contrast pMRI: rCBV, relative peak height, and
percentage of signal intensity recovery; among 27 patients
with necrosis or tumor recurrence or progression after single-
fraction radiosurgery for brain metastases, rCBV and relative
peak height were significantly higher and the percentage of
signal intensity recovery was significantly lower for tumor
versus necrosis [80, 81]. Relative CBV is the most widely
used hemodynamic variable derived from pMRI and has been
shown to correlate with tumor grade and tumor microvascular
attenuation [56, 79, 82–88]. Relative peak height, which rep-
resents the maximal change in signal intensity during the pas-
sage of contrast agent, has been shown to correlate with rCBV
measurements and tumor capillary blood volume. Finally,
percentage of signal intensity recovery, an indicator of the
blood–brain barrier integrity, reflects the degree of contrast
agent leakage through tumor microvasculature and provides
insight into the alteration of capillary permeability.
Several important limitations are associated with dynamic,
contrast-enhanced pMRI. Because the technique is suscepti-
bility weighted, it is extremely sensitive to structures or
lesions that induce strong magnetic field inhomogeneities
such as blood products, calcium, melanin, metals, or lesions
near brain–bone–air interfaces such as the skull base. When
there is a large amount of susceptibility artifact, pMRI fails
to provide any meaningful information [89]. Also, the calcu-
lation of rCBV can be grossly inaccurate in lesions with a
severe breakdown or absence of the blood–brain barrier.
FDG-PET
Positron emission tomography (PET) can be used to measure
the metabolism of glucose labeled with an 18 F analog.
Because radiation necrosis should be characterized by low
glucose consumption, 18 F-fluorodeoxyglucose (FDG) is
often used in PET studies to provide contrast with areas of
tumor, which should have higher uptake. Early studies
reported that 18 F-FDG-PET had a sensitivity of 81–86 % and
a specificity of 40–94 % for distinguishing between radiation
necrosis and tumor [90].
There are multiple limitations to the usefulness of PET in
the brain. Tumor glucose metabolism is highly variable, and
the overlap of 18 F-FDG uptake between radiation necrosis
and tumor can be considerable [91–93]. In addition, tumor
glucose metabolism is frequently lower than that of normal
brain tissue; thus, tumor uptake may be difficult to appreciate
amid the background of highly metabolically active normal
brain tissue or of treated brain tissue, which tends to have
792
lower glucose metabolism than untreated brain and may also
have a wide range of metabolic activity. Also, high 18 F-FDG
uptake can occur from inflammation that may be associated
with necrosis, resulting in misinterpretation. In general, it
has not been possible to define a reliable cutoff of standard-
ized uptake values to distinguish between tumor and necro-
sis. Strategies to improve predictive value include comparing
the ratio of the lesion to contralateral normal white or gray
matter or determining whether lesion activity is above the
expected background activity in adjacent brain tissue [94–
97]; in either case, it can be helpful to have the anatomic
information from coregistration with MRI [97, 98].
Amino Acid PET
Amino acid PET tracers and amino acid analog PET tracers
constitute another class of tumor imaging agents [99, 100].
These are particularly attractive for imaging brain tumors
because of the high uptake in tumor and low uptake in nor-
mal brain tissue; amino acids are transported into the cell via
carrier-mediated processes [100], and amino acid transport is
generally increased in malignant cells [101, 102]. The most
extensively studied amino acid tracer is 11C-methionine
[103]. Because of the short half-life of 11C (approximately
20 min), 18 F-labeled aromatic amino acid analogs (with a
half-life of approximately 109 min) have been developed for
tumor imaging [104].
Because amino acid tracers appear more sensitive than
18
F-FDG-PET in visualizing tumor, they also have poten-
tially better diagnostic accuracy in evaluating radiation
necrosis. However, the degree of amino acid uptake in radia-
tion necrosis is not known. 11C-methionine has been avail-
able for about two decades, but few studies have been
published on its performance in differentiating radiation
necrosis from brain tumor recurrence.147 In a study of 21
patients with brain metastases treated with SRS,
11
C-methionine correctly identified seven of nine recurrences
and 10 of 12 radiation injury lesions [95].
In rats, uptake of 18F-FET (18 F-fluoroethyl-L-tyrosine),
18
F-FDG, and 18 F-choline has been compared in acute
lesions caused by cerebral irradiation and cryotherapy [105].
Both 18 F-FDG and 18 F-choline accumulated in macrophages,
a common inflammatory cell type in radiation necrosis, but
18
F-FET uptake was absent from macrophages. Moreover,
the ratio of 18 F-FET uptake in radiation necrosis to that in
normal cortex was much lower than the corresponding ratios
for 18 F-FDG and 18 F-choline, suggesting that 18 F-FET may
be able to differentiate radiation necrosis from tumor recur-
rence. Absence of 18 F-FET uptake in a case of radiation
necrosis has been reported [106]. Although these results are
promising, larger systematic studies are needed to evaluate
the diagnostic performance of these tracers.
I.J. Barani and M.P. Mehta
SPECT
SPECT relies on the injection of a radionuclide such as 201Tl
(Thallium-201) and 99mTc (Technetium-99) and the use of a
gamma camera and computed tomography (CT) to detect its
distribution in the brain. Uptake of the radionuclide is greater
in tumor cells than in normal tissue and inflammatory cells
and depends on Na/K-ATPase pump activity [107]. Because
uptake requires a viable cell, it is correspondingly low in
necrotic areas. This technique is much less expensive and
more widely available than PET but has disadvantages with
regard to limited breadth of molecular processes that are
accessible, quantitation accuracy, and spatial resolution.
High-grade tumors have a higher thallium index than
low-grade tumors. In a series of 15 biopsy-proven cases,
Schwartz et al. [108] found excellent correlation between
imaging and histology (14/15 cases) using dual-isotope
SPECT scanning with 201Tl and 99mTc-hexamethylpropylene
amine oxime (HMPAO).161 A subsequent study revealed
high 201Tl uptake in recurrent tumor and low uptake in radia-
tion necrosis. In cases with intermediate uptake, 99mTc-
HMPAO uptake helped to differentiate tumor recurrences
from radiation necrosis by showing increased perfusion in
tumor [108]. After these initial exciting reports of sensitivi-
ties in excess of 90 % for detecting tumor recurrence with
specificity approximately 60 % [109], other reports citing
concerns about the diagnostic accuracy of the technique for
distinguishing recurrent tumor from radiation necrosis began
to surface, including cases of thallium-avid radiation necro-
sis [110–112].
More recently, Alexiou et al. [113] substantiated potential
superiority of 99mTc-tetrofosmin (99mTc-TF) over 99mTc-sestamibi,
a commonly used imaging agent, for brain tumor imaging,
owing to the fact that 99mTc-TF accumulation is independent
of the multidrug-resistance phenotype of some glioma cells
(167,168). 99mTc-TF is a tumor-seeking diphosphine that
does not cross the intact blood–brain barrier, and uptake is
dependent on regional blood flow and cell membrane integ-
rity, thus reflecting cellular metabolic status and viability.
Alexiou et al. also reported that 99mTc-TF could successfully
differentiate tumor recurrence from radiation injury [113,
114]. These results are yet to be confirmed by other groups.
Histological Examination
Given the limitations of the various imaging techniques, a
definitive diagnosis of radiation necrosis may require patho-
logic examination of surgical specimens. Because of the
potential for sampling error with biopsy alone, total resec-
tion is preferred. Resection also improves edema and mass
effect associated with radiation necrosis and/or active tumor.
If resection is not safe or feasible, the imaging modalities
65 Complications and Management in Radiosurgery
described above may be used to guide biopsies, so that the
region most suspicious for active tumor can be sampled to
maximize diagnostic yield.
Treatment
While the finding of radiation necrosis, or “treatment effect,”
is often met with relief that the changes seen on imaging do
not represent tumor growth, patients and their families and
health care providers need to understand the implication of
this condition. Radiation necrosis can produce symptoms that
are as disabling as tumor recurrence. Most patients with radia-
tion necrosis present with focal neurologic deficits related to
the necrotic lesion as well as headaches as a result of mass
effect from reactive vasogenic edema. Some cases stabilize or
improve with the treatments described below or with the pas-
sage of time, but some cases may be relentlessly progressive.
Steroids. Steroids are frequently used to treat radiation-
induced edema and necrosis. Animal models of radiation-
induced CNS necrosis demonstrate that edema precedes the
development of necrosis and that the anti-inflammatory effect
of dexamethasone, when provided early, can modify subse-
quent vascular and inflammatory changes to reduce and delay
the development of subsequent necrosis [115–117]. Thus,
controlling edema after irradiation or in the early stages of
necrosis may limit the subsequent development or course of
necrosis. Among patients with temporal lobe necrosis after
radiotherapy for nasopharyngeal cancer, dexamethasone
given at the onset of radiation necrosis, during which there
was marked reactive edema, resulted in significant objective
improvement of necrosis in 38 % of patients, whereas none of
the patients with cystic necrosis improved [118].
The optimal dose and timing of the corticosteroids have
not been prospectively studied; however, it appears that
administration early in the course of radionecrosis is more
effective than one that is delayed, and the doses given must
be adequate to control clinical symptoms. After symptoms
improve, the steroid dose should be tapered as tolerated.
Some patients become symptomatic when steroid treatment
is discontinued and thus require long-term treatment over
many weeks or months. Attention must then be directed
toward minimizing the medical complications associated
with steroid treatment, such as steroid myopathy, glucose
intolerance, secondary infections, gastric irritation, neuro-
psychologic issues, and osteopenia.
Surgical Resection. Radiation-induced necrosis is clearly a
dynamic process. Cases have been documented in which
necrosis spontaneously resolves, remains stable, or pro-
gressively enlarges to produce a space-occupying lesion
that becomes increasingly symptomatic. When steroid therapy
793
is poorly tolerated or when radiation necrosis becomes pro-
gressively larger and symptomatic despite the use of ste-
roids, surgical excision of the necrotic mass is indicated [3,
117, 119]. In general, surgical treatment is an effective
therapy for well-circumscribed areas of necrosis and much
less effective for diffusely necrotic lesions [120]. It is pre-
sumed that removal of the necrotic nidus, a source of
inflammation, reduces the associated edema and thereby
secondary mass effect. Surgery thus provides immediate
relief of symptoms and frequently enables patients to be
rapidly tapered off steroids.
Hyperbaric Oxygen (HBO). HBO therapy is the inhalation of
100 % oxygen at an elevated pressure, usually over 1.5 times
the atmospheric pressure, in a controlled and monitored envi-
ronment. When used after radiation therapy, HBO has been
shown to increase tissue oxygenation and angiogenesis and
improve capillary bed function [121]. HBO has been used in
the treatment and prevention of late complications after radio-
therapy in different sites, and many papers have been pub-
lished reporting its use [119]. Hulshof et al. [122] prospectively
evaluated HBO in patients with cognitive problems following
cerebral radiotherapy and found that only one out of seven
patients experienced significant improvement. Leber et al.
[123] reported two cases of successful HBO therapy for radi-
ation damage following Gamma Knife radiosurgery for
AVMs, with marked improvement in necrotic lesions on
imaging without the use of corticosteroids. Given the scarcity
of evidence and lack of controlled trials, there is considerable
uncertainty on the place of HBO in the management of late
neurological sequelae of radiation therapy.
Anticoagulants. Because it is thought that radiation necrosis
results mainly from vascular changes associated with isch-
emia, anticoagulants (heparin and warfarin [Coumadin]) and
antiplatelet medications such as pentoxifylline (Trental),
aspirin, and ticlopidine (Ticlid) have been used to attempt to
halt its progression. Five of eight patients with cerebral radi-
ation necrosis unresponsive to steroids had clinical improve-
ment on anticoagulation with heparin (Heparin) and warfarin
(Coumadin) [124]. The potential risk of bleeding from these
agents must be weighed against any expected benefit, and
these patients must be closely monitored for consumptive
coagulopathies, especially in the setting of concurrent che-
motherapy. Definitive conclusions are not available owing to
the small number of patients studied. However, in cases
where radiation necrosis is progressive and symptomatic,
full anticoagulation is reasonable assuming there are no con-
traindications. There are no published comparisons for anti-
platelet versus anticoagulant agents.
Antioxidant Therapy. Oral pentoxifylline (Trental) and
tocopherol (vitamin E) combination therapy has been reported
794
to benefit patients with skin and chest wall radionecrosis as
well as mandibular osteoradionecrosis [125]. Pentoxifylline
is thought to reverse radiation damage primarily through its
ability to increase locoregional blood flow; it improves red
blood cell deformability and promotes laminar blood flow by
inhibiting intercellular adhesion molecule expression, result-
ing in decreased adhesion between endothelial cells and leu-
kocytes. Pentoxifylline also decreases plasma fibrinogen
while increasing fibrinolytic activity [126], and it is a nonspe-
cific inhibitor of many inflammatory cytokines [127].
Tocopherol is an antioxidant compound that scavenges ROS
generated during oxidative stress and protects lipid mem-
branes against lipid peroxidation [125]. Williamson et al.
[128] reported on 11 patients with delayed adverse radiation
effects after treatment with Gamma Knife radiosurgery for
various benign and malignant disorders who were treated
with pentoxifylline (400 mg orally twice daily) and tocoph-
erol (400 IU orally twice daily). The edema volume measured
on serial FLAIR-MRI improved in 10 of 11 patients, with an
average volume decrease of 72.3 mL. The only patient with-
out improvement was found to have tumor recurrence. The
authors concluded that pentoxifylline and tocopherol may be
of benefit for treatment of adverse radiation effects. Further
studies are needed to determine the efficacy of this regimen
for the treatment of brain radionecrosis.
Bevacizumab. The premise for the use of bevacizumab for
radiation necrosis came from observations of radionecrosis-
associated endothelial cell dysfunction and hypoxia with lib-
eration of vasoactive compounds, including vascular
endothelial growth factor (VEGF). Bevacizumab is a human-
ized murine monoclonal antibody against the VEGF mole-
cule. It blocks VEGF from reaching its capillary targets and
is currently being used in the treatment of several solid
tumors. Gonzalez et al. [129] retrospectively evaluated 15
patients treated with bevacizumab or bevacizumab combined
with chemotherapy after radiation for malignant brain
tumors. Radiation necrosis was diagnosed in eight patients,
all of whom underwent therapy with bevacizumab on
either a 5 mg/kg/2-weeks or 7.5 mg/kg/3-weeks schedule.
Posttreatment MRI scans, performed approximately 8 weeks
after therapy, demonstrated measurable improvements in all
patients. The imaging findings correlated with clinical
improvement as evaluated by the average reduction in daily
dexamethasone requirement by 8.6 mg. The authors of this
study concluded that bevacizumab, alone or in combination
with other agents, can reduce radiation necrosis by decreas-
ing capillary leakage and the associated brain edema.
Torcuator et al. [130] reported on six glioma patients with
biopsy-proven brain radionecrosis treated with bevacizumab
at 10 mg/kg every other week, combined with irinotecan in
two cases of suspected tumor cells in addition to necrosis.
Compared with pre-bevacizumab imaging, the mean decrease
I.J. Barani and M.P. Mehta
in volume of contrast enhancement was 79 % and the mean
decrease in T2-FLAIR volume was 49 %. Similar results
were published in a recent case report of bevacizumab at
5 mg/kg every other week for temporal lobe necrosis that
developed 2 years after aggressive radiotherapy with chemo-
therapy for nasopharyngeal carcinoma [131] and in three of
four children with pontine gliomas suspected of having radi-
ation necrosis [132]. More recently, Gutin et al. [39] reported
no cases of radionecrosis among 25 patients with recurrent
malignant gliomas treated with fractionated stereotactic reir-
radiation to 30 Gy in six fractions along with bevacizumab,
10 mg/kg every 2 weeks. Optimal dosing, duration of treat-
ment, and efficacy of bevacizumab (or similar agents) need
further evaluation in prospective trials.
Rehabilitation. Depending on the symptoms and clinical
deficits caused by radiation necrosis, patients may benefit
from physical, occupational, or speech therapy.
Brain necrosis is associated with a significant degree of
morbidity and sometimes mortality. It has been recognized
as a potential complication of brain radiation therapy for at
least five decades, with higher risk for larger volumes, higher
total dose, and higher dose per fraction, especially above
about 50 Gy at 1.8–2.0 Gy per daily fraction or 12 Gy in one
fraction (three- and five-fraction radionecrosis thresholds are
not well know at this time) (see Table 65.1). The latency
period is highly variable, but the minimum latency is about 3
months after radiation exposure. The pathophysiology is not
completely understood; contributing factors appear to
include injury to vasculature, oligodendrocytes, and/or neu-
ral stem cells and chronic inflammation. It may be difficult to
distinguish radiation necrosis from progressive or recurrent
tumor following treatment for primary or metastatic brain
tumors. Techniques that have been used include MRI, MRS,
PET, and SPECT, short of surgical biopsy or resection for a
histopathologic diagnosis. The symptoms of radiation necro-
sis may be mild or reversible, but are sometimes significant
or progressive, warranting treatment with steroids and/or
surgical resection. Less well-proven but possibly effective
interventions include HBO therapy, anticoagulation, antioxi-
dant therapy, and therapy with VEGF inhibitors.
Complications for Common Radiosurgery
Indications
Brain Metastases. Metastases to the brain represent the most
common indication for radiosurgery [6]. In a series evaluating
radiosurgery for brain metastases, Shaw et al. report that the
most common complication was symptomatic cerebral edema
associated with radiosurgery [8]. Four patients in this series
experienced severe cerebral edema, two of whom responded
to corticosteroids. Six percent of patients in this series
65 Complications and Management in Radiosurgery 795

Table 65.1 Summary of suggested dose constraints for selected critical brain structures

One fraction Three fractions Five fractions

Max critical
volume above Threshold Max. point Threshold Max. point Threshold Max point End point
Tissue threshold dose (Gy) dose (Gy) dose (Gy) dose (Gy) dose (Gy) dose (Gy) (>-Grade 3)
Optic pathway <0.2 cm3 8 10 15.3 (5.1 Gy/fx) 17.4 (5.8 Gy/fx) 23 (4.6 Gy/fx) 25 (5 Gy/fx) Neuritis
Cochlea 9 17.1 (5.7 Gy/fx) 25 (5 Gy/fx) Hearing loss
Brainstem <0.5 cm3 10 15 18 (6 Gy/fx) 23.1 (7.7 Gy/fx) 23 (4.6 Gy/fx) 31 (6.2 Gy/fx) Cranial
(not medulla) neuropathy
Spinal cord and <0.35 cm3 10 14 18 (6 Gy/fx) 21.9 (7.3 Gy/fx) 23 (4.6 Gy/fx) 30 (6 Gy/fx) Myelitis
medulla <1.2 cm3 7 12.3 (4.1 Gy/fx) 14.5 (2.9 Gy/fx)
Spinal cord <10 % of 10 14 18 (6 Gy/fx) 21.9 (7.3 Gy/fx) 23 (4.6 Gy/fx) 30 (6 Gy/fx) Myelitis
subvolume subvolume
(5–6 mm above
and below level
treated per Ryu)
Adapted from Benedict SH, Yenice KM, Followill D, Galvin JM, Hinson W, Kavanagh B, et al. Stereotactic body radiation therapy: The report of
AAPM task group 101. Med Phys 2010, Aug;37(8):4078-101

required surgical resection for persistent and symptomatic
radionecrosis within 1 year of SRS. These investigators noted
that larger target volume >8.2 cm3 was significantly associ-
ated with increased acute and delayed complications due to
radiosurgery [8]. In a different series of 40 patients with intra-
cranial metastasis, Mehta et al. [133] reported a 10 % radia-
tion toxicity rate associated with radiosurgery.
Since most patients with brain metastases are exposed to
various systemic therapies, often involving novel targeted
agents, radiosensitizing effects of these new agents are not
well known and understood. There are some case reports sug-
gesting enhanced cutaneous toxicity with the combination of
BRAF inhibitors and radiotherapy but whether these effects
translate into greater neurotoxicity is not known [134].
Symptomatic cerebral edema is the most commonly
reported complication of SRS for intracranial metastases
with a range of 3–18 % [8, 135]. Typically, these complica-
tions occur over a broad time period. Focal symptoms are
usually closely related to the location of the injury and/or to
increased intracranial pressure. Whenever a patient becomes
symptomatic after radiosurgery with a headache, seizure, or
progressive neurologic deficit, the interval since radiosur-
gery and the clinical setting during which radiosurgery was
performed must first be considered. For example, was the
patient treatment with radiosurgery alone or after whole-
brain radiotherapy (WBRT)? Apart from radiation side
effects, tumor recurrence and growth must also be consid-
ered as possible causes of symptoms. Acute side effects in
the first few hours or days after radiosurgery can be treated
symptomatically for complaints of pain, nausea, and fatigue.
Seizures are quite rare in the acute setting, but if they occur,
anticonvulsant levels should be checked (if applicable), dose
adjusted (an additional half-loading dose given [orally or IV]
and the maintenance dose increased pending the results), or
the patients should be converted to anticonvulsants not
metabolized through the hepatic system (e.g., levetiracetam).
If the time from radiosurgery is weeks to months, then
edema, necrosis, tumor recurrence, and/or hemorrhage as
causes of symptoms should be considered. Evaluation in this
time period almost always necessitates evaluation with a CT
scan (if acute onset and suspicion of cerebral hemorrhage is
high; melanoma, renal cell carcinoma, and uterine carci-
noma metastases have higher propensity to bleed) or MRI. If
symptoms are relatively mild, then outpatient treatment with
corticosteroids (or increasing the dose) is a reasonable first
step. If there is no improvement in symptoms within several
days despite increased dose of steroids, then repeat MR
imaging is indicated to help distinguish radionecrosis from
tumor or rule out other causes of symptoms. If symptoms
resolve with steroids and the medication can be tapered and
withdrawn without symptomatic recurrence, then no further
intervention is required. Because long-term high-dose ste-
roids can cause a host of problems including hyperglycemia,
muscle weakness, Cushingoid facies, insomnia, irritability
and fatigue, other alternatives need to be investigated depend-
ing on the cause of symptoms (see Fig. 65.3).
Intracranial Meningiomas. Meningiomas are most com-
mon benign intracranial tumors and account for approxi-
mately 20 % of all primary brain tumors [136, 137].
Radiosurgery is often used as an alternative to surgery for
some skull base meningiomas or those in difficult locations
where complete surgical resection would not be possible or
subtotal resection would be associated with unacceptable
neurologic morbidity [138, 139]. This generally includes
petroclival, parasellar, and cavernous sinus locations.
Radiosurgery is also an excellent treatment option for many
elderly or those with significant comorbidities that make sur-
gical resection less appealing [7, 140]. In many cases, radio-
surgery is pursued as a therapeutic option even without a
tissue diagnosis [7]. Single session radiosurgery is generally
796 I.J. Barani and M.P. Mehta

Brain Metastases
SRS

Acute Phase Early-Delayed Phase Late-Delayed Phase

(days to weeks) (1-6 months) (>6 months)

Symptomatic Treatment: Symptomatic Treatment: Symptomatic Treatment:

1. Seizures - trial of steroids, if persistent - trial of steroids, if persistent
- check drug levels
- give 1/2 loading dose
- recheck levels in 7-10 days
- consider adding or changing to other drug
2. Headaches
- OTC medications
- trial of steroids, if persistent

Improvement No Improvement

Consider slow steroid taper

after 10-14 days of therapy

CT scan to rule out hemorrhage MRI to rule out recurrence

- renal cell carcinoma (RCC),
melanoma, choriocarcinoma

Suspected Radionecrosis: Tumor Recurrence:

1. additional imaging (pMRI, DWI, AA-PET) 1. Consider salvage therapy
2. institute empiric treatment - surgery (if symptomatic)
- start/continue steroids (adjust dose) - repeat radiosurgery
- pentoxyfilline, vitamin E (tocopherol) - whole-brain RT (WBRT)
- bevacizumab (Avastin) - other
- surgical resection

Fig. 65.3 Complications management algorithm in patients with brain metastases treated with stereotactic radiosurgery (SRS)

limited to lesions <3.5 cm in size and more than 2–5 mm
distant from the anterior optic structures [141–143]. Lesions
>3.5 cm in size may still be accessible to multisession radio-
surgery (three or five fractions) [144].
Radiosurgical complications after treatment for meningi-
oma include peritumoral edema (which can become symp-
tomatic), seizures, and cranial and optic neuropathies
[145–147]. Symptomatic peritumoral edema tends to occur
at a higher frequency at parasagittal and cerebellopontine
angle locations [148]. Cranial neuropathies, including optic
nerve injury, are the highest risk complications of cavernous
sinus meningioma radiosurgery [139, 149]. In a report by
Singh et al. on early complications of Gamma Knife radio-
surgery for intracranial meningiomas in 77 patients, seizures
and headaches occurred in about 10 % of patients, and a sig-
nificant number (22 %) of parasagittal meningiomas resulted
in symptomatic edema. For this reason, treatment of larger
tumors in the parasagittal location should generally be
avoided and fractionated techniques considered.
The optic apparatus is quite sensitive to radiation injury
[150]. For single-session radiosurgery, the studies have indi-
cated the relative incidence of radiation-induced optic neu-
ropathy to be rare for maximal doses to anterior optic
structures of <8 Gy. The risk increases in the range of
8–12 Gy and exceeds 10 % in the range of 12–15 Gy. One
major study indicates a low risk with maximal dose of
<12 Gy to the anterior optic structures [151], but there is
general agreement that Dmax ≤10 Gy is safe [152].
Other cranial nerves appear to be more resistant to radia-
tion than the optic apparatus, and doses up to 20 Gy can often
be tolerated [7]. Kondziolka et al. [153] reported on a series
of 50 patients treated for meningiomas with a mean marginal
dose of 17 Gy. In this series, the actuarial 2-year local control
rate was 96 % and only three patients exhibited delayed
radiosurgical complications of trigeminal hyperesthesia,
hemiparesis, and oculomotor neuropathy between 3 and 12
months after treatment. All of these complications slowly
improved over time [153].
65 Complications and Management in Radiosurgery
Meningioma
SRS
Acute Phase Early-Delayed Phase
(days to weeks) (1-6 months)
Symptomatic Treatment: Symptomatic Treatment:
1. Seizures - trial of steroids, if persistent
- check drug levels
- give 1/2 loading dose
- recheck levels in 7-10 days
- consider adding or changing to other drug
2. Headaches
- OTC medications
- trial of steroids, if persistent
3. Nausea/vomiting
- anti-emetics Improvement
- trial of steroids, if persistent
Consider slow steroid taper
after 10-14 days of therapy
MRI scan
T2 change only, no symptoms T2 change and symptoms
Continue Observation
Fig. 65.4 Complications management algorithm in patients with meningioma(s) treated with stereotactic radiosurgery (SRS)
Most cranial neuropathies after radiosurgery are mild and
improve with time, but uncommon severe complications
such as hemiparesis can develop after treatment [149, 154,
155]. For example, Chang et al. reported on a series of 179
patients treated with Gamma Knife radiosurgery for menin-
giomas and noted complications in nearly 25 %, mostly
asymptomatic edema found on follow-up imaging, and about
2 % cranial neuropathy and radionecrosis rate. Another study
by Hakim et al. [156] reported on 127 patients treated with
linac radiosurgery for meningiomas (benign, atypical, and
malignant). They reported 2 deaths (1.6 %) due to treatment-
related edema and subsequent herniation as well as relatively
high rates of hemiparesis. This study emphasizes the impor-
tance of patient selection for radiosurgery and the impor-
tance of not treating large tumor volumes with single-session
radiosurgery, and especially not in the retreatment setting.
In general, skull base meningiomas can be effectively
treated (local control rates >95 %) with radiosurgery with a
low complication profile (≤10 %). These complications typi-
cally involve cranial neuropathies, which are mild and often
recover over time, except for injury to the anterior optic
structures. Optic neuropathy may be a permanent
complication of radiosurgery but is preventable by limiting the
797
Late-Delayed Phase
(>6 months)
MRI scan
T2 change only Necrosis Tumor Recurrence
No Improvement
MRI scan Consider salvage surgery
Continue Steroids
(adjust dose as needed)
Suspected Radionecrosis:
1. additional imaging (pMRI, DWI, AA-PET)
2. institute empiric treatment
- start/continue steroids (adjust dose)
- pentoxyfilline, vitamin E (tocopherol)
- bevacizumab (Avastin)
- surgical resection
maximal dose to the anterior optic structures (chiasm, optic
nerves, and optic radiations) to <10 Gy. Many practioners
chose to limit the dose to ≤8 Gy. It is reasonable to manage
peritumoral edema (and associated symptoms) as well as
cranial neuropathies with a trial of glucocorticoids and then
follow basic clinical principles for complication manage-
ment as outlined in Fig. 65.4.
Vestibular Schwannomas. Vestibular schwannomas are com-
mon benign tumors that are frequently managed with micro-
surgery and/or radiosurgery. After radiosurgery or radiation
therapy, neurologic structures adjacent to vestibular schwan-
nomas are at risk for radiation toxicity. These structures
include the brainstem and trigeminal, facial, and vestibuloco-
chlear nerves. It has been suggested that oligodendrocytes of
the brainstem are more sensitive to radiation injury than
peripheral Schwann cells that myelinate the cranial nerves in
the transition zone and distally [7, 157, 158]. Because of this,
it has been suggested that vestibular schwannomas may be at
an increased risk of mild acute complications from SRS [159].
Miller et al. [160] reported on a series of 82 patients with
vestibular schwannomas treated with a single-session high-
versus low-dose SRS. This report suggested that a marginal
798 I.J. Barani and M.P. Mehta

dose in excess of 16 Gy is significantly associated with per-
manent facial neuropathy. Median onset to neuropathy was 6
months in this series. Interestingly, even though higher mar-
ginal dose appears to be a risk factor for trigeminal and facial
neuropathy, nearly half of the patients in this series with neu-
ropathies experience symptomatic improvement over time
[160]. Other factors that affect neuropathy rates are the length
of the cranial nerve irradiated and brainstem dose near the
root entry zone. Foote et al. [161] reported these correlations
in their study of 149 patients with vestibular schwannomas
who were treated definitively with SRS. They found that a
maximal brainstem dose (Dmax) in excess of 17.5 Gy was
found to closely correlate with trigeminal and facial neuropa-
thies in their series. For this reason, they recommended (and
it is also our institutional practice) to treat with a dose of
12.5 Gy at the tumor margin. This dose balances efficacy of
treatment with risks of complications. Surgical resection prior
to SRS was also identified as a significant risk factor for cra-
nial neuropathy in this study.
Andrews et al. [162] confirmed some of these findings in
a report of 69 patients treated with SRS for vestibular
schwannomas with a 12 Gy at the tumor margin. Facial and
trigeminal neuropathies occurred in only 2–5 % of treated
patients with a median follow-up greater than 2 years. In this
same study, audiometric data demonstrated that useful hear-
ing was preserved in only 33 % of patients; 67 % of the
treated cohort lost functional hearing after SRS [162]. Other
single institution reports noted 40–66 % hearing preserva-
tion rates [163–165].
Other less common late-delayed complications reported
after SRS for vestibular schwannomas include facial spasm
and hydrocephalus [166, 167]. In some cases, shunting may
be required to address the hydrocephalus.
Overall, the complication risk from radiosurgery using
dose of 12 or 13 Gy for vestibular schwannomas is quite
low. Most modern series report trigeminal and facial neu-
ropathy risks at less than 8 %, and in most cases these neu-
ropathies improve with time. Because the number of studies
that rigorously assess hearing preservation after radiosur-
gery is relatively small with limited sample sizes and retro-
spective design, the hearing preservation rate after
radiosurgery is not well defined, with more recent reports
being in the 50–70 % range (with variable follow-up). To
address the problem of inconsistent reporting, a consensus
meeting on reporting systems for vestibular schwannoma
was convened in 2003 and created reporting definitions;
however, these have not been widely adopted by investiga-
tors (Fig. 65.5) [168].

Vestibular Schwannoma
SRS

Acute Phase Early-Delayed Phase Late-Delayed Phase

(days to weeks) (1-6 months) (>6 months)

Symptomatic Treatment:
1. Nausea/vomiting
- anti-emetics
- trial of steroids, if persistent
2. Headaches
- OTC medications
- trial of steroids, if persistent
3. Exacerbation of existing symptoms
- trial of steroids, if persistent
MRI scan Symptomatic Treatment: Motor & Sensory Symptoms
T2 change only, no symptoms 1. Trigeminal pain
- carbamazepine, gabapentin
- trial of steroids, if persistent
2. Hearing loss or facial weakness
- trial of steroids, if persistent
Improvement No Improvement MRI scan

Continue Observation Consider slow steroid taper Continue Steroids

after 10-14 days of therapy (adjust dose as needed)

T2 change only and symptoms: Suspected Radionecrosis:

1. short-course steroids; consider
slow taper after 10-14 days of therapy
if improvement
2. if no improvement, consider surgery
1. additional imaging (pMRI, DWI, AA-PET)
2. institute empiric treatment
- start/continue steroids (adjust dose)
- pentoxyfilline, vitamin E (tocopherol)
- bevacizumab (Avastin)
- surgical resection

Fig. 65.5 Complications management algorithm in patients with vestibular schwannoma treated with stereotactic radiosurgery (SRS)
65 Complications and Management in Radiosurgery
AVMs. Radiosurgery is an effective treatment of AVMs in
any brain location for both children and adults, with oblitera-
tion rates depending primarily on the AVM size and prescrip-
tion dose. Complications of treatment also depend on the
AVM location, size, prescription dose, 12-Gy isodose vol-
ume, age, radiographic method used for target definition,
perforating artery supply, and era of treatment. Complications
of AVM treatment are highly variable and inconsistently
reported.
The treatment of pediatric AVMs poses unique challenges
because the effects of radiation on developing brain and the
risk of second malignancy need to be considered. Balanced
against these concerns are the mortality and morbidity of
hemorrhagic events over the number of remaining years of
life (assuming 2 % annual incidence of hemorrhage). For
example, Kaido et al. [169] reported on a development of a
glioblastoma 6.5 years in a boy who was treated for a peri-
ventricular AVM 6.5 years earlier with a marginal dose of
20 Gy. Levy et al. [170] reported on a series of 53 consecu-
tive children who underwent at least 3 years of imaging fol-
low up after radiosurgery of intracranial AVMs. They
grouped patients into three groups based on the volume of
the treated AVM: (1) group 1, ≤3 mL, (2) group 2, >3 mL but
≤10 mL, and (3) group 3, >10 mL. Twenty-eight patients
(80 %) in group 1 and 11 (64.7 %) in group 2 achieved com-
plete obliteration during the follow-up period, and only one
patient in group 3 did not achieve obliteration. This study
demonstrated effectiveness of radiosurgical treatment for
pediatric AVMs. Brainstem edema was the primary intracra-
nial complication, reported in 1 patient in the series. Four
patients experienced hemorrhagic events between 30 and 98
months after SRS. In this study, small target volume dose
were associated with likelihood of obliteration.
A comprehensive report by Flickinger et al. [171] did
much to solidify our understanding of the risk of complica-
tions after AVM radiosurgery. In an analysis of 85 patients
with a median follow-up of 45 months, the volume of brain
receiving ≥12 Gy was used to construct a post-radiosurgery
expression score (PIE). In addition to 12-Gy volume, ana-
tomic location was also associated with increased risk of
complication (from low to high risk: frontal, temporal,
intraventricular, parietal, cerebellar, corpus callosum, occipi-
tal, medulla, thalamus, basal ganglia, and pons/medulla).
Larger AVMs are associated with lower obliteration rates,
longer time to obliteration after treatment, and an increased
incidence of complications. Two prevailing approaches were
used to try to improve outcomes in these patients: (1) multi-
session radiosurgery and (2) volume-staged treatments.
Single-institution reports of these various approaches report
marginal success in achieving obliteration rates and there is
no convincing study to suggest that one approach should be
preferred over the other [172–176].
799
The management of complications in AVM patients is
more involved than that of brain metastases after SRS since
it is important to rule out intracranial hemorrhage via CT
urgently in patients who present with a new, severe head-
ache, nausea, vomiting, and/or new neurologic deficit. For
those patients with history of prior hemorrhage and who are
not candidates for surgical intervention and have intranidal
aneurysm, evaluation for endovascular treatment of the
aneurysm is recommended (but not of the entire AVM).
Patients with known feeding artery aneurysms should first
undergo surgical or endovascular treatment of these aneu-
rysms before radiosurgery. Early-delayed effects of SRS
such as edema are not uncommon but majority of patients
tend to remain asymptomatic. Cyst formation, as a late com-
plication of SRS, is rare and can be treated surgically if it is
symptomatic (see Fig. 65.6).
Conclusion
Radiosurgery is a very effective and popular treatment option
for several common intracranial diagnoses and represents a
major development in neurosurgery and radiation oncology
over the last 30 years. For some treatment indications, such
as small vestibular schwannomas and meningiomas, it is
becoming the de facto treatment of choice given its effective-
ness and favorable side effect profile. As with any other form
of therapy, there remains the risk of treatment-associated
complications, although these risks are small and have been
reduced as experience with various radiosurgical techniques
has grown. The key to management of radiosurgical compli-
cations is prevention (to the extent of possible) of known or
expected side effects by judicious and thoughtful application
of radiosurgical principles and available dose–volume con-
straints to guide treatment planning. Robust and rigorous
quality assurance and safety programs need to be in place to
maximize patient safety and achieve the desired clinical out-
comes. This requires a multidisciplinary team and constant
evaluation of outcomes data. Since most of the radiosurgical
data are generally of limited quality (retrospective, single-
institutional studies), it is imperative that further/future
research, including toxicity reporting and management, is
standardized and consistently reported to aid in interpreta-
tion of published outcomes and toxicity data. Use of consen-
sus outcomes definitions needs to be made part of daily
clinical practice and use of anecdotal data to justify treat-
ment decisions needs to be discouraged. This robust and pro-
spective approach must be applied to treatment-related
toxicity management, especially as new treatment approaches
(e.g., bevacizumab for radiation necrosis) become increas-
ingly available and applications of radiosurgery continue to
be extended.
800
Arteriovenous Malformation
SRS
Acute Phase Early-Delayed Phase
(days to weeks) (1-6 months)
Symptomatic Treatment: Severe headaches Mild worsening symptoms
1. Seizures New focal deficit
- check drug levels
- give 1/2 loading dose
- recheck levels in 7-10 days
- consider adding or changing to other drug
2. Headaches MRI scan
- OTC medications T2 change only, no symptoms T2 change and symptoms
- trial of steroids, if persistent
3. Nausea/vomiting
- anti-emetics Continue Observation
- trial of steroids, if persistent
CT to rule out hemorrhage
Hemorrhage No Hemorrhage
- Re-evaluate for surgery
Fig. 65.6 Complications management algorithm in patients with arteriovenous malformations (AVMs) treated with stereotactic radiosurgery
(SRS)
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Yamamoto M, Gorman DA, Schomberg PJ, Sneed P, Larson D,
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 Building a Radiosurgery Practice
Ali Farooqui and N. Scott Litofsky
Introduction
One of the major trends in medicine over the last decade is
the development of minimally invasive techniques for the
performance of surgical procedures. Both physicians and
patients prefer these techniques because they are typically
easier to perform and result in less pain and a quicker recov-
ery. Additionally, insurance companies also prefer these pro-
cedures because patients experience shorter hospital stays
due to the fast recovery period, which ultimately results in
fewer costs for insurance companies. In order to best develop
minimally invasive procedures, the medical community has
had to address several key issues. These include the develop-
ment of the necessary technologies to perform the proce-
dures, identification of appropriate patient profiles and
disease processes that lend themselves to these treatments,
and education of physicians—both those that treat the dis-
eases and those who refer patients for such treatments—
about the procedures.
In neurosurgery, one of the most prevalent minimally
invasive techniques is stereotactic radiosurgery. Stereotactic
radiosurgery is a technique in which a single, high dose of
ionizing radiation is focused on a three-dimensional target
volume using stereotactic guidance. A variety of radiation
sources, imaging technologies, and stereotactic localizing
devices have been developed to make this procedure read-
ily available to patients throughout the world. Neurosurgeons
beginning their own practice, joining an existing practice,
or becoming a hospital employee must determine if they
will perform radiosurgery and how they will incorporate
A. Farooqui, M.D.
N.S. Litofsky, M.D., F.A.A.N.S., F.A.C.S. (*)
Division of Neurological Surgery, Department of Surgery,
University of Missouri School of Medicine, One Hospital Drive,
DC048.00, MC326, Columbia, MO 65212, USA
e-mail: farooquia@health.missouri.edu;
litofskyn@health.missouri.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_66, © Springer Science+Business Media New York 2015
66
radiosurgical procedures into their practice. They must
determine how to interface with the various disciplines
involved in order to be part of a cohesive working group.
They must let physicians and patients inside and outside the
community know about radiosurgery as an available treat-
ment option. This chapter discusses from a neurosurgery
perspective many of the issues that one should consider
when building a radiosurgery practice from the ground up.
Current Utilization and Potential
Future Growth
The current neurosurgeon (and radiosurgeon) should be
aware of the tremendous growth of the field since its incep-
tion. As potential new indications for treatment develop,
patients who would previously not have been treated become
candidates for radiosurgery. In addition, the growth of radio-
surgery represents a paradigm shift in treatment, which
means that patients who previously have been treated by
other means, such as open craniotomy, may now defer those
treatments in favor of radiosurgery.
Lars Leksell of the Karolinska Institute introduced the
term stereotactic radiosurgery in 1951, and he treated his first
patient with the Gamma Knife, a cobalt-60 source of ioniz-
ing radiation, in Sweden in 1967. Dade Lunsford at University
of Pittsburgh introduced the Gamma Knife to the USA, treat-
ing his first patient in 1987 making the Pittsburgh unit the
fifth in the world. By 1999, 123 Gamma Knife units were in
use worldwide [1], and by 2012, that number grew to 257
[2]. Linear accelerator (LINAC) radiosurgery programs
developed later; the first unit was established in Barcia-
Solario, Spain, in 1982. Lutz and Winston started the first US
LINAC radiosurgery program in Boston in 1986, and its sub-
sequent growth has exceeded that of the Gamma Knife. In
1999, more than 200 LINAC programs existed in the USA
alone [1]; today linear accelerators are now found in almost
every major medical center in the USA [3]. A third form of
delivery of ionized radiation for radiosurgery—heavy
807
808
charged particles—has also been available since the 1950s
(initially at Lawrence Livermore in Berkeley). A handful of
programs are available in the USA and throughout the world
(41 in 2012) [4], but this technology has been limited by the
cost of building a cyclotron to produce the protons with the
final price of a proton therapy center currently on the order of
between 120 and 300 million dollars [5].
Clinical indications for treatment with stereotactic radio-
surgery have expanded as availability has increased. The
largest group of patients is those with metastatic tumors to
the brain, for which several studies have shown radiosurgery
to be more cost-effective than open surgery [6, 7]. Patients
with gliomas who have been treated with radiosurgery have
improved survival compared to others [8]. Benign tumors,
such as meningiomas, particularly those involving the skull
base or dural sinuses are frequent targets, as are schwanno-
mas and pituitary adenomas. Arteriovenous malformations
can be effectively treated with radiosurgery. Additionally,
epilepsy, trigeminal neuralgia, pain, and movement disorders
are all treatable with radiosurgery [1, 9]. Although Leksell
initially developed radiosurgery to create lesions for func-
tional neurosurgery, such use has become routine only in the
last few years.
Future Growth of Radiosurgery
Current clinical indications create a theoretical patient base
of about 171 patients per million in the USA who could be
candidates for stereotactic radiosurgery (Table 66.1) [10].
The number actually treated is not nearly this high because
other forms of therapy are often utilized due to lesion loca-
tion, size, or number. In actuality, according to data from the
Innovations Center, about 72,000 patients could be treated
with radiosurgery each year [11]. Because of increased cost-
effectiveness, lower procedural morbidity, and patient
choice, radiosurgery is used increasingly as the first line
treatment for its indications. As such, craniotomy as a treat-
ment is expected to slightly decline over the next decade,
with radiosurgery volumes increasing by almost double. For
instance, radiosurgery cases for neuro-oncologic indications
are expected to increase from about 18,000 in 2004 to
32,000 in 2014 [11]. Furthermore, many patients previously
thought to have inoperable lesions due to location or patient
health are now candidates for stereotactic radiosurgery.
Population aging and population growth will also increase
potential patient volumes. Lastly, as patient becomes more
informed about health-care options, they are more and more
frequently requesting treatment with minimally invasive
techniques like radiosurgery [12]. Clearly, the demand for
stereotactic radiosurgery treatment will encourage the
involvement of new providers where availability is low to
improve patient access.
A. Farooqui and N.S. Litofsky
As part of a current and continuing national trend to
develop centers for neuroscience care, radiosurgery pro-
grams are and will be a “hot” topic for the next several years.
Radiosurgery is also an important component of neurologi-
cal surgery residency training. The Residency Review
Committee (RRC) for neurological surgery has expanded the
specialty definition of neurological surgery to include treat-
ment of diseases of the brain and spinal cord and their cover-
ings and blood supply with stereotactic radiosurgery. This
expanded definition presupposes that neurosurgeons receive
clinical and didactic training in radiosurgery during resi-
dency training. Currently, the RRC requires neurosurgery
residents to complete and participate in a minimum of ten
adult cranial radiosurgery cases [13].
Concerns have been raised about potential market satura-
tion as new programs are built, which can limit individual
program patient volumes [11]. Despite these concerns, the
role of stereotactic radiosurgery as a tool to treat diseases of
the nervous system is quite high and should remain so for the
foreseeable future.
Radiosurgery in Residency Training
As mentioned above, exposure to radiosurgery is an integral
part of residency training. The Residency Review Committee
does not specify how that training should be accomplished,
leaving those details to each individual program.
Each training program tends to tailor the radiosurgery
experience for its residents to the unique circumstances of
the program. Didactic education may come in the form of
lectures, either as part of curriculum conference or as Grand
Rounds. Individualized reading will also likely be required.
Textbooks, such as this one, are an excellent source to expand
one’s breadth of knowledge. Recently, Kondziolka detailed
the 100 most cited radiosurgery papers written; a number of
these form the foundation of the principles of stereotactic
radiosurgery outlined in texts, including indications, out-
come, dose consideration, and complications [14]. Reading
the source literature, while perhaps more labor intensive, can
help crystallize one’s thinking about the information offered.
Recently, the University of Florida posted an online com-
puter module that was made available to all training pro-
grams to enhance didactic radiosurgery education [15].
Knowledge of the various radiosurgery systems in use is
helpful, as one does not always know what device will be
available in one’s practice setting.
Radiosurgical experience in the form of surgical cases is
paramount to incorporating stereotactic radiosurgery one’s
clinical practice. Although the RRC for neurologic surgery
did mandate that each resident participate in a minimum of
ten radiosurgery cases before the completion of residency
training [13], mechanisms by which the resident will obtain
66 Building a Radiosurgery Practice 809

Table 66.1 Population- Market Size

based market size for National
Incremental Total SRS
Annual Treatable with
diseases treatable by Lesion Treatable Incremental
Incidence per SRS
stereotactic radiosurgery Patients per Treatable
Million
Million Patients
Arteriovenous
19 70% $13 8
Malformation
Benign Neoplasms 20 40% $8 5
Neoplasms of
4 25% $1 1
Uncertain Behavior
Malignant
40 25% $10 6
Neoplams
Brain Metastases 425 25% $106 59
Meningioma 8 25% $2 2
Pituitary Adenoma 21 20% $4 3
Trigeminal Neuralgia 43 50% $21 12
Vestibular
9 70% $6 4
Schwannoma
Total 589 39% $171 100
From: Innovations Center, Health Care Advisory Board. Future of Neurosciences;
Strategic Forecast and Investment Blueprint. The Advisory Board Company 2008;
used with permission.

that case experience is not so certain. Almost always, radio-
surgery cases are performed as outpatient procedures and
frequently off-site from the hospital in which the residents
rotate. To solve this problem, some programs, including
Johns Hopkins, University of Pittsburg, and University of
Missouri-Columbia, have established elective or selective
rotations to ensure that residents receive adequate exposure.
At Johns Hopkins, for example, a 4-month block during the
PGY-4 year is devoted to functional and stereotactic radio-
surgery. In other programs, the resident may need to make
some additional effort to be able to participate; understand-
ing that minimum case numbers are required for residency
completion may provide the necessary impetus.
Practice Development
Decision to Proceed
The first step in developing a radiosurgery practice is making
the decision to include radiosurgery in one’s personal proce-
dural offerings to patients. Not all neurosurgeons perform all
procedures. Even neurosurgeons in general practice have the
option to chose the types of cases they wish to do and refer
other cases to other neurosurgeons, either within the same
group, to another group, to local academic center, or to a
distant academic center.
If one is in an academic neurosurgical practice or a large
group private practice, individuals in the group may have
subspecialty interests. Sometimes, a neurosurgeon can spe-
cialize in radiosurgery only. Colleagues within the group,
neurosurgeons and radiation oncologists who do not do
radiosurgery, and other physicians will refer potential cases
to that particular individual for evaluation and treatment. In
other instances, a neurosurgeon may have subspecialty inter-
ests for which radiosurgery can be a treatment option for
patients. Given the current indications for radiosurgery, such
subspecialties include neuro-oncology, functional neurosur-
gery (pain or movement disorders), epilepsy surgery, and
cerebrovascular surgery. Neurosurgeons focused on these
subspecialties may also chose to treat patients with other
“non-subspecialty” disease processes with radiosurgery;
while the targets and doses may be different, many of the
technical principles are similar.
A general neurosurgeon in private practice or academic
practice may also include radiosurgery as part of his/her clin-
ical offerings. Clinical volume may be, but is not necessarily
less than in the previous circumstances, depending on one’s
local environment. For instance, in a medical community
with a 500,000 catchment area, if four neurosurgeons are
each offering radiosurgery, one’s case volume may be less
than five cases per year; the neurosurgeon may decide that
for that volume, she/he would rather refer appropriate radio-
surgery cases to another colleague.
The neurosurgeon should consider a number of factors in
making the decision of whether or not to include radiosur-
gery as part of one’s practice. Perhaps the first factor is “what
is the potential volume of patients available to treat?” By
extrapolating data of potential case volume and population,
perhaps one radiosurgery case could be performed for every
4,000 people each year. Volume, however, is not usually this
high. One needs to assess the extent of out-migration from
his/her catchment area and how many other practitioners are
doing radiosurgery locally, as referral patterns may be diffi-
cult to break. Another factor is the proximity of radiosurgery
facilities to one’s office or hospital(s). Many planning
systems can permit remote planning, which makes distance
less of an issue; in contrast, travel time is not usually being
810 A. Farooqui and N.S. Litofsky

$12,000
$10,910 $10,910
$10,543 $10,543
$9,671
$10,000 $9,261

$7,752
$8,000 $7,262

$6,000 2007
2008
$4,000

$2,000

$0
Gamma Knife LINAC CyberKnife Robotic LINAC

Fig. 66.1 Changes in CMS reimbursement for outpatient SRS by Medicare over 1 year. From: Innovations Center, Health Care Advisory Board.
Future of Neurosciences; Strategic Forecast and Investment Blueprint. The Advisory Board Company 2008; used with permission

Table 66.2 Changes in physician charges and RVUs at a single institution for various CPT codes
2008 2009 2010 2011 2012
CPT Code Lesion
Charge RVU Charge RVU Charge RVU Charge RVU Charge RVU
61793 1 or more $4,825 17.75 N/A N/A N/A N/A N/A N/A N/A N/A
61796 Under 3.5 N/A N/A $1,717 10.79 $2,100 13.93 $2,100 13.93 $2,100 13.93
61797 Additional N/A N/A $478 3.48 $478 3.48 $500 3.48 $500 3.48
61798 Over 3.5 N/A N/A $1,717 10.79 $1,717 19.85 $2,800 19.85 $2,800 19.85
61799 Additional N/A N/A $616 4.81 $661 4.81 $1,152 4.81 $1,152 4.81
63620 Spinal N/A N/A $1,717 10.79 $1,717 15.6 $1,717 15.6 $1,717 15.6
63621 Additional N/A N/A $549 4 $549 4 $556 4 $556 4

used for other productivity. The expectations of one’s
employer may be an issue. A hospital-employed neurosur-
geon or one joining an existing group (academic or private
practice) may be expected to include radiosurgery to meet
service needs. The type of radiosurgery system(s) available is
also important to consider. The device may not be the same
as used during residency or other practice venues, and pur-
chase of a familiar device or system is not practical for an
individual and unlikely for an institution unless its present
system is ready for upgrade or replacement. Therefore, a
neurosurgeon may need to obtain additional training in
anticipation of including radiosurgery in practice. A vendor-
sponsored course or a trip to a center with the particular
radiosurgery platform can go a long way to increasing com-
fort with the existing system.
Current and potential future levels of reimbursement are
also an issue. The National Health Care Advisory Board had
suggested a potential decrease in reimbursement in 2008
[10]. Figure 66.1 shows the change in total radiosurgery
reimbursement per case by Medicare between 2007 and
2008. Table 66.2 illustrates the changes in physician billing
per case at the University of Missouri from 2008 to 2012,
which shows the dynamic change in the billing for radiosur-
gery. Over the span of one year the RVU for radiosurgery
dropped by seven units resulting in a significant decrease in
reimbursement. However, over the following years, the total
charges and RVUs have steadily increased. In addition, more
CPT codes were added to allow for better characterization of
the treatments being performed. Although there has been an
overall decrease in the reimbursement of stereotactic radio-
surgery, the earning potential may be equivalent due to the
unbundling of the CPT codes. The future of radiosurgery
reimbursement is difficult to predict, but the reality of the
situation is that it will depend heavily on the political and
socioeconomic condition of the country and its effects on the
health-care system at large.
66 Building a Radiosurgery Practice
Time spent on radiosurgery means time not spent on other
types of cases. Compensation for these other cases may
exceed reimbursement from radiosurgery; therefore, personal
economics also enters the equation.
One should also keep in mind that radiosurgery is just one
of several options for treating particular disorders. A physi-
cian’s selection of radiosurgery versus open surgery for a
procedure depends on the individual situation and patient, as
one method may be preferred or superior to the other for
various reasons. However, offering radiosurgery increases
the scope of one’s practice, thereby increasing procedure
volume and thus profits. For example, some patients have
absolutely no interest in an open operation if a minimally
invasive option is available, even if open surgery has some
clear advantages. By offering radiosurgery, one’s practice
volume can benefit from those patients who may otherwise
choose to leave the area to receive radiosurgery elsewhere
when it is not locally available. Lastly, as indications for
radiosurgery change, additional patient volumes may accrue.
Two examples are worth mentioning. A patient with multiple
brain metastases, one of which is very large and symptom-
atic, may be a candidate for radiosurgery for the smaller
lesions after surgical resection of the large one. In another
case, a patient with a single metastasis may be a candidate
for radiosurgery to the postoperative tumor bed instead of
whole-brain radiotherapy. In both circumstances, being able
to provide radiosurgery generates additional case volume to
the neurosurgeon that, in the absence of radiosurgery capa-
bilities, would not have been available.
Becoming Credentialed
Institutions and patients both want to be certain that physi-
cians who care for patients are qualified to do so. Radiosurgery
is no different from any other treatment in that regard. For
neurosurgeons, radiosurgery is not as technically demanding
as other procedures (microvascular surgery, for instance), but
it does require a significant cognitive skill set. The neurosur-
geon needs to know which patients and lesions are appropri-
ate for treatment, what structures are potentially in harm’s
way during treatment of a particular patient, what is an
appropriate target volume, etc. Knowledge of radiation
dosimetry is helpful when interfacing with the radiation
oncologist, who must frequently incorporate past radiation
treatments into a radiosurgery prescription to achieve an
effective dose without undue long-term sequela. Therefore,
neurosurgeons who provide radiosurgery need to be creden-
tialed. Such credentialing is particularly important if the
radiosurgery center is open to multiple physicians from out-
side the hospital/clinic in order for the center to maintain
quality control.
811
A few credentialing protocols have been described for
neurosurgeons [16, 17]. Some centers may incorporate all, a
portion, or none of these protocols. Completing the require-
ments for credentialing is usually not particularly arduous,
but should be anticipated. Most credentialing requirements
will probably include at least some of following features:
• Neurosurgeons should complete a radiosurgery course,
ideally sponsored by the vendor of the software/hardware
being used at the Center. The course should include simu-
lated cases. Most vendors provide such a course for phy-
sicians as part of the purchase of their devices. The
neurosurgeon may need to pay for the course; such costs
can be negotiated as part of the contractual process for
hospital or group-employed neurosurgeons.
• Neurosurgeons should have experience in stereotactic
surgery. Such experience demonstrates competence and
understanding of volumetric localization of targets in
three-dimensional space and insures that Halo ring immo-
bilization, which many systems require, will be well
accomplished. Cases providing such experience, in addi-
tion to radiosurgery, include deep brain stimulation and
stereotactic brain biopsy.
• The neurosurgeon should perform a number of radiosur-
gery cases under the direct supervision of an experienced
neuro/radiosurgeon. This supervised experience may
occur during residency training or as an attending
neurosurgeon.
Documentation of the experience is important as well.
Case number may vary. Cleveland Clinic specified that either
the neurosurgeon or radiation oncologist involved in a case
has residency experience of 50–100 cases or attending expe-
rience of 25–50 cases [17]. Initial supervision by a senior
colleague may also be necessary [16].
Building a Referral Base
Once a neurosurgeon decides to perform radiosurgery, she/
he should identify potential referring physicians. These phy-
sicians may be from within one’s hospital community or
from the surrounding area. Again, consideration of the indi-
cations for radiosurgery can help identify to which physi-
cians the neurosurgeon should reach out to explain the
available services.
One key group of potential referring physicians should be
radiation oncologists. Radiation oncology collaborates with
neurosurgery for patient treatment in most centers. The radi-
ation oncologist is usually responsible for the radiation dose,
as well as supervising the physics personnel involved with
developing the treatment plan. Radiation oncology is often,
but not always, the responsible party for upkeep and quality
assurance of the devices used to generate and deliver the ion-
812
izing radiation. In some centers, a single radiation oncolo-
gist may have radiosurgery responsibilities; in others, those
duties may be shared. Identification and dialogue with radia-
tion oncologists outside the locale or who would not be
participating in radiosurgery procedures is also helpful.
Discussion with these radiation oncologists is appropriate to
define groups of patients for to treat with radiosurgery.
Updating them on evolving radiosurgery indications, such as
radiosurgery to multiple lesions, radiosurgery to the tumor
bed after resection, fractionated radiosurgery for large
lesions, and radiosurgery for spinal lesions, is appropriate
[18–21]. Sharing references can be helpful, as some indica-
tions represent a paradigm shift for radiation oncology, as
well as for neurosurgery.
Although medical oncologists do not directly participate
in stereotactic radiosurgery treatment, their participation as
referring physicians is essential, since patients with meta-
static carcinoma represent the largest group of patients to
treat. Better patient referral can be expected when the medi-
cal oncologists understand the issues related to stereotactic
radiosurgery treatment.
While radiation oncologists and medical oncologists will
likely account for the majority of referrals, other physicians
should not be discounted. Endocrinologists should become
aware of the potential for radiosurgery to treat pituitary
tumors refractory to surgical resection. Otolaryngologists
often refer patients with vestibular schwannomas.
Neurologists may be a source of patients with trigeminal
neuralgia, epilepsy, movement disorders, or arteriovenous
malformations. Dentists and oral surgeons may also refer
patients with trigeminal neuralgia [11]. Because pediatric
patients can account for 10–15 % of patients in some centers
[22], pediatricians and pediatric oncologists are also a poten-
tial source of referrals that can be cultivated.
Marketing to the Community
Success in building a radiosurgery program can be related to
marketing to the medical community as well as to patients.
Potential referral sources as described above need to know
that radiosurgery expertise is available. Helpful information
includes a list of the clinical indications for radiosurgery,
inclusion and exclusion criteria, the sequence of events
involved in treatment of a patient, and how to refer patients
for treatment. A variety of means of communicating this
information are available. Presentations at medical staff
meetings, mailed brochures or letters, Grand Rounds presen-
tations, and conferences are all useful for marketing pur-
poses, particularly since they also provide appropriate
education about radiosurgery. The Internet has also increased
physician and patient access to information about radiosur-
A. Farooqui and N.S. Litofsky
gery. Additionally, direct phone calls from physicians per-
forming radiosurgery to referring physicians can be very
effective. Finally, promptly communicating back to referring
physicians after assessing patients enhances the process.
Marketing to patients directly is also important. Because
patients are using the Internet more often as their source of
medical information, physicians who do not utilize Web sites
are at a distinct disadvantage as patients look for options for
treatment of their ailments. Therefore, information on a Web
site should be written at a level that patients can compre-
hend. For example, reduction or simplification of medical
vocabulary is helpful to make the information more under-
standable. Television and radio spots, although more expen-
sive, can also be used to enhance one’s marketing to patients.
The physician can augment marketing also by partnering
with the institution housing the radiosurgery center. Two dif-
ferent strategies for marketing are available [11]. In the first,
marketing revolves around the radiation delivery device as
the key point of focus. The institution’s advertisements indi-
cate that it has the capability of treating patients with a
Gamma Knife, a Cyberknife, a Trilogy, or any other delivery
system that has been purchased for the program. This type of
product marketing appeals to patients by name-recognition
of a particular device. An alternative strategy focuses on the
particular disease process—like trigeminal neuralgia, or
AVMs, or brain tumors—and notifies the public that a nonin-
vasive treatment modality is available for that disease. Both
strategies, especially if used together, can be very effective.
Even though marketing is important to increase physician
and patient awareness about radiosurgery as a tool to treat
diseases, it is important to avoid exaggeration and misrepre-
sentation in information provided, particularly on the
Internet, where there are no truth-in-advertising regulations,
and where “data” can be promulgated directly to patients
without scientific peer review [23]. Brada and Cruickshank
[24] raised such concerns in an editorial in the British
Medical Journal. Unfortunately, these concerns were lost in
the authors’ own misrepresentations [25–28]. As centers and
physicians market their expertise and capabilities, they must
provide accurate information to maintain their credibility.
Practical Practice Issues
Common Radiosurgery Systems
In most circumstances, a neurosurgeon will utilize a radiosur-
gery system already in existence in a hospital or free-standing
clinic. While a detailed description of each potentially avail-
able system is beyond the scope of this chapter, an under-
standing of the potential pros and cons of each system in
terms of the neurosurgeon and patient interface with the sys-
66 Building a Radiosurgery Practice
tem is important. System cost, while important for the pur-
chaser, has less importance to the individual physician unless
that physician is involved with initial purchase in an advisory
capacity or as an investor. For purchase, factors such as
patient population base, institutional financial resources, and
physician preference all play a role in determining which
device may be most appropriate. Generally speaking, while
each device has its advantages and disadvantages, the treat-
ment efficacy of each is relatively equivalent [29].
Proton beam systems are the least common systems avail-
able. The few that are present are usually associated with
academic medical centers. Their scarcity likely relates to the
fact that proton beam systems are by far more expensive.
Since proton beam systems are so uncommon, their issues
will not be discussed further here.
Gamma Knife, which has the longest track record for
radiosurgical treatment, is probably the best technology from
a marketing perspective. As a radiosurgical tool, Gamma
Knife has the most widespread name recognition. When
patients inquire about radiosurgery, they usually ask, “Is that
the Gamma Knife?” Many physicians also generically refer
to radiosurgery as “Gamma Knife.” Gamma Knife planning
times are fairly short, so more than one patient can be treated
in one day. It has fewer moving parts than other systems, so
maintenance and downtime is less; more patients per year
can theoretically be treated [30, 31]. Purchase of a Gamma
Knife has allowed some programs to grow greatly, exceeding
expectations of programs’ directors [17]. For greater than
200 radiosurgery patients per year, Gamma Knife has lower
overall costs than a LINAC [31]. In a setting in which a large
treatment population is available, the Gamma Knife is a fre-
quent choice because of its ease of operation, ability to pro-
vide conformal dose plans for a wide variety of target shapes
and sizes, and general familiarity of the device [32].
Despite its advantages, Gamma Knife has several limita-
tions. Initial costs for Gamma Knife are higher than for
LINAC systems [30]; it costs approximately $3.2 million.
Also, because of the radiation decay half-life of 5.25 years,
the treatment time doubles after 5 years. The cobalt sources
therefore must be replaced every 5 years at considerable
expense (estimated at $750,000). An upgraded radiation
vault is also required, running about $700,000 when pur-
chased new. Maintenance contracts, which all systems
require, are about $145,000 [11]. Another drawback of the
Gamma Knife is that it can only be used for intracranial
applications. Because breakeven volume is estimated at 86
patients per year [11], small volume centers may have diffi-
culty recouping their investment. Gamma Knife also requires
rigid head immobilization; some new technologies can be
used without application of a Halo ring (required by most
Gamma Knife units), which improves patient comfort. Most
institutions utilizing Gamma Knife still require rigid head
813
immobilization with a frame; a few institutions across the
world, however, have begun to utilize the Extend program
for the Gamma Knife that relies on a mouthpiece and a head-
rest, thereby eliminating the use of a head ring.
CyberKnife is a robotic LINAC equivalent used for
stereotactic radiosurgery. It is a relatively new delivery system,
developed in 1997 at Stanford University, and approved by
the FDA in 2001 [33, 34]. It does not require rigid head
immobilization, and it can be used for intracranial and extra-
cranial indications, but only for stereotactic or IMRT indica-
tions; it cannot be used for standard LINAC applications. For
ease of the provider, it has the capability to accommodate
multiple remote planning stations. Cost is about $3.5 mil-
lion. Annual hardware and software upgrades may run
$225,000–$450,000; an upgraded vault is also required.
Most facilities will breakeven financially treating 109
patients per year [11]. Because Cyberknife is a small linear
accelerator, treatment times are somewhat longer than those
systems using a standard LINAC. Cyberknife also is devel-
oping name recognition, which helps marketing to physi-
cians and patients. Furthermore, because a rigid head frame
is not required for treatment, some patients specifically
request treatment with Cyberknife, as opposed to Gamma
Knife or other frame-based LINAC treatments.
A number of LINAC-based systems are available. Vendors
include Varian (Trilogy), Integra, and Brainlab. Each system
has somewhat different features, but all the systems have
remote planning capabilities. The Integra system requires a
head ring for treatment purposes. A new system cost about
$2.5–3.2 million in the early 2000s. Currently, the cost of
maintenance and cost of a new system are somewhat guarded
by the vendors and not open for publication due to various
financing options that each vendor allows. If used solely for
radiosurgery, breakeven patient volume for LINAC systems
has been 122 patients per year [10]. But because the LINAC
can be used for other radiation indications, radiosurgery vol-
ume does not need to be nearly that high. Retrofitting an
existing LINAC to perform radiosurgery with the usual cone
collimators is probably the most inexpensive means of begin-
ning a radiosurgery program. Software planning systems are
available for several hundred thousand dollars.
One feature of the LINAC system is a mini-multileaf col-
limator (MMLC) to enhance treatment options. MMLCs allow
shaping of X-ray beams to conform more precisely to the
shape of the lesion in the beam’s eye view. They permit more
homogenous radiation dosing to the lesion than can be
obtained with either the Gamma Knife or circular collimators
using noncoplanar arcs [35]. Using an MMLC, each lesion
can be treated using a single isocenter, or target, which permits
faster treatment time. Frequently, an MMLC can be added to
an existing LINAC. MMLCs tend to be a bit bulkier than cir-
cular cone collimators, so physics staff and radiation therapists
814
must be aware of the possibility of collision between the
LINAC and the patient/couch [36]. An MMLC and its accom-
panying software can be added to an existing LINAC.
Novalis, made by Brainlab, is an example of a standard
LINAC-based device. With its software and hardware addi-
tions, it can be used for intracranial and extracranial radio-
surgery. An additional feature is that it can also be used for
standard radiation therapy and IMRT. Therefore, it can func-
tion as a backup linear accelerator. Novalis, like CyberKnife,
does not require rigid head immobilization for most of its
radiosurgery indications; such immobilization is available
for functional indications such as trigeminal neuralgia to
improve accuracy. Novalis also includes an MMLC within
its platform. Beams can be shaped in either static or arcing
fields to increase flexibility. Treatment times with Novalis
(7 Gy/min) are faster than for CyberKnife (4 Gy/min)
because it is similar to a standard LINAC. For programs with
small anticipated radiosurgery volumes, a LINAC-based
program may make the most sense [32].
Identification of Space
Radiosurgery is a fluid surgical procedure. Components of
the procedure include patient assessment, treatment plan-
ning, and patient treatment. When building his/her radiosur-
gery practice, the neurosurgeon needs to consider where she/
he will perform these tasks. Consideration for efficient use of
time is essential.
Patient evaluation usually will occur during clinic, or
office, time. One option to consider for a physician with a
heavy radiosurgery practice is to see patients in the radiation
facility. This option has a number of advantages. First, the
neurosurgeon has easy access to his radiation oncology col-
league to discuss cases. Second, the neurosurgeon can also
do radiosurgery procedures while seeing patients, so that
she/he is readily available for the key portion of the proce-
dure. The neurosurgeon can do his/her portion of treatment
planning in between patients and can readily review dosim-
etry. Last, radiosurgery patients will have some familiarity
with the facility prior to treatment and can see the radiation
oncologist and neurosurgeon in close proximity in space and
time, making “one-stop shopping” possible, and thereby
improving patient satisfaction.
Treatment planning can easily occur in the radiation
dosimetry section. This location may not be convenient for
the neurosurgeon to review plans if his/her office is not in
the same facility. One alternative is a remote planning sta-
tion, available with many systems. A computer workstation
can be set up in the neurosurgeon’s office where plans can
be developed and reviewed whenever time permits. This
setup is particularly helpful for frameless treatments, when
planning can be accomplished days in advance of the treat-
ment. It is also ideal for resident training; the resident can
A. Farooqui and N.S. Litofsky
work on the plan between other patient responsibilities and
discuss the plan with the faculty as they review the work.
Less flexibility is present with treatment space since treatment
obviously needs to occur where the radiosurgery device is
located.
Staff Responsibilities
Patients being treated with stereotactic radiosurgery experi-
ence a significant amount of anxiety about the procedure
[37]. Therefore, efforts to reduce patient anxiety are war-
ranted. Since less patient anxiety is associated with higher
satisfaction, addressing anxiety can lead to practice growth.
Clear identification of staff responsibilities before, during,
and after treatment can be helpful to this end.
Prior to planning and treatment, patients need education
about the procedure. The neurosurgeon and his/her staff need to
provide a thorough explanation of the indications for the proce-
dure, its risks, and its alternatives, as with any surgical proce-
dure. Any required medications should be discussed. Plans for
follow-up after the procedure should be outlined. If a Halo ring
immobilization is planned, issues regarding treatment of pain
and sedation should be included in the preparation.
The radiation oncologist and his/her staff should discuss
the issues related to positioning the patient during planning
and treatment. They need to assess the potential need for
sedation or anxiolytics for the patient while immobilized on
the gantry. The timeline for planning and treatment should be
clearly outlined. In addition, considerations of dosing in
relation to surrounding critical structures, review of previous
radiation history, and risk of side effects should be reviewed
in the context of these considerations.
Nursing staff is an integral part for the success of the pro-
gram [38]. It is best to designate a program coordinator who
not only guides the patients’ through the procedure but also
can assist in the procedures, prescribe medications, discharge
patients from services, and provide follow-up care. This indi-
vidual ultimately allows the neurosurgeon and radiation
oncologist to focus on planning and treatment, ultimately
allowing for more efficient use of their time. While an
advanced practice nurse, or nurse practitioner (NP), is prob-
ably the best option to serve as the program coordinator
because he/she can write prescriptions if needed, a clinical
nurse specialist can also effectively function in this role. The
coordinator should keep a checklist on each patient to be
sure that all pretreating planning and education has been
completed and that the patient is ready on the day of treat-
ment. Nursing assistants, if available, can help with patient
transportation. Radiation oncology nursing staff are usually
involved with patient care when the patient is being treated
[38], particularly if the patient needs medication or assis-
tance with using toilet facilities while wearing the head ring
in the department before being placed on the gurney.
66 Building a Radiosurgery Practice
Participating staff should have a general idea of the poten-
tial benefits of radiosurgery to patients. Individuals who have
a better understanding of these treatment issues will feel more
like a part of the team. They will be better able to provide
emotional and knowledgeable support to minimize patient
fear and anxiety [6]; they will also be less likely to make unin-
formed remarks that may send the wrong message to patients.
Patient Follow-up
Follow-up visits after radiosurgery serve several purposes.
Treatment response and post-procedural complications can
be assessed. Patient evaluation can guide further interven-
tion, change the treatment plan, and monitor or treat radia-
tion side effects. The appropriate timing of follow-up visits
or their necessity, however, has not been well defined.
Numerous reports have described symptoms associated with
SRS, including seizure, new neurological focal deficits,
headache, nausea/vomiting, vertigo, and death [39–42].
However, studies guiding timing of clinical follow-up of
SRS patients based upon these symptoms are sparse.
New symptoms following SRS are common. Complication
rates range from 2.2 [39] to 64 % [41]. New symptoms in the
first 3 months after radiosurgery may occur in 24 [42]–35 %
of patients (personal data, unpublished). The majority of
these symptoms are self-limited, usually requiring reassur-
ance. Patients treated with a head ring for immobilization
may require analgesia for mild headache.
Telephone-based follow-up in the first several weeks fol-
lowing radiosurgery may be appropriate [43, 44]. Patient
interaction via telehealth is another means of evaluating
patients to avoid the costs in time and money for travel.
Video evaluation of patients near their home and electronic
review of any imaging are possible. Medication can be pre-
scribed and patients can receive appropriate physician
instruction and guidance. Patients generally experience vary-
ing rates of satisfaction with telehealth in other specialties,
including surgical subspecialties and neurology [45–49].
Telehealth evaluation has been shown to be more useful than
telephone sessions [48].
Subsequent follow-up remains necessary to assess patients
for radiation-induced changes and/or tumor recurrence. Every
3 months seems appropriate for malignant lesions, while every
6–12 months makes sense for benign lesions.
Data Management
Data management is essential in building a radiosurgery
practice. A checklist on each patient helps ensure that
the process is consistent and no gaps in the process occur.
A patient database can facilitate tracking of disease processes,
815
outcome, and complications. It can also include routes of
referral. Regular review can reveal areas for quality
improvement for patient care and communication with
referring physicians.
Conclusions
Radiosurgery is an effective treatment option for many
patients; neurosurgeons should be able to provide and per-
form radiosurgical procedures. Preparation is the key to suc-
cess. Identification of the issues involving radiosurgery and
effective marketing techniques that are outlined in this chap-
ter are one way to ensure success in this evolving field. A
thorough understanding of reimbursement and anticipation
of the changes in radiosurgery billing trends will allow a
practitioner to maximally expand his/her practice.
Acknowledgement This chapter is adapted, in part, from Litofsky NS,
D’Agostino-Demers A: Building a radiosurgery program. In Chin LS,
Regine WF (ed): Priniciples and Practice of Stereotactic Radiosurgery.
New York, Springer, 2007. Pp 691–698.
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 Patient Care in Stereotactic
Radiosurgery
Terri F. Biggins
Introduction
The intention of this chapter is to provide basic guidelines
surrounding the patient process in relation to stereotactic
radiosurgery, with the goal of providing a seamless and
pleasant experience for the patient and staff. Although the
role of the registered nurse (RN) is highlighted, additional
disciplines may gain insight into the patient perspective.
Expectantly, valuable information will be gained not only for
those opening a new center but for the established site as
well. Various methods of stereotactic radiosurgery have been
developed over the past several years, but essentially the
mechanics are similar. This author’s experience is with the
Leksell Gamma Knife, and therefore this will be the equip-
ment referenced in this chapter.
Historical Perspective
More than 50 years ago, a Swedish neurosurgeon pioneered
a method of treating brain disorders without opening the
skull. Approximately 17 years later in 1968, this same neu-
rosurgeon, Dr. Lars Leksell, installed the first Gamma Knife
using cobalt-60 at the Karolinska Institute in Stockholm.
This invention was considered the first stereotactic device.
Stereotactic radiosurgery delivers a single high dose of ion-
izing radiation to a radiographically well-defined, small
intracranial target without delivering a significant portion of
the prescribed dose to the surrounding brain tissue [1]. Some
of the first patients treated were afflicted with pain, move-
ment, or behavioral disorders [1]. The first Gamma Knife
center in the United States opened in 1987 [2].
T.F. Biggins, R.N., B.S.N., C.N.R.N. (*)
Department of Nursing, University of Maryland Medical Systems,
22 S. Greene St, Baltimore, MD 21201, USA
e-mail: tbiggins@unm.edu
L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery,
DOI 10.1007/978-1-4614-8363-2_67, © Springer Science+Business Media New York 2015
67
It is difficult to imagine what patient care must have
entailed in 1968. Nurses were limited in what role they
played and the duties they were allowed to perform. Short-
acting intravenous sedation and portable monitoring for
patient travel were not readily available. Although patients
today generally live longer and require much care, patients
in the 1960s presented their own challenges. In 1969, Dr.
Leksell delivered stereotactic radiosurgery to many people
suffering with severe pain. Parkinson disease was another
disorder treated in those early years [3]. Maintaining an
acceptable comfort level while undergoing a lengthy pro-
cedure must have been trying. Unlike the frames in use
today, the first patients treated by Dr. Leksell and his staff
needed to endure the placement of a plaster helmet [3].
The plaster had to dry before it could be used. All of the
dose planning needed to be completed by drawing on the
pneumoencephalogram. A trip across town in an ambu-
lance was required in some cases in order to deliver the
radiation [3]. One patient treatment could typically take
many hours to complete.
Stereotactic radiosurgery recipients benefit greatly from
today’s advancements in technology. Radiographic imaging
in association with the use of computed tomography (CT)
and magnetic resonance imaging (MRI), as well as updated
computerized treatment planning, has greatly reduced patient
waiting time. Advancements in patient monitoring make the
delivery of sedation drugs safer. Access to education through
home computers enhances a patient’s knowledge base.
Today’s focus on pain control allows for easier monitoring
and control of discomfort. “Frameless” systems are begin-
ning to emerge, promising even greater tolerance of treat-
ment in the near future.
Clearly, the life expectancy in the United States and many
regions throughout the world has increased dramatically. As
the world’s population lives longer and technology advances,
one looks for less invasive and debilitating healthcare treat-
ments. Dr. Lars Leksell’s vision some 50 years ago has
helped achieve this very goal [4].
817
818
Training and Staffing
The training required to perform radiosurgery can be very
specialized. In the case of Gamma Knife therapy, there are
less than 100 machines in the United States. Therefore, if an
institution is planning to open a new radiosurgery practice,
training will likely occur at one of the existing sites in the
United States. It is highly recommended that new staff attend
a course at an accredited center. Ultimately, each indepen-
dent radiosurgery center with input from the state radiation
safety department will set rules for professional staff train-
ing. Certificates of education completion will be presented to
professional staff at the conclusion of training. Physician
staff must be credentialed before independently using the
radiosurgery tool. The nurse should have access to this list
and ensure its strict adherence.
The registered nurse is a valuable member of the radiosur-
gery team and must not be forgotten during the training
phase. A background in various nursing specialties prepares
one to adequately care for the individual undergoing stereo-
tactic radiosurgery. A background in neurosurgery, neurol-
ogy, radiation-oncology, medical oncology, and pain
management can be great assets. Certainly, nursing certifica-
tion in any one or more of the above specialties would be
advantageous.
The volume of patients treated at each center will help
determine the number of nurses and supporting staff needed
to staff the center at any one time. If one nurse typically
staffs the area, it is strongly recommended that at least two
other nurses are trained and ready to step in secondary to
planned or unplanned absences or for an increase in patient
acuity. These “back-up” nurses should complete an orienta-
tion program with the “permanent” nurse and reorient them-
selves by assisting during a patient treatment day every 6–8
weeks (Table 67.1). Supporting staff such as nurse extenders
should also receive a thorough orientation period.
Quality Assurance
Every radiosurgery center needs a quality assurance pro-
gram in place. All patients should be interviewed after
treatment, possibly during a follow-up phone call from the
nurse. Questions regarding patient satisfaction and out-
come expectations are essential. Quarterly meetings involv-
ing the entire professional staff should be held to discuss
the results of the patient interviews. Patient satisfaction goals
can be set and constant reevaluation conducted to ensure
quality improvement.
Meetings can also be utilized to discuss any additions or
changes to current protocol. Radiation safety classes and
review of emergency patient procedures for all existing and
T.F. Biggins
new staff can be conducted in this medium. Documentation
of minutes and attendance will ensure all staff have been
properly included in the quality assurance process.
The Patient Flow Process
Intake
Patients will enter the radiosurgery program either by physi-
cian or self-referral. In the age of the Internet, more indi-
viduals are educating themselves about healthcare options
in the comfort of their own homes in front of computers.
Eventually, a phone call will be made to set up consultation
appointments.
All the usual information regarding the patient’s demo-
graphic data is collected at this time. Referring and primary
care physician information is gathered as well. Past hospi-
talizations and locations of treatment records, particularly
pertaining to the diagnosis that is relevant to the radiosur-
gery treatment, should be gathered. Radiographic imaging
such as MRI, CT, and angiography prints as well as reports
is an absolute must for the consultation process. A preprinted
comprehensive intake form will ensure consistent data col-
lection. A follow-up letter should be sent to each patient
after this phone call. The letter should contain directions,
appointment dates and times, and concise instructions on
what materials the individual is responsible for bringing to
the appointment.
Many patients are eager to ask questions about radiosur-
gery and what it entails during this initial intake call. It is
never too early to begin the education process. Having a
clinical person available to begin dialogue at the time of
intake is invaluable. Inappropriate referrals can be redirected
at this time as well. The RN is an excellent resource for this
role. The earlier the involvement of the nursing staff, particu-
larly the staff who will be present at the time of treatment,
the better the patient satisfaction and outcome with the entire
experience.
Preprocedure Consultation
At the time of initial intake, the patient will be given
appointment(s) with all the team members necessary to
properly evaluate the appropriateness of radiosurgery.
This may include consultations with neurosurgery,
radiation-oncology, neuroradiology, medical oncology,
and nursing. In that most patients who need to travel a
distance and also rely on others for transportation attempt
to combine as many appointments as possible into one
visit. The neurosurgery-oncology multidisciplinary clinic
is ideal for this type of referral. Prior to rendering a definite
Table 67.1 Sample orientation checklist for nursing staff
1. Introduction to facility Date: Initial:
a. Physical layout
b. Supply areas
c. Location of offices
d. Location of hospital and unit manuals
e. Medication stock and narcotics
f. ECG, crash cart, respiratory supplies
2. Flow of patients: introduction to areas
a. Admitting area
b. Minor surgery suite: frame placement
c. Radiology: MRI, CT, angiography suite
d. Gamma Knife: waiting area, treatment room, family waiting
e. Transfer to recovery suite
f. Discharge
3. Introduction to interdisciplinary staff
a. Physicians: neurosurgeons, radiation oncologist, physicist, medical director
b. Gamma Knife secretary
c. Radiology technicians and scheduling assistant
d. Neurosurgery anesthesiologist for pediatric cases
4. Equipment
a. G-frame, tray, and contents
b. Emergency equipment
c. Gamma Knife couch, video and audio monitoring
d. Physiologic monitoring
e. Fiducial indicators: MRI, CT, angiography, instructions for use
f. Filling of indicators
g. Assisting with “skull measurement”
5. Charting
a. Admission note
b. Special Procedure Nurses Note
c. Time-out signatures
d. Physician orders
e. Patient treatment log
f. Discharge documentation
g. Patient teaching: pre-and post-procedure
6. Policies, protocols, and procedures
a. Unit safety manual
b. Credentialing manual
c. Nursing procedure/policy manual (i.e., conscious sedation policy)
d. Radiation dosimetry badges and monthly reports
e. Routine patient care: adult
f. Patient care: pediatric
g. Radiation emergency procedures
7. Manage patient flow-through procedure
a. Readies necessary equipment in treatment and prep room
b. Greets patient, preps for procedure
c. Assist with frame placement
d. Assist with radiology procedures
e. Assist with skull measurements
f. Reunite family with patient
g. Provide ongoing education as well as post-procedure instructions
h. Administer medications (pre-procedure such as steroid, anticonvulsant, pain)
i. Assist with positioning during treatment
j. Monitor vital signs, chart treatment records in appropriate book
k. Assist with frame removal, apply dressings
l. Ready chart and transport patient to recovery
m. Clean, reassemble, and store G-frame, ready fixations pins for sterilization
n. Complete discharge instructions
Date and initial each item after completion during orientation
820
treatment plan, the patient’s case should be presented at a weekly
neurosurgery-oncology team conference for final approval.
It is imperative that the patient records are gathered prior
to the appointment so as to expedite the scheduling of the
appropriate treatments. After consulting with the appropriate
medical personnel, the patient should meet with a represen-
tative of the nursing staff. Viewing of a patient education
video, tours of the radiosurgery facility, and the answering of
questions can all help to ease anxiety. Appropriate consent
forms should be obtained at this time as well. The patient
should leave at the end of this consultation period with a firm
treatment plan in place.
Preauthorization and Collection
of Preoperative Data
The preauthorization process should be started when the
patient makes the decision and is scheduled for the radiosur-
gery treatment. Designated personnel from the treating insti-
tution contacts the patient’s insurance company. Information
to have handy at the time of contact may include:
• Diagnosis
• Procedure code
• Outpatient versus inpatient visit
• Date of procedure
• Referring physician consultation note
• Number of lesions to be treated
• List of treatments that have been completed related to the
diagnosis
Allow several days for preauthorization to be finalized.
Each institution has a policy regarding what preoperative
evaluations are required prior to procedures. The following
list should be considered as a guide regarding data collection
and chart completeness:
• Preauthorization obtained from insurance company
• Preoperative check list completed by RN (Table 67.2)
• History and physical complete
Table 67.2 Preoperative nursing check list
• Review patient allergy history
• Assess any contraindication to imaging studies (contrast
allergies, MRI metal concerns)
• NPO status
• Review of appropriate medications patient is to take prior to
procedure
• What to bring to hospital (music, appropriate clothing, snack,
medications)
• Assess anxiety level (help plan for proper sedation)
• Describe flow of the procedure and when and where family
members will be allowed to wait and visit
• Review post-procedure course
T.F. Biggins
• Anesthesia consult (select patient’s receiving deep or
general anesthesia)
• ECG
• Serum results (electrolytes, complete blood count,
coagulation)
• Pregnancy testing on women of child-bearing age
• Anticonvulsant serum levels (Dilantin, Tegretol, pheno-
barbital, etc.)
• All consents complete (including angiography, MRI,
CT, etc.)
• Acquisition of imaging and reports necessary for
localization
Completing the above list will minimize the risk of post-
ponement, cancellation, or a negative outcome on the day of
the procedure.
Patient Arrival and Preparation
The majority of radiosurgery centers require individuals to
arrive early on the morning of the procedure. Patient registra-
tion should be complete prior to arrival to minimize any
added anxiety. Patients should first change into comfortable
clothing as outlined in pre-procedure instructions. Intravenous
access is obtained, as well as any last-minute blood work.
Diabetic patients should be checked for baseline serum glu-
cose to determine any intervention. Vital signs are obtained,
and a baseline neurologic assessment is completed by nursing
staff. Medications taken in the past 12 h are reviewed, and a
final check of consent forms occurs.
Frame Application
After all pertinent paperwork is completed and approxi-
mately 60 min prior to frame placement, LMX-4 (Ferndale
IP, Inc., Ferndale, MI) cream (lidocaine 4 %) should be
applied to the forehead and to the back of the head in the
estimated region of insertion of the local anesthetic. Cover
the LMX-4 cream with a clear adhesive covering to keep
from dripping, particularly into the patient’s eyes (Fig. 67.1).
Early application of LMX-4 cream will yield the best patient
satisfaction during frame placement. Any oral sedation
medications should be administered 30 min prior to frame
placement.
After directing family members to the appropriate waiting
area, the patient is moved to a procedure room for applica-
tion of the stereotactic frame. The room should contain mon-
itoring capabilities (ECG, pulse oximetry, blood pressure),
as well as access to oxygen. The room lighting should be
adequate and room temperature comfortable for the patient.
Environmental stimuli should be kept to a minimum. When
the treating physician is present, a “time out” should occur,
67 Patient Care in Stereotactic Radiosurgery
verifying correct patient, correct diagnosis, and appropriate
site of treatment verification.
While sitting erect on a gurney the stereotactic frame is
suspended on the patient’s head by use of a Velcro strap
(Fig. 67.2). One may opt to use the magnetic resonance
(MR) indicator box during frame fitting to ensure a comfort-
able, accurate fit during imaging (Fig. 67.3). If conscious
sedation is to be used, it should be administered just prior to
frame application with strict adherence to policy surround-
ing this competency. Anesthesia staff may be utilized to
administer deeper sedation for appropriate individuals.
Before the fixation screws are advanced, local anesthetic is
injected. A small (25-gauge) needle and 10-mL syringe is
filled with lidocaine HCL 1 % and epinephrine 1:1,000,000.
Two milliliters of 8.4 % sodium bicarbonate is combined
with 20 mL of the lidocaine solution to help decrease the
“burning” sensation commonly associated with lidocaine.
Fig. 67.1 Apply LMX-4 cream at least 1 h prior to frame placement
Fig. 67.2 (a) Apply Velcro head holder to frame to create a sling. (b) Sit frame with holder easily onto the head
821
As a rule, 2–5 mL of anesthetic is injected at each site to
achieve satisfactory comfort (Fig. 67.4). Provided there is
proper physician credentialing, the use of moderate sedation
such as IV Versed (1–2 mg) may be helpful for relieving pain
and anxiety during the procedure. There is also the added
benefit of an amnestic effect after the frame has been placed.
All individuals in the room need to be versed with emer-
gency procedures in case of respiratory depression.
The majority of patients tolerate frame application with
minor discomfort (Fig. 67.5). Pre-procedure education is a
key component. Describing what to anticipate in regard to
sensations such as pressure during tightening of fixation
screws will assist in managing anxiety. Allow individuals to
view photos of previous patients wearing the device, or coor-
dinate patient-to-patient contact with previous radiosurgery
candidates. Time required for frame application rarely
requires longer than 15 min.
Skull measurements will be conducted after the frame is
securely in place (Fig. 67.6). The patient should be sitting
erect with support behind the back allowing for easy access
to the head. There is absolutely no discomfort associated
with this process.
Radiographic Imaging
After the frame is in place, the patient is moved via gurney to
the appropriate imaging machine(s). Individuals will undergo
MRI, CT, and/or angiography imaging (Fig. 67.7). Each of
these machines requires use of individualized fiducial local-
ization equipment. Prior screening regarding allergies, metal
risk factors, and claustrophobia will expedite safe, efficient
imaging. Care is taken to place the appropriate fiducial box
securely onto the frame seating all connections and to ensure
the side clips are tightly fastened (Fig. 67.8). Providing the
822
Fig. 67.3 Checking fit of indicator box during frame placement
Fig. 67.4 Neurosurgeon injects lidocaine
Fig. 67.5 Patient immediately after completion of frame placement
T.F. Biggins
patient with comfort measures such as warm blankets and
knee support makes this a more pleasant experience. Pressure
points, particularly at the shoulders, should be properly pad-
ded to reduce risk of impaired skin integrity. Administration
of conscious sedation is encouraged in the claustrophobic
individual. The MR fiducial should be filled with copper sul-
fate 0.25 L solution (Fig. 67.9). Air bubbles that collect
between the plastic panels could make image acquisition
impossible and may require a second trip to the imaging cen-
ter and a delay in the treatment. The imaging fiducials are
very fragile and costly and should be carefully stored and
cared for by a designee of the radiosurgery team.
Educate the patient regarding length of imaging and what
sensations may be experienced. The patient requiring angi-
ography will need explicit instructions specifically concern-
ing post-procedure monitoring and care. Radiology staff also
Fig. 67.6 The taking of skull measurements prior to treatment planning
Fig. 67.7 Patient within the head coil awaiting start of MRI
67 Patient Care in Stereotactic Radiosurgery
need to be educated about quick removal of the stereotactic
equipment subsequent to a medical emergency.
Before imaging is complete and prior to patient removal
from the table, the radiation physicist should ascertain that
the images have been completed correctly and that the trans-
fer to the planning computer can be successfully achieved.
Neuroradiology should be monitoring and reading all images
prior to patient treatment. Carefully remove the patient from
the imaging table. Great care is taken when fitting or removing
Fig. 67.8 Check that MRI fiducial is without air bubbles and correctly
attached to frame prior to imaging
Fig. 67.9 (a) A spinal needle, syringe, and copper is gathered. (b) Extracting the sulfate. (c) Spinal needle is narrow and makes for easy filling of
fiducial
823
the fiducial in that sound is magnified via the frame attached
to the skull. After imaging, the patient is transported to the
stereotactic center to await the treatment.
Treatment Planning
Treatment planning times vary according to the complexity
of the case. Typically, the patient will be waiting 1–2 h before
treatment begins. Allowing family to visit during this time
promotes a decrease in patient anxiety. Providing a light
snack is appropriate if conscious sedation is not expected
during the treatment phase. Ongoing monitoring of vital
signs, neurologic assessment, and the reinforcement of edu-
cation is completed at this time. Assess and treat pain prior to
the initiation of treatment.
The Stereotactic Treatment
Comfortable positioning during the treatment phase can be
achieved by using a combination of pillows and blankets to
provide support. The supine position is typically used for
treatment so elevating the knees will support the lower back.
Shoulder and head support may be used as long as it does not
interfere with machine operation. Meet individual patient
needs as necessary. ECG/BP/oxygen monitoring should be
used as appropriate. The availability of suction equipment
824 T.F. Biggins

Table 67.3 Treatment room supplies

• Oxygen set-up including ambu bag
• Suction set-up
• Crash cart
• Emergency patient removal equipment supplied by manufacturer
• Suture material/suture tray for uncontrolled bleeding from pin sites
• Pillows, blankets, etc., for patient support, comfort
• Gauge, Band-Aids, and all supplies for frame removal
• IV supplies, gloves
• Bedpans, urinals, emesis basins, tissues
• ECG, BP, oxygen monitoring

will help ensure patient safety. Assess all supplies needed the
day prior to treatment (Table 67.3).
Educate the patient prior to each step. Ensure that close
contact is maintained via audio and video monitoring. Fig. 67.10 Fixation screw sites immediately after frame removal
Describe the number of exposures to anticipate and the
amount of time each exposure will last. The use of two-way
microphones during treatment will assist in warning when
movement will occur. Most patients choose to rest or sleep
during treatment, and the playing of music into the room has
proved to be very relaxing. Keep the patient and family
informed of treatment progression. During helmet or equip-
ment changes, allow for bathroom breaks or change of posi-
tion. Total treatment time can vary greatly depending on
diagnosis.

Postoperative Care

Immediately upon completion of the procedure, the stereo-

tactic frame should be removed. Light massaging with
manipulation of the pin sites will help close the skin and
decrease scarring (Figs. 67.10 and 67.11). Antibiotic oint- Fig. 67.11 Fixation screw sites after the manipulation of skin
ment and some sort of dressing may be applied to the pin
sites (Fig. 67.12). Typically, patients experience discomfort
at the pin sites within 15 min of frame removal. Encourage
pain medications either for prophylaxis or at initial onset of
discomfort. Have anti-emetics on hand for the occasional
nausea. The convalescence period varies depending on
patient general condition and length of procedure. The
patient requiring cerebral angiography prior to treatment
may require a slightly longer recovery time.
Characteristically, patients who have undergone stereotactic
radiosurgery are prepared to return home within an hour or
two of procedure completion. Seizure-prone individuals
may require an overnight stay. Remind families that driving
is not recommended the day of treatment and prohibited if
any conscious sedation has been administered. Encourage
the consumption of food and drink prior to discharge.
Follow-up instructions should be carefully reviewed with the
patient and family. If follow-up appointment times are not Fig. 67.12 Band-Aids are commonly used to cover pin sites
assigned on discharge, provide appropriate contact individuals overnight
67 Patient Care in Stereotactic Radiosurgery
and phone numbers. Ensure prescriptions are made avail-
able as needed, although over-the-counter pain relievers
almost always are sufficient for any discomfort related to
the procedure. Patients taking anticonvulsant therapy should
be reminded of the importance of frequent monitoring of
serum levels of these drugs. Ensure that patients who are
taking steroid therapy understand which physician office
they are to contact regarding any concerns with these drugs.
Check to ensure that a gastrointestinal support drug has
been prescribed for anyone on steroid therapy. Stress the
importance of providing radiology imaging (MRI, CT, etc.)
at the time of follow-up with the radiosurgery team. Assist
with referrals so imaging can be completed in a timely man-
ner prior to the visit. Provide the imaging centers with phy-
sician phone and fax numbers.
Home Follow-up
Phone contact should be made within 24 h of discharge. The
RN is the best individual to complete this call. Reaffirm pre-
operative teaching as necessary. If home care or therapy
(nursing, PT, OT, etc.) was established at the time of the ste-
reotactic treatment, assess that these referrals have been
completed and the patient has been contacted by the appro-
priate persons. Assess pain status and make recommenda-
tions as appropriate. Assist with scheduling follow-up visits
as needed. The follow-up phone call is the ideal time to
assess patient satisfaction regarding the entire stereotactic
process.
Care of the Pediatric Patient
A small percentage of all stereotactic candidates fall under
the category of the pediatric population. Typically this group
is categorized as the following:
Newborn: birth to 3 months
Infant: 3 months to 1 year
Toddler: 1–4 years
Preschool: 4–5 years
School age: 6–12 years
Adolescent: 13–18 years
Brain tumors and arteriovenous malformations are some
of the conditions in this population that can be treated via
radiosurgery. The central nervous system continues to
develop throughout childhood, therefore careful consider-
ation is given to the appropriateness of the delivery of radia-
tion. Consultations are scheduled with the patient and parents
involving all the pertinent members of the radiosurgery team.
Risks and benefits of the procedure are discussed at length.
Once a decision has been made to proceed with radiosurgery,
825
the nursing staff should make a thorough assessment of the
patient and family needs.
Preoperative blood work is generally not necessary in the
young pediatric patient. The application of LMX-4 cream is
recommended before any needle sticks, such as an intrave-
nous (IV) start. Whenever possible, have the child in an age-
appropriate environment. The use of pediatric specialty
pre-and postoperative suites will help make transitions more
fluent. Classically, all children below the age of 13 years
require general anesthesia. Most adolescent children are able
to tolerate radiosurgery with some light to moderate seda-
tion. Nurses can help determine the maturity level of the ado-
lescent patient through patient and parent interview. Pediatric
anesthesia physicians can help determine the optimal seda-
tion plan for the individual child. Clearly, the younger child
will require parent involvement until anesthesia has occurred.
Encourage the young child to take a favorite tool or stuffed
animal and keep it with the child until they are anesthetized.
Allow family members to be with a child of any age during
appropriate intervals. As with any patient, provide frequent
updates to parents throughout the procedure to decrease
anxiety.
The identical stereotactic frame that is used for an adult
can be used for the child. Certainly, the longer fixation
screws will need to be used to compensate for a smaller head
circumference. The use of lidocaine at the pin sites may or
may not be used for the anesthetized patient. Supporting the
frame during application of a patient under general anesthe-
sia can be difficult and may require two people, one to sup-
port the frame and the second to support the head. In that the
child may be immobile for several hours during planning and
treatment, monitor pressure points on the skin, and a Foley
catheter may be practical. Monitor body temperature and
keep warm blankets near.
During the delivery of radiation, the anesthesiologist will
need to have visualization of key components. Certainly the
cardiac, BP, and oxygen monitor should be in plain view, and
the ability to change monitoring parameters accessible. If pos-
sible, two cameras should be available in the treatment room.
One camera should be focused on the patient for visualization
of respirations and the other focused on the ventilator, specifi-
cally the CO2 waveform. Prior to the start of treatment, evalu-
ate the length of all tubing and account for movement into the
machine. Ensuring that these features are in place will pro-
mote a safe atmosphere. Offering the adolescent music of their
choosing can decrease anxiety during treatment.
Removal of the stereotactic frame prior to reversal of anes-
thesia is recommended. Moving the patient to a pediatric
PACU (Post-anesthesia care unit) setting will allow for safe
recovery. Allow family to visit in the PACU as soon as pos-
sible. Observe the very young child for signs of discomfort
specifically immediately after frame removal and administer
826 T.F. Biggins

Table 67.4 Tricks of the trade

Pre-procedure
• Arrange initial consultations with all physicians/nurse for the same day
• When scheduling patients for the procedure, attempt to schedule the simplest treatment for the first case of the day progressing to the most
complex treatment for the last patient of the day
Frame placement
• Use Velcro strap instead of ear bars. The strap can be positioned to fit each patient individually. This increases comfort for patient and
individual supporting the frame
• Use LMX-4 cream on forehead prior to lidocaine injection. Strive for application at least 1 h prior to frame placement
• Add sodium bicarbonate to lidocaine to decrease “sting” at injection site
• If using CT scan, place fixation screws as far from the targeted area as possible to decrease artifact
• Always have patient films available for frame placement
• Use “curved” front posts for extreme lateral or very low (cerebellar) lesions
• Place front posts low on forehead to decrease risk of collision with treatment helmet
• Test all fiducials during frame placement. This will avoid the need to adjust the frame later in the process
• Know your patient’s surgical history, specifically past craniotomies, shunt placements, etc. Fixation screws need to be carefully placed to
avoid these areas
• Place fixation screws as “flush” as possible with the post to avoid collision
• While on a gurney, prop a pillow(s) behind patient’s back to make access to the back of the head adequate for frame placement
• Follow correct site protocol by marking side of treatment involving unilateral site, such as trigeminal neuralgia. Ask the patient to verbalize
side of pain prior to premedication
Radiographic imaging
• Place earplugs in patient prior to MRI
• Elevate knees during scans
• Provide padding anywhere pressure is a concern due to the frame or fiducial cradle touching shoulders, etc. (foam pads, 4 × 4 s)
• Do not dismiss a patient’s complaint of heating at a fixation screw site. Immediately check the screw for any magnetic components and the
patient’s skin for any burning
• Attempt to ensure that the imaging is acceptable to all involved (radiation physicist, neurosurgeon, radiologist) before leaving the imaging
area
• Check that MRI fiducial is filled with solution and free of air bubbles the day before needed
Treatment
• Suggest music be played while undergoing treatment
• Offer support for knees
• Make sure the mattress is at an acceptable height to ensure patient comfort throughout the entire procedure
• If plug patterns will be needed on different helmets, roll the subsequent helmet out of the room and prepare plug pattern while the patient is
being treated
Frame removal
• Massage or pinch screw sites closed immediately after frame removal to assist in the quick closure of screw openings and to decrease
scarring
Patient-specific issues
• CT cisternogram can be successfully used to visualize the trigeminal nerve when MRI is contraindicated
• Anticoagulant therapy will need to be stopped as per physician recommendation when angiogram or cisternogram are to be performed
• Use hardware that will cause the least amount of artifact when using CT imaging (i.e., carbon-filled posts, nonmetallic fixation screws)

analgesics as needed. Encourage the older child to request

pain medications as well. Admit to age-appropriate setting
until discharge.
Educate parents and the child regarding pain management,
pin site care, and follow-up appointments. Provide phone
numbers including emergency contact. After discharge, it is
recommended that nursing staff make phone contact with
families within 24 h.
Tricks of the Trade (Table 67.4)
Recognized colleagues have all learned the radiosurgery pro-
cess through some trial and error. Beginning with consulta-
tion, preoperative analysis, frame fitting, gathering of
equipment, proper imaging techniques, much can be learned
from the established center.
67 Patient Care in Stereotactic Radiosurgery
Conclusion
Care of the radiosurgery patient can initially be challenging
for the clinician. Proper training, communication with estab-
lished centers and clinical experts, as well as hands-on expe-
rience will support a thriving center. A support group for
radiosurgery nurses allows for the constant flow of ideas and
solutions to challenges that only this population can appreci-
ate. A strong quality assurance program with ongoing patient
satisfaction evaluation is crucial. Establishing concise guide-
lines beginning with the intake process and flowing through
827
the follow-up patient visit will assist in making the experi-
ence gratifying for patients and clinicians.
References
1. Mughaw SB. An overview of methods in stereotactic radiosurgery.
Radiol Technol. 1992;63:402–5.
2. Browner CM, Hendrickson K. A nursing perspective of Gamma
Knife treatment. Barrow Quarterly. 1997;13:41–8.
3. Lindquist C, Kihlstrom L, Hellstrand E. Functional neurosurgery—
a future for the Gamma Knife? Stereotact Funct Neurosurg.
1991;57:72–88.
4. A tribute to Dr. Lars Leksell. Another perspective—The Publication
for the International Radiosurgery Support Association. 1998:2–3.
 Index

A trigeminal nerve function, 343

Accelerated partial breast irradiation (APBI), 163–164 tumor control, 341–343
Acoustic neurinoma, 5 Acromegaly
Acoustic neuromas fractionated radiotherapy, 397–398
biologically effective dose, 357–359 SRS and, 371–373
derivation of hearing RET formula, 359, 364, 365 Active eye-immobilization techniques, 744
fractionated stereotactic radiotherapy Adenocarcinoma, 227–228
clinical outcomes, 363 Age-related macular degeneration (ARMD)
principles of late-responding tissues, 356 diagnosis, 759
treatment, 360 pathophysiology, 758
vs. Gamma Knife, 361, 362 proton beam therapy and photocoagulation, 759
vs. SRS, 363, 364 radiotherapy, 759
gadolinium-enhanced, 361–363 surgical approach, 768–769
microsurgical resection, 359, 360 Amino acid positron emission tomography, 792
middle fossa approach, 360 Angiofibroma
optic nerve sheath meningiomas, 356, 357 pathophysiology, 486
optimal treatment outcome, 365 treatment, 486–487
RET rosigmoid approach, 360 Anti-angiogenic therapy, 283
stereotactic radiosurgery, 17–18, 142, 360 Anxiety, 734
translabyrinthine approach, 360 Arteriovenous malformations (AVMs)
Acoustic schwannomas arterial aneurysms, 605
acoustic tumors, 343–344 clinical presentation, 606–607
brainstem tolerance, 342 dose selection, 130
cochlear tolerance, 342–343 endovascular therapy
complications, 341–343 embolization, 618–621
facial nerve preservation, 343 natural history, 617–618
G-R classification, 340 follow-up, 130
hearing preservation, 342–343 management, 589–590
House–Brackmann classification, 340 natural history, 605–606
hydrocephalus, 343 patient selection, 130
Koos classification, 340 presurgical embolization, 609–611
management, 340–341 presurgical planning
neurofibromatosis type 2, 339 diffusion tensor imaging, 609
patient assessment, 339–340 functional MRI, 608–609
radiosurgery failures, 345 grading systems, 607–608
surgery imaging studies, 608
age and tumor size, 350 radiosurgery, 564
conservative management, 347 case studies, 598–600
facial nerve preservation, 348 complications, 594–595
hearing preservation, 349–351 large AVMs, 596–597
management, 348 obliteration, 592–593
middle fossa approach, 348, 349 patient selection, 591
porus acousticus, 348, 351 post-radiosurgical hemorrhage, 593–594
radiosurgery vs. excision, 350 repeat SRS, 595–596
repeat retrosigmoid craniotomy, 351 Spetzler–Martin grading system, 597–598
retrosigmoid approach, 348, 349, 351 technique, 591–592
translabyrinthine approach, 349, 351 stereotactic image acquisition, 130
treatment method, 350 stereotactic radiation therapy, 61–62
treatment planning issues, 344–345 stereotactic radiosurgery, 18, 142, 410, 611

L.S. Chin and W.F. Regine (eds.), Principles and Practice of Stereotactic Radiosurgery, 829
DOI 10.1007/978-1-4614-8363-2, © Springer Science+Business Media New York 2015
830 Index

Arteriovenous malformations (AVMs) (cont.) brainstem, 645–646

surgical considerations clinical presentation, 639–640
anesthesia, 611 diagnostic imaging, 640–645
intraoperative angiography, 613 epidemiology, 637–638
tenets of surgical resection, 611–612 genetic basis, 638
University of Florida experience, 130–131 microsurgical treatment, 641–644
Astrocytic tumors, 249 molecular basis, 638
Atypical facial pain, 655–656 natural history, 638–639
prevalence, 637
radiosurgical treatment, 644–645
B treatment, 640–641
Baclofen, 650, 668 definition, 637
Beam’s-eye-view technique, 305 Gamma Knife radiosurgery, 628–630
Benign meningiomas intracranial
external beam radiation therapy, 325–328 clinical presentation, 624
grading criteria, 325 deep-seated, resection of, 627
gross total resection, 325 dural arteriovenous fistulas, 631–633
IMRT, 328 epidemiology, 623–624
radiotherapy, 327–328 management options, 625
Simpson grades, 326 molecular basis, 624
Benign pineal region tumors, 463 natural history, 626
Bevacizumab pathophysiology, 623
head and neck tumors, 552 radiobiological considerations, 631
malignant glioma, 283 radiologic features, 624–625
radiation necrosis, 794 radiosurgery, 625–631
Bilateral acoustic neurofibromatosis, 417–418 vein of Galen malformations, 633–634
Bilateral adrenalectomy, 405 Cavernous sinus, 379, 381, 383–386
Body tumor immobilization, 182 Central nervous system (CNS) tumors, 142
Brachytherapy Cerebral angiography, 18–19
ocular metastases, 757 Cerebral cavernous malformations (CCMs)
orbital and ocular metastases, 757 anatomical distribution, 638
in radioactive plaque, 767 brainstem cavernous malformations, 645–646
radionecrosis and, 251 clinical presentation, 639–640
surgical interventions, 755 diagnostic imaging, 640–645
use of, 274 epidemiology, 637–638
using intracavitary intubation, 530 genetic basis, 638
uveal melanomas, 748, 750 microsurgical treatment
Brain metastases, 14–15, 794–795. See also Metastatic infratentorial lesions, 642–644
brain tumors supratentorial lesions, 641–642
Brainstem astrocytomas, 463 molecular basis, 638
Brainstem cavernous malformations, 645–646 natural history, 638–639
Brain Tumor Cooperative Group (BTCG), 250 prevalence, 637
Breast immobilization apparatus, 166–167 radiosurgical treatment, 644–645
Bromocriptine treatment, 640–641
pituitary tumors, 380 Cerebral metastases, 128–129
prolactinomas, 404 Cetuximab, 552
somatotroph adenomas, 405 Charged particles
Bruch membrane, 748 acoustic neuroma, 142
BTCG. See Brain Tumor Cooperative Group (BTCG) arteriovenous malformations, 142
central nervous system tumors, 142
challenges, 143
C dose-distribution curves, 135–136
Cabergoline energy transfer pattern, 135
prolactinomas, 404 hepatocellular carcinoma
somatotroph adenomas, 405 clinical outcomes, 141–142
Capsaicin, 668–669 rationale, 141
Carbamazepine meningioma, 142
epilepsy, 725 non-small cell lung cancer
trigeminal neuralgia, 649–650, 666 advantages, 141
Carmustine (BCNU), 281, 282 anatomy and dose, 138–139
Cavernomas. See Cerebral cavernous malformations (CCMs) highly hypofractionated regimens, 139
Cavernous angiomas. See Cerebral cavernous malformations (CCMs) modestly hypofractionated regimens, 139–140
Cavernous hemangioma, 758 photon radiation, 135
Cavernous malformations physical and technical considerations, 135–137
CCMs pituitary tumors, 142
anatomical distribution, 638 radiobiologic advantages, 137
Index 831

uveal melanomas, 750 role of, 395

Chemodectoma. See Glomus jugulare tumors simulation, 395–397
Chemo-radiation therapy, 273 staging system for, 394
Chemotherapy therapeutic approaches, 394
head and neck tumors gross total resection, 509
altered fractionation, 554–555 hypothalamic involvement, 507
bevacizumab, 552 papillary, 506–507
definitive radiotherapy, 551 pediatric brain tumors, 416–417
human papillomavirus, 552–553 retrochiasmatic lesions, 507–508
hyperfractionated radiotherapy, 554 skull base tumors
IMRT, 553 pathophysiology, 488
locoregional control and survival, 549–550 surgical result, 489
reirradiation, 555–558 treatment, 488–489
stereotactic radiotherapy, 558–559 stereotactic radiosurgery, 412–413
neurofibromatosis-1, 417 Craniotomy, 461–463
pediatric brain tumors, 439–441 Cryptic vascular malformations. See Cerebral cavernous
pineal region tumors malformations (CCMs)
germ cell tumors, 477–479 Cumulative Ocular Melanoma Study (COMS), 766
pineal parenchymal tumors, 479–480 Cushing’s disease, 399
Children’s Oncology Group trial, 430 diagnosis, 404
Chondromas fractionated radiotherapy, 399
pathophysiology, 489 medical therapy, 404–405
radiosurgery, 491 SRS and, 370–371
treatment, 490–491 CyberKnife
Chondrosarcomas beam characteristics, 85
pathophysiology, 489–490 clinical indications
radiosurgery, 491 glioblastoma multiforme, 153–154
treatment, 490–491 intracranial, 153
Chordomas intrathoracic tumors, 155–156
features, 517 liver tumors, 156–157
fractionated stereotactic radiotherapy pancreatic tumors, 156–157
outcomes, 520–521 perioptic tumors, 154
patient selection, 519–520 spinal indications, 155
techniques, 520 trigeminal neuralgia, 154–155
histological appearance, 505 vestibular schwannomas, 154
malignant tumor of spine, 565 2D-3D image registration, 157
radiation therapy, 505–506 digitally reconstructed radiographs, 147–148
skull base tumors image guided tracking system, 151–153
pathophysiology, 489 imaging requirements, 85–86
radiosurgery, 491 intracranial lesions, 147
treatment, 490–491 IRIS collimator, 149
treatment, 518–519 isocentric beams, 148–149
Choroidal melanomas, 748 non-neurologic disorders, 157
Clonazepam, 668 overview, 84–85
Compton scattering, 39–41 planning process, 87–88
Computed tomography (CT) robotic manipulator, 147
meningioma, 316, 317 Synchrony™ respiratory tracking system, 147
paragangliomas, 522 treatment delivery, 148, 150–151
pineal region tumors, 470 treatment planning, 149–150
Contrast-enhanced perfusion MRI, 791 uses, 49, 100, 813
Conventional fractionated radiation therapy, 489, 596 Cyclophosphamide, 478
Convexity meningiomas, 317–319
Corpus callosotomy, 716
Corticobasilar degeneration (CBD), 695 D
Corticotroph adenomas, 404–405 DAT scan, essential tremor, 697
Costotransversectomy, 576 Deep brain stimulation (DBS)
Craniopharyngiomas pallidal, 686–687
adamantinomatous, 506 Parkinson disease, 697
chemotherapy, 441 subthalamic, 688–689
endoscope, 509 thalamic, 681–683
fractionated radiotherapy Depression, 734, 738
clinical presentation, 393 Diffusion tensor imaging (DTI), 7, 609
diagnostic evaluation, 393–394 Diffusion-weighted imaging (DWI), 790–791
epidemiology and histology, 392 Digital reconstruction radiography (DRR), 28–29
preparatory steps, 395–397 Dirty necrosis, 789
results, 399–400 Dopamine agonist therapy, 404
832
Dose and dosimetry, SRS, 41–42
isodose line and dose-volume histogram, 44–45
measurement-based dose calculation, 42
model-based dose calculation, 43
output, 43
pencil-beam kernel, 44
percent depth dose, 42–43
point kernel, 43–44
profile/off-axis ratio, 43
Drug-resistant epilepsy
differential effect concept, 699
radiosurgery
dose issue, 703–704
hypothalamic hamartomas, 700–703
indications, 706–707
mesial temporal lobe epilepsy, 703
patient selection, 705
potential concerns, 705–706
potential role, 700
target definition, 704–705
Dural arteriovenous fistulas (AVFs), 631–633
Dynamic contrast-enhanced MRI, 13
Dynamic susceptibility contrast MRI, 13
Dystonia, 686
E complications, 675
EBRT. See External beam radiation therapy (EBRT)
Electrical stimulation for epilepsy
brain stimulation, 717
vagal nerve stimulation, 716–717
Ellis formula, 786
EMA. See Epithelial membrane antigen (EMA)
Embolization
angiofibroma, 486
parasagittal meningiomas, 317
petroclival meningiomas, 318
sphenoid wing meningiomas, 318
Embryonal tumors
chemotherapy, 440–441
stereotactic radiosurgery, 411
En bloc spondylectomy, 576–577
Endoscopic biopsy, 461
Endovascular embolization, AVMs
curative strategies, 618–619
palliative, 621
preoperative, 618
pre-radiosurgery, 619–620
targeted, 620–621
Enucleation, 766–767
Ependymal tumors, 249
Ependymoblastomas, 421
Ependymoma
chemotherapy, 440
fractionated radiotherapy
cognitive effects, 435–436
endocrine effects, 436
side effects, 436–437
pediatric brain tumors, 418–420
stereotactic radiosurgery, 410–411
Epilepsy
acute/subacute effects of radiosurgery, 726
electrical stimulation
brain stimulation, 717
vagal nerve stimulation, 716–717
intracranial lesions, 723
localization-related, 711
Index
presurgical evaluation, 711–712
primary generalized, 711
seizure types and treatment considerations
antiepileptic therapy, 723–724
carbamazepine, 725
cavernous malformations, 724
focal structural lesions, 724
levetiracetam, 726
low-grade gliomas, 724
phenytoin, 725
primary motor cortex, 723
surgery
corpus callosotomy, 716
hemispherectomy, 715–716
hemispherotomy, 715–716
hypothalamus hamartomas, 714–715
medial temporal lobe epilepsy
medial temporal lobe epilepsy:
corroborative testing, 712
medial temporal lobe epilepsy: outcomes, 713–714
medial temporal lobe epilepsy: procedures, 712–713
multiple subpial transections, 716
treatment implications, 726–728
Epithelial membrane antigen (EMA), 295, 505, 518
Essential tremor (ET)
Gamma Knife thalamotomy, 671–672
dose for, 673
indications, 673
microelectrode recording, 675
radiation efficacy, 673–675
target coordination, 673
tolerance of internal capsule, 673
vs. conventional thalamic surgery, 675
medical therapy, 697
Esthesioneuroblastomas
craniofacial surgical resection, 506
endoscopy, 506
kadish staging, 506
skull base tumors, 487–488
Etomidate, 405
Evisceration, 766
External beam radiation therapy (EBRT)
anaplastic/WHO grade III, 332
arget volumes and dose, 333
atypical/WHO grade II meningiomas, 330
benign meningiomas/WHO grade I
FSRT, 327, 328
gross total resection, 325–326
IMRT, 328, 329
radiotherapy, 327–328
simpson grades, 325
cognitive morbidity, 334
fractionated, 326, 327
meningiomas, 296
ONSMs, 328–330
recurrent meningiomas, 330
technical factors, 333
toxicity, 333–334
Extracranial SRS, 7
Extracranial stereotactic localization, 29–30. See also Stereotactic
body radiation therapy (SBRT)
F
Fentanyl patch, 669
Fotemustine, 281
Index 833

Fractionated radiotherapy tolerance of internal capsule, 673

ONSM vs. conventional thalamic surgery, 675
modalities movement disorders, 683–685
modalities: doses, constraints and fractionation schemes, 774–776 GammaPod
modalities: techniques, 774–776 accelerated partial breast irradiation, 163–164
modalities: timeframe, 773–774 advantages, 175
modalities: volumes, 774 breast immobilization apparatus, 166–167
optimization, 778–780 continuous trajectory patient positioning system, 167
results dose painting, 173–174
results: endpoints, 774, 777 dosimetry, 168–170
results: oncologic outcome, 777 hypofractionated whole breast irradiation, 163–164
results: ophthalmologic examination outcome, 777 irradiation device, 165–166
results: visual outcome, 777 lumpectomy, 163–164
safety, 778 post-operative treatment planning, 169–172
vs. stereotactic radiosurgery, 473–474 preoperative RT role, 165
Fractionated stereotactic radiotherapy (FSRT) preoperative treatment planning, 172–173
benign meningiomas, 327, 328 technologic advances, 164–165
clinical outcomes, 363 treatment planning system, 167–168
pituitary adenomas, 396 Gardner-Robertson hearing (G-R) classification, 340
skull base tumors Germ cell tumors (GCTs), 441, 477–479
chondrosarcomas, 519–521 Germinomas
chordomas, 519–521 chemotherapy, 477–478
paragangliomas, 523–525 pineal region tumors, 465
Fractionation, 6–7 Glaucoma, 760–761, 769
Functional MRI, 608–609 Glial neoplasms, 262–263
Glioblastoma multiforme (GBM), 153–154
Glioblastomas, 418
G Glioma
Gabapentin, 667 low-grade, 415–416
Gamma Knife (GK) stereotactic brachytherapy
in adults, 409–410 benefits and risks, 272, 274–275
automatic positioning system, 112–113 brachytherapy (125I) advanced treatment, 273–274
brain disorders, 111–112 GliaSite brachytherapy, 272
cavernous malformations, 628–630 high-grade gliomas, 273
cobalt-60, 111 indications, 273
components and functions, 96–97 vs. EBRT, 273–274
conformal dose planning, 118 surgery
4C unit, 79–82, 113–114 benefits, 272, 274–275
daily quality assurance, 115–116 GliaSite radiation therapy, 273
docking mechanism, 114–115 high-grade, 269–270
drug-resistant epilepsies, 700 low-grade, 270–271
limitations, 813 management, 271, 273
meningiomas, 299–300 WHO grade I and II, 412
movement disorders, 690 WHO grade III and IV, 411–412
number and location of active sites, 111–112 Glomus jugulare tumors
pallidotomy, 675–677 microsurgical resection, 501–502
Perfexion, 81–82 skull base tumors
PERFEXION unit, 113–115 pathophysiology, 491
photon beam delivery systems, 45–47 radiosurgery, 493–494
pineal region tumors, 449, 452 side effects, 493
quality assurance of images, 117 surgical resection, 491–493
schematic diagram, 111, 113 treatment plan, 493, 494
stereotactic angiography, 117 SRS, 503
stereotactic CT imaging, 117 Goldmann perimetry tests, ONSM, 777
stereotactic guiding device, 116 Gonadotroph adenomas, 406–407
stereotactic MRI, 116–117
stereotactic radiation delivery, 118–119
target determination, 117–118 H
vs.MVD, 662 Head and neck tumors
Gamma Knife thalamotomy (GKT) chemotherapy/fractionated radiation therapy
intractable tremor, 671–672 altered fractionation, 554–555
complications, 675 bevacizumab, 552
dose for, 673 definitive radiotherapy, 551
indications, 673 human papillomavirus, 552–553
microelectrode recording, 675 hyperfractionated radiotherapy, 554
radiation efficacy, 673–675 IMRT, 553
target coordination, 673 locoregional control and survival, 549–550
834 Index

Head and neck tumors (cont.) magnetic resonance imaging, 11–12

reirradiation, 555–558 metabolic PET imaging, 14
stereotactic radiotherapy, 558–559 MR diffusion and diffusion tensor imaging, 13–14
nasopharyngeal carcinoma (see Nasopharyngeal carcinoma (NPC)) physiologic MR imaging and metabolic PET imaging, 12–13
risk factors, 543 post AVM follow-up imaging, 20
stereotactic radiotherapy radiologic and anatomic considerations, 12
basal cell carcinoma, 539 recurrent gliomas, 16–17
bilateral paragangliomas, 539 trigeminal neuralgia, 18
CyberKnife system, 540 IMSRS. See Intensity-modulated stereotactic radiosurgery
Gamma Knife/linac-based gantry system, 539–540 IMSRS)
hurtle cell carcinoma, 539 Intensity-modulated radiation therapy (IMRT)
squamous cell carcinoma, 539 benign meningiomas, 328, 329
surgery head and neck tumors, 553
evolution, 544–545 meningiomas, 301–302
stereotactic radiosurgery, 545–546 pituitary adenomas, 395, 397
treatment, 543–544 Intensity-modulated stereotactic radiosurgery (IMSRS), 301–302
Helium ion irradiation, 750 International Headache Society, 649
Hemangioblastomas, 563–564 Intraconal space, 765
Hepatocellular carcinoma, 141–142 Intracranial cavernous malformations
High-grade gliomas (HGG) clinical presentation, 624
chemotherapy, 440 epidemiology, 623–624
F-SRT, 258–259 management options, 625
pediatric SRS, 411–412 molecular basis, 624
perspective, 249–251 pathophysiology, 623
prognostic factors, 249 radiobiological considerations, 631
RTOG classes, 250 radiologic features, 624–625
stereotactic radiosurgery radiosurgery, 627–631
before and after EBRT, 257 dose planning technique, 625–627
bevacizumab, 257, 258, 262 dural arteriovenous fistulas, 631–633
comparison of treatment, 252 role, 625
EBRT, 252 vein of Galen malformations, 633–634
F-SRT, 252 Intracranial meningiomas, 795–797
glial neoplasms, 262–263 Intraoperative magnetic resonance imaging, 690
LINAC vs. Gamma Knife, 252 Intrathoracic tumors, 155–156
lumustine, 257, 258 Isocentric linear accelerator, 47–49
NovoTTF-100A, 257, 258
pre-EBRT boost, 257
primary management, 254–257 J
rationale, 251–252 Juvenile pilocytic astrocytomas (JPAs), 415–416
recurrent, 257–258
results, 260
temozolomide, 262 K
vandetanib, 262 Ketoconazole, 404–405
strategies, 262–263 Koos classification, 340
symptoms, 249
toxicities of treatment, 261–262
High-intensity focused ultrasound (HIFU), 690 L
Hospital-employed neurosurgeon, 810 Laminectomy, 575
House-Brackmann classification, 340 Lamotrigine, 667
Human papillomavirus (HPV), 544, 552–553 Leksell Gamma Knife, 745
Hydrocephalus, 343 Leukemia pathologic infiltrates, 758
Hyperfractionated radiotherapy, 554 Levodopa, 696
Hyperthyroidism, 380 LGK PERFEXION system, 745
Hypofractionated whole breast irradiation (HWBI), 163–164 Linear accelerators (LINACs)
Hypopituitarism, 375, 386 with circular cones, 82
Hypothalamus hamartomas (HH), 700–702, 714–715 microwave technology, 122
with multileaf collimators, 83
orbital and ocular diseases, 745–746
I photon beams, 122
Imaging techniques pituitary adenomas, 370
acoustic neuroma, 17–18 radiosurgery
arteriovenous malformations, 18 arteriovenous malformations, 130–131
assessment of treatment response, 15–16 cerebral metastases, 128–129
AVM radiosurgery treatment planning, 20 collimated X-ray beam, 123
brain metastases, 14–15 conformal dose, 124
cerebral angiography, 18–19 fundamental concepts, 121
dynamic susceptibility contrast MRI, 13 intensity modulated radiation therapy, 124
Index 835

malignant gliomas, 129–130 oligoastrocytoma, 286

meningiomas, 126–128 oligodendroglial tumor, 286–288
sphere packing technique, 124 procarbazine, 282
stralkniven, 123 temozolomide, 281–283
Talairach stereotactic localization system, 123 toxicity and quality of life, 288
traveling-wave technology, 123 vs. stereotactic radiosurgery, 288–290
TrilogyT system, 124–125 radiosurgery, 129–130
vestibular schwannomas, 125–126 Mask fixation technique, 744
rhumbatron, 122 McGill pain score, 653
SRS units, 97–100 Medial temporal lobe epilepsy (MTLE)
vs. Gamma Knife, 252–254 corroborative testing, 712
Linear-quadratic (LQ) model, 787 outcomes, 713–714
formalism, 63–64 procedures, 712–713
lethal lesions, 66 Medulloblastoma
mechanistic basis, 62–63 fractionated radiotherapy
pairwise production of chromosome aberrations, 65–66 cognitive effects, 428–431
repair mechanisms, 66 endocrine effects, 431
single doses, 66 neurovascular effects, 431
in vitro, 64–65 treatment evolution, 428–431
in vivo, 64–65 young children, 431–432
Liver tumors, SBRT, 156–157 pediatric brain tumors, 420–421
clinical outcomes and patient selection, 196–199 Meningiomas, 126–128, 142
complications, 200 atypical and malignant, 295, 302–303
treatment planning, 195–196 case study, 306–310
Localization-related epilepsy, 711 characteristics, 295
Low-grade gliomas clinical follow-up results, 297
chemotherapy, 439–440 complication avoidance, 305
pediatric disorders, 415–416 fractionated radiotherapy
surgical management, 270–271 classification, 324
Lumustine, 257, 258 clinical presentation, 393
Lung tumors, SBRT diagnostic evaluation, 393–394
clinical outcomes, 192–194 EBRT (see External beam radiation therapy)
complications, 193–195 epidemiology and histology, 392
fractionation, 191–192 etiology, 324–325
gross tumor volume, 190 histopathology, 325
patient selection, 190 preparatory steps, 395–397
radiation-induced meningioma, 324
results, 399
M roles, 395
Magnetic resonance imaging (MRI), 11–12 simulation, 395–397
arteriovenous malformation, 608–609 staging system for, 394
dynamic contrast-enhanced, 13 therapeutic approaches, 394
dynamic susceptibility contrast, 13 Gamma Knife radiosurgery, 299–300
meningiomas, 298–300, 302, 303, 316 intensity-modulated radiation therapy, 301–302
pineal region tumors, 447 MRI scan, 298–300, 302, 303
pituitary adenomas, 393 optic nerve sheath, 302
Malignant gliomas patient algorithm, 303–305
chemotherapy pediatric brain tumors, 418
advantages, 288–290 procedure, 305
anaplastic astrocytoma, 285–286 progesterone and estrogen receptors, 323
anti-angiogenic therapy, 283 radiation therapy, 296
antitumor activity, 280–281 radiographic diagnosis, 316
bevacizumab, 281, 283 signs and symptoms, 316
brain barrier blood, 279 SRS, 297–299
carmustine, 281, 282 SRT, 300–301
complexity of glioma biology, 279–280 stereotactic radiation, 296–297, 302–303
concomitant medications, 280 surgery
EORTC/NCIC trial, 287, 288 case reports, 318–321
fotemustine, 281 considerations, 295–296
of glioblastoma, 283–284 convexity region, 317
irinotecan, 281 decision-making and techniques, 316
lomustine, 281, 282 parasagittal region, 317
methylguanine methyltransferase, 284–285 petroclival region, 318
miscellaneous agents, 283 and radiosurgery, 303
nimustine, 281 sphenoid wing, 317–318
nitrosoureas, 281 treatment planning, 305
obstacles, 279–281 WHO grade classification, 315–316
836 Index

Mesial temporal lobe epilepsy, 703 radiosurgical pallidotomy, 687–688

Metabolic PET imaging, 14 radiosurgical subthalamotomy, 689
Metastatic brain tumors radiosurgical thalamotomy
adenocarcinoma, 227–228 complications, 685
complications, 236–237 Gamma Knife thalamotomy, 683–685
cost-effectiveness, 237–238 merits, 683
patient selection, 233–235 MR spectroscopy imaging, 13
prognostic factors, 211–212 MR venography, 317
quality of life, 238–239 Multicenter Collaborative Ocular Melanoma Study
renal cell carcinoma, 227 (COMS), 755
single brain metastasis, 211 Multileaf collimators (MLC)
stereotactic radiosurgery 3D conformal delivery, 83
acute complications, 223 dynamic conformal arcs, 84
biologically effective dose, 215 fixed-field intensity-modulated fields, 84
brainstem metastases, 220–221 volumetric modulated arc therapy, 84
chemotherapy and radiosensitizers, 225 Multiple sclerosis, 655–656
chronic complications, 223–225
costs, 225
ionizing radiation, 214 N
large brain metastases, 222–223 Narcotics, 669
large institutional/multi-institutional results, 218–219 Nasopharyngeal carcinoma (NPC)
morbidity, 218 local control and survival rates, 529–530
multiple brain metastases, 220 local failures
neurocognitive testing, 218 case study, 531
phase II/III trials, 219–220 complications, 534–536
quality-of-life issues, 217 conventional salvage treatment, 530–531
recurrent metastatic disease, 216 radiosurgery planning and treatment, 533–534
surgical resection cavity, 222–223 target localization, 532
vs. surgery, 215–216, 233–234 tumor control, 534, 535
treatment outcome, 235 outcomes, 538
tumor local control and recurrence, 235–237 treatment results
whole-brain radiation therapy external reirradiation, 536
chemotherapy and radiosensitizers, 225 fractionated stereotactic radiation, 536–537
fractionation schemes, 212 gamma knife radiosurgery, 536
phase II/III trials, SRS, 219–220 prognostic scoring system, 537
Radiation Therapy Oncology Group, 212–213 radiotherapy for, 537
radiosurgery, 216–217 National Health Care Advisory Board, 810
and surgery, 213–214 Neurofibromatosis-1 (NF-1), 417
Metastatic tumors Neurofibromatosis-2 (NF-2), 417–418
orbit, 766 NGGCT. See Nongerminomatous germ cell tumor (NGGCT)
spine, 195 Nimustine (ACNU), 281
Metyrapone, 405 Nitrosoureas, 281
Microelectrode recording (MER), 682 Nongerminomatous germ cell tumor (NGGCT)
Microvascular decompression (MVD), trigeminal neuralgia, 650 chemotherapy, 478–479
economical and patient’s perspective, 662 GKRS, 452
in elder patients, 662 pineal region tumors, 446–447, 465
procedure, 660–661 platinum-based multiagent chemotherapy, 472
radiofrequency ablation, 662 stereotactic radiosurgery, 465
results, 661–662 teratomas, 479
vs. Gamma Knife, 662 Non-small cell lung cancer
vs. glycerol rhizotomy, 662 advantages, 141
Middle fossa approach, 348, 349, 360 anatomy and dose, 138–139
Mini-multileaf collimator (MMLC), 813–814 highly hypofractionated regimens, 139
Mitotane, 405 modestly hypofractionated regimens, 139–140
Monoamine oxidase (MAO) type B inhibitors, 696 Novalis, 814
Movement disorders
DBS
pallidal, 686–687 O
subthalamic, 688–689 Obsessive-compulsive disorder (OCD), 734, 737–738
thalamic, 681–683 Ocular and orbital disease
Gamma Knife radiosurgery, 690 fractionated radiotherapy (see Optic nerve sheath meningioma
high-intensity focused ultrasound, 690 (ONSM))
intraoperative magnetic resonance imaging, 690 surgeon’s application, SRT, 770
medical therapy surgical approach
essential tremor, 697 ARMD, 768–769
Parkinson’s disease, 695–697 glaucoma, 769
Index 837

retinoblastoma, 767–768 Pancreatic tumors, 156–157

uveal melanoma, 766–767 Papillary tumor of pineal region (PTPR), 464
Olfactory neuroblastomas. See Esthesioneuroblastomas Paragangliomas
Oligoastrocytoma, 286 features, 521–522
Oligodendroglioma, 249, 286 fractionated stereotactic radiotherapy
Onyx, 610 outcomes, 524–525
Optic nerve sheath meningioma (ONSM), 302, 328–330 patient selection, 523–524
fractionated radiotherapy techniques, 524
modalities skull base tumors
modalities: doses, constraints and fractionation schemes, pathophysiology, 491
774–776 radiosurgery, 493–494
modalities: techniques, 774–776 side effects, 493
modalities: timeframe, 773–774 surgical resection, 491–493
modalities: volumes, 774 treatment plan, 493, 494
optimization, 778–780 treatment, 522–523
results Parasagittal meningiomas, 317, 319
results: endpoints, 774, 777 Parkinson’s disease
results: oncologic outcome, 777 medical therapy, 695–697
results: ophthalmologic examination outcome, 777 posteroventral pallidotomy, 675–677
results: visual outcome, 777 Partial lamellar sclerouvectomy, 767
safety, 778 Pediatric brain tumors
origin, 773 chemotherapy
Orbital and ocular diseases craniopharyngiomas, 441
psychosocial aspect, conservative treatment, 755 embryonal tumors, 440–441
stereotactic radiosurgery/radiotherapy ependymoma, 440
ARMD, 758–760 germ cell tumors, 441
dosimetry, 746, 747 high-grade gliomas, 440
eye fixation, 744 low-grade gliomas, 439–440
glaucoma, 760–761 fractionated radiotherapy
Leksell Gamma Knife, 745 ependymoma, 435–437
leukemia pathologic infiltrates, 758 fractionated irradiation, 428
LINAC, 745–746 medulloblastoma, 428–432
malignant lymphomas, 758 primary brain tumors, 432–435
metastatic lesions, 757 radiosurgery, 428
retinoblastoma, 756 RT-1 protocol, 433–435
side effects and complications, 761–762 target volume, 433
uveal melanomas (see Uveal melanomas) surgery
vascular lesions, 758 case studies, 423
Orbital lymphoproliferative disease, 766 high-grade tumors, 418–421
Organized radiosurgery, 8 low-grade tumors, 415–418
Otolaryngologists, 812 surgical management, 415
Oxcarbazepine, 666 vascular malformations, 421–422
Pegvisomant, 405
Percutaneous balloon compression, 660
P Percutaneous glycerol rhizotomy (PGR)
Pain and psychiatric disorders trigeminal neuralgia, 659–660
pathophysiology, 732 vs. MVD, 662
pharmacological treatment, 735 Percutaneous radiofrequency ablation
stereotactic radiosurgery trigeminal neuralgia, 660
anxiety, 734–735 vs. MVD, 662
arguments, 735 Perioptic tumors, 154
chronic pain, 733 Petroclival meningiomas, 318
complications, 738–739 Phenytoin, trigeminal neuralgia, 668
depression, 734 Photon beam delivery systems
dosimetry, 736 CyberKnife, 49
obsessive-compulsive disorder, 734 Gamma Knife, 45–47
outcomes, 737–738 isocentric linear accelerator, 47–49
somatic pain, 731 Pineal astrocytomas, 463
trigeminal neuralgia, 731–733 Pineal parenchymal tumor (PPT)
Pallidal deep brain stimulation, 686–687 chemotherapy, 479–480
Pancreatic ductal adenocarcinoma (PDAC) fractionated radiation therapy, 470, 473
definitive treatment, 201–203 pineal region, 461–463
neoadjuvant therapy, 201 Pineal region tumors
palliative setting, 201 anatomy, 445–446
resectability, 203 case studies, 453–456
treatment planning considerations, 203 chemotherapy
838 Index

Pineal region tumors (cont.) gonadotroph adenomas, 406–407

germ cell tumors, 477–479 nonfunctioning adenoma, 406–407
pineal parenchymal tumors, 479–480 prolactinomas, 403–404
fractionated radiation therapy somatotroph adenomas, 405
benign cyst, 469 thyrotropin adenomas, 405–406
computed tomography, 470 meningiomas (see Meningiomas)
NGGCTs, 469, 473 surgery
pineoblastomas, 469–470 ACTH-secreting, 386, 387
pineocytomas, 469 anesthetic, 380–381
platinum-based multiagent chemotherapy, 472 bromocriptine therapy, 380
radiotherapy, 470–471 cavernous sinus, 379, 381, 383–386
spinal failure, 471–472 endocrinologic, 380–381
spinal seeding, 470 endoscopic advancement, 382–383
symptoms, 470 GH-secreting, 379, 381, 387
teratomas, 469 hyperthyroidism, 380
GKRS for, 452 hypopituitarism, 386
imaging, 447 indications for, 379–380
management, 447–448 microscopic endonasal, 382
pathology, 446–447 modifications of transsphenoidal approch, 384–386
presentation and natural history, 446 and planning, 380–381
radiosurgery in, 449–452 radiation therapy, 386–388
surgical approaches, 448–449 and radiographic considerations, 380–381
benign tumors, 463 transcranial, 386
craniotomy, 461–463 transsphenoidal approach, 381, 382
endoscopic biopsy, 461 Platinum-based multiagent chemotherapy, 472
glial tumors, 463–465 Polymethylmethacrylate (PMMA), 574, 576
radiographic appearance, 459–460 Post-anesthesia care unit (PACU), 825
results, 463 Posteroventral pallidotomy (PVP), 675–677
stereotactic biopsy, 460–461 Post-herpetic neuralgia, 655–656
surgical management, 460 Pregabalin, 667–668
Pineoblastomas (PBs) Primary generalized epilepsy, 711
chemotherapy, 479–480 Primitive neuroectodermal tumors (PNET), 420
pediatric brain tumors, 421, 447 Procarbazine, 282
Pineocytomas Prolactinomas
chemotherapy, 479 fractionated radiotherapy, 398–399
pineal region tumors, 447 medical therapy, 403–404
Pituitary adenomas Proton beam systems, 813
fractionated radiotherapy Proton beam therapy (PBT), 5–6, 750
classification, 392 Proton SRS
clinical presentation, 392–393 clinical treatment planning, 90–92
diagnostic evaluation, 393–394 considerations, 90
epidemiology and histology, 391–392 dose modeling, 88–89
results, 395–397 pre-planning, 89
role of, 395 proton delivery systems, 88
simulation, 395–397
staging system for, 394
therapeutic approaches, 394 R
stereotactic radiosurgery Radiation necrosis
and acromegaly, 371–372 complications
and cushing’s disease, 370–372 brain metastases, 794–795
CyberKnife, 370 intracranial meningiomas, 795–797
devices, 370 management algorithm, 800
endocrine remission and late recurrence, 373–375 vestibular schwannomas, 797–799
Gamma Knife, 370 diagnosis
hypopituitarism, 375 amino acid PET, 792
LINAC, 370 diffusion-weighted imaging, 790–791
and nonfunctioning, 370, 371 FDG-PET, 791–792
and prolactinomas, 370–374 histological examination, 792–793
proton beam unit, 370 magnetic resonance spectroscopy, 790
transsphenoidal approach, 370 MRI, 789, 790
Pituitary tumors, 142 perfusion MRI, 791
adenomas (see Pituitary adenomas) SPECT, 792
craniopharyngiomas (see Craniopharyngiomas) dose and volume dependence, 786–788
medical therapy histopathologic features, 788–789
corticotroph adenomas, 404–405 historical perspective, 786
diagnosis and classification, 403 incidence, 788
Index 839

latency, 788 chondromas, 489–491

radiation toxicity, 786 chondrosarcomas, 489–491
treatment chordomas, 489–491
anticoagulants, 793 clinical entities, 486
antioxidant therapy, 793–794 craniopharyngiomas, 488–489
bevacizumab, 794 dose limitations, 484–485
hyperbaric oxygen, 793 esthesioneuroblastomas, 487–488
rehabilitation, 794 fractionated/stereotactic radiotherapy
steroids, 793 chondrosarcomas, 517–521
surgical resection, 793 chordomas, 517–521
Radiation safety program, 103 paragangliomas, 521–525
Radiation Therapy Oncology Group (RTOG), 254, 256 glomus jugulare tumors/chemodectoma/paraganglioma, 491–494
Radiobiological principles radiosurgical tolerance, 484–485
accelerated repopulation, 60 re-irradiation, 486
applications surgery
AVMs, 61–62 chordomas, 503–504
benign tumors, 62 considerations, 500
malignancies, 60–61 craniopharyngiomas, 506–509
dose distributions, 66–67 esthesioneuroblastomas, 506, 507
linear-quadratic model glomus jugulare tumors, 501–503
formalism, 63–64 meningiomas, 509–511
lethal lesions, 66 trigeminal schwannomas, 500–501
mechanistic basis, 62–63 technique evolution, 484
pairwise production of chromosome aberrations, 65–66 Somatic pain, 731
repair mechanisms, 66 Somatostatin analog (SSA)
single doses, 66 somatotroph adenomas, 405
in vitro, 64–65 thyrotropin adenomas, 406
in vivo, 64–65 Somatotroph adenomas, 405
malignant tumors, 67–68 Spetzler–Martin grading system
reoxygenation, 57–59 arteriovenous malformations, 597–598
repair, 59–60 AVMs, 607
Radiosurgical pallidotomy, 687–688 Sphenoid wing meningiomas, 317–318
Radiosurgical subthalamotomy, 689 Spiegel–Wycis frame, 4
Radiosurgical thalamotomy Spinal metastases
complications, 685 adjuvant postoperative, 566–568
Gamma Knife thalamotomy, 683–685 brachy P32 plaques, 568–569
merits, 683 fractionated radiation therapy
Recurrent gliomas, 16–17 clinical results, 584–587
Registered nurse, 818 single-fraction SBRT, 583–584
Renal cell carcinoma, 227 hypofractionation, 568
Residency Review Committee (RRC), 808 primary irradiation, 565–566
Retinoblastoma salvage reirradiation dose, 568, 569
diagnosis and treatment, 756 Spinal tumors
pathophysiology and radiosurgery, 756 benign tumors
surgical approach, 767–768 arteriovenous malformation, 564
Retrosigmoid approach, 348, 349, 351 hemangioblastomas, 563–564
RTOG 0539 study, 331, 333 combined therapy timing, 575
curative resection, 574
diagnosis, 574
S immobilization, 182
SBRT. See Stereotactic body radiation therapy (SBRT) malignant tumors, 565
Scandinavian Glioblastoma Study Group (SGSG), 250 metastases
Simpson grades system, 325, 326 adjuvant postoperative, 566–568
Single-fraction radiosurgery, 788 brachy P32 plaques, 568–569
SJMB03 trial, 429 hypofractionation, 568
SJMB96 trial, 429 primary irradiation, 565–566
Skull base meningiomas salvage reirradiation dose, 568, 569
cavernous sinus, 509 neural decompression, 573
cerebellopontine angle, 511 pain control, 574
petroclival meningiomas, 510 stabilization, 574
sphenoid wing, 509 surgical approach
stereotactic radiosurgery, 300 anterior approaches, 576
stereotactic radiotherapy, 301 case studies, 578–579
tuberculumsellae, 511 decompressive posterior laminectomy, 575
Skull base tumors en bloc spondylectomy, 576–577
angiofibroma, 486–487 location, 571–572
840 Index

Spinal tumors (cont.) Stereotactic brachytherapy (SBT)

posterolateral approaches, 576 advent of GliaSite brachytherapy, 272
spinal cord decompression, 575–576 benefits and risks, 272, 274–275
vertebroplasty and kyphoplasty, 577 brachytherapy (125I) advanced treatment, 273–274
surgical decision making algorithm, 573 high-grade gliomas, 273
treatment modality, 572 indications, 273
Spongioblastoma multiforme, 249 vs. EBRT, 273–274
Squamous cell carcinomas of head and neck (HNSCC) Stereotactic instrument, 4–5
human papillomavirus in, 552–553 Stereotactic localization techniques
IMRT, 553 digital reconstruction radiography, 28–29
recurrent, 553, 559 extracranial, 29–30
SRS. See Stereotactic radiosurgery (SRS) frame-based to frameless system, 28
SRT. See Stereotactic radiotherapy (SRT) history of stereotaxis, 25–27
Stereotactic biopsy, pineal region tumors, 460–461 image-guided, 26–28
Stereotactic body radiation therapy (SBRT), 164 immobilization and target tracking, 30–31
high-dose fractions, 177 robotic tools, 30
historical perspective, 178 Stereotactic radiosurgery (SRS), 355–356
image guidance accuracy, 101
equipment quality assurance, 189–190 in children
in-room CT, 187 arteriovenous malformations, 410
kV cone beam CT, 187–188 craniopharyngiomas, 412–413
MV cone beam CT, 188 embryonal tumors, 411
MV TomoTherapy, 189 ependymomas, 410–411
overview, 186 Gamma Knife, 409–410
patient safety, 189 goal of, 409
real-time tumor tracking, 189 high-grade gliomas, 411–412
strategies, 186–187 low-grade astrocytomas, 412
three-dimensional volumetric, 187 clinical indications, 808
two-dimensional equipment, 187 components and functions
imaging response, 180–181 Cyberknife, 100
immobilization Gamma Knife, 96–97
body tumor, 182 linear accelerator-based units, 97–100
breathing motion assessment, 182–183 Tomotherapy unit, 101
overview, 182 Compton scattering, 39–41
spinal tumor, 182 cost and budget, 106–107
immune response, 179–180 design principles, 95–96
liver tumors dose and dosimetry, 41–42
clinical outcomes and patient selection, 196–199 isodose line and dose-volume histogram, 44–45
complications, 200 measurement-based dose calculation, 42
treatment planning, 195–196 model-based dose calculation, 43
lung tumors output, 43
clinical outcomes, 192–194 pencil-beam kernel, 44
complications, 193–195 percent depth dose, 42–43
fractionation, 191–192 point kernel, 43–44
gross tumor volume, 190 profile/off-axis ratio, 43
patient selection, 190 dose characteristics, 51
mechanism of action, 179 Gamma Knife SRS, 302
metastatic tumors, spine, 195 head and neck tumors, 545–546, 558–559
normal tissue response, 181–182 installation and acceptance, 103–105
pancreatic ductal adenocarcinoma meningiomas, 296–299
definitive treatment, 201–203 movement disorders
neoadjuvant therapy, 201 application, 671
palliative setting, 201 gamma knife pallidotomy, 675–677
resectability, 203 gamma knife subthalamotomy, 677
treatment planning considerations, 203 gamma knife thalamotomy, 671–675
planning target volume, 177 pair production, 40–41
radiobiologic models, 178–179 patient process, 826
spinal metastases frame application, 820–821
clinical results, 584–587 home follow-up, 825
single-fraction SBRT, 583–584 intake, 818
treatment planning patient arrival and preparation, 820
heterogeneity corrections, 185–186 pediatric patient care, 825–826
imaging, 183–184 postoperative care, 824–825
overview, 183 preauthorization process, 820
plan evaluations, 185 preprocedure consultation, 818, 820
target volumes, 184 radiographic imaging, 821–823
Index 841

stereotactic treatment, 823–824 T

treatment planning, 823 Tardive dyskinesia, 695
pediatric brain tumors, 439–441 Temozolomide (TMZ)
personnel training and qualifications, 105–106 high-grade gliomas, 262
photoelectric absorption, 39–40 malignant glioma, 281–283
photon beam delivery systems Teratomas, 469–471
CyberKnife, 49 Thalamic deep brain stimulation, 681–683
Gamma Knife, 45–47 Thyroid eye disease, 766
isocentric linear accelerator, 47–49 Thyrotropin adenomas, 405–406
pituitary adenoma Tomotherapy unit, 101
and acromegaly, 371–372 Topiramate
and cushing’s disease, 370–372 epilepsy, 725, 726
CyberKnife, 370 trigeminal neuralgia, 667
devices, 370 Translabyrinthine approach, 349, 351, 360
endocrine remission and late recurrence, 373–375 Transoral robotic surgery (TORS), 544–545
Gamma Knife, 370 Transpupillary thermotherapy, 767
hypopituitarism, 375 Transsphenoidal approach, 381
LINAC, 370 Treatment planning, SRS
and nonfunctioning, 370, 371 contouring structures, 77
and prolactinomas, 370–374 CyberKnife
proton beam unit, 370 beam characteristics, 85
transsphenoidal approach, 370 imaging requirements, 85–86
population-based market size, 808, 809 overview, 84–85
potential issues and challenges, 102 planning process, 87–88
practice development design, 77–78
credentialing protocols, 811 dose calculation, 78
decision making, 809–811 forward vs. inverse planning, 78
marketing, 812 Gamma Knife, 73
referral base, 811–812 4C unit, 79–82
practice issues Perfexion, 81–82
data management, 815 image registration, 75–76
identification of space, 814 linac-based SRS
patient follow-up, 815 with circular cones, 82
radiosurgery systems, 812–814 with multileaf collimators, 83
staff responsibilities, 814–815 mini multileaf collimators, 74
proton’s interaction with matter, 50–51 patient imaging, 75–76
proton therapy, 50 prescription, 77
quality control, assurance and management, 51–53, 105–106, 818 proton SRS
radiation safety program, 103 clinical treatment planning, 90–92
radiation source considerations, 90
accelerator tube, 37–38 dose modeling, 88–89
bending magnet, 37–38 pre-planning, 89
cobalt-60, 35–36 proton delivery systems, 88
electromagnetic spectrum, 35–36 quality evaluation, 78–79
electron gun, 36 sphere packing technique, 74
flattening filter free mode, 39–40 stereotactic localization, 74–75
modulator, 36 technical improvements, 73
power supply, 36 three-dimensional image data, 73
radiofrequency source, 37 Trigeminal neuralgia (TN), 18, 154–155
treatment head, 38–39 ablative percutaneous, 650
waveguide system, 37 atypical facial pain, 655–656
X-ray production, 36–37 Barrow Neurological Institute, 653
residency training, 808–809 case studies, 652
service and maintenance, 104–105 complications, 654
shielding design, 102–103 dose and dose rate, 651–652
training and staffing, 818, 819 dose selection, 736
vs. fractionated radiation therapy, 473–474 GK-SRS effect, 650, 653–655
Stereotactic radiotherapy (SRT) See also Radiobiological principles linac and CyberKnife SRS, 650
applications, 302–303 McGill pain score, 653
atypical meningiomas, 297 medical management, 735
benign meningiomas, 297 antiepileptic drugs, 666–668
meningiomas, 296–297, 300–301 clinical features, 665
ONSM, 302 GABA-related agents, 668
Subperiosteal space, 765 Trigeminal neuralgia (TN) (cont.)
Subthalamic deep brain stimulation, 688–689 local anesthetics, 668–669
Synchrony™ respiratory tracking system, 147 narcotic agents, 669
842
neuropathic pain, 665–666
pathophysiology, 665
medical therapy, 649–650
microvascular decompression, 736
multiple sclerosis, 655–656
MVD, 650
oxcarbazepine, 666
pathophysiology, 733
post-herpetic neuralgia, 655–656
and radiosurgery, 731–732
secondary, 655
SRS, 650
surgery
balloon micro-compression, 660
microvascular
decompression, 660–662
radiofrequency ablation, 660
trigeminal neuralgia, 659–660
Trigeminal schwannomas
gross total resection, 500–501
SRS, 501
TrilogyT system, 124–125
U efficacy, 241
Uveal melanomas
anatomic stage/prognostic
groups, 750
brachytherapy, 748, 750
charged particle therapy, 750
clinical trials, 755
MRI, 751–752
pathophysiology, 746–747
prognosis, 754–755
proton beam therapy, 750
radiosurgery, 750–751
radiotherapy, 747
stereotactic radiotherapy, 750
TNM staging system, 748
toxicity scoring system, 751
treatment, 752, 755–756
tumor location, 747–748
tumor response, 752–753
Index
V
Vagal nerve stimulation (VNS), 716–717
Vandetanib, 262
Vascular endothelial growth factor-A (VEGF)
ARMD, 768
bevacizumab, 262
head and neck tumors, 552
Vascular lesions, 758
Vein of Galen aneurysms, 633–634
Vein of Galen malformations (VGMs), 633–634
Vertebroplasty, spinal metastases, 577
Vestibular schwannomas, 125–126, 154, 797–799.
See also Acoustic neuromas
VGMs. See Vein of Galen malformations (VGMs)
Volumetric modulated arc therapy (VMAT), 84
Von Recklinghausen neurofibromatosis, 417
W
Wada test, 711
Whole-brain radiation therapy (WBRT)
chemotherapy and radiosensitizers, 225
complications, 242
effectiveness, 242
focal treatment of brain metastases
Aoyama trial, 244
cranial radiation therapy, 246
long-term neuropsychological side effects, 243
low-grade glioma, 245
mini-mental state examinations, 246
neurocognitive functioning, 245
neuroimaging, 243
Patchell study, 244
postoperative radiotherapy, 244
fractionation schemes, 212
issues, 241–242
phase II/III trials, SRS, 219–220
Radiation Therapy Oncology Group, 212–213
radiosurgery, 216–217
recurrent brain metastases, 246
and surgery, 213–214
with/without SRS, 242–243